Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12]([N:19]1[CH:23]=[CH:22]N=[CH:20]1)(N1C=CN=C1)=[O:13].COC(OC)CN[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40]C=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>>[O:13]=[C:12]1[N:19]([C:20]2[CH:38]=[CH:37][C:36]([O:35][C:32]3[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=3)=[CH:41][CH:40]=2)[CH:23]=[CH:22][N:9]1[C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
4-Acetaminoaniline was reacted with carbonyidiimidazole and (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine as described in example 92, followed by treatment of the crude product with trifluoroacetic acid at 80° C. The product is precipitated on addition of ethyl acetate/heptane 1:1. The precipitated solid was filtered off and dried in a vacuum oven at 40° C. The product with the molecular weight of 385.43 (C23H17N3O2); MS (ESI): 386 ([M+H]+) was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)=CC=1)([O-])=O>CO>[CH:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:37]([N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:13][CH2:14]2)=[O:36])=[CH:40][CH:41]=1)([CH3:48])[CH3:47]
Reactant: Clc1ccc2c(C3CCNCC3)ncnc2c1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(Cl)ccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (29b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (29c) as a di-HCl salt. To a suspension of (29c) in anhydrous MeOH, was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol) and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5 mg (12% overall yield from 29a) of pure 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.25 (s, 1H), 8.15-8.06 (m, 2H), 7.62 (d, 1H), 7.23 (d, 2H), 6.85 (d, 2H), 6.30 (s, 1H), 4.49 (m, 1H), 4.26 (m, 2H), 3.70 (m, 1H), 3.15 (m, 2H), 2.23-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 424.2, found 425.4 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:16]=2[CH3:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(S(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1cc(S(C)(=O)=O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of 2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give 2-methyl-4-(methylthio)benzoic acid. 430 mg of 2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide. MS (Q1) 401.0 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15](=N)[NH:16][CH2:17]C)=[O:13])[CH3:2].CO[CH:22](OC)[N:23](C)C.Cl.CO.[CH3:31][C:32]#[N:33]>C(Cl)(Cl)Cl.CO>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[CH:17]=[N:16][C:15]([C:22](=[NH:23])[NH:33][CH2:32][CH3:31])=[N:14][C:12]1=[O:13])[CH3:10]
Reactant: CCNC(=N)NC(=O)Nc1c(CC)cccc1CC
Reactant: COC(OC)N(C)C
Reactant: CC#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(=N)c1ncn(-c2c(CC)cccc2CC)c(=O)n1
Temperature: 25 °C

Procedure:
To a magnetically stirred stined suspension of 10/5 g (40 mmol) of 1-(2',6'-diethylphenyl)-3-ethylamidinourea in 10 ml of CH3CN is added 9.52 g (80 mmol) of N,N-dimethylformamide dimethylacetal and another 20 ml of CH3CN. The reaction mixture is heated to reflux at which point all of the solid dissolves. The solution is refluxed for one hour, allowed to cool to ambient temperature and then concentrated in vacuo to yield an off-white solid which is taken up in CHCl3, washed with H2O) (2×50 ml) and saturated aqueous brine (2×25 ml). All aqueous wash layers are combined and back-extracted with CHCl3, (2×25 ml). All organic layers are combined, dried (Na2SO2), filtered and the filtrate concentrated in vacuo to yield a yellow oil. The oil is taken up in MeOH and acidified with HCl/MeOH then concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]3[O:28][CH2:29][CH2:30][C:26]=3[CH:25]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccc2c(c1)CCO2
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (2.3 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (2.0 g), triethylamine (2.3 ml) and methanol (23 ml) was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (8 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with diethyl ether to give the title compound (1.98 g).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:35][C:34]=1[F:48])[S:14]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][N:22]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:21][CH2:20]2)(=[O:16])=[O:15].C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl>[F:48][C:34]1[CH:35]=[C:36]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH:37]=[CH:38][C:33]=1[NH:13][S:14]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][N:22]([C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])[CH2:21][CH2:20]2)(=[O:15])=[O:16]
Reactant: COc1ccc(CN(c2ccc(OCCc3ccccn3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(OCCc4ccccn4)cc3F)ccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of N-(2,4-dimethoxybenzyl)-N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (350 mg) in a mixture of anisole (5 mL) and chloroform (5 mL) while cooling in ice, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=70:30→chloroform:methanol=95:5) to afford N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as a colorless oil (12 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C1CCNCC1
Reactant: Nc1sc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1sc2ccccc2c1C(=O)N1CCC(=O)CC1
Yield: 84 %

Procedure:
A solution of 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 g, 1.0 equivalent) and 4-piperidone (1.0 equivalent) in DMF (0.33 M) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and volatiles removed under reduced pressure. Residue was purified by SiO2 chromatography (5%-10% MeOH/CH2Cl2 gradient) to afford the 1-(2-aminobenzo[b]thiophene-3-carbonyl)piperidin-4-one (6A, 84%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:53]>CCCCO>[ClH:53].[NH2:28][C:22]1([CH3:21])[CH2:27][CH2:26][CH2:25][N:24]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:23]1
Reactant: ClCCl
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CC1(N)CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.96 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol), tert-butyl 3-methylpiperidin-3-ylcarbamate (192 mg, 0.895 mmol) and DIEA (0.052 mL, 0.298 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate), and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M+ column, 10-80% CH3CN/water gradient; 30 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was then removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (12.8 mg, 7.96% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.09 (s, 1H), 10.54 (s, 1H), 9.37 (s, 1H), 8.91 (d, 1H), 8.70 (m, 1H), 8.29 (s, 1H), 8.05 (s, 3H), 7.83 (m, 1H), 7.54 (s, 1H), 3.40 (m, 2H), 3.27 (m, 1H), 3.17 (m, 2H), 1.65 (m, 2H), 1.46 (m, 1H), 2.00 (s, 3H); LCMS (APCI+) m/z 429 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26]C(OCC)=O)=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[OH-].[NH4+].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 42.7 %

Procedure:
43.20 g (0.081 Mol) of 6-[((2E)-{4[(ethoxycarbonyl)oxy]phenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate are dissolved in 66 ml (0.815 Mol) of pyridine and 400 ml of acetone at room temperature. 61 ml (0.815 Mol) of ammonium hydroxide solution 25% are added dropwise to the solution at room temperature. After 12 h reaction, the mixture is thrown on water and acidified by the addition of HCl 25% (up to pH=3-4). A paste is obtained which is filtrated and dissolved in ethyl acetate and extracted with water. The organic phase is dried with sodium sulfate, filtrated, concentrated by rotary evaporation. Filtration of the residue over silica gel with tert-Butyl methyl ether as eluant and crystallization of the residue in 200 ml of ethyl acetate and 1200 ml of hexane at 0° C. give 15.84 g of 6-[((2E)-{4-hydroxyphenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[C:13]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)ccc(O)c21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(Br)c2c1C(=O)NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A solution of Example 106D (103 mg, 0.45 mmol) in DMF (4 mL) was treated with Cs2CO3 (162 mg, 0.5 mmol) and methyl iodide (0.03 mL, 0.48 mmol), stirred at room temperature for 3 hours, then poured into water. The resulting precipitate was filtered to give 76 mg (70%) of the desired product. MS (ESI(+)) m/e 242,244 (M+H)+.
Reaction SMILES: C1(C2[CH:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:18][CH:17](N4CCNCC4)[CH2:16]3)=O)=CC=2)CCCCC1.[C:25]([BH3-])#N.[Na+].O.[OH-].[Na+].[C:32]([OH:35])(=[O:34])[CH3:33]>>[NH:15]1[C:18]2[C:11](=[CH:12][C:33]([C:32]([O:35][CH3:25])=[O:34])=[CH:16][CH:17]=2)[CH2:10][CH2:13]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1CC(N2CCNCC2)C1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1H-indole-5-carboxylate 1j (2 g, 11.4 mmol) in glacial acetic acid (15 mL) at 0° C. was added sodium cyanoborohydride (1.08 g, 17.2 mmol) slowly. The mixture was allowed to warm up and stirred at room temperature for 2 h. Water was added to the resulting mixture at 0° C., and pH of the solution was adjusted to ˜12 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give compound 55a (1.79 g). MS m/z (M+H+) 178.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26]C=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(Cl)Cl>[CH2:22]([NH:21][C:20](=[O:30])[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[C:23]1[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCc3ccccc3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccccc1)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-phenethylcarbamoyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg) in MeOH (5 ml) was cooled to 0° C. and slowly treated with 4N HCl (2.52 ml). The reaction mixture was stirred at r.t. overnight, then diluted with CH2Cl2 and directly purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give N-benzyl-6-piperazin-1-yl-nicotinamide as off-white solid. MS (ISP): 297.5 ([M+H]+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[O:11].[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]3[C:9](=[O:10])[CH2:8][S:7][C:6]3=[O:11])[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CSC(=O)N1CCCBr
Reactant: Cc1cccc(N2CCNCC2)c1
Product: Cc1cccc(N2CCN(CCCN3C(=O)CSC3=O)CC2)c1

Procedure:
Reaction of 3-(3-bromopropyl)-2,4-thiazolidinedione with 1-(3-methylphenyl)piperazine according to the procedure of Example I(c) affords 3-[3-[4-(3-METHYLPHENYL)-1-PIPERAZINYL]PROPYL]-2,4-THIAZOLIDINEDIONE.
Reaction SMILES: [OH:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:14](=O)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([SH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:23])[C:22]3[C+:9]=[CH:10][CH:11]=[CH:12][C:13]2=3)=[CH:29][C:28]=1[CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: O=C1c2ccccc2S(=O)c2ccccc21
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)Cc1ccccc1OC
Solvent: ClCCl
Product: COC(=O)Cc1cc([SH]2C3=C([C+]=CC=C3)C(=O)c3ccccc32)ccc1OC
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Yield: 85.3 %

Procedure:
Triflic acid (7.3 mL, 43.4 mmol) was added dropwise to a solution of thioxanthone oxide (5.00 g, 21.7 mmol) and methyl 2-(2-methoxyphenyl)acetate (4.31 g, 23.9 mmol) in DCM (60 mL) at −78° C. and slowly warmed to 25° C. overnight. The reaction mixture was quenched with water (100 mL), the layers separated, and the aqueous phase washed with water (4×100 mL) and concentrated to a crude solid. The crude solid was dissolved in minimal acetone, precipitated into MTBE (1 L), and filtered to afford the title compound (10.0 g, 85%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.66-8.69 (m, 2H), 8.19-8.22 (m, 3H), 8.10-8.13 (m, 4H), 7.91 (d, J=2.5 Hz, 1H), 7.37 (d, J=9 Hz, 1H), 3.96 (s, 3H), 3.61 (s, 2H), 3.57 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:39]O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:39][CH:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CCCc2ccccc21
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(OCC4CCCc5ccccc54)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (1,2,3,4-tetrahydro naphthalen-1-yl)-methanol. MS (ESI) m/z 524.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.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.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:15]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)NC(C)C
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.061 mL, 0.4 mmol), 5-bromo-7-methyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.105 g, 0.3 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropylamine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.100 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24](O)=[O:25])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C[N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([NH2:29])=[O:25])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid (0.0259 g, 0.059 mmol) in DMF (2 mL) was added HATU (0.2298 g, 0.60 mmol), DIPEA (0.5 mL), and 0.8 M NH3 in THF (4 mL). The mixture was stirred at rt for 2 d. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0146 g (57%) of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide. LC-MS Method 1 tR=1.55 min, m/z 435, 437 (MH+), 391, 393; 1H NMR (400 MHz, CD3OD) δ 7.30-7.26 (m, 2H), 7.19-7.16 (m, 2H), 7.04-6.99 (m, 2H), 6.74 (d, J=8.5 Hz, 2H), 5.39 (q, J=7.0 Hz, 1H), 3.06-3.01 (m, 1H), 2.72-2.58 (m, 3H), 2.42-2.34 (m, 1H), 2.26-2.19 (m, 1H), 1.41 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −116.70 (m).