Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[O:23]=[C:18]1[CH2:19][O:20][CH2:21][CH2:22][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:25](=[O:26])[O:27][CH3:28])=[CH:16][CH:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g, 130.07 mmol) in CH2Cl2 (750 mL). The reaction mixture was stirred at room temperature for 15 min and methyl chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10 min. The resulting thick suspension was stirred for another 1 h and filtered through a Buchner funnel. The solid was washed with CH2Cl2 (2×75 mL) and dried under vacuum to obtain methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) as a crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:9]=2[C:10]#[N:11])[CH2:4][CH2:3]1.Cl>[Fe].C(Cl)Cl>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:9]=1[C:10]#[N:11]
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc(N)c2C#N)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 2-(4-methyl-1-piperazinyl)-6-nitrobenzonitrile in 11 ml. of concentrated hydrochloric acid is added 3.4 g. of iron powder. The mixture is stirred for 30 minutes, poured into ice water and the pH is adjusted to 12. Methylene chloride is added, the whole mixture is filtered through celite, the methylene chloride is separated, dried and evaporated to give solid, crude product, 2-amino-6-(4-methyl-1-piperazinyl)benzonitrile.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:33])[C@@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:48][CH2:49][CH2:50][C:51](=O)[CH2:52][CH2:53][CH3:54].CC(O)=O>C(Cl)Cl>[CH2:5]([C@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[C@H:3]([OH:33])[CH2:2][NH:1][CH:51]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:49][CH3:48])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC(=O)CCC
Reactant: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN)cc(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(CCC)CCC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 92 h
Yield: 11.5 %

Procedure:
To a solution of N-((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (E182) (30 mg, 0.066 mmol, 1 equiv) in (CH2Cl)2 (5 ml) were added sodium triacetoxyborohydride (20 mg, 0.094 mmol, 1.4 equiv), 4-heptanone (10 μl, 0.070 mmol, 1.1 equiv) and CH3COOH (4 μl, 0.070 mmol, 1,1 equiv). The resulting mixture was stirred at room temperature for 92 hours, diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/ethyl acetate: 3/2) gave N-[(1S,2R)-1-benzyl-2-hydroxy-3-(1-propyl-butylamino)-propyl]-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (4.2 mg, 11%) as a colourless oil. [M+H]+=552.2, RT=2.98 min
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCCC>ClCCl>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(N)cn1
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2)cn1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A solution of 5-amino-2-methoxypyridine (2.48 g, 20.0 mmol) and N-ethyldiisopropylamine (2.84 g, 22.0 mmol) in dichloromethane (20 ml) was cooled in an ice-bath. Benzoyl chloride (3.09 g, 22 mmol) was slowly added by means of a syringe. The cooling bath was removed and stirring was continued at room temperature for 18 hours. Dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo leaving a dark solid. Crystallisation from ethyl acetate:heptane yielded the title compound (3.44 g, 75% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:41](=[O:44])/[CH:42]=[CH:43]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Temperature: 100 °C
Yield: 85.3 %

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (9.42 g), triethylamine (25 ml), palladium acetate (0.85 g), triphenylphosphine (0.98 g) and methyl acrylate (9.68 g) in anhydrous DMF (95 ml) was heated to 100° C. for 1 h under nitrogen. The mixture was allowed to cool to room temperature, filtered through Celite and washed with diethyl ether/water. The filtrate was extracted with ether, then with EtOAc. The aqueous phase was acidified to approximately pH 1 with 2 M aqueous hydrogen chloride. The solid was filtered, washed with water and dried at 40° C. under vacuum, to afford the title compound (8.2 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[C:20]([S:24]([NH2:26])=[O:25])([CH3:23])([CH3:22])[CH3:21]>CCO.C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4]/[C:3](=[N:26]/[S:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:25])/[C:2]([F:19])([F:18])[F:1])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a mixture of 500 mg (1.8 mmol) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 1) and 0.86 mL (3.6 mmol) of a solution of Ti(OEt)4 in EtOH (˜20% Ti) in 7 mL of THF was added 240 mg (2 mmol) t-butylsulfinamide. The reaction was warmed at reflux for 6 h and then cooled to room temperature, diluted with 1 mL of brine and EtOAc, filtered through diatomaceous earth and concentrated to afford an oil. The residue was absorbed onto silica gel and chromatographed on silica gel eluting with hexanes-EtOAc (98:2) to afford 300 mg (44%) of 2-methylpropane-2-sulfinic acid [3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut-(Z)-ylidene]-amide as an orange oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][O:7][N:8]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14](I)[CH:15]=2)[CH:10]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:9]1=[O:32])[CH3:2].[CH:35]#[C:36][CH2:37][OH:38]>>[CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][O:7][N:8]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([C:35]#[C:36][CH2:37][OH:38])[CH:15]=2)[CH:10]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:9]1=[O:32])[CH3:2]
Reactant: CCN(CC)CCCON1C(=O)C(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCO
Product: CCN(CC)CCCON1C(=O)C(c2ccc3ccccc3c2)c2c1cc(C#CCO)cc2C(F)(F)F
Yield: 34 %

Procedure:
The title compound (3.7 mg, 34%) was prepared from 3-diethylaminopropyloxy-4-trifluoromethyl-6-iodo-3-(2-naphthyl)oxindole (12.4 mg, 0.0213 mmol) and 1-propyn-3-ol by the procedure similar to that described in Reference Example 21.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)(=O)C>[C:25]([O:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1)(=[O:27])[CH3:26]
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid (9.0 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The resulting mixture is cooled to room temperature and dissolved in ethyl acetate providing a clear solution which is extracted with an ice-cold solution of sodium hydroxide (8 g.) in water (150 ml.). The basic solution is quickly separated and acidified with concentrated hydrochloric acid. The oily acid which separates is extracted with ether. The organic extract is washed with water, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves a residual oil which is purified via application to a silica gel (150 g.) column with chloroform. Elution with chloroform-methanol (99:1; v:v) provides the title compound as a colorless, viscous oil.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C(C2C=CC=CC=2)(C2C=CC=C(C(F)(F)F)C=2)N2C=NC=N2)C=CC=CC=1>>[C:1]1([C:7]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]#[CH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccc(C(c2ccccc2)(c2ccccc2)n2cncn2)c1
Reactant: COC(=O)C(c1ccccc1)(c1ccccc1)n1ccnc1
Product: C#CC(c1ccccc1)(c1ccccc1)n1ccnc1

Procedure:
methyl α,α-diphenyl-1H- imidazole-1-acetate; and 1-[diphenyl[3-(trifluoromethyl)phenyl]methyl]-1H-1,2, 4-triazole, generically designated as fluotrimazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)=[CH:5][CH:4]=1.[OH:28]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methoxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[S:25]1[CH:29]=[C:28]([CH:30]=O)[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]1=2>>[S:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([CH2:30][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)=[CH:29]1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1csc2ccccc12
Product: Clc1cccc2c(-c3cccc(NCc4csc5ccccc45)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and benzo[b]thiophene-3-carbaldehyde according the procedure of Example 5 Step 5.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.Cl[C:14]1[C:22]([Cl:23])=[C:21]2[C:17]([C:18]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)=[CH:19][NH:20]2)=[CH:16][CH:15]=1>>[Cl:23][C:22]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][CH:19]=[C:18]2[C:24]1[CH2:25][CH2:26][N:27]([C:10]([CH:2]2[CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)=[O:12])[CH2:28][CH:29]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Reactant: O=C(O)C1Cc2ccccc2C1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
Prepared from 9a and 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH2:10].C([O-])(=O)C.[Na+]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH3:10]
Reactant: C=Cc1c(F)cccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1c(F)cccc1Cl
Yield: 87.8 %

Procedure:
To a solution (120 mL) of 1-chloro-3-fluoro-2-vinylbenzene (9.45 g) in ethyl acetate were added sodium acetate (4.92 g) and 10% Pd/C (50% water-containing product, 0.95 g), and the mixture was vigorously stirred under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was partitioned with ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a colorless oil (yield: 8.4 g).
Reaction SMILES: O1CCCC1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([N-]C(C)C)(C)C.[Li+].[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C(OCC)(=O)C>[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[C:16]=1[Cl:30])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1Cl
Temperature: 0 °C
Yield: 29.5 %

Procedure:
A tetrahydrofuran solution (10 mL) of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluoropyridine (469.1 mg, 1.94 mmol) was mixed with lithium diisopropylamide (1.08 M in tetrahydrofuran, 2.16 mL, 2.33 mmol) under cooling with ice. The reaction mixture was stirred at 0° C. for an hour, then added to hexachloroethane (840.0 mg, 3.50 mmol) and warmed slowly to room temperature for 12 hours with stirring. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1) to give the desired product (157.7 mg, 30% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1ccccc1
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Benzaldehyde (2.2 g, 21.0 mmol) was added to a stirred solution of 3-amino-4-methoxy-N-phenyl-benzamide (5.0 g, 21.0 mmol) in dichloromethane (250 mL) under an inert atmosphere at room temperature, followed by acetic acid (1.26 g, 21.0 mmol). After 1 hour, sodium triacetoxyborohydride (4.7 g, 21.0 mmol) was added in one portion. After 18 hours, saturated aqueous sodium bicarbonate (200 mL) was added and the mixture stirred for 2 to 3 hours. The layers were separated, the organic phase was washed with water then saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to afford the product (6.5 g); m.p. 164-165° C. after recrystallization from ethanol.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[C:22]([F:34])[C:23]([CH:30](O)[CH2:31][CH3:32])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[C:18]=1[F:35])[CH2:13][CH2:14][CH3:15].O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:12]([O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[C:22]([F:34])[C:23]([CH2:30][CH2:31][CH3:32])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[C:18]=1[F:35])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(C(O)CC)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(CCC)c1F
Reaction time: 3 h

Procedure:
After the addition of approx. 0.5 g of 4-toluenesulfonic acid and a few drops of concentrated sulfuric acid, a solution of 14 mmol of 2-butoxy-1,8-difluoro-7-(1-hydroxypropyl) fluorene in 50 ml of toluene is heated on a water separator for 3 h. After cooling, the mixture is extracted using 5 percent sodium hydrogencarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. Then 0.5 g of palladium catalyst (10 percent on activated carbon) are subsequently added and the mixture is hydrogenated at room temperature. The reaction mixture is filtered and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel and recrystallization from heptane. 2-Butoxy-1,8-difluoro-7-n-propylfluorene is obtained.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][N:3]=1.C[O:8][C:9]([C:11]1[N:15]=[CH:14][NH:13][N:12]=1)=[O:10]>>[O:4]1[CH2:5][CH2:6][C:2]([N:13]2[CH:14]=[N:15][C:11]([C:9]([OH:10])=[O:8])=[N:12]2)=[N:3]1
Reactant: Brc1ccon1
Reactant: COC(=O)c1nc[nH]n1
Product: O=C(O)c1ncn(C2=NOCC2)n1

Procedure:
1-(4,5-dihydroisoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acid I-171a and I-171b were prepared using the analogous procedure to Example 35 except that racemic compound I-75 was used as the starting bromo-isoxazole and 1H-1,2,4-triazole-3-carboxylic acid methyl ester as the nucleophile Additionally, at some point during the course of the reaction or workup, the ester hydrolyzed to the corresponding acid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M−H]−=356.6 m/z. Activity: C
Reaction SMILES: C(OC([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29]([C:36]6[CH:62]=[CH:61][C:39]7[N:40]=[C:41]([CH:43]8[CH:48]9[CH2:49][CH:45]([CH2:46][CH2:47]9)[N:44]8[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[NH:42][C:38]=7[CH:37]=6)=[CH:30][CH:31]=5)[C:26]([F:64])([F:63])[C:25]=4[CH:24]=3)=[CH:21][CH:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[CH3:59][O:58][C:56](=[O:57])[NH:55][CH:51]([C:50]([N:44]1[CH:43]([C:41]2[NH:42][C:38]3[CH:37]=[C:36]([C:29]4[CH:30]=[CH:31][C:32]5[C:33]6[C:25](=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:14][CH2:15]9)[CH2:12][NH:11]8)=[CH:22][CH:21]=7)=[CH:35][CH:34]=6)[C:26]([F:64])([F:63])[C:27]=5[CH:28]=4)[CH:62]=[CH:61][C:39]=3[N:40]=2)[CH:48]2[CH2:49][CH:45]1[CH2:46][CH2:47]2)=[O:60])[CH:52]([CH3:54])[CH3:53]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc(C6CC7(CC7)CN6C(=O)OCc6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc(C6CC7(CC7)CN6)[nH]5)ccc3-4)cc2[nH]1)C(C)C
Reaction time: 18 h

Procedure:
A mixture of 6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-pyrrol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (127 mg) and 10% palladium on carbon, wet (29 mg) in ethanol (4 mL) was stirred under an hydrogen atmosphere for 18 h. Added more and 10% palladium on carbon, wet (50 mg) and continued reaction for 30 h. Reaction mixture was filtered through a pad of CELITE, concentrated and purified by flash column chromatography (silica gel, 5 to 20% methanol/dichloromethane) to give {1-[3-(6-{7-[5-(5-Aza-spiro[2.4]hept-6-yl)-1H-pyrrol-2-yl]-9,9-difluoro-9H-fluoren-2-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester as a pale yellow film (21 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]([CH3:38])([CH3:37])[CH2:8][CH2:9][C@H:10]1[C:14](=[O:15])[O:13][C@H:12]([C@@H:16]([NH:24][C:25]([C:27]2[CH:36]=[N:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11]1>CO>[CH2:17]([CH:16]([NH:24][C:25]([C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH:12]([OH:13])[CH2:11][CH:10]([C:14](=[O:15])[NH:2][OH:3])[CH2:9][CH2:8][C:7]([F:6])([CH3:38])[CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NO
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Hydroxylamine hydrochloride (1.55 g, 22.4 mmol) and KOH (1.51 g, 26.7 mmol) were combined in anhydrous methanol (20 mL) and stirred for 30 minutes under a dry nitrogen atmosphere, and then filtered. To the resulting filtrate was added the product from Method E (500 mg, 1.17 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue solvated in EtOAc (50 mL) and transferred to a separated funnel. The organic layer was washed with water and brine and dried (MgSO4). After filtration the solvent was removed in vacuo and the remaining residue recrystallized (methylene chloride/Hexanes) to give a pale yellow solid (330 mg, 58%) m.p. 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.[I:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:22])[N:10]=[C:11]([C@H:12]3[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]3)[N:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-(2-amino-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.200 g, 0.000686 mol) and N-iodosuccinimide (0.278 g, 0.00124 mol) in anhydrous DMF (4.0 mL) was stirred at rt for 48 h. The reaction was concentrated in vacuo then partitioned between H2O and EtOAc. The aqueous material was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (2×), Na2S2O3 (2×) and brine (1×). The aqueous was re-extracted with CHCl3 and combined with the EtOAc fractions dried over Na2SO4, filtered and concentrated in vacuo resulting in 229 mg, (79.9% yield) of the title compound as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.65 (m, 4H), 1.88-2.06 (m, 4H), 2.33-2.45 (m, 1H), 2.91-3.01 (m, 1H), 3.61 (s, 3H), 6.17 (s, 2H) and 10.82 (br. s., 1H); MS (ES+): m/z 417.82 [MH+].