Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:18]([N:19]=O)=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:15]=1)=[O:13])[CH3:10].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.O>[CH2:9]([O:11][C:12]([C:14]1[C:18]([NH2:19])=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N

Procedure:
The product obtained from the last step was dissolved in 200 ml of ethyl acetate and 200 ml of water. Sodium dithionite was added until the disappearance of 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylic acid ethyl ester was confirmed by TLC (ethyl acetate/hexane, 50/50). Then the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo. The red solid obtained was further purified by plug filtration (silica, ethyl acetate/hexane, 50/50) to give 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4a (21.86 g, 76%). MS: 376.1 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)#[N:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.CC(C)=O.O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]3[N:11]([C:12](=[O:13])[C:3]=2[C:1]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7]3)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c(=O)n2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(N)cc2)c(C#N)c(=O)n2ccccc12
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 100 mg of 3-cyano-1-ethoxycarbonyl-2-(4-nitrophenyl)-4H-quinolizin-4-one (S-20) in 10 ml of ethanol and 5 ml of acetone was added dropwise a solution of 240 mg of sodium hydrosulfite in 5ml of water during 10 minutes. The reaction mixture was heated under reflux for 1 hour and poured into ice-water. The solution was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from methanol to obtain 40 mg of 2-(4-aminophenyl)-3-cyano-1-ethoxycarbonyl-4H-quinolizin-4-one.
Reaction SMILES: C(=[N:8][CH:9]([P:23]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>C(OCC)C>[NH2:8][CH:9]([P:23]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(N=Cc1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCCCC1
Product: NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of p-nitrobenzyl N-benzylidene-α-aminodiphenylphosphonoacetate (16.43 g) in ethyl ether (100 ml) is added dropwise over 30 minutes to a stirring solution of p-toluenesulfonic acid monohydrate (6.48 g) in ethyl ether (150 ml). Cyclohexane (100 ml) is added to the mixture and the solvents are decanted from the precipitate. The precipitate is washed with more 2:1 ethyl ether-cyclohexane which is again decanted off. The precipitate is treated with 1 M aqueous dipotassium hydrogen phosphate (60 ml) and extracted with four portions of methylene chloride. The methylene chloride solution is dried over magnesium sulfate, filtered, and evaporated to give p-nitrobenzyl α-aminodiphenylphosphonacetate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc2ccccc2c1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: COc1ccc(COc2ccc3ccccc3c2C(c2ccccc2)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 and 5 from 2-naphthol, benzylidene-dimethyl-ammonium chloride and 4-methoxybenzyl chloride. The structure was demonstrated by means of ESI-MS: mass calculated 397.52 g/mol. mass found M+H=398.0.
Reaction SMILES: C(OC(=O)[N:7](C(=O)C)[C@H:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[CH2:9]1)(C)(C)C.C([Li])CCC.C(O)(=O)C>CO.CCCCCC>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][C@H:10]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Agent: [Li]CCCC
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.32 mmol) of (2R*,4S*)-N-acetyl-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-nitro-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester is added in 5 ml of methanol to a solution, stirred under an inert gas, of 0.04 ml (0.06 mmol) of n-butyllithium in hexane (1.6 M). After 1 hour, 5 mg (0.08 mmol) of acetic acid are added and the mixture is concentrated to dryness by evaporation. The residue is taken up in 2 ml of methylene chloride and 1.2 ml of trifluoroacetic acid and the mixture is stirred for 2.5 hours at room temperature. The mixture is diluted with methylene chloride and washed with 2 N sodium hydroxide solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness. The title compound is obtained in the form of a beige foam. TLC: dichloromethane/methanol/conc. ammonia (90:9:0.5) Rf =0.38. 1H-NMR (200 MHz, D2O): rotameric mixture; δ: 8.28-8.08 (m, 2H), 7.94-7.79 (m, 1H), 7.60-7.40 (m, 2H), 7.21-7.02 (m, 2H), 5.40-5.22 (m, 0.5H), 4.85-4.68 (m, 0.5H), 4.00-3.86 (m, 0.5H), 3.56-3.00 (m, 3H), 2.82-2.70 (m, 0.5H), 2.20-1.86 (m, 2H), 1.6-1.2 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].Cl[CH2:16][CH2:17][O:18]C1CCCCO1>>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH2:16][CH2:17][OH:18])[C:3]1=[O:13]
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: ClCCOC1CCCCO1
Product: COc1ccc2c(c1)C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3-dimethyl-5-methoxy-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=1[N:46]=[C:47]=[O:48]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:47]([NH:46][C:40]2[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:39]=2[F:38])=[O:48])[CH:32]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cc(C)ccc3F)c2)c1
Yield: 93.8 %

Procedure:
The reaction solution of dimethyl 5,5′-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate (140 mg, 0.265 mmol, 1.0 equiv.) and 2-fluoro-5-methylphenyl isocyanate (38.8 μL, 0.292 mmol, 1.1 equiv.) in DMF (3 mL) was stirred at room temperature for 3 hours. It was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:5 to 5:1) yielding the title compound as clear oil (169 mg). 1H NMR (DMSO-d6) δ: 9.14-9.15 (m, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.54 (d, J=2.3 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.81 (t, J=−1.8 Hz, 1H), 7.40 (dt, J=7.7, 1.9 Hz, 1H), 7.30-7.35 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 7.00 (br. s., 2H), 6.79-6.83 (m, 1H), 3.52-3.64 (m, 10H), 2.39 (t, J=7.3 Hz, 4H), 2.27 (s, 3H), 1.72-1.85 (m, 4H), 1.65-1.71 (m, 4H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reaction time: 3 h

Procedure:
3-Amino-2,4-dichloro-benzylamine (2.28 g, 11.9 mmol) is added to a mixture of 2,2-dimethylpropionic acid chloride (1.47 mL, 11.9 mmol) and TEA (4.14 mL, 29.8 mmol) in THF (90 mL) and it is stirred for 3 h. The reaction mixture is concentrated, diluted with EtOAc, washed with 5% aq. NaHCO3 solution and water, dried with Na2SO4 filtered and concentrated to give the sub-title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)#[N:15]>>[O:13]=[C:9]1[NH:10][CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:19][C:18]3[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=3)[C:14]#[N:15])[CH2:3][CH2:2]2)=[CH:8]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: N#Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
3-[4-(6-Oxo-1,6-dihydro-pyrimidin-4-yl)-piperazin-1-ylmethyl]-benzonitrile was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-cyanobenzaldehyde. Mass spectrum (ES) MH+=296.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20].Cl>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(OS(=O)(=O)c2nc[nH]n2)c(C)c1

Procedure:
4.1 g of 2,4,6-trimethylphenol was dissolved in 15 ml of dichloromethane, and 4.2 ml of triethylamine was added while stirring the solution. Further, 4.6 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while being cooled with ice and stirred. Then, the solution was stirred at room temperature for 14 hours. After that, 2N hydrochloric acid was added to separate the components. The organic layer was washed with water, and then it was dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 3.0 g of the titled compound was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@H:36]4[OH:48])=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O=[C:12]([CH2:18][CH3:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:18]([C:12]1[O:3][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccccc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of phenacyl bromide (10 g) and methyl 3-oxopentanoate (6.5 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (7.5 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (1.9 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (6.7 g, 58%) as an oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Cl:13][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CC([O-])=O.[Na+]>OS(O)(=O)=O.CC(O)=O.O>[Cl:13][CH2:14][C:15](=[O:22])[CH:16]([N:1]=[N:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[F:5])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccccc1F
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(N=Nc1ccccc1F)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of NaNO2 (0.96 g) in conc. H2SO4 (4 mL) was added to a solution of 2-fluoroaniline (1.52 g) in AcOH (23 mL) at 0° C., and the mixture was stirred for 1 hour at 0° C. The reaction mixture was added to a solution of ethyl 4-chloro-3-oxobutanoate (2.16 g) in a mixture of AcOH (10 mL) and H2O (20 mL) at 0° C. and the reaction mixture was stirred for 15 minutes at 0° C. A solution of NaOAc (12.2 g) in H2O (20 mL) was added to the reaction mixture at 0° C., and the reaction mixture was stirred for 1 hour at room temperature to produce a precipitate. The precipitate was collected by filtration and washed with H2O to yield 2.75 g of the title compound. AcOH and NaOAc means acetic acid and sodium acetate, respectively.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])([CH2:7][F:8])[CH2:5][F:6].[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO>[F:8][CH2:7][C:4]([NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@@H:15]3[CH2:27][C@@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)[N:19]=1)=[O:11])([CH2:5][F:6])[CH2:3][OH:2]
Reactant: COC(=O)C(CF)(CF)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC(CO)(CF)CF)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 2-{[(1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-2-fluoromethyl-propionic acid methyl ester (130 mg, 0.316 mmol) in THF (2 mL) and MeOH (0.200 mL) was added sodium borohydride (23.94 mg, 0.633 mmol). The reaction was stirred at 23° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added. The mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound (106 mg) as a white solid. LCMS m/z=383.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.6, 3.5 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 2.25-2.31 (m, 1H), 2.80-2.85 (m, 1H), 2.89 (d, J=16.9 Hz, 1H), 2.99 (dd, J=16.6, 6.3 Hz, 1H), 3.96 (d, J=5.9 Hz, 2H), 4.25 (t, J=6.8 Hz, 1H), 4.55-4.84 (m, 4H), 7.23 (dd, J=5.3, 1.8 Hz, 1H), 7.27 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36](O)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(NC(C)C)(C)C.[CH2:50]([NH2:55])[CH2:51][CH:52]([CH3:54])[CH3:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CCOC(C)=O>[CH2:50]([NH:55][C:36]([C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:39])([CH2:18][CH2:19]2)[C@@:16]2([CH3:40])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:42])([CH3:41])[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1)=[O:37])[CH2:51][CH:52]([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (358.0 mg, 0.625 mmol) in THF (10 mL) was added N,N-diisopropylamine (0.327 mL, 1.875 mmol), isoamylamine (0.110 mL, 0.937 mmol) and HATU (356 mg, 0.937 mmol). The reaction mixture was stirred at 25° C. After 16 h, the reaction mixture was diluted with EtOAc (50 mL), washed with 1N HCl (5 mL), 5% NaHCO3, brine, dried over MgSO4, filtered and concentrated to a foam product. The residue was absorpted on to 4 g of silica gel, loaded on to a silica gel column (40 g cartridge) and eluted with 0% B to 50% B for 240 mL then 50% B (solvent: A=hexanes, B=5:1 hex:EtOAc) to afford the title compound as a white solid (229 mg, 0.342 mmol, 54.8% yield). LCMS: m/e 642.6 (M−H)+, 3.24 min (method 5); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.9 (2H, m, J=8.2 Hz), 7.2 (2H, m, J=8.5 Hz), 5.6 (1H, t, J=5.6 Hz), 5.3 (1H, dd, J=6.3, 2.0 Hz), 4.8 (1H, d, J=2.1 Hz), 4.6-4.6 (1H, m), 3.9 (3H, s), 3.3-3.4 (1H, m), 3.2-3.3 (2H, m), 2.5-2.6 (1H, m), 2.1 (1H, dd, J=17.1, 6.4 Hz), 2.0-2.1 (1H, m), 1.9-2.0 (1H, m), 1.8 (2H, dd, J=11.7, 7.5 Hz), 1.7 (3H, s), 1.6-1.7 (2H, m), 1.6 (1H, s), 1.6 (1H, dd, J=13.3, 2.6 Hz), 1.4-1.5 (11H, m), 1.2-1.3 (2H, m), 1.1 (1H, dd, J=12.5, 4.6 Hz), 1.0 (6H, s), 1.0 (3H, s), 1.0 (3H, s), 0.9 (3H, s), 0.9 (6H, d, J=2.4 Hz); 13C NMR(CHLOROFORM-d) δ ppm 14.4, 15.6, 16.2, 19.3, 19.5, 20.7, 21.1, 22.2, 22.3, 25.5, 25.7, 29.2, 30.6, 33.4, 33.6, 36.0, 37.2, 37.7, 38.2, 38.5, 40.3, 41.5, 42.2, 46.5, 49.3, 49.9, 51.7, 52.6, 55.4, 65.6, 109.0, 123.9, 127.6, 128.2, 129.8, 145.9, 148.5, 150.8, 167.0, 175.6.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 86.9 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL), methanesulfonyl chloride (0.77 mL, 0.01 mol) was added dropwise at 0-5° C. with stirring. The reaction mixture was stirred overnight at room temperature, and then diluted with water. The resulting solid was filtered and dried to afford N-[3-(quinoxalin-2-yl)phenyl]methanesulfonamide (2.6 g, 87% yield). LCMS calculated for C15H13N3O2S (M+H): 300.07. found 300. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.01 (1H, br. s), 9.50 (1H, s), 8.20-8.00 (4H, m), 7.95-7.70 (2H, m), 7.60-7.52 (1H, m), 7.48-7.40 (1H, m), 3.04 (3H, s).
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH:22]1([Mg]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=3)=[CH:9][CH:10]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(C(F)(F)F)on2)cc1)C1CCCCC1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide (Preparative Example 15, 300 mg, 1.0 mmol) in THF (10 mL) was treated with a 1 N THF solution of cyclohexylmagnesium bromide (4 mL, 4 mmol) and stirred for 2 hr then quenched with a saturated ammonium chloride solution (2 mL) and diluted with EtOAc (10 mL). The organic layer was then washed with brine (2×10 mL), dried over MgSO4, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (81 mg, 25%). 1H NMR (CDCl3) 1.26-1.58 (m, 5H), 1.74-1.94 (m, 5H), 3.23-3.32 (m, 1H), 7.09 (s, 1H), 7.79 (d, J=8.3, 2H), 7.87 (d, J=8.3, 2H). 19F NMR −64.6. LC/MS 7.79 min, [M+1]+ 324.