Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:34]=[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]4[N:29]([CH3:30])[N:28]=[CH:27][C:26]=4[C:31](O)=[O:32])=[O:24])=[CH:21][N:16]3[N:15]=2)[CH2:10]1>>[CH3:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:34]=[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]4[N:29]([CH3:30])[N:28]=[CH:27][C:26]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:24])=[CH:21][N:16]3[N:15]=2)[CH2:10]1
Reactant: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1
Reactant: C1COCCN1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)cn3n2)C1

Procedure:
Using morpholine and 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off white solid (42 mg, 51%). MS: m/z=455 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][C:28]([NH2:30])=[O:29])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][C:44]([F:47])([F:46])[F:45])[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][C:35]=1[O:43][C:44]([F:45])([F:46])[F:47])(=[O:41])=[O:40])[C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][C:28]([NH2:30])=[O:29])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N[C@@H](CC(N)=O)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CC(N)=O)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 55.9 %

Procedure:
With 296 mg of the compound obtained in Step 67-3 and 204 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 263 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1]I.[OH-].[Na+].C[O:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH2:15][S:14](=[O:24])(=[O:23])[C:13]=2[CH:25]=1)=[O:8].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH3:1][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][S:14](=[O:24])(=[O:23])[C:13]2[CH:25]=[C:9]([C:7]([OH:6])=[O:8])[CH:10]=[CH:11][C:12]1=2
Reactant: CI
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN1c2ccccc2CS(=O)(=O)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 8.8 %

Procedure:
Methyl iodide (0.03 ml, 0.49 mmol), tetrabutylammonium hydrogen sulphate (0.112 g, 0.33 mmol) and 50% aqueous sodium hydroxide (0.5 mL) were added to a solution of Example 166e (0.1 g, 0.33 mmol) in benzene (2 mL). The reaction mixture was stirred for 7 h at room temperature, treated with water and extracted with ethyl acetate. The organic extract was washed with water, 10% aqueous HCl, dried, concentrated and subjected to hydrolysis as described in Example 1i to obtain the title compound. (Synthesis 124, (1976)). Yield: 8.80%; 1H NMR (DMSO-d6): δ 3.50 (s, 3H, CH3), 5.00 (s, 2H, CH2), 7.30-7.60 (m, 5H, Ar), 8.01 (d, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (ES+) 304 (M+).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:10]([C:9]4[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[C:7]([CH3:13])[CH:8]=4)=[O:11])=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A dry 25 mL flask was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl chloride (1.03 g, 5.17 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.0 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.654 g, 1.68 mmol, 42%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)[CH:6]=[CH:7][CH3:8].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:14][CH:11]1[CH2:12][CH2:13][CH:9]([CH2:5][CH:6]=[CH:7][CH3:8])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC=CCC1CCC(O)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC=CCC1CCC(OC(C)=O)C1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A solution of 2 ml of acetyl chloride in 5 ml of benzene was added at 0° C. to a solution of 1 g of 3-(2-butenyl)-cyclopentanol in 20 ml of benzene and 2 ml of pyridine and the mixture was stirred at 20° C. for 17 hours and was poured into 2N hydrochloric acid solution with stirring. The decanted aqueous phase was extracted with benzene and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 1.4 g of 1-acetyloxy-3-(2-butenyl)-cyclopentane.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1ncc(N)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To a suspension of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[1-(4-fluorophenyl)ethyl]-5-nitropyrimidine-2,4-diamine (Method 9; 0.8 g, 2.0 mmol) and zinc dust (0.7 g, 10.0 mmol) in MeOH:THF (1:1, 50 ml) was slowly added saturated NH4Cl solution (10 ml) at 25° C. After 3 hours, the reaction mixture was treated with saturated aqueous NH4OAc solution (40 ml) and allowed to stir for 30 minutes. The reaction was then filtered through a plug of celite with EtOAc (100 ml), and the resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give the title compound (0.04 g, 5%). MS: Calcd.: 353; Found: [M+H]+ 354.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].I[CH2:19][CH2:20][CH3:21]>>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:19][CH2:20][CH3:21])[C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17]
Reactant: CCCI
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Product: CCCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 36 %

Procedure:
Using a procedure analogous to that described in Example 2, the product 6,11-dihydro-6-methyl-11-propyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 96°-98° C. (recrystal from petroleum ether) was prepared from 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 1-iodopropane. The yield was 36% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH3:16].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([N:19]1[N:20]=[CH:21][CH:22]=[N:18]1)[N:6]2[CH3:16]
Reactant: CC(O)CCc1nc(N)c2nc(Br)n(C)c2n1
Reactant: c1c[nH]nn1
Solvent: CN(C)C=O
Product: CC(O)CCc1nc(N)c2nc(-n3nccn3)n(C)c2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-2-ol (1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added CsCO3 (5.9 g, 18.24 mmol) and 1H-1,2,3-triazole (1.2 g, 1.0 ml, 18.24 mmol). The mixture was stirred overnight at 90° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: O1C=CC(C2C=CC3CS(=O)(C4C=CC=CC=4)=NC(=O)C=3C=2OC)=C1.[O:26]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([O:60][CH3:61])=[C:33]([C:41]([CH2:44][S:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)(=[N:47]C(=O)C(F)(F)F)=[O:46])=[CH:42][CH:43]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:27]1>>[O:26]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([O:60][CH3:61])=[C:33]([C:41]([CH2:44][S:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)(=[NH:47])=[O:46])=[CH:42][CH:43]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:27]1
Reactant: COc1c(-c2ccoc2)ccc(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)c1C(=O)OC(C)(C)C
Agent: COc1c(-c2ccoc2)ccc2c1C(=O)N=S(=O)(c1ccccc1)C2
Product: COc1c(-c2ccoc2)ccc(CS(=N)(=O)c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 214, starting from t-butyl 3-(furan-3-yl)-2-methoxy-6-{[S-phenyl-N-(trifluoroacetyl)sulphonimidoyl]methyl}benzoate (Intermediate 220).
Reaction SMILES: Cl.C([O:6][C:7](=[O:28])[CH2:8][NH:9][S:10]([C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:27])=[CH:18][N:19]=[C:20]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.[C:29]([C:33]([OH:35])=[O:34])([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:33]([OH:35])=[O:34].[Cl:27][C:17]1[C:16]2[C:21](=[CH:22][C:13]([S:10]([NH:9][CH2:8][C:7]([OH:28])=[O:6])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine t-butyl ester hydrochloride (50 mg, 0.11 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1.5 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was triturated with Et2O and EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine trifluoroacetate (36 mg, 0.073 mmol) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[F:22])[C:30]#[N:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccccc1F
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C#N)c1ccccc1F)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (5.00 g, 15.19 mmol) in DMF (20 mL) was added cesium carbonate (5.44 g, 16.71 mmol) and the mixture was stirred at 23° C. for 2 h. (2-Fluorophenyl)acetonitrile (5.87 mL, 45.6 mmol) and cesium carbonate (7.42 g, 22.8 mmol) were added and the resulting mixture was stirred for 1 h. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→50% ethyl acetate/hexane) gave the title compound as a racemic mixture of cis and trans diastereomers. MS: m/z=378.1 (M+CH3CN+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN1CCCC1=O>>[CH2:21]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Temperature: 120 °C
Yield: 86 %

Procedure:
A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.63 mmol), dibenzylamine (913 mg, 890 μL, 4.63 mmol), triethylamine (1.2 mL, 8.61 mmol) and 1-methyl-2-pyrrolidone (6 mL, 62.22 mmol) was heated at 120° C. for 9 h. The reaction mixture was cooled to the room temperature and poured into ice-water, extracted with EtOAc (20 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (2%-10% EtOAc in petroleum ether as eluant) to give N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 7.37-7.21 (m, 10H), 6.32 (d, J=8.7 Hz, 1H), 4.80 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:12]([OH:14])=O.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: COc1cccc2c1CCC2C(=O)O
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCc3c(OC)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 61.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide (0.39 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13]O2.[CH3:29][NH2:30].O>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:30]([CH3:29])[CH:13]=[CH:14][N:15]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[N:22]=1
Reactant: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: CN
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n(C)ccn34)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
6-(2,4-Difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)imidazo[2,1-b]oxazole (0.200 g, 0.526 mmol, Example #8), 40% methylamine in water (1.50 mL, 15.4 mmol) and 1,4-dioxane (1 mL) were heated in a CEM® microwave at about 120° C. (250 psi maximum pressure, 10 min ramp, 300 max watts) for about 55 min. The mixture was concentrated under reduced pressure then treated with HOAc (1.5 mL). The solution was stirred at ambient temperature for about 1 h then the material was purified by RP-HPLC (Table 1, Method f). The desired fractions were collected and concentrated under reduced pressure to remove most of the ACN. The precipitate which formed was collected by filtration and washed with water (3 mL) then dried overnight under vacuum at about 70° C. to give the title compound (0.115 g, 56%): LC/MS (Table 1, Method g) Rt=1.88 min; MS m/z: 394.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:32][C:23]1[C:24]2[CH2:25][O:26][C:27](=[O:31])[C:28]=2[CH:29]=[CH:30][C:22]=1[C@@H:2]([NH:1][C:41](=[O:42])[O:43][CH3:44])[CH2:3][N:4]1[CH2:5][CH2:6][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:20][CH2:21]1
Reactant: COC(=O)Cl
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 62) (35 mg, 0.08 mmol) and triethylamine (17 μL, 0.12 mmol) in dichloromethane (2 mL) was added methyl chloroformate (11 mg, 0.12 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stir for 2 h. TLC indicated half of starting material remained. The reaction mixture was re-cooled to 0° C. and triethylamine (17 μL, 0.12 mmol) was added thereto, followed by methyl chloroformate (11 mg, 0.12 mmol). The reaction mixture was allowed to warm to room temperature and stirred for another 2 h. TLC showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was taken up into small amount of DCM and purified by preparative TLC (dichloromethane:methanol=15:1) to afford the title compound. MS-ESI (m/z): 498 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[C:17](=S)=[S:18].Cl>O.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:17]([SH:18])=[N:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(C(=O)NN)cc21
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid hydrazide (2.8 g, 14.8 mmol), potassium hydroxide (0.91 g, 16.3 mmol) and methanol (50 ml) was stirred at room-temperature for 30 min. Carbon disulfide (2.25 g, 29.6 mmol) was added and the mixture was stirred for 15 h at reflux. The mixture was allowed to cool to room-temperature, water was added, pH was adjusted to 3 by adding concentrated aqueous hydrochloric acid. The crystalline product was isolated by filtration and washed with water. Yield 2.75 g (80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7]3([CH2:35][O:34][C:26]4[CH:27]=[C:28]5[C:29](=[CH:33][C:25]3=4)[CH2:30][CH2:31][O:32]5)[C:8]2=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 183-184° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ7.45-7.22 (m, 10H), 7.13-7.05 (m, 3H), 6.98 (s, 1H), 6.44-6.43 (m, 2H), 4.91 (d, J=9.5 Hz, 1H), 4.80 (d, J=9.5 Hz, 1H), 4.51 (t, J=8.9 Hz, 2H), 2.97 (t, J=8.6 Hz, 2H); MS (ES+) m/z 463.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH:7](O)[CH2:6]1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:32]([NH2:34])[CH3:33]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C@H:5]1[S:10](=[O:12])(=[O:11])[C:9]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[C@@H:7]([NH:34][CH2:32][CH3:33])[CH2:6]1)[CH3:2]
Reactant: CCOCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCN[C@H]1C[C@@H](COCC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: -10 °C
Reaction time: 5 h

Procedure:
5,6-Dihydro-6-ethoxymethyl-4-hydroxy-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (4.25 g, 0.0123 mol) was dissolved in dry pyridine (25 ml) and the solution was cooled to -10° C. p-Toluenesulfonyl chloride (5.14 g, 0.027 mol) was added and the mixture was stirred at -10° C. for 5 hours. Anhydrous ethylamine (26 ml, 0.4 mol) was added and the mixture was stirred for 2 hours at room temperature. Finally, 70% ethylamine (32 ml. 0.40 mol) was added and the mixture was heated at 50° C. overnight. The dark mixture was concentrated in vacuo and the residual oil was taken up in ethyl acetate (100 ml) and saturated sodium bicarbonate (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined ethyl, acetate solutions were washed with saturated sodium chloride, dried, filtered and concentrated in vacuo. The oil obtained was a 2:1 mixture of cis and trans isomers which were separated by silica gel chromatography using 7.5% methanol-chloroform. Total recovery was 2.43 g. Yield of 33 was 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10]C)=[C:6]([O:8][CH3:9])[CH:7]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)cc(OC)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Cl)cc(OC)c1O
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution 37a) (4.67 g, 23.1 mmol) in dry DCM (40 mL) at 0° C. under nitrogen was added BCl3 (1M in DCM, 24 mL, 24.0 mmol) drop-wise. The solution was allowed to warm to room temperature over 3.5 h. The reaction was quenched with the addition of H2O (40 mL) and the product extracted with EtOAc (3×30 mL). The organics were pooled, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, EtOAc/Petroleum Spirit, 2:8) to give the title compound as a white solid (4.29 g, 98%). 1H NMR (300 MHz, CDCl3) δ 6.58 (s, 2H), 5.41 (s, 1H), 3.88 (s, 6H), ESIMS m/z [M+H]+ 187.3.