Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(=O)(=O)C.[CH2:6]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[N:33][C:34]([Cl:40])=[C:35]([CH:39]=1)[C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:6]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:36]([C:35]2[C:34]([Cl:40])=[N:33][CH:32]=[C:31]([F:30])[CH:39]=2)=[O:37])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
cis-4-Amino-cyclohexanecarboxylic acid benzyl ester mesylate (5.34 g, 13.2 mmol) was dissolved in dimethylformamide (75 ml) and triethylamine (5.5 ml, 39.5 mmol) was added followed by 5-fluoro-2-chloronicotinic acid (2.31 g, 13.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.77 g, 14.5 mmol) and 1-hydroxybenzotriazole (1.96 g, 14.5 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (50 ml) and ethyl acetate (75 ml) and the aqueous phase was extracted with ethyl acetate (2×75 ml). The combined organic extracts were washed with water (2×20 ml), brine (20 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:pentane (1:1, by volume) to give cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid benzyl ester (2.14 g) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[C:4]([CH3:10])([CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].ClCCl>C1COCC1.CO>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][C:4]1([CH3:10])[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CC(N)CCC1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(NC(=O)OCc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a mixture of 4-amino-2,2-dimethylcyclohexanol (1.0 equiv.) in 1.7 M sodium carbonate solution (1.3 equiv.) and THF (1.3 M) was added benzyl chloroformate (1.5 equiv.) slowly at 0° C. After addition, the mixture was stirred at room temperature overnight. TLC (dichloromethane:MeOH=10:1) showed that the reaction was completed. The mixture was filtered and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give crude racemic product, which was purified by silica gel column chromatography (DCM:MeOH=20:1) to afford benzyl (4-hydroxy-3,3-dimethylcyclohexyl)carbamate (110 g, 49.4%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C=O)c1
Temperature: 85 °C
Reaction time: 0.58 h
Yield: 89.5 %

Procedure:
3-Hydroxybenzaldehyde (61 g) was added over 40 minutes to a suspension of sodium hydride (13.0 g) in dimethylformamide (700 cm3), the temperature of the reaction mixture being kept below 10° C. by means of a CO2 /oxitol bath. After stirring for 35 minutes, 1-bromobutane (73 g) was added dropwise over one hour and the mixture was then stirred at room temperature for 2.5 hours followed by heating at 85° C. for a further 2.5 hours. The resulting mixture was poured into ice water (1000 cm3) and was allowed to stand overnight before extracting with 40°-60° petrol/ether (3:1) (5×200 cm3). The combined organic layers were washed with 1M sodium hydroxide solution containing sodium chloride, dried over sodium sulphate, treated with activated charcoal, filtered and then evaporated down to give a golden brown mobile oil (79.7 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:41]=[CH:40]2.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Triethylamine (253 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (258 mg) in dichloromethane (15 ml), 6-chloronaphthalene-2-sulfonyl chloride (196 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (255 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[C:22]=1[Br:23].[C:24](Cl)(Cl)=[O:25]>ClCCCl.C1(C)C=CC=CC=1.ClC(Cl)C>[Br:23][C:22]1[C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:8][C@@H:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:24]=[O:25]
Reactant: O=C(Cl)Cl
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N=C=O)c2Br)N(C)C1=O

Procedure:
50 g (0.127 mol) of (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of 1,2-dichloroethane while warming and the still hot solution is added dropwise while stirring and cooling to a mixture of 90 ml (0.173 mol) of a 20 percent solution of phosgene in toluene and 500 ml of dichloroethane in such a manner that the temperature does not exceed 10°. The mixture is subsequently heated to boiling under reflux while stirring for 1 hour, 500 ml of 1,2-dichloroethane are distilled off, the solution is cooled to 10°, made basic with triethylamine and evaporated, there being obtained (S)-[6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate as a foam which can be stored for several days in a refrigerator with the exclusion of moisture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[S:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[CH:29]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(O)cc(C(F)(F)F)c3)cs2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(OCc4cccnc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (300 mg, 0.75 mmol) obtained in Example 86a, 3-pyridinemethanol (0.088 mL, 0.91 mmol) and triphenylphosphine (260 mg, 0.98 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (1.9M toluene solution, 0.51 mL, 0.98 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (370 mg, 100%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23]([CH3:24])=[O:33])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.0 mg (0.21 mmol) of the compound from Example 9 were introduced into 12 ml of dichloromethane at 0° C., 50.8 mg (0.21 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. It was concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 25 mg (30% of theory) of the title compound which are contaminated with meta-chlorobenzoic acid. It was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to result in 23 mg (29% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I.O>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]3[CH:6]=[N:7][N:8]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[C:9]=3[CH:10]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Yield: 30.1 %

Procedure:
To a stirred solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (5 g, 15.527 mmol) in DMSO (25 mL), 1-Boc piperazine (4.3 g, 23.3 mmol), K2CO3 (4.28 g, 31.05 mmol), CuI (0.295 g, 1.55 mmol) and L-proline (0.357 g, 3.1 mmol) were added in given order and resulting reaction mixture heated to 100° C. for 48 h. On completion, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain crude residue which was purified by column chromatography over silica gel affording methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-cyclopentyl-1H-indazole-4-carboxylate (2 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=O)[CH2:6][C:5]2([CH3:14])[CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH2:11])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)CN(N=O)c2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CN(N)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.03 g, 20.75 mmol) in THF (70 mL) at 0° C. is added a solution of LiAlH4 (40 mL, 40 mmol) in THF dropwise. The mixture is allowed to warm to rt and stirred overnight. The mixture is quenched with a saturated aqueous solution of Rochelle's Salt. The resulting mixture is stirred until a slurry is obtained. The organic phase is separated, washed with 10% aqueous HCl, saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 25% EtOAc in heptane to afford 5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (3.51 g, 94%) as an oil. MS: 181 (M+H). 1H NMR (300 MHz, CD3Cl)): δ 6.85-6.78 (m, 1H), 6.75-6.68 (m, 2H), 3.44 (br s, 2H), 3.14 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.), triphenylphosphine (52 mg, 2 eq.), and diisopropyl azodicarboxlyate (43 μL, 2 eq.) in order, and stirred at room temperature for 4 hr. The reaction solution was poured to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (37 mg, 76%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[C:5]([F:11])[C:4]=1[N+:12]([O-])=O.O.N.[ClH:17]>C(O)(=O)C.CCOCC.[Zn].C(OCC)(=O)C>[F:11][C:5]1[C:6]([F:10])=[C:7]([F:9])[CH:8]=[C:3]([NH:2][CH3:1])[C:4]=1[NH2:12].[ClH:17]
Reactant: CNc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNc1cc(F)c(F)c(F)c1N
Temperature: 20 °C

Procedure:
A solution of methyl(3,4,5-trifluoro-2-nitrophenyl)amine (0.5 g) in acetic acid (7.5 ml) is treated portionwise with zinc powder (793 mg). The reaction medium is stirred at ambient temperature (20° C.) until complete reduction. Water (13 ml) and 28% ammonia are added to pH 7, and then the reaction medium is depleted using ethyl acetate (3×50). The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is taken up in ether (50 ml) and then 2N HCl is added thereto. The solid formed is filtered off. 3,4,5-Trifluoro-N1-methylbenzene-1,2-diamine is isolated in its hydrochloride form (508 mg), and is used in the next stage.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[NH:16][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[N:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:25])[NH:26][CH:27]([C:28]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:15]1[NH:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:13][N:14]=1)=[O:29])[CH:31]([CH3:33])[CH3:32]
Reactant: Brc1ccc(-c2cnc(C3CCCN3)[nH]2)c2ccccc12
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
5-(4-bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-1H-imidazole (0.925 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.441 g), and HATU (1.00 g) were dissolved in anhydrous DMF (15 mL), and N-methylmorpholine (0.497 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and evaporated under vacuum. The oil was dissolved in DCM, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(4-bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27](O)=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.CO.CCOC(C)=O>[OH:28][CH2:27][C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(CO)c21
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of Example 598 (0.01 g, 0.022 mmol) in toluene (0.4 ml) under N2 was added thionyl chloride (0.1 ml) and heated at reflux for 3 h. The solution was concentrated using toluene to azeotrope and the residue was dissolved in dichloromethane (0.5 ml). To this solution was added NaBH4 (0.008 g, 0.22 mmol) in THF (0.5 ml) and stirred overnight. The mixture was diluted with MeOH (1 ml) and EtOAc, washed (0.1 N NaOH, H2O, and brine), dried (MgSO4), filtered, and concentrated to give the title compound (0.005 g, 53%) without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=C)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:30]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=C(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(=O)c3ccccc3)cc21
Yield: 65 %

Procedure:
To a solution of 3,3-dimethyl-6-(1-phenyl-vinyl)-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (914 mg, 2.6 mmol) in THF (10 mL), acetone (5 mL) and water (5 mL) was added NaIO4 (2.8 g, 13.05 mmol), then OsO4 (2 mL of 4% solution in water, 0.3 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, water (20 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by column chromatography on silica, eluted with petrol-EtOAc 0-40% to afford the title compound (654 mg, 65%). MS: [M+H]+=353.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([Cl:13])=[C:6]([O:11][CH3:12])[C:7]=1[N+:8]([O-])=O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:6]([O:11][CH3:12])=[C:5]([Cl:13])[N:4]=[C:3]([C:14]([O:16][CH3:17])=[O:15])[C:2]=1[Cl:1]
Reactant: COC(=O)c1nc(Cl)c(OC)c([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(OC)c(N)c1Cl
Temperature: 70 °C
Yield: 93.9 %

Procedure:
To methyl 3,6-dichloro-5-methoxy-4-nitropyridine-2-carboxylate (0.300 g, 1.06 mmol) in 5 mL of ethyl acetate was added SnCl2×2H2O (1.60 g, 7.1 mmol). The reaction mixture was heated to 70° C. for 30 min and then cooled to room temperature. Saturated sodium bicarbonate and a saturated solution of KHF2 were added to reaction mixture. The mixture was extracted with ethyl acetate and the layers were separated. The aqueous layer was washed 2 more times with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated to dryness to give 0.250 g of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([NH:15][C:16](=O)[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N-:50]=[N+:51]=[N-:52].[Na+]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([N:15]2[C:16]([CH3:17])=[N:52][N:51]=[N:50]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(NC(C)=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
To a suspension of 5.54 g (16.1 mmoles) of ethyl 3,3-bis(4-fluorophenyl)-2-(acetylamino)-2-propenoate and 9.3 g of triphenylphosphine in 120 mL of dry acetonitrile at room temperature was added dropwise 6.82 mL of carbon tetrachloride. The pale suspension was stirred for 45 minutes. To this clear orange solution was added 2.3 g of sodium azide and 0.6 g of tetra n-butyl ammonium bromide and stirring was continued. The orange suspension soon became pale with the formation of a white precipitate. After 3 hours, the mixture was filtered and the solution was concentrated under reduced pressure. More triphenylphosphine oxide was removed and the desired product was purified by crystallizations from ethyl acetate-hexanes to give 5.3 g (88%) of the title compound; m.p.=102.9°-103.5° C.