Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N+:3]=1[O-].C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1.C(OCC)(=O)C>ClC(Cl)C>[Cl:25][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2[n+]1[O-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
2-Methyl-6-nitroquinoline N-oxide (13.0 g, 63.72 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (13.5 g, 70.81 mmol) in dichloroethane (200 mL). The reaction was stirred overnight at 100° C. and then stirred at room temperature for 2 days. To the reaction mixture was added ethyl acetate. A solid precipitated and was filtered and recrystallized from acetone/water to afford 7.91 g (56%) of pure product.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1.CO>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The propionic acid ethyl ester prepared in step D was dissolved in THF (6 mL) and MeOH (3 mL). A solution of 2 M LiOH (3 mL) was then added and the reaction was stirred at room temperature for 30 minutes. The solvents were evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1 N HCl (2×), brine (2×), dried over MgSO4, filtered, and concentrated to a syrup. Addition of hexane followed by trituration precipitated the title compound (270 mg, 0.48 mmol) as a cream colored solid.
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[CH:25]=[CH:24][C:23]2=[N:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:42]([F:45])([F:44])[F:43])=[C:33]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=3)=[CH:28][N:22]2[N:21]=1>O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36]([NH:35][C:33]1[CH:34]=[C:29]([C:27]2[N:26]=[C:23]3[N:22]([CH:28]=2)[N:21]=[C:20]([N:10]2[CH2:11][CH2:12][CH:7]([CH3:6])[CH2:8][CH2:9]2)[CH:25]=[CH:24]3)[CH:30]=[CH:31][C:32]=1[C:42]([F:44])([F:43])[F:45])=[O:41]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCN(c2ccc3nc(-c4ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c4)cn3n2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
An 8 mL vial is charged with DMF (1 mL), 4-methylpiperidine (0.030 g), Cs2CO3 (0.130 g), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0396 g, 0.1 mmol). The mixture is stirred at 120° C. for 16 hr, then diluted with H2O (5 mL) and extracted with Et2O (3 mL×2). Organics are dried and concentrated onto celite, purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.020 g, 43% yield). LCMS m/z=460.6 [M+H]+, tR=3.14 min. (compound same as Example 233)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:10]([C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1)=[CH2:11]>>[CH:10]([C:12]1[CH:13]=[C:14]([C:1]([OH:3])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:2])[CH:15]=[CH:16][CH:17]=1)=[CH2:11]
Reactant: CC(=O)c1ccccc1
Reactant: C=Cc1cccc([Mg]Br)c1
Product: C=Cc1cccc(C(C)(O)c2ccccc2)c1

Procedure:
A method to use acetophenone as a starting material will be described. Acetophenone is reacted with a Grignard reagent of m-vinylphenylmagnesium bromide to obtain 1-(3-vinylphenyl)-1-phenylethyl alcohol (formula IV) (hereinafter referred to as "VPA"). The reaction product is then dehydrated in the presence of potassium hydrogensulfate to form 1-(3-vinylphenyl)-1-phenylethylene (formula III). This Grignard addition reaction is carried out at a temperature in the range of 0° to 100° C., preferably 20° to 80° C. The dehydration is carried out at 170° to 250° C., preferably 190° to 230° C., at a reduced pressure. The quantity of Grignard reagent is 1.0 to 1.2 equivalents relative to the acetophenone. ##STR9##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[F:11])(=[O:3])[CH3:2].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH2:33])[CH:26]=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:14](=[O:16])/[CH:13]=[CH:12]/[C:7]2[CH:8]=[CH:9][C:10]([F:11])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH:26]=[N:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc2cnn(Cc3ccccc3)c12
Reactant: CC(=O)Oc1cc(/C=C/C(=O)O)ccc1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)Oc1cc(/C=C/C(=O)Nc2cccc3cnn(Cc4ccccc4)c23)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 8.3 %

Procedure:
A mixture of (E)-3-(3-acetoxy-4-fluoro-phenyl)-acrylic acid (119 mg, 0.53 mmol), 1-benzyl-1H-indazol-7-ylamine (118 mg, 0.53 mmol), EDC (123 mg, 0.64 mmol) and HOBT (36 mg, 0.27 mmol) in DMF (3 ml) was stirred at RT for 48 hrs. The mixture was then diluted with water and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to dryness. The crude was purified by column chromatography (petroleum ether:AcOEt from 9:1 to 1:1) to give the title (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(4-fluoro-3-acetoxy-phenyl)-acrylamide (19 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][Br:11].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][Br:11]
Reactant: COc1ccc(C(=O)c2ccc(OCCBr)c(Br)c2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a stirred solution of (3-bromo-4-(2-bromoethoxy)phenyl)(4-methoxyphenyl)methanone (0.6 g, 1.0 e q) in 50 mL CH2Cl2 was added BBr3 (3.0 eq, 0.4 mL) dropwise. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography with petroleum ether:EtOAc=2:1 to give the desired product (0.36 g, 62% yield). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.70-7.79 (m, 3H), 6.90-7.00 (m, 3H), 4.43 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH3:11])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1cc(F)cc(F)c1
Yield: 98.8 %

Procedure:
Following a similar procedure to that described in Example (1b), 1.41 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3,5-difluorophenyl)ethyl]amine [prepared as described in step (a) above], 1.66 g of nickel chloride hexahydrate and 558 mg of sodium borohydride were reacted, to obtain 1.29 g of the title compound as a pale yellow oil.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][C:28]=1[F:45]>>[Br:26][C:27]1[CH:32]=[C:31]2[C:30](=[CH:29][C:28]=1[F:45])[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)C1CC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(c1cnc2cc(F)c(Br)cc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To Dowtherm at 250° C. was added methyl 3-(4-bromo-3-fluorophenylamino)-2-(cyclopropanecarbonyl)acrylate (7.5 g, 21.9 mmol) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (5.38 g, 79%) as a brown solid: ESI MS m/z 311 [C13H9BrFNO2+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.Cl.[N:20]1[C:25]2[CH:26]=[CH:27][C:28](B(O)O)=[CH:29][C:24]=2[N:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:20]1[C:25]2[C:24](=[CH:29][C:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)[CH:3]=3)=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc2nccnc2c1
Reactant: FC(F)(F)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: FC(F)(F)c1ccc(Nc2cc(-c3ccc4nccnc4c3)ncn2)cc1
Temperature: 120 °C

Procedure:
A mixture of 6-chloro-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (273 mg, 1.0 mmol), benzopyrazine-6-boronic acid hydrochloride (Asymchem, 211 mg, 1.0 mmol), Na2CO3 (529 mg, 5.0 mmol) and PdCl2(PPh3)2 (Strem, 60 mg, 0.1 mmol) in 7 mL DME/3 mL H2O/2 mL EtOH was heated to 120° C. for 17 min in the Smith Optimizer microwave. The reaction mixture was partitioned between EtOAc/brine and the aqueous layer was extracted with EtOAc (3×). The combined organics were evaporated onto SiO2 and purified by flash column chromatography eluting with EtOAc/Hexane/2M NH3 in MeOH/CH2Cl2 (0:1:0:0→1:1:0:0→0:0:19:1). The fractions containing desired compound were combined and concentrated in vacuo giving a solid. The solid was washed with a minimal amount of CH2Cl2 and dried in vacuo to give a light pink amorphous solid. MS (ESI, pos ion.) m/z: 368 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[CH:16]=[N+:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]([C:15]1[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=1[O:13][CH3:12])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2ccc(Cl)cc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 40.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:16][CH:17]([F:20])[CH2:18]I>CN(C=O)C>[F:16][CH:17]([F:20])[CH2:18][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: FC(F)CI
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2CC(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 59 mg, 1.48 mmol) in DMF (2 mL) was slowly added a solution of 1H-indole-5-carboxylic acid methyl ester 19a (200 mg, 1.14 mmol) in DMF (1 mL) at 0° C. The resulting solution was stirred at 0° C. for 20 min and 1,1-difluoro-2-iodoethane 23a (263 mg, 1.37 mmol) was added. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to afford compound 23b.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C:7]1[CH:8]=[C:9]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.Cl.[NH2:19][OH:20].Cl>O>[OH:20][N:19]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccc(O)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of sodium bicarbonate (5.56 g.) in water (200 ml.) was added and dissolved with stirring 3-hydroxyphenylglyoxylic acid (11 g.) under cooling. On the other hand, hydroxylamine hydrochloride (4.60 g.) was added and dissolved into a solution of sodium bicarbonate (5.56 g.) in water (70 ml.) with stirring at room temperature. Thus obtained solution was added with stirring to the above obtained solution under cooling. The mixture was stirred for 20 hours at room temperature and was subjected for salting-out treatment. Then, the reaction solution was acidified with hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried. After solvent was distilled off, the residue was crystallized from benzene. The crystals were collected by filtration to obtain 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6 g.).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13])(=O)C.[Br-].[O:23]1CCO[CH:24]1[CH2:28][P+](CCCC)(CCCC)CCCC.CC(C)([O-])C.[K+].[Cl-].[Na+]>CN(C)C=O.Cl.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:28][CH:24]=[O:23])=[CH:20][CH:21]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCO1
Reactant: CCCCN(CCCCOC(C)=O)c1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCCO)c1ccc(C=CC=O)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 29.1 g (0.1 mole) of 4-(N-4-acetoxybutyl-N-butylamino)benzaldehyde in dimethylformamide is added 73.9 g (0.2 mole) of 1,3-dioxolan-2-ylmethyltributylphosphonium bromide in dimethylformamide, and the mixture is heated at 90° C. Potassium t-butoxide (22.4 g, 0.2 mole) is added, and heating is continued at 90° C. for 16 hours. After cooling to room temperature, the product solution is poured into a seven-fold excess of water, the aqueous mixture is saturated with sodium chloride and the solution is extracted with three portions of ether. The combined organics are dried over 4A sieves, filtered through cotton, and evaporated. The crude reaction product is then dissolved in 3M HCl, and the reaction is stirred at room temperature for 16 hours. After neutralization with saturated sodium bicarbonate, the aqueous mixture is extracted with three portions of ether, and the combined organics are passed through silica gel, dried over 4A sieves, filtered through cotton, and evaporated to yield compound A. The product is purified by flash chromatography (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]>CN(C=O)C>[C:5]([NH:4][C:3]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:2]=1[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6])(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1I
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1-c1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 150 °C
Yield: 116.1 %

Procedure:
A mixture of 2'-iodo-4'-nitroacetanilide (II) (50.02 g, 0.164 mole), copper-bronze (87.9 g) and N,N'-dimethylformamide (350 ml) was stirred and heated at 150° C. under nitrogen for 1 hour and filtered. The filter cake was washed with tetrahydrofuran, and the combined filtrate and washings were concentrated under vacuum to 100 ml and poured, with stirring, into 1200 ml of concentrated ammonium hydroxide. The resultant precipitate was filtered, washed with water, and dried at 100° C. and 1 mm Hg to yield 34.1 g (58 %) of 2,2'-bis-(acetamido)-5,5'-dinitrobiphenyl. An analytical sample, m.p. 263°- 265° C., was obtained by recrystallization from ethanol.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:9]1([CH2:12]O)[CH2:11][CH2:10]1>>[C:1]([O:8][CH2:12][CH:9]1[CH2:11][CH2:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: OCC1CC1
Product: CCCCCC(=O)OCC1CC1

Procedure:
Prepared from hexanoic acid and cyclopropanemethanol according to the ester preparation method A described above.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][CH:14]=[C:15](Br)[CH:16]=1)=[O:11])[CH2:2]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=1)=[O:11])[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc(-c2ccccc2)cs1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) and phenylboronic acid, using tetrakis(triphenylphosphine)palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol, and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloride salt was prepared by evaporation of the product-containing fractions, dissolution of the residue in methanol, addition of excess hydrogen chloride solution (1M in diethyl ether) and evaporation. Recrystallisation from ethyl acetate gave the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 313 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([CH2:31]O)[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.[CH3:33]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1>ClCCl>[OH:1][C:2]([CH3:33])([CH3:31])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2F)=CC1=O
Agent: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
A solution of (S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 166, 200 mg, 0.65 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (110 mg, 0.72 mmol) and 1-hydroxybenzotriazole (93 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 1 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 121 mg, 0.78 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (177 mg, 74%) as a light yellow powder: LR-ES-MS m/z calculated for C23H29FN4O4 [M+H]+ 444, observed 445; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.37-1.65 (m, 2H), 1.69-1.84 (m, 1H), 3.89 (s, 2H), 4.22 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.68 (s, 1H), 4.86 (s, 1H), 4.87-4.93 (m, 1H), 6.44 (d, J=1.8 Hz, 1H), 7.25-7.52 (m, 4H), 7.53 (d, J=1.8 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]Br.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CBr)cc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(Cc2ccc(F)cc2)cc1Br
Temperature: 60 °C
Yield: 40.1 %

Procedure:
In a 250 mL round-bottomed flask equipped with a stir bar was placed 3-bromo-4-methoxybenzyl bromide (5.0 g, 17.9 mmol), 4-fluorophenylboronic acid (2.76 g, 19.7 mmol), potassium phosphate (tribasic) (7.60 g, 35.8 mmol), dimethoxyethane (30 mL) and 50% aqueous ethanol (30 mL). The mixture was degassed with nitrogen for 30 minutes and then added tetrakis(triphenylphosphine)palladium(0) (5.17 g, 4.48 mmol). The mixture was heated to 60° C. for 4 hours and then the palladium catalyst was filtered off. To the filtrate were added water (100 mL) and a saturated ammonium chloride solution (150 mL). After extracting with ethyl acetate (3×100 mL), the organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was purified by column utilizing 5% EtOAc/hexanes as the eluent to produce 2.12 g of 2-bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene as a colorless oil in 40% yield.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:12][N:13]=[N+:14]=[N-:15]>C(O)C>[NH2:3][C:2]1[N:13]([CH2:12][C:11]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:9]([Cl:8])[CH:10]=2)[N:14]=[N:15][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: [N-]=[N+]=NCc1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Sc3ccc(Cl)cc3)c(Cl)c2)c1N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a stirred solution of sodium (276 mg, 12.0 mmol) in absolute ethanol (28 ml) at 60° C. was added 2-cyanoacetamide (952 mg, 11.3 mmol). The mixture was stirred 5 minutes, 3-chloro-4-(4-chlorophenylthio)benzyl azide (1.8 g, 5.8 mmol) was added, and the mixture was refluxed for 1 hour. The mixture was cooled to 0° C. and filtered. The solid product was washed with ethanol (2X), water (4X), ethanol (2X), and diethyl ether, and air dried to provide 1.67 g (73%) of 5-amino-1-(3-chloro-4-[4-chlorophenylthio]-benzyl)-1,2,3-triazole-4-carboxamide, m.p. 202°-203.5° C.