Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27]CC=C)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:35]CC1.[CH3:39][C:40]([CH3:42])=[O:41]>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:39][CH:40]([OH:41])[CH2:42][OH:35])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OCC(O)CO)c3ccccc3n2)CC1

Procedure:
A mixture of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2-propen-1-yl)oxy]quinazoline (1.00 g), a solution of osmium tetroxide in t-butanol (osmium tetroxide 106 mg/t-butanol 8.36 g) (248 mg) and 4-methylmorpholine N-oxide (305 mg) in water (9 ml)--acetone (28 ml) is stirred at room temperature for 21 hours. Acetone is distilled off from the reaction mixture under reduced pressure, and the resultant is diluted with ethyl acetate, and the mixture is washed with 10% aqueous sodium sulfite solution and water. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=50:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(RS)-(2,3-dihydroxypropyl)oxy]quinazoline (1.03 g) as crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:16])[CH:4]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.O>ClCCl>[Br:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:16])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)/C=C/c1ccc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(CBr)cc1C
Reaction time: 8 h

Procedure:
A solution of ethyl(2E)-3-[4-(hydroxymethyl)-2-methylphenyl]prop-2-enoate (intermediate 19, 1.389 g) in dry dichloromethane (40 ml) was cooled to 0° C. and treated with carbon tetrabromide (2.3 g) followed by, in small portions, triphenylphosphine (1.82 g). The resulting solution was stirred thus overnight, then poured into dichloromethane/water and the organic phase separated and washed with more water, brine and dried over sodium sulfate then evaporated in vacuo. The isolated product was further purified by flash column chromatography using cyclohexane:ethyl acetate (9:1) as an eluent which gave the title compound as a white solid.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([C:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[O:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1
Reactant: O=C1CCc2cc(C(=O)N3CCC4(CC3)OCCO4)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 100 °C

Procedure:
46 Grams of 6-(4,4-ethylenedioxy-1-piperidylcarbonyl)-3,4-dihydrocarbostyril was dispersed in 400 ml of dioxane and 150 ml of water, then 15 ml of concentrated hydrochloric acid was added thereto and the whole mixture was heated at 100° C. for 7 hours with stirring. After the reaction mixture was allowed to stand for cooling, then was made alkaline by adding sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=10:1) to yield 37.6 g of 6-(4-oxo-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([F:20])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]=O.C(O)(=O)C>CCO>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([F:20])[C:12]=3[C:3]3[C:4]([CH3:11])=[N:5][N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:2]=3[N:1]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Cc1nn(C(C)(C)C)c(N)c1-c1cc(F)cc(O)c1F
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 46.6 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@@H:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of (R)-2-benzyl 1-tert-butyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (D39) (210 mg, 0.6 mmol) in THF (10 ml) cooled at −78° C., LiEt3BH 1M sol in THF (0.6 ml) was added and the mixture stirred 2 hrs at −78° C. The reaction was warmed to 0° C. and quenched with slow addition of NaHCO3 sat sol (4 ml) and 1 drop of H2O2. Stirring was continued for 20 min then THF was removed under reduced pressure and the remaining residue was taken up in water (5 ml) and extracted with DCM (3×10 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The obtained residue was dissolved in DCM (10 ml) and cooled at −78° C. under N2. Et3SiH (0.09 ml, 0.6 mmol) was added followed by addition of BF3.OEt2 (0.1 ml, 0.63 mmol) and the reaction stirred 30 min, prior further addition of Et3SiH (0.09 ml, 0.6 mmol) and BF3.OEt2 (0.1 ml, 0.63 mmol). The final reaction mixture was stirred at −78° C. for 3 hrs then quenched by the slow addition of saturated NaHCO3 and water. The reaction mixture was extracted with DCM (3×10 ml), the organic layers washed with NaCl sat sol, dried over Na2SO4 and evaporated to afford the title compound (D40) (168 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[Br:19][CH2:14][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[O:13][N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(-c2cccc(C(F)(F)F)c2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2cc(CBr)no2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of {5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl}methane-1-ol (0.28 g, 1.15 mmol) and carbon tetrabromide (0.5 g, 1.5 mmol) in methylene chloride (10 mL) at 0° C. was added dropwise a solution of triphenylphosphine (0.41 g, 1.58 mmol) in methylene chloride (5 mL). The resulting mixture was stirred at 0° C. for 1 hour, then the reaction mixture poured into ethyl acetate and Hexanes (ethyl acetate:Hexanes=1:4, 50 mL). The resulting suspension was filtered through a thin layer of silica gel and washed with ethyl acetate and Hexanes (ethyl acetate:Hexanes=1:4). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=1:4) to afford 3-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]isoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]

Procedure:
20 g of 2-chloro-5-fluoro-4-methylbenzoic acid are initially introduced into 60 ml of concentrated H2SO4. 12.3 g of KNO3 are added in portions, while cooling with ice. The mixture is then warmed to 50° for 2 hours and subsequently poured onto ice. After isolation and recrystallization from toluene, 18.8 g of 2-chloro-5-fluoro-4-methyl-3-nitrobenzoic acid of melting point 186°-88° are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.Cl>CN(C=O)C.O>[CH3:33][O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:10]2[C:8]3=[N:9][C:4]([CH3:3])=[CH:5][C:6]([CH3:15])=[C:7]3[N:12]=[C:11]2[CH2:13][CH3:14])=[CH:23][CH:22]=1)=[O:31]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a suspension of sodium hydride (345 mg, 60% in oil, 8.6 mmol) in dry DMF (10 mL) was added 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.5 g, 8.6 mmol) under an atmosphere of dry nitrogen. The reaction mixture was stirred at room temperature until the evolution of gas subsided. The reaction mixture was cooled to 0° C. and a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (2.7 g, 8.84 mmol) in dry DMF (5 mL) was added dropwise. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into water (250 mL), the pH was adjusted to pH 6 by the addition of 1N HCl, and the product was extracted into ethyl acetate. Flash chromatography (silica, ethyl acetate) gave 4'-[[5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester (2.05 g, 61%) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][CH:20]=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].C([O-])(=O)C.[Na+].[I:27]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]3[N:18]=[CH:19][C:20]([I:27])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: ClI
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 15.2 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.36 g, 16.6 mmol) and drop wise a solution of iodine monochloride (2.69 g, 16.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.96 g, 93%) as a yellow solid. MS (EI) 436.9 [(M)+]; mp 151° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:17]2[CH:18]=[C:19]([CH2:23][N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[N:20]=[N:21][CH:22]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(-c3ccccc3)cc2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=327.4 (M+H+), was prepared from 4-biphenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A dry flask was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.122 g, 0.791 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.169 g, 0.440 mmol, 56%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Phenyl-1,3-thiazol-2-yl)piperazine (330 mg, 0.673 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (326 mg, 0.673 mmol), diisopropylethylamine (0.117 ml, 0.673 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to yield 115 mg (42.1%) of the desired product.
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:9]1(O)[CH2:12][CH2:11][CH2:10]1)(C)(C)C.[H-].[Na+].O>C1COCC1>[F:21][C:16]1[CH:15]=[C:14]([CH:8]2[C:9]3([CH2:10][CH2:11][CH2:12]3)[O:22][C:6](=[O:5])[NH:7]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)c(F)c1)C1(O)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)c(F)c2)C2(CCC2)O1
Temperature: 35 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a well stirred solution of [(3,4-difluorophenyl)-(1-hydroxy-cyclobutyl)-methyl]-carbamic acid-tert-butyl ester (1.0 g, 3.2 mmol) in THF (20 mL) was added 95% NaH (0.2 g, 8.3 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 8-(3,4-difluorophenyl)-5-oxa-7-aza-spiro[3.4]octan-6-one in racemic form as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9](C)[CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:12]([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[CH3:12][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: [Li]C(C)(C)C
Product: Cc1cc2[nH]ncc2cc1C(=O)O

Procedure:
This compound was prepared in a manner similar to the preparation of example 88 using commercially available 4-bromo-2,5-dimethylaniline as starting material. After an acylation step, N-(4-bromo-2,6-dimethylphenyl)acetamide was treated with isoamyl nitrite, and then 10% aqueous HCl to yield 5-bromo-7-methyl-1H-indazole. 5-bromo-7-methyl-1H-indazole was treated with t-butyl lithium and carbon dioxide to yield 6-methyl-1H-indazole-5-carboxylic acid, which is in turn was treated with thiosemicarbazide and polyphorsphoric acid to form 5-(7-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 232 (100%, M++1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:31][C:32]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35]>C(Cl)Cl.CN1CCOCC1.CC(O)=O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:20]2[O:22][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:43])[F:44])[C:32]=3[N:31]=2)=[CH:12]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 22.8 g of BOC-L-Tryptophane in 150 ml of methylene chloride and 20.6 g of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride, 15.4 g of 2-amino-3-trifluoromethyl benzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted to obtain 20.7 g of 1,1-dimethylethyl N-[(S) 2-[1H-indol-3-yl]-1-[4-oxo-8-trifluoromethyl-4H-3,1-benzoxazin-2-yl]-ethyl-carbamate melting at 166° C. and having a specific rotation of [α]D =-52°±2.5° (c=0.4% in CH3COOH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]3[CH2:28][CH2:27][CH2:26][C@@H:22]3[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([NH:29][C:30]([NH2:32])=[NH:31])=[N:10][CH:9]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>C(Cl)Cl.CN(C=O)C>[NH3:10].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]3[CH2:28][CH2:27][CH2:26][C@@H:22]3[C:23]([NH:36][CH2:35][CH2:33][OH:34])=[O:24])(=[O:19])=[O:20])=[CH:15][CH:16]=2)[C:11]([NH:29][C:30]([NH2:32])=[NH:31])=[N:10][CH:9]=1
Reactant: NCCO
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)NCCO)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127.8 %

Procedure:
##STR81## Oxalyl chloride (40 μl, 0.46 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline (100 mg, 0.23 mmol) in CH2Cl2 (10 ml), followed by DMF (1 drop), and the reaction stirred at room temperature for 30 min. The mixture was evaporated in vacuo and azeotroped with toluene. The residue was dissolved in CH2Cl2 (5 ml), and added to a solution of ethanolamine (17 μl, 0.28 mmol) in CH2Cl2 (5 ml), the reaction stirred at room temperature for 2 h, then concentrated in vacuo. The crude product was purified by column chromatography upon silica gel using an elution gradient of CH2Cl2 -MeOH-0.880 NH3 (95:5:0.5 to 90:10:1) to afford (2R)-1-({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)-N-(2-hydroxyethyl)-2-pyrrolidinecarboxamide (65 mg, 0.147 mmol) as a yellow foam.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12](Cl)[C:11]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1)=[C:10]2[Cl:29].[CH3:30][N:31]1[C:35]([C:36]([C:38]2[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)=[O:37])=[CH:34][N:33]=[CH:32]1.[C:48](=O)=[O:49].CC(C)=O>C1COCC1>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:36]([C:35]3[N:31]([CH3:30])[CH:32]=[N:33][CH:34]=3)([C:38]3[CH:39]=[N:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=3)[OH:37])[CH:8]=2)[N:13]=[C:12]([O:49][CH3:48])[C:11]=1[CH2:18][C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1
Reactant: O=C=O
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 2.75 mL, 6.88 mmol) was added drop-wise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolone (3.00 g, 6.95 mmol, Intermediate 65: step c) in dry THF (35 mL) in a dry ice-acetone bath. After 1.5 min, a solution of 1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (1.69 g, 6.61 mmol, Intermediate 36: step c) in dry THF (25 mL) was added drop-wise via syringe. An additional 10 mL of THF was used to complete the quantitative addition. The reaction mixture was stirred for 7 minutes in the dry ice-acetone bath, then placed into an ice-water bath. After 10 min, the ice-water bath was removed and the mixture was allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was further extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=2.1 Hz, 1H), 8.71 (d, J=2.1 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 7.88 (ddd, J=8.3, 2.4, 0.9 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.76 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 7.62 (dd, J=8.2, 0.9 Hz, 1H), 7.58-7.54 (m, 2H), 7.17-7.15 (m, 1H), 6.71 (s, 1H), 6.22 (d, J=1.2 Hz, 1H), 4.34 (s, 2H), 4.08 (s, 3H), 3.32 (s, 3H). MS m/e 608.0 (M+H).