Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:17][C:14]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=1)=[O:16]
Reactant: CC(C)Cn1nc(C(=O)O)c2ccccc21
Reactant: Nc1nccs1
Product: CC(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 36.6 %

Procedure:
1-(Isobutyl)-indazole-3-carboxylic acid (340 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-iodo-2-methylpropane (0.33 mL, 2.84 mmol) following general procedures G and E. 1-(Isobutyl)-indazole-3-carboxylic acid thiazol-2-ylamide (66 mg) was prepared from 1-(isobutyl)-indazole-3-carboxylic acid (130 mg, 0.60 mmol) and 2-aminothiazole (150 mg, 1.5 mmol) following the general procedure H.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:27]([CH2:24][CH2:25][CH3:26])[C:28]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CCCN=C=O
Product: CCCn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 39.6 %

Procedure:
1-Cyclopentyl-7-methoxy-3-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (14 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and propyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 7.82 (d, 1H), 7.59 (t, 1H), 7.24 (d, 1H), 5.01 (m, 1H), 4.15 (s, 3H), 4.03 (t, 2H), 2.40 (m, 2H), 2.09 (m, 4H), 1.76 (m, 2H), 1.63 (m, 2H), and 1.16 (t, 3H) ppm.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][S:21]([CH3:23])=[O:22])=[C:15]([NH:25][CH3:26])[CH:14]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][S:21]([CH3:23])(=[O:6])=[O:22])=[C:15]([NH:25][CH3:26])[CH:14]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1cc(F)ccc1C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (8.29 g) in dichloromethane (200 ml) was added to a solution of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (10.0 g), prepared in a similar manner to that described in Example 1, in dichloromethane (175 ml) over a period of 7 minutes whilst maintaining the temperature below 30°. The mixture was stirred at ambient temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution (244 ml) was added and the mixture stirred at ambient temperature for a further 2 hours. The dichloromethane layer was isolated and the aqueous layer extracted with dichloromethane (2×60 ml). The organic phases were combined, dried (magnesium sulphate) and evaporated in vacuo to give a solid which was crystallised from acetone to give 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphonylethanone, m.p. 143.5°-145°.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH:8]=1)=[O:5].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C>[Br:35][C:25]1[CH:24]=[N:23][N:22]([CH3:26])[C:21]=1[C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:27])[CH3:1])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)CC(=O)Nc1ccc(OCCN2CCCC2)c(-c2ccnn2C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)=CC(=O)Nc1ccc(OCCN2CCCC2)c(-c2c(Br)cnn2C)c1
Yield: 24.8 %

Procedure:
3-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-butyramide (20 mg, 0.054 mmol) was treated with NBS (10 mg, 0.054 mmol) in DMF (2 mL) at room temperature for 2 hours. The crude was purified by HPLC to provide the title compound as an off-white solid (6 mg, 25%). Exact mass calculated for C21H27BrN4O2 446.1, found 447.2 (MH+).
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH:6]=[CH:7][O:8]CC)CCC.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[C:22]([Cl:42])[CH:21]=1>C1(C)C=CC=CC=1>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:7](=[O:8])[CH3:6])=[CH:21][C:22]=3[Cl:42])=[O:27])[CH2:29][C:30]=12
Reactant: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Tributyl(ethoxyvinyl)tin (1.17 g) was added to a solution of (4-bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.24 g) in toluene (10 ml). The resultant solution was purged with nitrogen for 10 minutes, then bis(triphenylphosphine)palladium (II) chloride (0.11 g) was added. The reaction mixture was heated to reflux for 24 hours. The solution was cooled to room temperature and 5% aqueous hydrochloric acid (10 ml) was added. After stirring for one hour, the mixture was filtered through a pad of diatomaceous. Diethyl ether (5 ml) was added to the filtrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield a brown glass. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in a white solid (0.30 g), MS, m/z: 364 (M)+.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[SH:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.O>OS(O)(=O)=O>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[S:11][CH2:1][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: Sc1nc2ccccc2s1
Reactant: C=C(CCC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCC(CSc1nc2ccccc2s1)C(=O)O
Reaction time: 2 h

Procedure:
20.9 g of 2-methyleneglutaric acid are dissolved at 50°, with stirring, in 150 ml of 75% H2SO4, and 24.2 g of 2-mercaptobenzthiazole are added slowly. The reaction is exothermic and the temperature rises to 60°. The reaction mixture is then stirred for 2 hours at 55°. The resulting brown solution is poured into 500 ml of water and stirred for 1 hour. 600 ml of water are then added, and the white precipitate is filtered off. Recrystallisation from aqueous methanol gives 4-(benzthiazol-2-ylthio)-butane-1,3-dicarboxylic acid, melting at 152°-154°.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][CH2:6][C@@H:7]([CH3:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1.S(Cl)([Cl:32])(=O)=O.Cl>N1C=CC=CC=1>[C:1]([OH:4])(=[O:3])[CH3:2].[Cl:32][C:16]1[C:17](=[O:27])[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15]=1[CH2:14][CH2:13][C@@H:12]1[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]1[CH2:10][CH2:9][C@@H:8]2[C@H:7]([CH3:28])[CH2:6][OH:5]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a stirred solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one acetate (10.2 g, 27.38 mmol) in pyridine (100 mL) cooled to 15° C. there was added sulfuryl chloride (4.4 mL, 54.76 mmol) dropwise. After 30 minutes, the reaction mixture was poured into 1N hydrochloric acid and extracted with ether. The combined organic extracts were successively washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The solution was then dried over magnesium sulfate and concentrated to give an orange solid. Flash chromatography of this material [eluting with ethyl acetate-hexane (3:7)] gave (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate as a white solid (8.5 g, 72%).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](Cl)=[O:7])[CH3:2].[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>N1C=CC=CC=1>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:6](=[O:7])[CH:5]=[CH:4][O:3][CH2:1][CH3:2]
Reactant: Nc1ccccc1Br
Reactant: CCOC=CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccccc1Br
Reaction time: 1 h

Procedure:
10 g (74.31 mmol) of 3-ethoxy-acryloyl-chloride are added dropwise at 0° C. to a solution of 11.6 g (67.43 mmol) of 2-bromo-aniline in 60 ml of pyridine and stirred for one hour at this temperature. The mixture is allowed to come up to ambient temperature and stirred for two hours. Then the reaction mixture is extracted with water and ethyl acetate. The organic phase is extracted with water and 1 N hydrochloric acid, combined with activated charcoal and dried over sodium sulphate. The solvent is distilled off and the residue is recrystallised from isopropanol/water 2:1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC>CC#N.CCOC(C)=O.[Cu]I.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>[CH2:17]([O:16][C:14]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[CH2:15])[CH3:18]
Reactant: Fc1ccc(Br)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=C(OCC)c1ccc(F)cn1
Temperature: 80 °C
Yield: 119.6 %

Procedure:
A mixture of 2-bromo-5-fluoropyridine (200 mg, 1 mmol), tributyl(1-ethoxyvinyl)tin (500 mg, 1 mmol), copper(I) iodide (20 mg, 0.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (50 mg, 0.07 mmol) in MeCN (5 mL) was heated to 80° C. for 30 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc, washed with 5% NH4OH, brine, dried over MgSO4, filtered and concentrated to give a crude oil. The product was purified by flash column chromatography on silica gel eluting with a hexane; EtOAc gradient (0-30%) to give 2-(1-ethoxyvinyl)-5-fluoropyridine as a clear oil (0.2 g, 90%). LCMS calc. for C9H11FNO (M+H)+: m/z=168.1. found: 168.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.N1CCCC1>C(O)C>[CH3:10][N:11]1[CH2:12][CH:13]=[C:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[N:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: CN1CCC(=O)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: CN1CC=C(c2c[nH]c3ccncc23)CC1

Procedure:
from 5-azaindole (2.0 g, 16.9 mmol); N-methyl-4-piperidone (1.92 g , 16.9 mmol) and pyrrolidine (12.04 g, 169 mmol) in ethanol (20 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:40]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccc(F)cc3Cl)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (170 mg, 0.52 mmol) and N,N-diisopropylethylamine (140 mg, 1.03 mmol) in 5 mL of dichloromethane was dropwise added a solution of 2-chloro-4-fluorobenzoyl chloride (120 mg, 0.62 mmol) in 3 mL dichloromethane under nitrogen. Then the resulted mixture was stirred at R.T. for overnight. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The solvent was removed by rotary evaporation. The residue was purified by silica gel (petroleum ether/ethyl acetate=3:1) to afford 189 mg of methyl 2-(3-(2-chloro-4-fluorobenzamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid; yield: 76%. MS (ESI+APCI) M+1=485.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Yield: 92.2 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (2.65 g, 10.0 mmol) was treated with cyclopentylamine (1.06 g, 1.2 eq. 12.0 mmol) following a method similar to general procedure B to afford 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (2.9 g). The obtained amino-ester (0.5 mmol) was subjected to reaction with ethyl isocyanate (2.0 mmol) according to general procedure C to furnish 1-cyclopentyl-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (83 mg). LCMS: m/z 340 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 7.78 (d, 1H), 7.55 (t, 1H), 7.20 (d, 1H), 4.99 (p, 1H), 4.13 (s, 3H), 4.11 (q, 2H), 2.42 (m, 2H), 2.06 (m, 4H), 1.62 (m, 2H) and 1.32 (t, 3H) ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:8]3[C:22]([C:23]#[N:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:22]1[C:8]2[C:7]([O:6][CH:4]3[CH2:3][CH:2]([NH:1][C:33](=[O:36])[CH:34]=[CH2:35])[CH2:5]3)=[N:12][C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[N:10][C:9]=2[N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=1)#[N:24]
Reactant: C=CC(=O)Cl
Reactant: Cn1cc(Nc2nc(OC3CC(N)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CC(Oc2nc(Nc3cnn(C)c3)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a solution of 4-[(3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (cis:trans 1:1) (380 mg, 0.84 mmol) in DCM (10 mL) was added acryloyl chloride (68 μL, 0.84 mmol) and DIPEA (146 μL, 0.84 mmol). The reaction solution was stirred at rt for 10 min. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4 and evaporated. The product was purified via flash chromatography eluting with a gradient of 0%-100% EtOAc in heptanes to give the title compound (317 mg, 75% yield) as a 1:1 cis:trans isomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H) 8.42-8.63 (m, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.43-7.62 (m, 1H) 6.00-6.31 (m, 2H) 5.61 (ddd, J=9.69, 7.05, 2.64 Hz, 3H) 4.07-5.26 (m, 2H) 3.81 (d, J=5.79 Hz, 3H) 3.56 (t, J=7.93 Hz, 2H) 2.84-2.99 (m, 1H) 2.51-2.58 (m, 2H) 2.08-2.20 (m, 1H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C24H32N8O3Si 509.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 135.9 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (48 g) and 2-(4-fluorophenyl)ethyl p-toluenesulfonate (38 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (65 g), melting point 114-116° C. The obtained free basic compound (65 g) was dissolved in ethyl acetate, and 20% hydrochloric acid-isopropanol solution (35 g) was added thereto. After cooling, the precipitated crystals were collected by filtration to yield 57.4 g of crystals. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue. After cooling, the precipitated crystals were collected by filtration to yield 10.9 g of crystals. The obtained crystals were combined and recrystallized from a mixed solvent of ethanol (400 mL) and water (1500 mL) using activated carbon to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride monohydrate (54 g), melting point 201-204° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccccn1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2ccccn2)c1
Temperature: 90 °C

Procedure:
2-Bromopyridine (2.00 mL), 3-aminophenylboronic acid (5.40 g) and palladium tetrakistriphenylphosphine (1.2512 g) were added to a mixture of 130 mL of dimethoxyethane and 32 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (300 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 2.75 g of 3-(pyridin-2-yl)benzenamine.
Reaction SMILES: C[O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16].B(Br)(Br)Br>ClCCl.O>[OH:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[C:4]=1[CH3:16]
Reactant: COc1c(C)c(=O)c2ccccc2[nH]c1=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 70.5 %

Procedure:
To a solution of 3-methoxy-4-methyl-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.47 g) in dichloromethane was added boron tribromide (6.5 mL). The precipitate which formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was recrystallized from hot toluene to give the title compound (0.31 g); mp 252.3° C.; NMR: 2.07 (s,3); MS(EI): m/z=203(M). Analysis for C11H9NO3 ·0.2 H2O: Calculated: C, 63.89; H, 4.58; N, 6.77; Found: C, 63.79; H, 4.49; N, 6.73.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(Br)ccc(OC(C)C)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.30 g, 4.80 mmol) in DCM (5 mL) was added oxalyl chloride (810 mg, 6.19 mmol) followed by DMF (10 mL). The reaction mixture was stirred at 0° C. for 1.5 hours, then concentrated under vacuum. The residue was dissolved in MeOH (15 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (0-50%, EtOAc/heptane) to give the title compound (Cpd PP, 894 mg, 65%) as an amber oil. 1H NMR (400 MHz, chloroform-d) δ 1.33 (d, J=6.11 Hz, 6H) 2.16 (s, 3H) 3.95 (s, 3H) 4.50 (dt, J=12.04, 6.08 Hz, 1H) 6.75 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 1H); MS 287 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[N:25][O:24][CH3:23])[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-4,4,4-trifluorobutan-1-one (821.7 mg), O-methylhydroxylamine hydrochloride (656 mg) and pyridine (5.239 mL) was stirred at room temperature overnight, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (842.7 mg).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[C:13](O)(=O)[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>Cl>[CH:14]([C:16]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:15])[CH3:13]
Reactant: CC(C)C(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 10 °C
Reaction time: 2 h
Yield: 769.2 %

Procedure:
A slurry of 2,3-diaminobenzoic acid methyl ester (21.5 g, 0.13 mol) and isobutyric acid (36.2 mL, 0.39 mol) in aqueous hydrochloric acid (4M, 210 mL) was stirred under reflux for 24 h to afford a homogenous solution. The solution was cooled to 10° C. and the pH raised to 3.5 using aqueous sodium hydroxide solution (4M, approx. 210 mL), while maintaining the temperature below 30° C. The reaction mixture was stirred at room temperature for 2 h, cooled to 10° C., and the resultant precipitate filtered off. The solid cake was transferred to a beaker and acetonitrile (300 mL) was added. The slurry was stirred at room temperature for 1 h then and filtered to afford a grey solid. The solid was dried under vacuum to afford the title intermediate (23 g, 0.1 1 mol, 87%). (m/z): [M+H]+ calcd for C11H12N2O2 calcd. 205.09; found 205.3. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.27 (d, 6H), 3.39 (m, 1H), 7.29 (t, 1H), 7.78 (m, 2H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccccc1C(F)(F)F
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccccc3C(F)(F)F)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.5. HPLC (Condition A), Rt: 4.78 min (HPLC purity: 95.4%).