Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Br:13])[C:3]=1[NH2:4].C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[NH2:4][C:3]1[C:5]([Br:13])=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1c(Br)cc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
2,6-Dibromo-4-(trifluoromethyl)aniline (3.19 g, 10.0 mmol, 1.00 eq) was dissolved in THF (50 mL) and cooled to −78° C. A 2.5 M solution of n-butyllithium in hexanes (8.40 mL, 21.0 mmol, 2.10 eq) was added dropwise over 15 min. The mixture was stirred at −78° C. for 1 h. A solution of DMF (1.03 mL, 14.0 mmol, 1.40 eq) in THF (5 mL) was added, and the mixture was stirred an additional 1 h at −78° C. The reaction was allowed to come to −15° C. over 30 min and then quenched with brine. The mixture was diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 1.74 g of the desired product as a pale yellow, crystalline solid. ES/MS m/z 268, 270 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[I:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Temperature: 25 °C

Procedure:
A mixture of 6.69 g (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester in 180 ml dichloromethane and 18.1 ml TFA is stirred at ambient temperature over the weekend. The reaction mixture is evaporated and the crude product is washed with toluene and dried in vacuo.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]1=2>>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: Cc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using m-tolylboronic acid (61 mg, 0.45 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (119 mg, 0.37 mmol) provides the title compound. GC/MS data: retention times in minutes (MS data for M+.ion): 19.60 (330), 19.95(330) Mass Spec (EI+) 330.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 198.2) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.99 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=478.1/480.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:31]([OH:32])=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:38][NH2:39]>>[OH:32][C:31]1[C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=[C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:39][CH3:38])=[O:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Reactant: CN
Agent: Cl
Product: CNC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (49), from (4′-([2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy)-1,1′-biphenyl-4-yl)acetic acid (216 mg, 0.431 mmol) obtained in Example (7) and methylamine hydrochloride (50 mg, 0.74 mmol), the title compound was obtained as a colorless crystal (160 mg, yield: 72%).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:12])=[N:6][C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[C:20](OCC)(=[O:22])[CH3:21]>C(O)(=O)C>[CH3:12][C:5]1[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=1[C:1]([CH2:2][C:20](=[O:22])[CH3:21])=[O:3]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1c(C)cc(C)nc1C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)c1c(C)cc(C)nc1C
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of 172.0 g of 3-acetyl-collidine, 4.5 l of anhydrous toluene, 195 g of ethyl acetate and 282.5 g of potassium tert.-butylate is heated at 100° for 4 hours under nitrogen. The reaction mixture is cooled and poured into 1/2 l of ice water and 140 ml of acetic acid, and the phases are separated and worked up in the customary manner to give 186.1 g of 2,4,6-trimethyl-nicotinoyl-acetone ##SPC8##
Reaction SMILES: [C:1]12([NH:7][C:8]3[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=3)[CH2:6][CH:4]([CH2:5]1)[CH2:3][CH2:2]2.[OH:18]O.[OH-].[Na+]>CS(C)=O>[C:1]12([NH:7][C:8]3[C:13]([C:14]([NH2:15])=[O:18])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=3)[CH2:5][CH:4]([CH2:6]1)[CH2:3][CH2:2]2
Reactant: CSc1ncc(C#N)c(NC23CCC(C2)C3)n1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(NC23CCC(C2)C3)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of 4-(bicyclo[2.1.1]hexan-1-ylamino)-2-(methylthio)pyrimidine-5-carbonitrile (502.0 mg, 2.0 mmol) in DMSO (5 mL) was added aqueous hydrogen peroxide solution (1.2 g, 30%, 10.2 mmol) and aqueous sodium hydroxide solution (1.7 mL, 6 mol/L, 10.2 mmol) at 0° C. The mixture was stirred at 50° C. for 15 min and then quenched by the addition of water (30 mL). The solid formed was collected and dried under vacuum to give the desired product (500 mg, 1.9 mmol, 93% yield). MS (ESI) m/z=265.3 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](I)=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:22](=[O:28])[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH:22]([C:23]2[O:27][CH:26]=[CH:25][CH:24]=2)[OH:28])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=Cc1ccco1
Reactant: Cc1cc(F)cc(C)c1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(F)cc(C)c1C(O)c1ccco1
Temperature: -75 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 5-fluoro-2-iodo-1,3-xylene (11 g, 44 mmol) in tetrahydrofuran (110 ml) is added 1.6 molar solution of n-butyl lithium in hexane (33 ml, 52 mmol) under nitrogen atmosphere at −75° C. The resulting solution is stirred at −75° C. for 60 minutes and to this mixture, a solution of furfural (6.3 g, 65.6 mmol) in THF (20 ml) is added over 20 minutes. The resulting solution is stirred at −75° C. for 2 hours. The cooling bath is removed and the mixture is allowed to reach room temperature, and then stirred for 5 hours. The reaction mixture is quenched with ice cold water (1000 ml) and extracted with ethyl acetate (3×250 ml), dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo to give a residue which is purified by flash chromatography (hexane/ethyl acetate) to afford (4-Fluoro-2,6-dimethylphenyl)furan-2-ylmethanol (6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC(C)=O.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g 0.209 mmol) and cesium carbonate (80 mg; 0.245 mmol) in acetone (2 mL) was added a solution of chloroacetic acid, 1,1-dimethylethyl ester (0.04 mL; 0.279 mmol) in dichloromethane (0.1 mL) by syringe. The reaction mixture was stirred at 40° C. in a sand bath for 16 h, cooled to room temperature and concentrated. The reaction was diluted with DCM and water. The organics were concentrated and purified by ISCO (0-10% MeOH/DCM) to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)acetate.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C@@H:9]1[NH:14][CH2:13][C:12]2[O:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][C:27]=3[CH:28]=2)=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:2]([O:6][C:7]([C@@H:9]1[N:14]([S:33]([C:30]2[CH:31]=[CH:32][C:26]3[O:25][C:24]([C:21]4[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=4)=[CH:28][C:27]=3[CH:29]=2)(=[O:34])=[O:35])[CH2:13][C:12]2[O:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc2oc(-c3ccncc3)cc2c1
Reactant: CC(C)(C)OC(=O)[C@H]1Cc2ccoc2CN1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H]1Cc2ccoc2CN1S(=O)(=O)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 60 °C

Procedure:
30 mmol of (5R)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-5-carboxylic acid tert-butyl ester hydrochloride are placed in 150 ml of pyridine. 30 mmol of 2-(4-pyridyl)-1-benzofuran-5-sulphonyl chloride described in Preparation C are then added at room temperature and the whole is heated at 60° C. overnight.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: OB(O)c1ccsc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Under an argon atmosphere, a suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (232 mg), 3-thienylboronic acid (138 mg), tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 189 mg, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]Cl>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: O=C1CCN(Cc2ccccc2)C1
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
Benzyl-3-methyl-pyrrolidin-3-ol was prepared as described in Tett Lett 1996, 37, 8, 1297, by addition of 1-benzylpyrolidin-3-one to methyl magnesium chloride.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:32]=[CH:31][C:17]([C:18]([NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2].[ClH:41]>O1CCOCC1>[ClH:41].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:32]=[CH:31][C:17]([C:18]([NH:20][CH2:21][CH2:22][NH2:23])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:6][C@@H:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of tert-butyl (2-(4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate (for a preparation see Intermediate 40)(35 mg, 0.064 mmol) in 1,4-dioxane (1 mL) at room temperature was treated with hydrogen chloride in 1,4-dioxane (4N, 2 mL, 8.00 mmol) and the resulting suspension was stirred for 1 h at this temperature then concentrated in vacuo. The residue was triturated with Et2O the solid isolated by filtration and dried under house vacuum to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-aminoethyl)benzamide, hydrochloride (30 mg, 0.062 mmol, 97% yield) as a very pale yellow solid. LCMS (HpH, 2 min), Rt=0.74 min, MH+=444.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Oc1nccc2ccc(Cl)nc12)C(F)(F)F
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1

Procedure:
The title compound, MS: m/e=277 (M+H+), was prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester (Example G) and 2-amino-4-methylthiazole.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[H-].[Na+].Br[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=1
Reactant: Cc1cc(O)no1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(Oc1cc(C)on1)C(=O)OCC
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 3.468 g of 3-hydroxy-5-methylisoxazole in 35 ml of hexamethylphosphoric triamide was added dropwise to a suspension of 1.527 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of hexamethylphosphoric triamide, whilst ice-cooling. The mixture was then stirred at room temperature for an hour. A solution of 8.367 g of diethyl 2-bromomalonate in 35 ml of hexamethylphosphoric triamide was then added dropwise to the mixture, whilst cooling it with ice-water. The mixture was stirred at room temperature for 1 hour and then poured into ice-water. It was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 200 g of silica gel. 7.593 g of the title compound were isolated as an oily material from the fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:10 to 15:100 by volume.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][N:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=3[C:7](=[O:20])[C:8]1=2
Reactant: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2n1C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of methyl 8-chloro-4,10-dihydro-4,10dioxo-1H-1-benzopyrano-[3,2-b]pyridine-2-carboxylate (7.0 g, 0.023 mole), methyl iodide (14 g, 0.099 mole) and potassium carbonate (3.22 g, 0.023 mole) in dimethyl formamide (100 ml) was stirred at 100° under nitrogen for 3 hrs. The reaction mixture was cooled. The product, which precipitated, was filtered, washed with water and dried. Recrystallization from DMF gave white crystals (6.3 g, 86%), m.p. 276°-278°.
Reaction SMILES: [NH2:1][C:2]1[N:6](C(NC)=O)[CH:5]=[N:4][C:3]=1[C:11]([NH2:13])=[O:12].CCN(CC)CC>CO>[NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:11]([NH2:13])=[O:12]
Reactant: CNC(=O)n1cnc(C(N)=O)c1N
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)c1nc[nH]c1N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Amino-N1-methyl-1H-imidazole-1,4-dicarboxamide 15 (10.72 g, 0.057 mol, 97% pure against a standard sample by HPLC analysis), Et3N (5 mL) and MeOH (100 mL) were placed into a 250 mL round-bottom flask equipped with a magnetic stir bar. The heterogeneous reaction mixture was heated at 80° C. (oil bath) for 4 hour with vigorous stirring, gradually cooled to room temperature (the reaction mixture is a dark homogeneous solution), and concentrated under reduced pressure. The residue (a viscous oil) was treated with t-BuOMe/acetone/MeOH (50 mL/20 mL/5 mL) and stirred for 2 hour. Precipitation was induced by scratching the glass surface. The precipitate was collected by vacuum filtration to yield 7.21 g of 5-amino-1H-imidazole-4-carboxamide (as free base). The free base was converted into 5-amino-1H-imidazole-4-carboxamide hydrochloride 16.HCl by slurrying in HCl/MeOH (2.6 M, 40 mL, 0.104 mol, prepared by bubbling HCl gas into MeOH). The solid product 16.HCl was collected by filtration and air dried (2 hour) to yield 8.5 g of product (0.051 mmol, 97% pure against an Aldrich sample by HPLC analysis).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[O:20][CH2:21][C:22]([OH:24])=[O:23].O=S(Cl)Cl.[CH3:34][CH:35](O)[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[O:20][CH2:21][C:22]([O:24][CH:35]([CH3:36])[CH3:34])=[O:23]
Reactant: Cc1ccc(OCC(=O)O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(OCC(=O)OC(C)C)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Yield: 90 %

Procedure:
A solution of 2-[3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-dimethyl-phenoxy]acetic acid (I(j)) (120 mg, 0.3 mmol, 1 eq) and SOCl2 (1 mL) in i-PrOH (4 mL) was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was taken up in water and basified to pH 8 by addition of aqueous NaHCO3. The mixture was extracted with EtOAc and the organic extract was dried (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by column chromatography to give the title compound as an oil (120 mg, 90%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1cccc(O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-Methoxyphenyl)acetonitrile (3.6 g, 25.4 mmol) in dry methylene chloride (20 ml) was added BBr3 (55 ml, 1M in CH2Cl2, 55 mmol) at −78° C. under argon atmosphere. The reaction mixture was warmed to ambient temperature for 48 hours, quenched by crushed ice, and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (CH2Cl2:ethyl acetate 4:1) to give the title compound as oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH2:11]([OH:15])[C:12](=[CH2:14])[CH3:13].[OH-].[K+]>CS(C)=O>[F:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:15][CH2:11][C:12]([CH3:14])=[CH2:13])[CH:9]=[CH:8][CH:7]=1
Reactant: C=C(C)CO
Reactant: N#Cc1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=C(C)COc1cccc(F)c1C#N
Temperature: 0 °C
Yield: 88 %

Procedure:
In a flask were placed 250.0 g (1.80 moles) of 2,6-difluorobenzonitrile, 129.8 g of (1.80 moles) of methallyl alcohol, and 1500 mL of dimethyl sulfoxide. This mixture was stirred vigorously while 124.76 g (1.89 moles) of 85% powdered potassium hydroxide was added in portions. This addition required 2 hours during which the temperature was maintained below 45° C. The reaction mixture was stirred at ambient temperature for approximately 21 hours. At the conclusion of this period the mixture was poured into 4 L of an ice/water mixture. This mixture was divided into two equal portions, and each was extracted twice with 1 L of ethyl acetate. The extracts were combined and washed twice with a saturated aqueous solution of sodium chloride. The extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving 302.7 g of 6-fluoro-2-(2-methyl-2-propen-1-yloxy)benzonitrile as a residue. The NMR spectrum was consistent with the proposed structure.