Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].C1C([N+]([O-])=O)=CC=C([Cl-][C:30]([O-])=[O:31])C=1.C(N(CC)CC)C.[Cl:40][C:41]1[C:49]2[NH:48][C:47](=[O:50])[N:46]([CH:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>O1CCCC1>[Cl:40][C:41]1[C:49]2[NH:48][C:47](=[O:50])[N:46]([CH:51]3[CH2:56][CH2:55][N:54]([C:30]([NH:1][C@@H:2]4[CH2:8][CH2:7][C@@H:6]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH2:5][N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]4=[O:19])=[O:31])[CH2:53][CH2:52]3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: COCCN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O
Reactant: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4c(Cl)cccc43)CC2)C1=O
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A solution of (3R,6S)-3-amino-1-(2-methoxyethyl)-6-phenylazepan-2-one (0.015 g, 0.057 mmol) and 4-nitrophenylchloroformate (0.012 g, 0.057 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.006 g, 0.057 mmol) was added and the reaction stirred for 1 h. Solid 4-chloro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.057 mmol) followed by triethylamine (0.055 g) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was diluted with dicholoromethane and extracted with 1N NaOH until the yellow color of the organic layer disappeared. The organic layer was dried over sodium sulfate, concentrated and purified by normal phase chromatography (silica gel, 0 to 7% methanol in methylene chloride gradient elution), which gave the title compound (9 mg). MS 540.2370 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:29](#[N:33])[CH:30]([CH3:32])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:30]([C:29]#[N:33])[CH3:32])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NCc1ccc(O)cc1F)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: CC(O)C#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#N)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Yield: 26.3 %

Procedure:
To a stirred solution of 2-(benzo[1,3]dioxol-5-yloxy)-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide (5 g, 13.1 mmol), (+/−)-lactonitrile (0.93 g, 13.1 mmol) and triphenylphosphine (3.78 g, 14.4 mmol) in tetrahydrofuran (200 mL) at room temperature, diethyl azodicarboxylate (2.3 mL, 14.4 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight. Solvents were stripped in vacuo, diluted with ethyl acetate and washed with dilute aqueous sodium hydroxide, brine, and dried (MgSO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was purified by flash column chromatography (35% ethyl acetate/hexane), affording 1.5 g white solid (26% yield).
Reaction SMILES: [O:1]=[C:2]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OC)[CH:13]=2)[NH:8][CH:7]=1.[CH2:29](Cl)Cl.CO.C(OCC)(=O)C>>[O:1]=[C:2]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:29]
Reactant: COc1ccc2[nH]cc(CSCC(=O)N3CC=C(c4ccccc4)CC3)c2c1
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]c2ccccc2c1CSCC(=O)N1CC=C(c2ccccc2)CC1

Procedure:
3-[4-oxo-4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxyindole, Rf 0.78 (CH2Cl2 /methanol/ethyl acetate 7:2:1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)([C:13]#[N:14])[C:9]2=[O:26])[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)C>C(O)CCC>[C:13]([C:10]1([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:39][CH:38]=3)[N:7]=2)[C:9]1=[O:26])#[N:14]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Cl)n3)C2=O)C1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)C2=O)C1
Yield: 25.5 %

Procedure:
A solution of tert-butyl 3-(1-(2-chloropyrimidin-4-yl)-3-cyano-2-oxopyrrolidin-3-yl)azetidine-1-carboxylate (100 mg) obtained in Step D of Example 309, 4-morpholinoaniline (61 mg) and acetic acid (50 μL) in n-butanol (4.0 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=[O:4].[Br-].[Mg+2].[CH:12]#[CH:13].[Br-]>>[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]([OH:4])[C:12]#[CH:13]
Reactant: C#C
Reactant: CCCCC(C)(C)C=O
Agent: [Br-]
Agent: [Mg+2]
Product: C#CC(O)C(C)(C)CCCC

Procedure:
The acetylenic alcohol intermediates are produced by reaction of the appropriate carbonyl compounds with an organometallic acetylene reagent, e.g. acetylene magnesium bromide. Typically, 2,2-dimethyl-n-hexaldehyde is contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 4,4-dimethyl-1-octyn-3-ol. The acetylenic alcohols in which the alcohol group is tertiary are obtained from the appropriate ketones. 2,2-Dimethyl-n-hexaldehyde, for example, is converted to 3,3-dimethyl-2-heptanone by reaction with methyl magnesium bromide followed by hydrolysis of the adduct and oxidation of the secondary alcohol group with chrominum trioxide. That ketone is then contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 3,4,4-trimethyl-1-octyn-3-ol.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)[C@H]1C=C[C@@H](N)C1)c1cn(-c2cccnc2)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C=C[C@H](C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Reaction time: 24 h

Procedure:
To a suspension of (1R,4S)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide dihydrochloride (0.065 g, 0.17 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.084 g, 0.83 mmol) followed by acetyl chloride (1 M in CH2Cl2, 0.25 mL, 0.25 mmol). After stirring for 24 hours, the reaction product was purified by direct application to silica gel chromatography eluting with MeOH/CH2Cl2 to provide the title compound F86 as yellow foam (0.040 g, 67%).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([NH:25][CH3:26])=[O:24])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1.Br[CH2:34][CH2:35][O:36][CH3:37]>>[Cl:31][C:30]1[C:21]([NH:20][C:18]2[C:17]([Cl:32])=[CH:16][N:15]=[C:14]([NH:13][C:4]3[CH:5]=[CH:6][C:7]4[CH2:8][CH:9]5[N:12]([CH2:34][CH2:35][O:36][CH3:37])[CH:1]([CH2:11][CH2:10]5)[C:2]=4[CH:3]=3)[N:19]=2)=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][CH3:26])=[O:24]
Reactant: COCCBr
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2CCOC)ncc1Cl
Yield: 33.5 %

Procedure:
Following a procedure analogous to 68a, 2-[2-(12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-chloro-N-methyl-benzamide (60 mg, 0.13 mmol), 1-bromo-2-methoxy-ethane (120 mg, 0.48 mmol) were converted to the title compound as a yellow solid (23 mg, 34%). 1HNMR (400 MHz, DMSO-d6) δ 9.2 (bs, 1H), 9.0 (bs, 1H), 8.3 (m, 1H), 8.1 (s, 1H), 7.7 (d, 1H, J=7.6 Hz), 7.6 (d, 1H, J=7.3 Hz), 7.4 (t, 1H, J=8.1 Hz), 7.1 (s, 1H), 7.0 (m, 1H), 6.7 (m, 1H), 3.6-3.4 (m, 4H), 3.2 (s, 3H), 2.9 (m, 1H), 2.7 (d, 3H, J=4.3 Hz), 2.5-2.4 (m, 2H), 2.2 (m, 1H), 2.1-2.0 (m, 2H), 1.5-1.4 (m, 2H); MS (m/e) 527 (M+1); mp 240-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5]([NH2:7])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S-:19])=[CH:15][CH:14]=1.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Reactant: [S-]c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of 3,4-dichlorobenzamide (95.0 g, 0.500 mole) in dry dimethylformamide (1 liter) was added in one portion potassium 4-chlorothiophenolate (118.8 g, 0.650 mole). The mixture was stirred under nitrogen at 100° C. for 8 hours and at ambient temperature for 16 hours. Solvent (750 ml) was removed by vacuum distillation at 45° C. and the residue was poured into ice water (3 liters) containing concentrated hydrochloric acid (25 ml). The precipitate was filtered, partially dried, and crystallized from hot ethanol (1.2 liters). The crystals were filtered, washed with ethanol, and dried at 45° C. for 18 hours under vacuum to provide 102.0 g (68%) of 3-chloro-4-(4-chlorophenylthio)benzamide, m.p. 176°-177° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccccc1-c1cccs1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2cccs2)cc1
Temperature: 100 °C

Procedure:
A vigorously stirred solution of 3.4 g (14 mmol) of 1-bromo-2-(2-thienyl)benzene and 3.77 g (15 mmol) of 4-methylphenyltrimethylstannane in 50 mL of dimethylformamide under a nitrogen atmosphere was treated with 427 mg of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 100° C. for 4.5 hours. The reaction mixture was cooled, poured into 250 mL of water and the resultant mixture extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in hexane/ether (100:5) and chromatographed on silica gel, eluting with hexane/ether (100:5) to give 2.25 g of he product. 1H NMR (200 MHz, CDCl3): 2.33 (s, 3H), 6.48 (dd, 1H), 6.83 (dd, 1H), 7.08 (m, 4H), 7.16 (dd, 1H), 7.35 (m, 3H), 7.46 (dd, 1H).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[BH3:7].[OH-].[Na+].N=O>O1CCCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]1([B:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: B
Reactant: C1=CCCCC1
Agent: [Ag+]
Agent: N=O
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C1CCC(B(C2CCCCC2)C2CCCCC2)CC1
Temperature: 40 °C
Yield: 98.7 %

Procedure:
Into a solution of 2.85 g (35 mmol) of cyclohexene in 20 mL of tetrahydrofuran at ambient temperature under nitrogen is added dropwise 12.5 mL (12.5 mmol) of a 1M tetrahydrofuran solution of borane. During addition, reaction temperature is kept under 35° C. Reaction mixture, after addition, is then heated to 40° C. for 2 hours. After cooled to ambient temperature, the reaction is added dropwise into a suspension of 2.15 g (12.5 mmol) of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 1.50 g (37.5 mmol) of sodium hydroxide and 3.17 g (18.8 mmol) of silver nitrate in 40 mL of water at ambient temperature under nitrogen. Thin layer chromatography detects no more starting nitroxyl after 2 hours. Reaction mixture is extracted with 2×10 mL of ethyl acetate and dried over sodium sulfate. Filtration removes inorganic and filtrate is concentrated to an off-white oil. Purification of product by dry-column flash chromatography (20:80/ ethyl acetate:heptane eluent) gives 3.14 g of a white crystalline solid in 98.7% yield: 1H NMR (CDCL3)(300.08 MHz)δ 1.15 (s, CH3, 6 H), 1.20 (s, CH3 ,6H), 1.22, 1.46 (m, CH2, 4H), 1.76, 1.81 (m, CH2, 10H)3.60 (m, CH, 1H),3.90 (m, CH, 1H); MS [M+1]256.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]2[N:4]([CH:15]=[N:2][N:1]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1-c1ccccn1
Reactant: CCOC(OCC)OCC
Product: c1ccc(-c2cccn3cnnc23)nc1

Procedure:
A mixture of 1.7 g of 2'-hydrazino-2,3'-bipyridine and 50 ml of triethyl orthoformate was heated on a steam bath for 3 hours. Standing and chilling gave crystals which were collected, washed with hexane and dried, giving 1.5 g of the desired product as cream colored crystals, mp 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: C1CCOC1
Reactant: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCCC4)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCCC3
Yield: 76.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.231 g; 0.61 mmol), LHMDS 1N in THF (0.67 mL; 0.67 mmol), 1-iodopropane (0.089 mL; 0.913 mmol) in DMF (2.4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.197 g (77%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH3:28])[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:36][S:37]([O:1][CH2:2][CH2:3][C:4]1([CH3:28])[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(C)(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C)(CCOS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-5-methyl-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.75 g) and triethylamine (0.50 mL) in tetrahydrofuran (10 mL) was slowly added methanesulfonyl chloride (0.20 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.56 g, yield 65%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 149-150° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CCCCCC3

Procedure:
Reaction of ethyl 5,6,7,8,9,10-hexahydro-4-chlorocycloocta[b]pyridine-3-carboxylate with phenylhydrazine according to the procedure analogous to that described in example 1 yields 2,3,6,7,8,9,10,11-octahydro-2-phenylcylcoocta[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 310°-312°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8].CO.O.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cccc(F)c1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of ethyl 3-fluorophenoxy-acetate (2 g, 10 mmol) in 24 mL of a 1:1:1 solution of MeOH:H2O:THF is added lithium hydroxide monohydrate (2.25 g, 54 mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated under reduced pressure to ⅓ of its volume. The remaining solution is acidified to pH=3 with 1N HCl (aq.). The aqueous solution is extracted with EtOAc. The organic layer is washed with a saturated solution NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated to give the product (1.65 g, 9.7 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ9.8 (bs, 1H), 7.28 (m, 1H), 6.69 (m, 3H), 4.70 (s, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:3]=1[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:37][O:36][C:31]1[C:30]([C:3]2[N:4]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:5]3[C:10]([C:2]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:7][CH:6]=3)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ncccc1-c1c(Br)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1c(-c2ccccc2)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-bromo-2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-1H-indole-1-carboxylate (0.38 mmol), phenylboronic acid (69 mg, 0.57 mmol), Cs2CO3 (0.18 g, 0.57 mmol) in dioxane (3 ml) and water (1 ml) was added Pd(PPh3)4 (43 mg, 0.038 mmol). The reaction mixture was heated at 100° C. for up to 3 h. The reaction mixture was quenched by adding ethyl acetate (15 ml) and saturated NaHCO3 (10 ml). The ethyl acetate layer was separated and washed with brine (10 ml), dried with Na2SO4, filtered and concentrated to give a crude product. The crude product was purified using flash column chromatography (SiO2, 5% EtOAc in hexanes to 10% EtOAc in hexanes). The desired product, tert-butyl 2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-3-phenyl-1H-indole-1-carboxylate was obtained as a light yellow solid (0.017 g, 47%); 400 MHz 1H NMR (DMSO-d6) δ: 8.57 (t, J=5.2 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.17 (dd, J=1.2 Hz, 4.4 Hz, 1H), 8.10-7.98 (m, 1H), 7.92 (dd, J=1.2 Hz, 8.4 Hz, 1H), 7.45 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.40-7.23 (m, 3H), 7.23-7.19 (m, 1H), 6.94-6.89 (m, 1H), 3.87 (s, 3H), 3.57-3.50 (m, 4H), 3.34-3.25 (m, 2H), 2.35-2.28 (m, 6H), 1.71-1.62 (m, 2H), 1.24 (s, 9H); LCMS: 571 [M+H]. Hydrolysis as described in example 33 provides compound 1 in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-:15].[K+].O>C(O)CCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:9]([NH2:10])=[O:15])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCC(C#N)(CC)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCCCCO
Solvent: O
Product: CCC(CC)(C(N)=O)c1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenyl)-2-ethylbutyronitrile (104.9 g) was added to a boiling solution of potassium hydroxide (40.3 g) in pentan-1-ol (450 ml) with stirring. The mixture was boiled under reflux for 24 hours. The mixture was cooled and poured into an equal volume of water. The mixture was washed with ether and then the aqueous layer was extracted with dichloromethane to give an oil which solidified on standing. The solid was triturated with cyclohexane and filtered to give 2-(4-chlorophenyl)-2-ethylbutyramide, m.p. 107°-109° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.CO.[C:12](O)(=O)[CH3:13].C(C=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[C:4]([N:3]=1)=[N:9][CH:12]=[CH:13][N:8]=2
Reactant: Nc1ncc(Br)nc1N
Reactant: CC(=O)O
Agent: O=CC=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Brc1cnc2nccnc2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 50 mg (0.27 mmol) of 5-bromopyrazine-2,3-diamine in 2 mL of a 10:1 solution of methanol/acetic acid was added 0.046 mL (0.40 mmol) of glyoxal solution (40 wt. % in water) and the resulting solution was stirred at 50° C. for 4 h. The reaction mixture was cooled to ambient temperature, diluted with 10 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (5 mL each). The organic phase was then dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as a tan crystalline solid which was used without further purification. LC/MS 211.1, 213.1 (M+1, M+3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[CH3:21]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.7 %

Procedure:
To 6-hydroxy-3,4-dihydro-2(1 H)-quinolinone (90.2 g, 0.55 mol, 1 equiv) in DMF (1.8 L) was added potassium carbonate (228 g, 1.65 mol, 3 equiv). The slurry was stirred for 45 min. at 25° C., then iodoethane (114 g, 0.73 mol, 1.33 equiv) was added and stirring was continued for 12 hours. The mixture was filtered, the filtrate was poured into water, and the white precipitate was collected via filtration, washed with water (500 mL), and dried under high vacuum to provide 6-(ethyloxy)-3,4-dihydro-2(1H)-quinolinone (72.3 g, 69%). 1H NMR (400 MHz, DMSO) δ, 1.25 (t, J=7.2 Hz, 3H), 2.35 (m, 2 H), 2.78 (m, 2H), 3.90(m, 2H), 6.70-6.73 (m, 3H), 9.83 (br, 1H).