Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:32]1[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=1[Cl:30])=[O:34]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 58.6 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (100 mg, 0.23 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (200 μL, 1.2 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 45:55 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (74 mg, 58%). Obs. Mass 397.1313. Calcd. Mass 397.1320 (M+H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:11]2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:11]2)[CH2:8][CH2:9]1)=[O:35]
Reactant: COC(=O)Cl
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCN(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)NCCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A mixture of 1-[1-(2-aminoethyl)-4-piperidyl]-3-(4-fluorophenyl)-5-methyl-1H-indole 12a (8.9 g), K2CO3 (4.2 g) and dichloromethane (80 ml) was cooled to 0°-5° C. and a solution of methyl chloroformate (2.9 g)in dichloromethane (50 ml) was added during 15 min. After reaction for further 2 h at room temperature the reaction mixture was washed with water (2×50 ml), dried (MgSO4) and the solvents were evaporated in vacuo. This afforded the 1-[1-(N-methoxycarbonyl-2-aminoethyl)-4piperidyl]-3-(4-fluorophenyl)-5-methyl-1H-indole, as an oil, which was used without further purification. Yield: 8.8 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[C:22]([F:29])[CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and N-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add 4-Bromo-2-fluorobenzoic acid chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for one hour. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e): 355.1/357.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)c(C=O)c(Cl)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(N)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.59 (s, 3H), 5.78 (br s, 1H), 7.11-7.32 (m, 2H), 7.42-7.58 (m, 2H), 8.65 (br s, 1H), 9.71 (s, 1H). LC MS (m/e)=264 (MH+).
Reaction SMILES: COC(=O)[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[Cl:22])[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:6].[Cl-].[Na+].O>CS(C)=O>[Cl:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:6]
Reactant: COC(=O)C(C(=O)c1ccnc(C)c1)c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)c2ccnc(C)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of 2-(2-chloro-4-methoxy-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propionic acid methyl ester (13.95 g), sodium chloride (2.71 g), water (1.14 mL) and DMSO (400 mL) was heated to 140° C. for 3 hours. Stirring was continued overnight at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow solid (7.56 g, 62%). MS (m/e)=276.2 [MH+].
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH:25]=[O:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][CH2:23][CH2:24][C@@H:25]([OH:26])[C@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: O=CCCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)CCCl
Reaction time: 0.5 h

Procedure:
A vigorously stirred solution of 3-propionyl-2-benzoxazolone (19.1 g) in 200 mL of CH2Cl2 at 0° C. was treated with titanium tetrachloride (12.0 mL) followed by slow addition of triethylamine (16.7 mL). After stirring for 30 minutes, the dark red solution was treated with 60 mL of 1.8 M 3-chloropropanal in CH2Cl2 for 30 minutes, then quenched by addition of 200 mL of 2 N HCl. The phases were separated, and the organic phase was filtered through a pad of silica gel. The aqueous phase was extracted with ether, and the extract was used to wash the pad of silica. The combined silica eluate was concentrated under reduced pressure, resulting in crystallization. The white crystals were collected by vacuum filtration and dried to provide 19.9 g of product; mp=116-117° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:34]([NH2:38])[CH2:35][CH2:36][NH2:37]>CN1CCCC1=O>[NH2:37][CH2:36][CH2:35][CH2:34][NH:38][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH2:24][CH2:25]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: NCCCN
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1NCCCN

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), 1,3-propanediamine (177 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 190° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-[(3-aminopropyl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (123 mg) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (3.0 g) and imidazole (2.03 g) in N,N-dimethylformamide (30 mL) was added tert-butylchlorodiphenylsilane (4.66 mL), and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-bromo-4-[2-(tert-butyldiphenylsilyloxy)ethyl]benzene (6.27 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH3:11])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH3:11])[CH2:12][CH2:13][CH2:14][O:15][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)c(C#N)cc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 2-chloro-5-fluoro-6-[(3-ydroxypropyl)(methyl)amino]nicotinonitrile (Example 311) (0.50 g, 2.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.25 g, 1.14 mmol) in THF (9 mL) were added PPh3 (0.54 g, 2.05 mmol) and ADDP (0.52 g, 2.05 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.41 g, 81%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.29 (d, 1H), 7.04 (d, 1H), 6.73 (d, 1H), 6.66 (dd, 1H), 4.16 (q, 2H), 3.99 (t, 2H), 3.82 (t, 2H), 3.51 (qt, 1H), 3.25 (d, 3H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.12 (qt, 2H), 1.82-1.72 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([C@H:8]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:20]3=[N:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]([OH:29])=[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:42][C@H:12]3[O:11][C:10](=[O:43])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][C:2]1([C@H:8]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:20]3=[N:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]([O:29][CH:64]4[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]4)=[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:42][C@H:12]3[O:11][C:10](=[O:43])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C)CC1)O2
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
A reaction tube was charged with the product of step 5 (400 mg, 0.674 mmol) and triphenylphosphine (1414 mg, 5.39 mmol). The tube was sealed and THF (6737 μl) was added via syringe at 0° C. 4-hydroxy-1-methylpiperidine (633 μl, 5.39 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (1044 μl, 5.39 mmol). After 5 min, the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40° C. LCMS showed complete reaction after 2 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (120 g) column (gradient: 0 to 50% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (450 mg, 0.651 mmol, 97% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](=O)[C:11](=[O:16])[C:12]=2[O:13]CC)=[C:4]([OH:18])[C:3]=1[S:19]([CH3:22])(=[O:21])=[O:20].[S:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:16])[C:10]=2[NH:28][CH:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[C:4]([OH:18])[C:3]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: NC1CCSC1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(C)(=O)=O)c2O)c(=O)c1=O
Solvent: CCO
Product: CS(=O)(=O)c1c(Cl)ccc(Nc2c(NC3CCSC3)c(=O)c2=O)c1O

Procedure:
The title compound is prepared from 3-(4-chloro-2-hydroxy-3-methanesulfonyl-phenylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione analogously to 6-chloro-2-hydroxy-N,N-dimethyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide (Example 3) by replacing (R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamine p-toluenesulfonate salt with tetrahydrothiophen-3-ylamine. The reaction is carried out in EtOH. The title compound is obtained. MH+ 403.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:8]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=O.[C:20]1([CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([NH2:30])=[S:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]2[S:29][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[O:12][CH2:13][C:14]([OH:16])=[O:15])[C:3]=3[N:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Reactant: NC(=S)CC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(CC(c3ccccc3)c3ccccc3)nc1-2
Yield: 19 %

Procedure:
Using ethyl [(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate and 3,3-diphenylthiopropionamide, the procedure of Example 52 was otherwise repeated to synthesize the title compound. Yield 19%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:33]1[C:37]2[CH:38]=[CH:39][C:40](B(O)O)=[CH:41][C:36]=2[CH:35]=[CH:34]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([C:40]3[CH:41]=[CH:36][C:35]4[C:39]=3[CH:38]=[CH:37][O:33][CH:34]=4)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Reactant: OB(O)c1ccc2occc2c1
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: O
Solvent: C1COCCO1
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(-c2ccc3coccc2-3)c1=O
Yield: 40.9 %

Procedure:
A mixture of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.45 mmol), benzofuran-5-boronic acid (120 mg, 0.68 mmol), Pd(PPh3)4 (26 mg, 0.05 mmol) and 2M Na2CO3 (0.9 mL) in 1,4-dioxane (200 mL) was refluxed overnight under N2 atmosphere. The reaction mixture was diluted with water and extracted with EA (3×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica chromatography to give 100 mg of the title product (42%). [M+H] Calc'd for C30H30FN5O4, 543. Found, 543.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([N:38]([CH3:39])[CH3:37])=[O:5]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N,-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring until all was dissolved dissolved. The solvent was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 533 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][S:39][C:37](=[O:40])[CH3:38])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Yield: 106.5 %

Procedure:
A solution of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester (0.37 g, 0.73 mmol) and potassium thioacetate (0.092 g, 0.8 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaHCO3, dried over Na2SO4, and concentrated to give 0.32 g of 3-(2-acetylsulfanyl-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester as a yellow oil (100% crude yield): 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H), 3.20 (q, J=6.87 Hz, 2H), 3.40 (q, J=6.87 Hz, 2H), 3.74 (s, 3H), 3.91 (s, 3H), 7.01 (d, J=7.82 Hz, 1H), 7.20–7.31 (m, 3H), 7.44 (d, J=8.02 Hz, 1H), 7.48–7.52 (m, 1H), 7.59(t, J=7.82 Hz, 1H), 7.88 (d, J=7.82 Hz, 1H), 7.97(t, J=1.53 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35](Cl)=[O:36])[CH2:29][C:28]2=[O:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:24].[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]([C:35]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:36])[CH2:29][C:28]2=[O:38]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CC(=O)c3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of 2.0 g of 4-methyl-2-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride in 150 ml of methylene chloride was added 4.3 ml of triethylamine with vigorous stirring in an atmosphere of nitrogen. After stirring for 20 minutes, the mixture was cooled to -10° C. in an ice and salt bath and 50 ml of methylene chloride solution containing 1.9 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride was added dropwise to it. The reaction mixture was stirred at -10° C. for an hour and a half and subsequently at room temperature for two hours and a half and poured into a saturated aqueous solution of sodium bicarbonate. The resulting aqueous mixture was extracted with diethyl ether and the extract was washed with a saturated aqueous solution of sodium chloride followed by drying over anhydrous magnesium sulfate and distilling off the solvent. The residue was purified by column chromatography through silica gel and 1.60 g of the desired compound was obtained from the fractions eluted with a 10:3 mixture of ethyl acetate and triethylamine. To a solution of the product dissolved in methylene chloride was added a two molar quantity of a 4N 1.4-dioxane solution of hydrogen chloride and the mixture was concentrated. The residue was recrystallized from a mixture of ethanol and acetone to afford the title compound, melting at 250°-255° C. (dec.).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:26]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2

Procedure:
tert-Butyl 1-benzyl-7-(propylsulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.628 g, 1.33 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.487 g, 1.31, 98%)