Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+]>[C:15]([N:3]1[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
This compound was prepared according to Hein et. al., J. Amer. Chem. Soc.; 1962, 84, 4487-4494, incorporated by reference herein in its entirety. Thus, a slurry of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (20.3 g, 95 mmol) in 2N NaOH (150 ml) was treated with benzoyl chloride (13.4 ml, 114 mmol) dropwise over 30 minutes. The mixture was stirred a further 1.5 hours, acidified to pH 2-3 (4N HCl), and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 16.4 g (61) of the title compound following recrystallization (acetone/water); MS: 280 m/z (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL, 1.40 mmol, 2M in tetrahydrofuran) at −78° C. over 5 minutes. After 30 minutes, 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 4 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to afford a dark solid residue. The residue is purified by flash column chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 190-191° C.; 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([NH2:6])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[C:8]([F:13])[C:9]=1[Cl:12])[CH2:4][NH2:6]
Reactant: NC(=O)c1cc(F)c(Cl)c(N)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(F)c(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,4-Dichloro-5-fluoro-3 amino-benzamide (6.00 g, 26.9 mmol) in THF (175 mL) is added dropwise to LiAlH4 (1 M in THF, 28.0 mL) in THF (175 mL). The reaction mixture is stirred for 1 h at rt and 5 h at reflux. Excess LiAlH4 is destroyed under cooling as described by L. F. Fieser & M. Fieser Vol 1, p 584 Wiley 1967. After 30 min the mixture is filtered, the filtrate is concentrated, diluted with Et2O and the precipitate is collected.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25]([O:27][CH2:28][CH2:29]Cl)[CH3:26]>>[CH2:25]([O:27][CH2:28][CH2:29][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: CCOCCCl
Product: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 6 using 1-(t-butoxycarbonyl)-4-(1H-benzoimidazole-2-carbonyl)-piperidine and 2-chloroethyl ethyl ether to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9](=[O:15])[N:8]([OH:16])[C:7]1=[O:17].[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[C:28]([C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][N:6]3[C:11]4[CH:12]=[CH:13][S:14][C:10]=4[C:9](=[O:15])[N:8]([OH:16])[C:7]3=[O:17])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: O=c1c2sccc2n(Cc2cccc(Br)c2)c(=O)n1O
Product: CC(=O)c1cccc(-c2cccc(Cn3c(=O)n(O)c(=O)c4sccc43)c2)c1

Procedure:
The title compound was prepared from 1-(3-Bromo-benzyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) and 3-acetyl-phenyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][C:13](=O)[NH:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.P(Br)(Br)([Br:24])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:24][C:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:6]2[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][N:7]=2)[N:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Reaction time: 0.33 h
Yield: 149 %

Procedure:
To a 500 mL flask, acetonitrile (200 mL), ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate (21.28 g, 94%, 74.17 mmol) and phosphoryl bromide (14.88 g, 51.92 mmol) were added. The reaction mixture was heated to reflux for 2 hours. 150 mL solvent was distilled from the reaction mixture. The concentrated reaction mixture was added to the mixture of sodium carbonate (10.56 g, 155.7 mmol) and water (40 mL). The reaction mixture was stirred for 20 minutes until no more gas released, and then diluted with dichloromethane (100 mL), stirred for 50 minutes. The mixture was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with water, dried over anhydrous magnesium sulfate, and concentrated by rotary evaporator to give ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (25.73 g) as a amber oil in 97% yield. HPLC area normalization method content is 93% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([CH2:27][P:28]([CH3:31])(=[O:30])[OH:29])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1(O)[CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:34]1([O:30][P:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])[NH:20][C:10]3[CH:11]=[C:12]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[CH:14][C:9]=3[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:33][CH:32]=2)([CH3:31])=[O:29])[CH2:37][CH2:36][CH2:35]1
Reactant: OC1CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)OC2CCC2)cc1
Reaction time: 18 h

Procedure:
To a solution of [4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid (57 mg, 0.117 mmol), cyclobutanol (0.038 mL, 0.703 mmol), and Hunig's Base (0.031 mL, 0.176 mmol) in DMF (2 mL) was added BOP (78 mg, 0.176 mmol). After 18 h, the reaction was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water plus 0.025% TFA (40-100%) to give material after extraction of fractions with EtOAc. 1H NMR (DMSO-d6) δ 9.88 (s, 1H), 8.74 (br s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.79 (br s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 3H), 7.12-7.09 (m, 1H), 4.64 (m, 1H), 3.27 (dd, J=23.2, 17.6 Hz, 1H), 3.25 (dd, J=23.2, 17.6 Hz, 1H), 2.25-21.4 (m, 2H), 2.05-1.94 (m, 2H), 1.67-1.60 (m, 1H), 1.49-1.42 (m, 1H), 1.43 (s, 9H), 1.31 (d, J=14.1 Hz, 3H). MS: cal'd 441 (MH+; -Boc), exp 441 (MH+; -Boc).
Reaction SMILES: Cl[C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18](O)([CH3:20])[CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>[Cl-].[Na+].O.O>[CH3:25][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[CH:36]=[C:35]([NH:37][C:2]3[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18]([CH3:20])=[CH2:19])=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=4)[N:7]=3)[CH:34]=[N:33]2)[CH2:30][CH2:31]1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(C3CCN(C)CC3)c2)nc1Oc1cccc([N+](=O)[O-])c1
Yield: 52.1 %

Procedure:
A mixture of 3-chloro-6-(2-hydroxypropan-2-yl)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (184 mg), diisopropylethylamine (291 μL), and N-methylpyrrolidone (3 mL) was reacted in a microwave reaction device at 180° C. for 2 hours. To the reaction mixture were added water and saturated brine, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1). The obtained solid was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-98:2) to obtain 3-{[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (212 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([NH:36][CH3:37])=[O:35]>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][N:24]([CH2:33][C:34]([NH:36][CH3:37])=[O:35])[C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CNC(=O)CBr
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Agent: Cc1ccc(F)c(-c2cc(Nc3ccnc4c[nH]nc34)c(C)cn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 85 °C

Procedure:
A mixture N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (54 mg, 0.162 mmol) and Cs2CO3 (52.6 mg, 0.162 mmol) were stirred in DMF (2 mL) for 5 minutes. 2-Bromo-N-methylacetamide (24.55 mg, 0.162 mmol) was added; the vessel was sealed and heated in a microwave at 85° C. for 35 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-30% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give 2-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)-N-methylacetamide: 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.46 (s, 3H) 2.58 (s, 3H) 2.78 (s, 3H) 5.23 (s, 2H) 7.01 (d, J=4 Hz, 1H) 7.30-7.42 (m, 1H) 7.56-7.67 (m, 1H) 7.96 (s, 1H) 8.32 (d, J=4 Hz, 1H) 8.45 (s, 1H) 8.52 (s, 1H); MS [M+H] found 406.4; and 2-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)-N-methylacetamide; 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.42 (s, 3H) 2.54 (s, 3H) 2.75 (s, 3H) 5.24 (s, 2H) 7.29-7.41 (m, 2H) 7.52-7.59 (m, 1H) 7.61 (d, J=4 Hz, 1H) 8.18 (s, 1H) 8.40 (s, 2H); MS [M+H] found 406.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[N:20]1([CH2:26][C:27]2[CH:41]=[CH:40][C:30]3[NH:31][C:32]([C:34]4[C:38]([NH2:39])=[CH:37][NH:36][N:35]=4)=[N:33][C:29]=3[CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(C1C=CC(OC)=C(C=1)C(Cl)=O)#N.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:39][C:38]1[C:34]([C:32]2[NH:31][C:30]3[CH:40]=[CH:41][C:27]([CH2:26][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:28][C:29]=3[N:33]=2)=[N:35][NH:36][CH:37]=1)=[O:10])#[N:2]
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: COc1ccc(C#N)cc1C(=O)O
Agent: COc1ccc(C#N)cc1C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
5-Cyano-2-methoxy-benzoic acid (Example 1F) (40 mg, 0.22 mmol) was dissolved in DCM (5 ml) and oxalyl chloride (34.4 mg, 0.264 mmol) was then added drop wise followed by DMF (1 drop). The reaction mixture was stirred at ambient temperature for 1 hour, reduced in vacuo, then re-evaporated using toluene (×2). A mixture of 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), 5-cyano-2-methoxy-benzoyl chloride and diisopropylethylamine (1.83 μl, 0.9 mmol) in THF (5 ml) was stirred at 0° C. and then allowed to warm to room temperature over 2 hours. The reaction mixture was then concentrated in vacuo. The residue was purified by flash column chromatography SiO2, 5-7% MeOH-DCM] to give 5-cyano-2-methoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (12 mg). (LC/MS Acidic: Rt 2.02 min [M−H]+458).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH:27]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1/[CH:27]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (0.73 g, 4.4 mmol) and 2-(4-Chloro-5-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (1 g, 3.65 mmol) in methanol (15 mL) was added pyrrolidine (0.26 g, 4.4 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was concentrated to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([O:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:7](=[O:11])[N:8]2[CH2:20][CH2:19][C:18]#[N:21])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: O=C1Nc2cc(Cl)ccc2C12OCCCO2
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCN1C(=O)C2(OCCCO2)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 65 h
Yield: 72.2 %

Procedure:
A mixture of 6′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (8.85 g, 36.9 mmol), and benzyltrimethylammonuim hydroxide (40% aqueous solution, 1.46 mL, 3.69 mmol, 0.1 mole % ) in anhydrous DMF was heated to 65° C. Acrylonitrile (4.86 mL, 73.9 mmol, 2 eq) was added drop-wise by syringe under a dry N2 atmosphere. After stirring 65 hr. the reaction was cooled to room temperature and poured into water (750 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of 100% CH2Cl2 followed by CH2Cl2/CH3OH/NH4OH (99.7/0.2/0.1) to give the title compound as a white solid (7.80 g, 73% yield). Anal: Calc'd for C14H13ClN2O3: C, 57.45; H, 4.48; N, 9.59. Found: C, 56.39; H, 4.35; N, 9.35. NMR (400 MHz, DMSO-d6): consistent. IR: consistent; MS: (EI+) m/z 292 [M+] 1 chlorine pattern observed. m.p.163-164° C.; HRMS: consistent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([NH:31][C:32]([N:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[CH:16][CH:17]=3)[CH2:22]2)=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1cc(N2CCC(COc3ccc4c(c3)CNCC4)CC2)ccn1
Reactant: S=C=Nc1ccccc1
Solvent: ClCCl
Product: S=C(Nc1ccccc1)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (30 mg) in methylene chloride (0.5 ml) was added phenyl isothiocyanate (0.012 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1, 1% triethylamine) and dried under reduced pressure to give the title compound (40 mg).
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.[BH4-].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: OC1CCN(Cc2ccccc2)C1

Procedure:
1-benzyl-3-pyrrolidinone was reduced with sodium borohydride according to Example 117-(1), and the target compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH3:15])[C:13]2[C:16]([Br:20])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:20][C:16]1[C:13]2[N:14]([CH3:15])[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Br)c2n1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccc(Br)c2n1C
Yield: 100.3 %

Procedure:
A solution of [(S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.8 g, 5.1 mmol) in TFA (7.5 mL) and DCM (22.5 mL) was stirred for 45 min at RT. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale red solid (1.3 g, 99%). Marfey's test: 98% de. LCMS (Method C): RT 1.49 min [M+H]+ 415 (for 79Br).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18](=[O:28])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:8]=1)C.O>CO.O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:18]([C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:29])=[O:5])=[O:28])=[CH:25][CH:24]=1)#[N:27]
Reactant: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)Nc2ccc(C#N)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)[C@H]2CCCN2c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
Add lithium hydroxide (0.03 g, 1.3 mmol) to the crude 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid ethyl ester (0.05 g, 0.14 mmol) in a 1:1:1 mixture of water:MeOH/tetrahydrofuran (3 mL). Stir the mixture at room temperature for 15 h then wash with EtOAc. Adjust the pH of the aqueous phase to slightly acidic by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with methylene chloride, dry the combined organic phase over anhydrous sodium sulfate and concentrate under a stream of nitrogen to provide 0.020 g of 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid as a yellow oil.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl.CO>[C:1]([NH:9][CH2:10][CH:11]([CH:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Reactant: [H][H]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)c1ccccc1)C(C)O
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Into a 200-ml stainless steel-made autoclave was placed 3.56 g (0.0143 mole) of methyl 2-benzamidomethyl-3-oxobutyrate. After nitrogen replacement, 7 ml of a separately prepared dichloromethane/methanol (7/1 by volume) mixed solvent solution containing 0.01 g (0.00894 mmole) of [RuI(p-Cymene)((-)-OcH-BINAP)]I as obtained in Example 5 was added. The resulting mixture was stirred at a hydrogen pressure of 50 kg/cm2 and a temperature of 65° C. for 20 hours. After the reaction, the reaction mixture was analyzed- by high-speed liquid chromatography. As a result, it was found that 2.79 g (percent yield: 78%) of methyl 2-benzamidomethyl-3-hydroxybutyrate had been formed and that the conversion was 80%, diastereomer selectivity 91.6%, and optical percent yield 99% ee.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC#N>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][N:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][N:10]3[CH2:15][C:16]([O:18][CH3:19])=[O:17])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:31][CH2:32]1
Reactant: COC(=O)Cn1ccc2c(NS(C)(=O)=O)cccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2c(N(CCN3CCOCC3)S(C)(=O)=O)cccc21
Yield: 77.1 %

Procedure:
To a solution of methyl 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetate (1.0 g, 3.54 mmol) (prepared in an analogous manner as described Example 15, Scheme 15, Steps 1, 2, 3) in CH3CN (30 ml), K2CO3 (0.734 g, 5.31 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (0.989 g, 5.31 mmol) were added, and the resulting mixture heated to reflux for 3 hours. The insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness affording methyl 2-(4-(N-(2-morpholinoethyl)-methylsulfonamido)-1H-indol-1-yl)acetate (1.08 g, 2.73 mmol, 77% yield, MS/ESI+ 395.9 [MH]+) which was used without any additional purification.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[NH+:5]([CH2:9][CH3:10])[CH:6]=[CH:7][N:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1)[CH3:10]
Reactant: CC[NH+]1C=CN=C1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccnc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
A mixture of 2-(chloromethyl)-1-ethyl-1H-imidazol-1-ium chloride (1.0 g, 5.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (650 mg, 4.6 mmol), and potassium carbonate (2.0 g, 14.4 mmol) in anhydrous DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The solid residue was treated with dichloromethane (20 mL) and brine (60 mL). The aqueous layer was recovered and evaporated. The residue was purified by flash chromatography (0-20% MeOH/CH2Cl2), affording 2-{[(1-ethyl-1H-imidazol-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (244 mg, 21% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.27 (t, 3H, J=7.2 Hz), 2.17 (s, 3H), 4.00 (m, 2H), 4.50 (s, 2H), 6.00 (s, 1H), 6.81 (s, 1H), 7.15 (s, 1H); M+ 251. The product was used without further purification.