Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:20]([OH:22])=[O:21])[CH2:13]3)[CH:10]=[CH:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClC(O[CH2:34][CH:35]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=O>O>[CH:37]1[C:36]2[CH:35]([CH2:34][O:5][C:6]([N:8]3[C:19]4[C:11](=[C:12]5[C:16](=[CH:17][CH:18]=4)[NH:15][CH:14]([C:20]([OH:22])=[O:21])[CH2:13]5)[CH:10]=[CH:9]3)=[O:7])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)O)C3
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1
Reaction time: 3 h
Yield: 84.4 %

Procedure:
3-(tert-Butyloxycarbonyl)pyrrolo[3,2-e]indoline-7-carboxylic acid 8 (Boger et. al, J. Org. Chem. 52:1521 (1987)) (0.76 g, 2.4 mmol) was deprotected by a treatment with 5 mL of TFA for 1 h. TFA vas evaporated and the resultant trifluoroacetate dissolved in a mixture of 11% Na2CO3 (10 mL) and 5 mL of THF. 9-Fluorenylmethyl chloroformate (0.75 g, 2.9 mmol) was added and the reaction mixture was stirred for 3 h. The reaction was diluted with water (200 mL) and extracted with ethyl ether (2×50 mL). The aqueous phase was acidified by adding 1N HCl to pH 1-2. Precipitated product was collected by centrifugation, washed with water and dried under vacuum to afford 0.86 g (83%) of 9 as a yellow-gray solid.
Reaction SMILES: O1CCCC1.C([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19]2)C1C=CC=CC=1>[Pd].CO>[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19]2
Reactant: COC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2cccc(O)c2n1C
Yield: 101.6 %

Procedure:
In a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol was dissolved 2.31 g (7.82 mmol) of methyl 7-benzyloxy-1-methyl-2-indolecarboxylate. After 0.5 g of 10% palladium/carbon was added to the solution, catalytic hydrogenation was performed at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.63 g (>99%) of methyl 7-hydroxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][C:8]2[O:12][C:11]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:7][C:8]2[O:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
5-Acetoxy-4,6-di-tert-butyl-2-(1-octenyl)benzofuran (3.1 g) was dissolved in ethyl acetate containing 10% acetic acid (50 ml) and, after addition of 10% Pd on carbon (0.3 g), the solution was stirred under a hydrogen atmosphere for 3 h. After filtering off the Pd on carbon, the filtrate was concentrated under vacuum. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-octylbenzofuran [2.95 g (yield, 96%)] as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[C:10]2[Br:33])[CH2:8]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The title compound is prepared in analogy to Example 103 starting from 12.9 g (30.11 mmol) cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester (see Step 3.1 above) and 6.07 g (33.12 mmol) N-bromosuccinimide in 250 ml dry N,N-dimethylformamide. After work-up, the raw material is purified by chromatography on silicagel (solvent: hexane-ethyl acetate 1:1). Analytical HPLC: tR=11.85 min (Grad 1); ES-MS: m/eo=506.9 and 509.9; NMR (DMSO-d6): 8.14/s (1H), 7.3-7.5/several m's (6H), 7.09/“d” (1H); 7.05/s (1H); 6.98/“d” (1H); 5.5-6.5/b (NH2); 5.13/s (2H); 5.11/m (1H); 3.66/s (3H); 3.35-3.5/m (2H); 3.08/m (1H); 2.58-2.7/m (2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[O:35]1CCC(O)C1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH:20]4[CH2:21][CH2:22][O:35][CH2:25]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OC1CCOC1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC1CCOC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with tetrahydro-3-furanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (14 mg, 0.031 mmol). 1H NMR (CDCl-d) δ 2.07(m, 6H), 3.66(m, 2H), 3.96(m, 7H), 4.13(m, 2H), 4.98(m, 1H), 5.26(s, 2H), 5.40(m, 1H), 6.97(s, 1H), 7.04(s, 1H), 7.08(d, J=8.2 Hz, 1H), 7.26(s, 1H), 8.30(s, 1H), 8.32(s, 1H). LC/MS MH30 =455.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH3:13])[C:3]=1[OH:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH2:26][CH2:25][CH2:24][CH2:23][S:22][C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: Cc1cc2c(c(C)c1O)COC(=O)N2
Product: Cc1ccc(SCCCCOc2c(C)cc3c(c2C)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5,7-dimethyl-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@@H]4Cc4ccccc4)cc3)CC2)c(C)c1
Yield: 47.5 %

Procedure:
By reaction and treatment in the same manner as in Example 34 and using methyl (S)-4-(4-benzyl-2-oxooxazolidin-3-yl)benzoate (142 mg) described in Preparation Example 197 and 1-(2,4-dimethylphenyl)piperazine (87 mg), the title compound (101.8 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1([CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14](OCC)=[O:15])[C:4]1=[O:19])#[N:2].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:1]([C:3]1([CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:15])[C:4]1=[O:19])#[N:2]
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O

Procedure:
Ethyl 1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.225 g, 0.829 mmol), glycine tert-butyl ester hydrochloride (0.167 g, 0.995 mmol), and glycine tert-butyl ester hydrochloride (0.167 g, 0.995 mmol) were refluxed in dioxane (50 mL) for 14 hours. The solvent was then removed in vacuo. The resulting residue was concentrated in vacuo and purified using silica flash chromatography (10-40% EtOAc/hexanes). MS (m/z)=301 (M+H)+(hydrolyzed product) 379.1 (product+Na).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)=O.B.CSC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][C:12]1[CH:13]=[C:14]([CH2:18][OH:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccccc1Br)Nc1cccc(CO)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cccc(NCCc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-bromophenyl)-N-[3-(hydroxymethyl)phenyl]acetamide was dissolved THF (0.2 M), followed by addition of BH3·DMS (3 eq), and the reaction was heated to reflux with stirring. After 2 hrs, the mixture was cooled to room temperature, and quenched with excess 10% HCl. The mixture was heated to reflux for 1 hr, and then cooled to room temperature. After washing with EtOAc, the aqueous phase was made alkaline with 10% sodium carbonate, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with EtOAc to afford a colorless solid. EI-MS m/z 307/309 (M+H)+
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19]O>>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Agent: Cl
Product: COC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Temperature: 68 °C

Procedure:
11.8 grams of 5-tert.-butyl-2,3-dimethyl-4-hydroxyphenylacetic acid was added at 20°C to 200 ml of methanol previously saturated with hydrogen chloride gas. The slightly pinkish solution was heatd at reflux (68°C) for 3 hours after which about one-half of the solvent was removed at reduced pressures and the reaction mixture then poured into about 500 ml of an ice-water mixture with stirring until all the ice had melted. The precipitated crystals were filtered, washed with water and dissolved in benzene. The benzene solution was successively washed with water, saturated sodium bicarbonate solution and finally with water to pH 7, the benzene solution being dried over anhydrous sodium sulfate. The clear benzene solution, freed of drying agent by filtration, was concentrated at reduced pressure. The resulting solid residue was triturated with hexane to remove color bodies. After recrystallization from methanol, the desired product was obtained as white crystals melting at 117° to 119°C (Compound 14).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCCC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol) in DCM (2 mL) was added piperidine (4.0 ul, 0.04 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (23.0 mg, 0.109 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was removed under reduced pressure. The resulting residue was dissolved in 1.2 mL DMSO and all undissolved solid was filtered off. This DMSO solution of crude product was purified by reverse phase HPLC(H2O/CH3CN, 0.1% TFA 10-90%) to give the title compound (8.8 mg, 50.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[C:20]([O:24][C:25]([NH:27][C:28](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])SC)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.CO.C1COCC1>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCCCCCCCCNCCCCCCCCN
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCCCCCCCNCCCCCCCCN)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,17-diamino-9-azaheptadecane 3 (4.9 g, 15.06 mmol) in THF/CH3OH 5/3 (80 mL) at 50° C., a solution of N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea (1.456 g, 5.02 mmol) in THF (25 mL) was added dropwise over 1 h. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (6% methanol, 4% triethylamine, 90% ethyl acetate), affording 12 as a pale yellow oil, 3.51 g (70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH2:8][CH2:7]2)([O-])=O.C([O-])=O.[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH2:8][CH2:7]2
Reactant: CCOC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1C(=O)CCc2cc(N)ccc21
Yield: 31 %

Procedure:
To a suspension of 1 ethyl 2-(6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate in EtOH (10 mL) and H2O (5 mL) was added ammonium formate (1.5 g, 23.8 mmol) and Fe (0.3 g, 5.4 mmol). After stirring at reflux for 2 h, the black mixture was filtered, the filtrate was diluted with EtOAc and water, EtOAc layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated in vacuo to provide ethyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (0.2 g, 31%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][S@:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[NH:33])=[O:32]>C1COCC1>[CH3:30][S:31](=[O:32])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:33][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11][CH:12]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[S@](=N)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=NC(=O)c1cncc(C#Cc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 262.7 %

Procedure:
To a slurry of 5-(2-phenyleth-1-ynyl)nicotinic acid (339 mg, 1.5 mmol) in 6.0 mL THF at room temperature was added 1,1′-carbonyldiimidazole (271 mg, 1.7 mmol). After stirring 1.25 hour, a solution of (S)-(+)-S-methyl-5-phenylsulfoximine (260 mg, 1.7 mmol) in 1.5 mL THF was added and the mixture heated at 50° C. for 22 hours. Then an additional 50 mg (0.32 mmol) (S)-(+)-S-methyl-S-phenylsulfoximine was added and heating continued at 60° C. for 3.5 hours. The reaction was quenched with NaHCO3 solution and then extracted into EtOAc. The EtOAc layer was washed with NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil obtained was chromatographed eluting with hexane/EtOAc to give N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide as a white foam (303 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[C:24]1([CH3:34])[C:25]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:34])[C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31])=[O:6]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: Cc1cccc(C(=O)c2cc(Br)c(Oc3ccc(O)c(C(C)C)c3)c(Br)c2)c1S(N)(=O)=O
Yield: 73.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 2-toluenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 15 mg (74%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]2[O:9][CH:8]([C:10]3([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:17]=1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]2[O:9][CH:8]([C:10]3([OH:16])[CH2:11][CH2:12][N:13]([C:20]4[N:25]=[CH:24][C:23]([CH2:26][CH2:27][CH3:28])=[CH:22][N:21]=4)[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:17]=1
Reactant: OC1(C2Cc3cc(Br)cc(F)c3O2)CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(O)(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A mixture of 4-(5-bromo-7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidin-4-ol (0.17 g, 0.531 mmol), 2-chloro-5-propylpyrimidine (0.11 g, 0.691 mmol) and K2CO3 (0.22 g, 1.594 mmol) in DMF (2.6 mL) were heated in 90° C. oil bath for 10 hours. At the conclusion of this period, the reaction mixture was cooled to room temperature, quenched with H2O (5 mL), and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with H2O (3×5 mL) and brine (5 mL), dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 30 to 40% EtOAc) to afford Compound 1H as a light yellow solid (0.122 g, 52.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (s, 2 H), 6.99-7.10 (m, 2 H), 4.67 (t, J=9.2 Hz, 1 H), 4.47-4.62 (m, 2 H), 3.23-3.41 (m, 3 H), 3.10 (dd, J=15.8, 9.2 Hz, 1 H), 2.39 (t, J=7.6 Hz, 2 H), 1.84-2.00 (m, 2 H), 1.74 (td, J=13.1, 4.8 Hz, 1 H), 1.46-1.66 (m, 4 H), 0.93 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=437 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O:34][CH2:35][CH3:36])C>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:1]4[CH2:2][CH2:3][CH2:36][C:35](=[O:34])[C:5]=4[CH3:6])=[CH:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)OC1(C)C
Reactant: CCOCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1=O

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 19, Step B (0.350 g, 0.87 mmol) and 3-oxo-2-methyl-cylclohex-1-en-1-yl trifluoromethanesulfonate (0.248 g, 0.96 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 20 to 50% ethyl acetate in hexane afforded a light yellow oil. The oil thus isolated was dissolved in boiling diethyl ether and precipitated by addition of petroleum ether. The precipitate was filtered and dried to afford the title compound (0.297 g) as a white solid, m.p. 95–97° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:33])[CH3:28]
Reactant: CN(C)CC(=O)N(Cc1ccccc1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(Cc2ccccc2)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(dimethylaminomethyl-carbonyl)-N-benzyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H32N4O4
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:28]([O-:29])=[O:27])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: O=[N+]=O
Reactant: CN1CCC(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CN1CCC(c2nc(-c3ccncc3)c([N+](=O)[O-])c(=O)n2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-2-(1-methyl-piperidin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one (0.64 mmol) in acetonitrile (2.5 mL) at 0° C. was added 2.5 mL 0.5M solution of nitronium tetrafluoroborate. After 30 min, the reaction product was isolated and purified on silica. M+1=329.