Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.09 g of the compound obtained in EXAMPLE 13, 1 ml of 1,1-dimethylpropylamine, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl, with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent to give 0.88 g of the expected product in the form of white crystals. M.p.=219° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:6]4[CH2:5][CH2:4][NH:3][C:2]([CH3:8])([CH3:1])[CH2:7]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: CC1(C)CNCCN1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCNC(C)(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
2,2-Dimethylpiperazine (343 mg, 3.00 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (217 mg, 47%) as a yellow solid.
Reaction SMILES: N[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:13]>>[O:13]=[C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CC=C(N)c1ccsc1
Reactant: CO
Agent: Cl
Product: N#CCC(=O)c1ccsc1
Reaction time: 3 h

Procedure:
A 1.2 g. portion of β-amino-3-thiopheneacrylonitrile is added to 10 ml. of 1 N hydrochloric acid. A 40 ml. portion of methanol is added and the mixture is stirred for 3 hours. The mixture is evaporated in vacuo to a residue which is dissolved in 35 ml. of hot methanol and treated with charcoal. After cooling, petroleum ether is added, the mixture is filtered and the solid collected is discarded. The filtrate is allowed to evaporate and the residue is dissolved in 35 ml. of hot isopropanol and isoluble material filtered and discarded. The filtrate is cooled and the solid is collected giving the desired product as white plates, m.p. 87°-88° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33]1>C(Cl)Cl.CO>[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:3])=[CH:33]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(C)CCn1ccc(N)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccn(CCN(C)C)c3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 1-(2-dimethylamino-ethyl)-1H-pyrrol-3-ylamine (Step 121.1) and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 482.1 [M+H]+; tR=3.66 min (System 1); TLC: Rf=0.21 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1]O.[C:3]1([CH2:9][CH2:10][P:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([CH2:9][CH2:10][P:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:1])[OH:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: OP(CCc1ccccc1)CCc1ccccc1
Solvent: CO
Product: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reaction time: 16 h
Yield: 30.6 %

Procedure:
Hydrogen peroxide (0.45 mL, 30%, 4.36 mmol) was added dropwise over 1 minute to crude bis(2-phenylethyl)phosphinous acid (1.12 g, 4.34 mmol) in methanol (6.5 mL). After 16 hours, the solvent was evaporated. The residue was basified with 1M NaOH and extracted twice with hexanes. The aqueous layer was acidified with 12M HCl, and the precipitate was filtered, rinsed with water, and dried in vacuo, affording crude product (628 mg) mp 70°-77° C., which was recrystallized from hot ethanol-water (50:50) to give bis(2-phenylethyl)phosphinic acid (364 mg) as a white solid, mp 84°-87° C. NMR δ2.02 (4H, m), 2.94 (4H, q), 6.8 (1H, br. s), 7.24 (10H, m).
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:19].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:18]
Reactant: [OH-]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCCO
Reaction time: 8 h
Yield: 97 %

Procedure:
A 5 liter three neck round bottom flask, equipped with a mechanical stirrer and reflux condenser, was charged with 300 g (1.16 moles) of 99% hexadecanolide, 1000 mls of 50% sodium hydroxide, 1500 mls of toluene and 5.6 g (0.01 6 moles) of 97% tetrabutylammonium hydrogen sulfate. The reaction mixture stirred at 85°-95° C. overnight, the reaction was cooled, and filtered under vacuum. The filtered solid was washed with diethyl ether before being added to water and acidified to pH=1.5 with concentrated hydrochloric acid. The precipitated product was filtered under vacuum, washed several times with water and dried at 50°-60° C. under high vacuum to give 353 g (1.2 moles) of 97% 16-hydroxy hexadecanoic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:21]3[CH:22]=[N:23][O:24][C:20]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.75 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.72 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-(4-chlorophenyl)-2-thiazolyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.58 g, yield 43%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 172–173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:22])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of 4.45 g (28.9 mmol) of 4-fluorophenylacetic acid in 3.26 g (31.8 mmol) of triethylamine and 275 mL of acetonitrile was added 8.9 g (28.9 mmol) of 2-bromo-4'-(methylsulfonyl)acetophenone (prepared in Step 3) at ambient temperature. The reaction mixture was stirred for 30 minutes, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate/hexane (1:1) gave 6.87 g (68%) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone as a colorless solid: NMR (CDCl3) δ3.08 (s, 3 H), 3.79 (s, 2 H), 5.35 (s, 2 H), 7.06 (s, t, J=9 Hz, 2 H), 7.32 (dd, J=6 and 9 Hz, 2 H), 8.06 (s, 4 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]1[CH2:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1)([O-:3])=[O:2].[CH3:21]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]1[C:16](=[CH2:21])[C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1)([O-:3])=[O:2]
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)Oc2ccccc21
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Product: C=C1C(=O)c2ccccc2OC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 1.35 g (5 mmol) of 3'-nitroflavanone [prepared as described in J. Chem. Soc. Japan, Pure Chem. Sect. 74, 827 (1953)], and 12 ml of bis-(dimethylamino)methane was stirred at room temperature; 12 ml of acetic anhydride was added dropwise over 15 minutes. The temperature rose to 77°. After cooling to ambient temperature, the reaction was partitioned between 100 ml portions of ether and 100 ml portions of cold water. The aqueous phase was separated, washed with two 100 ml of ether, and discarded. The combined ether extracts were washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated. The residual oil was chromatographed on 100 g of silica gel, eluting with benzene to yield 548 mg of 3'-nitro-3-methylene flavanone, isolated as a white solid, m.p. 131°-132° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])OC1C=CC=CC=1)#[N:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:3]=[C:4]([N:12]([CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CCOC(=O)CN(CC=C(C)C)C(=NC#N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC=C(C)C)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1

Procedure:
Prepared by reacting cyanimino-[N-(3-methyl-2-buten-1-yl) -N-(ethoxycarbonylmethyl)-amino]-phenyloxy-methane with 3-(tert.-butyloxycarbonylamino)-piperidine in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(O)(C)C>[OH:46][C:43]([C:41]1[CH:40]=[CH:39][C:30]2[O:31][CH2:32][C:33]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:28](=[CH:27][CH2:26][CH2:25][N:10]3[CH2:11][CH2:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:13])[CH2:8][CH2:9]3)[C:29]=2[CH:42]=1)([CH3:45])[CH3:44]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 49.6 %

Procedure:
To a solution of the 4-phenyl-piperidin-4-ol (0.212 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.240 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.140 g, 50%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57(s, 6H), 2.67–2.80 (m, 4H), 1.95–2.11 (m, 2H), 2.34–2.41 (m, 2H), 2.43–2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.43 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21–7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 534 (M+1), retention time 2.47.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2C=C3C=CC=C3O[C:18]=2CC(O)=O)[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Br:1][C:2]1[C:3]2[O:8][CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1Br
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccc(Cl)c(Cl)c1
Product: Clc1ccc(-c2coc3c(Br)cccc23)cc1Cl

Procedure:
Starting with 2-bromophenol and alpha-bromo-3,4-dichloroacetophenone and using Process A as described in Examples 1 and 2, the compound 7-bromo-3-(3,4-dichlorophenyl)benzofuran is prepared. Using Process F as described in Examples 6 to 9, this compound is converted to 3-(3,4-dichlorophenyl)-7-benzofuranacetic acid, m.p. 158.5°-160° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([C:10]([O:12]C)=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22].[CH:23]1([CH2:26][O:27][NH2:28])[CH2:25][CH2:24]1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([C:10]([NH:28][O:27][CH2:26][CH:23]2[CH2:25][CH2:24]2)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22]
Reactant: NOCC1CC1
Reactant: COC(=O)c1nn(C)c(=O)c(Br)c1Nc1ccc(Br)cc1F
Product: Cn1nc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield by the procedure described in Example 166 (step I) using methyl 5-bromo-4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (31 mg, 0.071 mmol) and O-cyclopropylmethyl-hydroxylamine (20 mg, 0.23 mmol). MS APCI (−) m/z 487, 489, 491 (M−1, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.31 (dd, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 3.65 (d, 2H), 1.13 (m, 1H), 0.58 (q, 2H), 0.31 (q, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:18]#[C:19][C:20](O)=[O:21])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.Cl.[CH3:35][N:36](C)CCCN=C=NCC>C(Cl)Cl>[CH3:35][NH:36][C:20](=[O:21])[C:19]#[C:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:12][CH:13]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)CN(c1ccc(C(O)(C#CC(=O)O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 4-[4-(benzenesulfonyl-isobutyl-amino)-phenyl]-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid (see Example 69; 0.439 mmol) and 0.26 mL of methylamine (2M in THF) were combined in 3 mL of CH2Cl2 at rt. 0.1 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.527 mmol) was added. The resulting mixture was stirred at rt for 16 h. After addition of 80 mL of CH2Cl2 the resulting solution was washed with an aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and brine. The organic layers were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica(EtOAc:hexanes, 1:1) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 0.90 (m, 6H), 1.56 (m, 1H), 2.91 (d, J=5.0 Hz, 3H), 3.31 (m, 2H), 3.72 (br s, 1H), 6.26 (d, 5.0 Hz, 1H), 7.11 (d, J=8.7 Hz, 2H), 7.44–7.60 (m, 5H), 7.64 (d, J=8.7 Hz, 2H). Mass Spectrum (CI+) m/e=486 (M+18).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].Br[CH2:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:23])=[CH:20][CH:19]=1>CO.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:34][CH:35]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C(=O)c2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 2-butyl-4-chloro-5-(hydroxymethyl)imidazole (11.12 g, 54 mmol, 1 eq) in 200 mL methanol was added dropwise a freshly prepared sodium methoxide solution (1.36 g Na, 59 mmol, 1.1 eq in 50 mL MeOH). After stirring for 0.5 hours, the methanol was removed in vacuo and the resultant glass was dissolved in 200 mL DMF. To this mixture was added a solution of methyl 2-[4-(bromomethyl)benzoyl]benzoate (18.00 g, 59 mmol, 1.1 eq) in DMF and the entire contents was stirred overnight under N2 at room temperature. The solvent was then removed in vacuo and the residue dissolved in 500 mL ethyl acetate and 500 mL H2O. The layers were separated and the aqueous layer was extracted twice with 500 mL portions of ethyl acetate. The organic layers were dried and concentrated and the crude product flash chromatographed to separate the two regioisomers in 60:40 hexane/ethyl acetate over silica gel. The faster moving isomer was isolated to yield 14.72 g of a glassy solid. NMR (200 MHz, CDCl3) δ8.03 (d, 1H, J=7 Hz); 7.67 (m, 4H); 7.36 (d, 1H, J=7 Hz); 7.05 (d, 2H, J=7 Hz); 5.28 (s, 2H); 4.43 (s, 2H); 3.63 (s, 3H); 2.53 (t, 2H, J=7 Hz); 1.60 (t of t, 2H, J=7,7 Hz); 1.30 (t of q, 2H, J=7,7 Hz); 0.87 (t, 3H, J=7 Hz). Mass Calcd. for C25H26ClF3N4O5S: 586.1264. Found: 586.1285.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccnc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg) and 3-bromopyridine (226 mg) were dissolved in DMF (4 ml), and K2CO3 (536 mg) and a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (249 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7]C(=O)[C:5]2=[O:12].[OH:13]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:12])=[O:13]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(F)cc1C(=O)O
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A stirred solution of 5-fluoroisatin (39 g, 0.236 mol) in NaOH (5%, 500 mL) was treated dropwise over 10 min with 30% H2O2 (57 g, calculated to contain 17 g, 0.5 mol). After another 20 min of being stirred, during which became warm and effervesced, the solution was cooled in an ice-bath and acidified to pH=4 with 3 M HCl. The precipitated solid was collected and dried in air to obtain 2-amino-5-fluoro-benzoic acid 1 as a beige powder (29.6 g, 80%). 1H NMR (DMSO-d6) δ 7.3-8.2 (m, 2H), 7.08 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=438.02.