Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19]C4CCCCO4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][OH:19])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:41])[F:42])[CH:34]=2)=[CH:44][CH:45]=1
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: Cn1c(=O)n(CCO)c(=O)c2c1nc(OCCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.09 mmol,) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h; then it was partitioned between ethyl acetate and water. The organic phase was separated and dried over sodium sulfate. This organic layer was then filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)1H-purine-2,6(3H,7H)-dione (20 mg, 39.2% yield) as a white solid. 1H-NMR (DMSO-d6) δ 7.40(t, 1H), 7.28-7.33(m, 4H), 6.92(dd, 2H), 6.85(s, 1H), 5.23(s, 2H), 4.76(t, 1H), 4.62(t, 2H), 4.08(t, 2H), 3.93(t, 2H), 3.49(q, 2H), 3.33(s, 3H), 2.18-2.24(m, 2H). LCMS retention time 3.058 min; LCMS MH+ 569.
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:30][CH:31]=[CH2:32])[CH2:18][N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:14]=[CH:15][CH:16]=1.[OH-:33].[Na+].OO>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:18][N:19]([CH3:29])[S:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: C=CCC(CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC(CCCO)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
9-BBN (119 mg, 0.488 mmol) was added in one portion to an ice cold solution of N-(2-(3-chlorophenyl)pent-4-enyl)-N-methylbenzenesulfonamide (100 mg, 0.286 mmol) in 1.0 mL of THF, and the mixture was allowed to warm to room temperature. After 15 h, an additional portion of 9-BBN (26 mg, 0.11 mmol) was added and stirring was continued for another 1 h. Aqueous 2.5 N sodium hydroxide solution (0.29 mL, 0.73 mmol) and aqueous 30% hydrogen peroxide solution (0.176 mL) were added and the mixture was stirred 45 min at room temperature, 5 h at 50 ° C., and overnight at room temperature. The reaction was concentrated and the residue was partitioned between 25 mL of ethyl acetate and a mixture of 20 mL of water and 5 mL of brine. The aqueous layer was extracted with 2×25 mL of ethyl acetate. The combined organic layers were washed with 25 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5-50% ethyl acetate in dichloromethane to give 39 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.72 (d, 2H, J=8 Hz), 7.63 (tt, 11H, J=8, 1 Hz), 7.56 (t, 2H, J=8 Hz), 7.29 (dd, 1H, J=9, 8 Hz), 7.24-7.20 (m, 2H), 7.16 (dt, 1H, J=8, 1 Hz), 3.49 (t, 2H, J=7 Hz), 3.24 (dd, 1H, J=13, 8 Hz), 3.13 (dd, 1H, J=13, 7 Hz), 2.97-2.88 (m, 1H), 2.59 (s, 3H), 1.87-1.77 (m, 1H), 1.65-1.54 (m, 1H), 1.45-1.27 (m, 2H). Mass spectrum (NH3 /CI): m/z=368 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:25]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:26](=[O:35])[CH2:27][CH2:28][C:29]([CH3:34])([S:31][S:32][CH3:33])[CH3:30])[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:25]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:26](=[O:35])[CH2:27][CH2:28][C:29]([CH3:34])([S:31][S:32][CH3:33])[CH3:30])[CH:13]=[C:14]([CH2:16][OH:17])[CH:15]=1
Reactant: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOCCOCCN(C(=O)CCC(C)(C)SSC)c1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred solution of N-(3,5-bis((tert-butyldimethylsilyloxy)methyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267b) (315 mg, 0.447 mmol) in anhydrous acetonitrile (7.0 mL) at 0° C. was added anhydrous pyridine (7.00 mL) followed by dropwise addition of HF.Pyridine (3.1 mL, 1 mL/100 mg). The reaction stirred at 0° C. for two hours. It was diluted with ethyl acetate and slowly quenched with saturated sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography, eluting with 5% MeOH/CH2Cl2, yielded N-(3,5-bis(hydroxymethyl)phenyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-methyl-4-(methyldisulfanyl)pentanamide (267c) (190 mg, 89%). 1H NMR (400 Hz, CDCl3): δ 7.21 (s, 1H), 7.16 (s, 2H), 4.63 (s, 4H), 3.79 (t, J=5.2, 5.6 Hz, 2H), 3.53 (m, 6H), 3.48 (m, 4H), 3.29 (s, 3H), 2.53 (s, 2H), 2.27 (s, 3H), 2.07 (m, 2H), 1.84 (m, 2H), 1.08 (s, 6H); MS (m/z). found 498.2 (M+Na)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:20])([F:21])[F:19])=[O:43])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
60 mg of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 30 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 53mg of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.[Br:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](F)[CH:31]=1.Cl>CN1C(=O)CCC1.ClCCl>[Br:25][C:26]1[CH:31]=[C:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(F)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 120 °C

Procedure:
This example describes the procedure for conversion of (A1) to (A3) as shown in Scheme 1. Tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate was purchased from Small Molecules, Inc. (CAS: 365996-30-1, Hoboken, N.J.). DIPEA (18.5 mL, 106 mmol) and tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (17.7 g, 82.7 mmol) were added to 3-bromo-5-fluoropyridine-2-carbonitrile (Frontier Scientific; CAS: 950670-18-5, Logan, Utah) (16.4 g, 81.6 mmol) dissolved in NMP (16.3 mL) in a 150 mL sealed tube. The reaction was heated to 120° C. for 24 hours before cooling to ambient temperature. Hydrochloric acid (1.0 M in water, 100 mL, 100 mmol) was added. Dichloromethane was then added dropwise until a freely stirring suspension was formed. The precipitate was collected by filtration, washed with cold diethyl ether (30 mL), and dried under reduced pressure to afford a portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)-amino]cyclohexyl}carbamate. The mother liquors were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and water to yield an additional portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. MS ESI calc'd. for C17H24BrN4O2 [M+H]+ 395 and 397. found 395 and 397. 1H NMR (500 MHz, CD3OD) δ 8.02 (d, J=2.3 Hz, 1H), 7.23 (br s, 1H), 6.59-6.46 (m, 1H), 3.83 (s, 1H), 1.65 (s, 6H), 1.56-1.17 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 92 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 and tert-butyl piperidin-4-ylcarbamate gave tert-butyl (S)-{1-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperidin-4-yl}carbamate (yield 92%) a yellow oil in the same manner as in Example 277.
Reaction SMILES: C1(C)C=CC(S[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>>[C:18]1([S:24]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(Sc2c[nH]c3ccccc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21

Procedure:
The preparation of compounds in which L1 is --SO2 -- is shown in Scheme 7. According to Scheme 7, the desired substituted indole is reacted with p-tolyldisulfide and sulfonyl chloride in the presence of triethylamine to form 3-(p-tolylthio)indole 44. Reaction of 44 with phenylsulfonyl chloride and KOH gives 1-phenylsulfonylindole derivative 45 which is oxidized to 46 with H2O2 in acetic acid. Bromination of 46 with N-bromosuccinimide and benzoyl peroxide gives bromomethyl compound 47. Displacement of bromide with potassium bis(t-butyloxycarbonyl)amide and deprotection with trifluoroacetic acid followed by sodium carbonate gives benzyl amine 49. Reaction of 49 with ethoxynitropyridine 34, in which any one of A, B, C, or D is nitrogen, followed by reduction with iron and NH4Cl gives diamine 51 which is converted to imidazopyridine 52 as described in Scheme 3b. The desired final product 53 is then prepared as described in PCT/US92/05890 (international publication no. WO 93/1813). ##STR16##
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)(=[O:15])=[O:14]
Reactant: OC[C@@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Temperature: 2.5 °C
Yield: 78.4 %

Procedure:
To a solution of 6.7 g of (R)-glycidol (0.09 mol)(optical purity: 99.4% ee) and 50 ml of water, 0.17 g of N,N-dimethylaminopyridine (0.0014 mol) and 17.2 g of p-toluenesulfonyl chloride (0.09 mol) in 50 ml of toluene, and then 18.1 g of 24% sodium hydroxide (0.11 mol) were added under stirring at 0-5° C. And the solution was stirred for one hour. After separation with a separating funnel, the organic layer was washed with 50 ml of 1% hydrochloric acid and 50 ml of water. The excess solvent was removed under vacuo. The chemical purity by HPLC and optical purity at that time were 99.5%, 99.5% ee respectively. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 16.1 g of (S)-glycidyl tosylate (yield 78%). Chemical purity: 99.9%, Optical purity: 99.6% ee
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](OC2C=CC=CC=2)=[N:17][C:18]#[N:19])=[CH:11][CH:10]=1.CCOCC.CO.C(Cl)(Cl)Cl>C=C>[C:18]([N:17]=[C:16]([O:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[NH:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1)#[N:19]
Reactant: Nc1ccc(Cl)nc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: C=C
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#CN=C(Nc1ccc(Cl)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A stirred mixture of 5-amino-2-chloropyridine (1.3 g, 0.01 mol) and diphenylcyanocarbonimidate (2.4 g, 0.01 mol) in 15 ml of ethylene glycoldimethyl ether (DME), under nitrogen, was kept at 60° C. for 24 hours and at 85° C. for 6 hours when it was allowed to cool to room temperature. The solvent was removed in vacuo and the residue was heated to a melt at 120° C., under nitrogen, for 1 hour to complete the reaction as shown by TLC (5% MeOH/CHCl3). This was allowed to cool and was triturated with Et2O to give a solid that was collected by filtration. The solid was washed with Et2O to give 2.61 g of the titled product.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(OCC)(=O)C>C(Cl)(Cl)Cl.O>[CH3:20][S:21]([O:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0° C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z [M+H]+ 252.0
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]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=1>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: Cl
Product: C[C@@H]1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of (S)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one is introduced portionwise into 10 ml of concentrated hydrochloric acid while cooling with ice at 0° C. The solution obtained is treated slowly at 0° C. with 2 g of stannous chloride, stirred for 30 minutes while cooling with ice, poured into ice/sodium bicarbonate solution and extracted several times with methylene chloride. The organic phase is dried over sodium sulphate, filtered and concentrated. After crystallisation from ether, there is obtained (S)-7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one which crystallises with 1 mol of ether; melting point 100°-110° C. (with decomposition); [α]25D =+77.1° (in methylene chloride; 1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:31])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>COC(OC)N(C)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][N:18]([C:17]([C:16](=[O:31])[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][N:18]([CH3:23])[CH3:19])[CH2:19][CH2:20]1)=[O:25])([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)cc2OCc2ccccc2)CC1
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(F)cc1OCc1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2′-(benzyloxy)-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]4′-fluoroacetophenone (270 mg, 0.63 mmol) in dimethylformamide dimethylacetal (1.5 mL) was heated in a sealed microwave tube at 200° C. for 15 minutes. A white precipitate formed. The mixture was evaporated to dryness in vacuo to give crude 4-[1-(2-benzyloxy-4-fluoro-benzoyl)-2-dimethylamino-vinyl]-piperazine-1-carboxylic acid tert-butyl ester. Ethanol (2 mL) and hydrazine hydrate (2.0 mL) were added and the mixture heated in a sealed microwave tube at 120° C. for 30 minutes. The crude mixture was loaded onto a dry pre-packed silica cartridge and dried overnight. The product was eluted with 2:1 hexane:EtOAc to give 4-[3-(2-benzyloxy-4-fluoro-phenyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (95 mg, 33%) as a yellow gum; LCMS retention time 2.75 min, M+H+ 453.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:10]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=3)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:10]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cn2c(ccc3ccc(OC)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc3nc(C(=O)O)cn3c2c1
Temperature: 25 °C

Procedure:
1.35 g of ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were dissolved in 60 ml of ethanol and 2.5 ml of 2 N sodium hydroxide were added thereto. The mixture was refluxed for 1 hour whereupon a colorless gel was produced and after 3 ml of 2 N hydrochloric acid were added, and the mixture was refluxed for another 60 minutes and then was allowed to cool to room temperature. The cream precipitate thus formed was filtered off and was recrystallized from glacial acetic acid and then was washed with methanol to obtain off-white crystals of 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 272°-273° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([O:34][Si](CC)(CC)CC)[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[CH3:42][S-:43].[Na+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>C1(C)C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([S:43][CH3:42])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3c(F)cccc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reactant: C[S-]
Agent: I[Cu]I
Agent: [Na+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(SC)cc3C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-chloro-6-fluorophenyl)-1-[trans-3-(diethylamino)-cyclobutylmethyl]-4-trifluoromethyl-3-triethylsilyloxy-6-iodo-1,3-dihydro-2H-indol-2-one (200 mg, 0.276 mmol) in toluene (1.0 mL) were added sodium thiomethoxide (193 mg, 2.76 mmol), 1,10-phenanthroline (5 mg, 0.028 mmol) and copper iodide (5 mg, 0.028 mmol), and the mixture was stirred at 100° C. for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then filtered, concentrated and purified by silica gel column chromatography (chloroform/methanol=10/1). To a solution of the resulting oil in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (excess amount). The mixture was stirred at room temperature for 3 hours, and then the reaction solution was concentrated and purified by silica gel column chromatography (chloroform/methanol=10/1) to give the titled compound (122 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][C:10]1=[O:28])=[N:5]2.FC(F)(F)C1C=CC=CC=1CNC1C2C(N=C3C=1C(O)CCC3)=CC=CC=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:25])([F:27])[F:26])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH:10]1[OH:28])=[N:5]2
Reactant: O=C1CCCc2nc3cc(F)ccc3c(NCc3ccccc3C(F)(F)F)c21
Agent: OC1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(F)ccc3c(NCc3ccccc3C(F)(F)F)c21
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a cooled solution of 5.7 g of 3,4-dihydro-6-fluoro-9-(2-trifluoromethylbenzylamino)acridin-1(2H)-one in 80 ml of tetrahydrofuran was added 7.5 ml of 1 of molar solution of lithium aluminum hydride in THF. This was stirred for 0.5 hour and then quenched with 6 ml of saturated ammonium chloride solution. The inorganics were filtered, rinsed with ethyl acetate and the combined organics were dried over anhydrous magnesium sulfate. This was concentrated to a solid which was triturated with ether to give 5.1 g of a powder. This was twice recrystallized from ethyl acetate/hexane to give 3.1 g of analytically pure crystals, mp 149°-153° C.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH2:3][N:2]([OH:1])[C:17](=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Cl
Reactant: ONCc1ccc2c(c1)Cc1ccccc1-2
Product: CC(C)C(=O)N(O)Cc1ccc2c(c1)Cc1ccccc1-2

Procedure:
Using the method in Example 4, N-hydroxy-9H-fluorene-2-methanamine is reacted with isobutyryl chloride to give N-(9H-fluoren-2-ylmethyl)-N-hydroxy-2-methyl-propanamide as white crystalline solid. Yield 3.5 g (62%); mp 163°-166° C.