Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.[C:21](#[N:23])[CH3:22]>>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([CH2:22][C:21]#[N:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1
Reactant: CC#N
Agent: C[O-]
Agent: [Na+]
Product: N#CCC(=O)c1cccc(Oc2ccccc2)c1
Yield: 65 %

Procedure:
A solution of sodium methoxide (from 1.2 g sodium in 25 ml methanol) was added dropwise over 2 hours to a refluxing solution of methyl-3-phenoxybenzoate (11 g) in acetonitrile (100 ml) under a nitrogen atmosphere while distilling off methanol and excess acetonitrile. After complete removal of methanol the reaction mixture was poured onto ice-water (200 g) and acidified with 50% HCl. The solid was filtered off and dried to give the title compound (7.5g, 65%) as a white solid of m.p. 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]S(N)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:3]=1.ClC1N=C(Cl)N=CN=1.NC1C=C(C[CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])C=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Nc1cccc(CCS(N)(=O)=O)c1
Agent: Clc1ncnc(Cl)n1
Product: NS(=O)(=O)CCc1cccc(Nc2ncnc(Cl)n2)c1

Procedure:
A4 was prepared following the general procedure reported for A1 using 2,4-dichloro-1,3,5-triazine and 2-(3-aminophenyl)ethanesulfonamide A3 as reacting agents. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 4:1) to yield the desired product A5 (54%, 65% purity) as a brown solid. MS (ES) C11H12ClN5O2S requires: 313. found: 314 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: CN1c2ccc(O)cc2C2CCC(N)C21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1c2ccc(O)cc2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture was stirred for 2 hours, extracted with water, dried (Na2SO4) and concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethoxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:14])[CH3:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 4-bromophenylacetate (2.137 g, 8.8 mmol) in THF (20 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1M in hexane; 11.4 mL, 11.4 mmol), and the solution was stirred for 1 hour at −78° C. Iodomethane (0.71 mL, 11.4 mmol) in THF (5 mL) was added, and the reaction was warmed to room temperature. The mixture was quenched with water and concentrated. The residue was dissolved in EtOAc and washed three times with water and once with brine. The organic layer was dried and concentrated, and the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give 2-(4-bromo-phenyl)-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:25]1([C:2]2[C:7]3[N:8]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C3CC3)c2N(c2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 200 mg), cyclopropylboronic acid (65 mg), potassium phosphate (410 mg), tetrakis-(triphenylphosphine)palladium(0) (66 mg), water (0.1 mL) and toluene (5 mL) was heated at 100° C. under argon atmosphere for 4 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 5-cyclopropyl-4-(4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (146 mg) as a pale yellow powder.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.[CH3:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:6]([CH2:5][CH:3]2[CH2:4][N:1]([C:33]([C:30]3([CH3:29])[CH2:32][CH2:31]3)=[O:34])[CH2:2]2)=[N:10][NH:9][C:8]1=[O:11]
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CC(Cc3n[nH]c(=O)n3-c3ccc(-c4ccc5cccnc5c4)cc3F)C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
In a round bottom flask under nitrogen, a solution of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (1.07 mmol) in N,N-dimethylformamide (5 mL) was treated with 1-methylcyclopropanecarboxylic acid (1.285 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.14 mmol), N,N-diisopropylethylamine (3.21 mmol) and then 1H-1,2,3-benzotriazol-1-ol (2.14 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequent silica gel chromatography (0-3% methanol/ethyl acetate) followed by trituration in ethanol provided the title compound as a white solid (45 mg, 9.2%). MS(ES)+ m/e 458.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13](=[O:21])[O:12]1.C(O)(=O)C>CCOC(C)=O>[OH:12][CH2:11][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][C:13]([N:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:21]
Reactant: CNNC(=O)OC(C)(C)C
Reactant: O=C1Cc2ccccc2CO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1CO
Temperature: 100 °C

Procedure:
N-(t-Butoxycarbonyl)-N′-methylhydrazine (100 mmol) (Lenman, et al., J. Chem. Soc. Perkin Trans., 1997, 16, 2297-2312; Dutta, et al., J. Chem. Soc. Perkin Trans., 1986, 1655-1664) was added to 3-isochromanone (7.4 g, 50 mmol) (Cheng, et al., J. Heterocyclic Chem., 1995, 32, 73) in a sealed tube followed by 0.2 mL of acetic acid and heated for 12 h at 100° C. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL),1 M HCl (50 mL), brine (50 mL) and dried (Na2SO4). The desired alcohol 2-[2-[2-(Hydroxymethyl)phenyl]-1-oxoethyl]-2-methylhydrazinecarboxylic acid, 1,1-dimethylethyl ester was purified by flash chromatography (silica) using 50% EtOAc in hexane as eluent. MS (ESI) 295 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH2:7][NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-benzyloxybenzaldehyde (7.2 g) and ethyl 2-[4-aminophenyl]acetate (4.45 g) were heated on a steam bath for 2 hours. The mixture was cooled and dissolved in ethanol (100 ml) and NaBH4 (0.94 g) was added. The mixture was stirred at ambient temperature for 30 minutes, NaBH4 (0.5 g) added and stirred at ambient temperature for 2 hours. Acetic acid (2 ml) was added dropwise and the solvent evaporated to half volume. The mixture was partitioned between water (100 ml) and diethyl ether (3×75 ml) and the combined organic extracts washed with NaHCO3 (2×50 ml), dried (MgSO4) and evaporated. The residue was subjected to chromatography eluting with CH2Cl2 to give ethyl 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]acetate: (yield 6.4 g, m.p. 73° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][CH:12]=[N:11][C:10]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:24][C:12]1[S:13][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:10]([C:14]([OH:16])=[O:15])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1scnc1C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.72 g, 10 mmol) in DCM (50 mL) was added in three portions NBS (1.95 g, 11 mmol); the reaction mixture was stirred at ambient temperature for 1 h. Reaction was concentrated in vacuo; resulted residue was purified by silica gel column chromatography (6:1 Pet-ether-EtOAc) to afford 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.75 g, 70%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 13.65 (s, 1H), 10.03 (s, 1H), 1.49 (s, 9H). MS (ESI) m/z: 324 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4].[BH4-].[Na+].CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9][CH:8]([OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
The compound of step 1 (67 mg, 0.148 mmol) was dissolved in THF (1 ml) and cooled in an ice bath. Sodium borohydride (5.7 mg, 0.148 mmol) was added. Subsequently methanol (0.3 ml) was added dropwise. The ice bath was removed and after stirring for 45 min at room temperature the mixture was partitioned between EA and 2 N hydrochloric acid. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (65 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F-].[Cs+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:29]1[CH2:28][C@H:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
4-Hydroxyindole (3.0 g) was dissolved in DMF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (10.12 g) was added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (5.84 g, 99.3% e.e.) was added thereto and the mixture was stirred for 30 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/isopropyl alcohol; 20:1) to give 4.01 g of (S)-4-(2,3-epoxypropoxy)indole (yield 94.1%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH3:20].CO.[BH4-].[Na+]>CCO>[NH2:20][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (5.35 g, 20.0 mmol) in EtOH (40 mL) were added a solution of NH3 in MeOH (7M, 40 mL, 280.0 mmol) and Ti(Oi-Pr)4 (11.30 g, 40.0 mmol), the mixture was stirred at room temperature overnight. And then NaBH4 (1.51 g, 40.0 mmol) was added portionwise. After addition, the resulting mixture was stirred at room temperature for another 5 h, then quenched with water (40 mL), stirred for 1 h and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the product as a light yellow solid (1.20 g, 22.4%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.O>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a solution of 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (131 mg, 415 μmol) in NMP (5 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture stirred at 140° C. for 24 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (162 mg, 756 μmol) was added and the mixture heated at 140° C. for a further 24 h. The reaction mixture was cooled, and then diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) then the combined organic phases were washed with brine (50 mL), then concentrated in vacuo, and finally purified by chromatography (silica, 12 g RediSep Gold, 2 to 6% of a 99.5:0.5 methanol:ammonium hydroxide solution in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol, 34%) as a beige solid. MS (EI/CI) m/z: 494.3 [M+H].
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[ClH:19]>O>[ClH:19].[CH2:17]([NH:16][S:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][NH2:1])=[CH:7][CH:8]=1)(=[O:15])=[O:14])[CH3:18]
Reactant: O=N[O-]
Reactant: CCNS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCNS(=O)(=O)Cc1ccc(NN)cc1
Reaction time: 0.25 h

Procedure:
Sodium nitrite (1.01) in water (12 ml) was slowly added to a stirred suspension at -5° of the finely ground product of stage (a) (3.14 g) in concentrated hydrochloric acid (30 ml) keeping the temperature below 0°. The resulting mixture was stirred at -5° for 15 min. the slowly added to a cold (-5°) stirred solution of stannous chloride (16.52 g) in concentrated hydrochloric acid (30 ml) keeping the solution below 0°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Reactant: OCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere, a solution of 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.36 g, 6.37 mmol), 4-(hydroxymethyl)phenyl boronic acid (1.07 g, 7.01 mmol), and 2 M Na2CO3 (7 mL, 12.7 mmol) in 16 mL of toluene and 4 mL ethanol (0.3 M) was treated with tetrakistriphenylphosphine palladium (Pd(Ph3)4) (0.37 g, 0.32 mmol) and heated to 80° C. for 2 hours. After cooling to room temperature the solution was extracted with ethyl acetate, dried over MgSO4, and concentrated. Purification by flash chromatography (30% ethyl acetate in heptane) provided [3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-yl]-methanol. 1H NMR (CDCl3, 300 MHz) δ 7.49-7.32 (m, 6 H), 7.16-7.13 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.73-6.60 (m, 2 H), 4.66 (s, 2 H), 4.48 (s, 2 H), 3.30 (t, J=5.7 Hz, 2 H), 2.76 (t, J=6.3 Hz, 2 H), 1.98-1.90 (m, 2 H); ESI-LCMS m/z calcd for C24H22F3NO: 397.4; found 398.7 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20].ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[C:13]1([S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[C:3]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=2)=[O:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1nc(S(=O)c2ccccc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as follows: 50 mg of [(4-hydroxy-1-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid, Example D-110, was dissolved in 0.3 ml 1-methyl-2-pyrolydinone and 0.7 ml dichloromethane. The solution was cooled to 0° C. and 26 mg of 75% 3-chloroperoxybenzoic acid was added. The solution was stirred for 2 hours at room temperature, then concentrated under high vacuum. The resultant residue was triturated with ethyl acetate to provide 32 mg of the product as a white solid; MS (−) m/z 369.08 (M−1)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)C(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 42 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethyl amine and 20 ml of dichloromethane were added 98 μl (0.935 m mol) of isobutyryl chloride with stirring at the room temperature, followed by further stirring for four hours. After the completion of the reaction, the mixture was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 109 mg (yield: 42%) of the pure intended compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:28]([CH:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(Br)CC
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Product: CCC(CC)Oc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
Using the compound obtained in Example 17 and 3-bromopentane, white powdery N-{2-[3-(1-ethylpropoxy)-4-methoxy phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1.[CH2:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38])[C:26]#[CH:27].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[C:26][CH2:25][N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:29]3=[O:38])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=N[C@H]2C
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=N[C@H]2C

Procedure:
The title compound was prepared by coupling (S)-6-(2-fluorophenyl)-8-iodo-4,1-dimethyl-4H[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 100. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue crystallized very slowly from ethanol/ether to give colorless crystals of (S)-1-{3-[6-(2-fluorophenyl)-4,1-dimethyl4H-[1,2,4]-triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160° with foaming. These crystals contained both ethanol and water according analytical and spectral data. [α]D=+87.5° (c=1.0091 in CH2Cl2)