Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[N:9][C:8]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>N.CO>[NH2:13][C:10]1[CH:11]=[CH:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:17])[N:9]=1
Reactant: CCCCCCn1ccc(NC(C)=O)nc1=O
Agent: N
Solvent: CO
Product: CCCCCCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
N-(1-Hexyl-2-oxo-1,2 dihydropyrimidinyl)-acetamide (B) (0.100 g, 0.400 mmol) was dissolved in a 7 N solution of ammonia in MeOH (15 ml). The solution was stirred at room temperature in a sealed tube for 48 h. The solvents were removed under vacuo to afford a crude solid. Purification using flash silica chromatography (CHCl3/MeOH, 7:1) afforded 4-Amino-1-hexyl-1H-pyrimidin-2-one (C) as a colourless solid (0.052 g, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:10][C:11]1[CH:18]=[C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Temperature: 25 °C

Procedure:
4-Hydroxy benzaldehyde (1 equiv), 2-chloro-4-fluorobenzonitrile (1 equiv) and K2CO3 (2.5 equiv) in anhydrous DMF (0.2 M) were heated at 110° C. under nitrogen during 1 hour (the reaction can be monitored by tlc). After cooling down to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum (toluene was added to aid DMF evaporation). The crude mixture was purified by flash chromatography using hexanes/ethyl acetate (4:1) as eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:34])C=CC=CC=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16]([CH3:17])=[O:34])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.3 g, 3.45 mmol, prepared according to Example 8) was added to 50:50 dichloromethane/methanol (12 ml) followed by 2-benzenesulfonyl-3-phenyl-oxaziridine (1.08 g, 4.14 mmol). The mixture was stirred at 25° C. for 3.5 hours, evaporated to an oil and eluted through silica gel with chloroform. Fractions containing the product were evaporated to yield (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester as a solid (1.2 g, 89%). MS (APCI); M++1: Calc'd, 393.15. Found 393.1.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C[O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[NH:18][CH:19]1[CH2:25][CH:24]2[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]2)[CH2:20]1)[C:13]#[N:14].C(N(CC)C(C1C=CC2N(C3CC4N(CCC5C=CC=CC=5)C(CC4)C3)C3C(OC=2C=1)=C(OC)C=CC=3)=O)C>>[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[NH:18][CH:19]1[CH2:25][CH:24]2[N:26]([CH3:27])[CH:21]([CH2:22][CH2:23]2)[CH2:20]1)[C:13]#[N:14].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COc1cc(C#N)ccc1NC1CC2CCC(C1)N2C
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C2CCC1CC(Nc1ccc(C#N)cc1O)C2

Procedure:
Using an adaptation of Procedure 13, substituting the TFA salt of 3-methoxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile, 1p for the TFA salt of 6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 6e, the title compound 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile, 2p was obtained as TFA salt and as a mixture of endo and exo isomers after purification via reverse phase HPLC (eluent gradient: 20% to 45% CH3CN in water containing 0.1% TFA). MS m/z=258 (M+1).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH3:32])[C:25]([C:33]([O:35]C)=[O:34])=[CH:24][C:23]=5[C:22]4=[O:37])[CH2:17][CH2:16]3)[C:11]([O:38][CH2:39][CH3:40])=[CH:10][C:9]=2[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH3:32])[C:25]([C:33]([OH:35])=[O:34])=[CH:24][C:23]=5[C:22]4=[O:37])[CH2:17][CH2:16]3)[C:11]([O:38][CH2:39][CH3:40])=[CH:10][C:9]=2[C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(CC)c(C(=O)OC)cc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(CC)c(C(=O)O)cc3C2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (260 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (149 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[OH-].[Na+]>[Pd].CO>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(Oc3ccccc3)ccc(Cl)c2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(Oc3ccccc3)cccc2n1
Reaction time: 4.5 h
Yield: 101 %

Procedure:
A Parr bottle was charged with 8-chloro-2-methyl-5-phenoxyquinoline (0.93 g, 3.45 mmol), methanol (20 mL), and 3 M aqueous sodium hydroxide solution (3.79 mL, 11.38 mmol). The bottle was flushed with nitrogen, and 10% palladium on carbon (0.5 g, 0.470 mmol) was added. The mixture was then shaken under an atmosphere of hydrogen (30 psig). After 4.5 h, the mixture was filtered through a pad of Celite. The bottle and filter pad were rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was then partitioned between ethyl acetate and 5% aqueous sodium chloride solution (25 mL). The layers were separated, and the organic layer washed again with 5% aqueous sodium chloride solution (25 mL). The aqueous washes were extracted once with ethyl acetate, and the combined extracts were concentrated to afford crude 2-methyl-5-phenoxyquinoline (0.82 g, 101%) as a pale yellow-orange syrup which was used without further purification. MS (ESI, pos. ion) m/z 236 [M+1].
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([C:32]#[C:33][P:34]([O:61][CH3:62])([CH2:36][C@@H:37]([O:43][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35])=[C:30]([CH:63]([CH3:65])[CH3:64])[N:29]=[C:28]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[N:27]=2)=[CH:22][CH:21]=1.C(O)(=O)C>C1COCC1.CCOCC.CCOC(C)=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:31]([C:32]#[C:33][P:34]([O:61][CH3:62])([CH2:36][C@@H:37]([OH:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35])=[C:30]([CH:63]([CH3:65])[CH3:64])[N:29]=[C:28]([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)C[C@@H](CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
Tetrabutylammonium fluoride ((Bu)4NF) (1.0M in THF, 2.91 ml, 2.91 mmol) was added to a mixture of (S)-4-[[[4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-pyrimidinyl]-ethynyl]-methoxyphosphinyl]-3-((t-butyl)diphenylsilyloxy)-butanoic acid, methyl ester obtained in step (vi) above (0.709 gm, 0.97 mmol) and acetic acid (0.233 gm, 3.89 mmol) in THF (10 ml). The solution was allowed to stir for 20 hours at room temperature. The solution was diluted with ether and then washed with 5% KHSO4 (3x). The aqueous layers were back-extracted with EtOAc (3x). The organic layers were pooled and washed with brine, then dried over Na2SO4, filtered and concentrated to afford a yellow gum. The gum was redissolved in EtOAc, then washed with saturated NaHCO3, 5% KHSO4 and brine, then dried over Na2SO4 filtered and concentrated to a yellow oil. The oil was dissolved in methanol (15 ml) at 0° C. and treated with CH2N2. Excess CH2N2 was removed in a stream of argon, and the solution was concentrated to a yellow oil. The oil was purified by flash chromatography on Merck silica gel in 40% acetone in hexane. The desired fractions were pooled and concentrated to afford the title compound as a clear oil (0.315 gm, 64%). TLC: Rf =0.49 (50% acetone in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=O)=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)N4CCOCC4)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylic acid (200 mg) obtained in Example 5 is suspended in chloroform-pyridine (1:3) (8 ml) and thereto are added successively morpholine (68 mg), 1-hydroxybenzotriazole (79 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue is suspended in ethanol-diethyl ether. The precipitates are collected by filtration and dried to give the title compound (174 mg)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCc2ccccc2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)Nc1nc(C)cc(OCc2ccccc2)n1

Procedure:
Acetic anhydride (15.3 g., 0.15 mole) is added to a stirred suspension of 2-amino-4-methyl-6-benzyloxypyrimidine (23.6 g., 0.11 mole) in 150 ml of benzene. The mixture is heated at reflux for 4 hours. It is cooled, neutralized with aqueous sodium carbonate and the benzene layer separated. The benzene solution is concentrated under vacuum to an oil from which 2-acetamido-4-methyl-6-benzyloxy-pyrimidine melting at 121°-122° C. is isolated by crystallization from hexane n-butyl chloride.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[H][H].C[C@H]1CC(=O)[C@H](C(C)C)CC1.CC1CC(=O)C(C(C)C)CC1>[O-2].[Cr+3].[Cu+2]>[CH:9]1[C:10]([OH:11])=[C:4]([CH:2]([CH3:3])[CH3:1])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)=CCCC(C)CCO
Reactant: [H][H]
Agent: [Cr+3]
Agent: [Cu+2]
Agent: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Product: Cc1ccc(C(C)C)c(O)c1
Reaction time: 4 h
Yield: 5.1 %

Procedure:
Citronellol (156 g; 1 mole) and 7.8 g of a copper-chromium oxide catalyst (CuO:Cr2O3 = 50:50 by weight; mainly as CuCr2O4 ; less than 200 mesh, a product of Nikki Chemical Co., Ltd.) were charged into a pressure reactor, and reacted at 230° C under a hydrogen pressure of 2 kg/cm2.G. In about 4 hours, the evolution of hydrogen ended. The amount of hydrogen evolved was 24 liters. The catalyst was separated from the reaction product by filtration, and the residue was distilled under reduced pressure to afford 140 g of a fraction having a boiling point of 82° to 90° C/12 mmHg. This fraction was a mixture of menthone and iso-menthone in a ratio of 6:4 by weight. The theoretical yield was 90%. Also, 7.7 g of thymol boiling at 108° to 110° C/12 mmHg was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:12]=1[CH3:13])=[N+:8]([O-])[O:9][N:10]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2=[N:10][O:9][N:8]=[C:7]2[C:12]=1[CH3:13]
Reactant: COc1ccc2no[n+]([O-])c2c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2nonc2c1C

Procedure:
To a solution of 6-methoxy-7-methyl-2,1,3-benzoxadiazole 1-oxide (6.80 g, 37.7 mmol) in 150 mL of toluene was added PPh3 at one portion and the mixture was refluxed for 3 hours under Ar. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column to give the title compound.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])([OH:16])[CH2:12]2)C1C=CC=CC=1.ClC(OC(Cl)=O)C>CO>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:11]1([OH:16])[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: OC1(c2ccccc2Cl)CC2CCC(C1)N2Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: OC1(c2ccccc2Cl)CC2CCC(C1)N2
Yield: 54.3 %

Procedure:
8-Benzyl-3-(2-chloro-phenyl)-8-aza-bicyclo[3.2.1]octan-3-ol (0.30 g, 0.93 mmol) was dissolved in methanol (5 mL) and 1-chloroethylchloroformate (0.14 mL) was added. The mixture was heated at reflux for 6 hours and allowed to cool. The solvent was removed by evaporation under vacuum and the residue precipitated from ethyl acetate with ether to give a white solid (0.12 g, 56%). LCMS m/z 287.2 [M+H]+. R.T.=1.96 min (Analytical Method 4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[C:17]2[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:16]=2[O:15][C:14]1=[O:23])([O-:3])=[O:2].[N+](C1C=C([N+]([O-])=O)C=CC=1Cl)([O-])=O.ClC1C=CC2OC(=O)NC=2C=1>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]1=[O:23])([O-:3])=[O:2]
Reactant: O=c1oc2ccc(Cl)cc2n1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=c1[nH]c2cc(Cl)ccc2o1
Product: O=c1oc2ccccc2n1-c1ccccc1[N+](=O)[O-]

Procedure:
N-(2,4-dinitrophenyl)-5-chloro-2-benzoxazolinone by reaction between 2,4-dinitro-chlorobenzene and 5-chloro-2-benzoxazolinone. The product was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=O)C>Cl>[NH2:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 2.5 gm (9.2 mMol) 5-(N-acetylamino)-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 40 mL 2N hydrochloric acid was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, basified (pH~11) with 2N aqueous sodium hydroxide, concentrated under reduced pressure, and extracted well with 3:1 chloroform:isopropanol. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to provide 1.98 gm (93%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:13])[CH2:9][CH3:10])=[C:4]([F:27])[C:3]=1[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:29].Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH2:9][CH3:10])=[C:4]([F:27])[C:3]=1[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:29]
Reactant: CC[C@H](NC(=O)C1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H](NC(=O)C1CCCNC1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of tert-butyl 3-{[(1S)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}-propyl]carbamoyl}piperidine-1-carboxylate (220 mg, 0.44 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.44 mL, 1.75 mmol, 4 eq) and the reaction stirred for 18 h. The mixture was concentrated and then triturated with diethyl ether (˜5 mL) and the pale green solid filtered off and dried in a vacuum oven to give N-[(1S)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]piperidine-3-carboxamide as a white solid (80.0 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].Cl.[NH2:17][CH2:18][C:19]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:18][C:19]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: NCC1(O)CCCC1
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(NCC2(O)CCCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2), 1-(aminomethyl)cyclopentanol hydrochloride (J. Med. Chem. 1981, 24, 12-16) and triethylamine.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[NH:8]3)=[CH:4][C:3]=2[O:2]1.ClS([N:18]=[C:19]=[O:20])(=O)=O>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[N:8]3[C:19]([NH2:18])=[O:20])=[CH:4][C:3]=2[O:2]1
Reactant: O=C1Cc2cc3c(cc2N1)OCO3
Reactant: O=C=NS(=O)(=O)Cl
Product: NC(=O)N1C(=O)Cc2cc3c(cc21)OCO3

Procedure:
5,6-Methylenedioxy-2-oxindole-1-carboxamide was prepared by reaction of 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis, using the procedure of Example 3. The product melted at 237°-238° C. (dec.) after recrystallization from acetic acid.
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)=[C:13]([F:24])[CH:12]=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:36]([O:41][CH2:42][C@@H:43]1[O:45]C1)(=[O:40])CCC>>[F:17][C:15]1[CH:16]=[C:11]([N:10]2[CH2:9][C@H:42]([CH2:43][OH:45])[O:41][C:36]2=[O:40])[CH:12]=[C:13]([F:24])[C:14]=1[N:18]1[CH2:19][CH2:20][S:21][CH2:22][CH2:23]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1cc(F)c(N2CCSCC2)c(F)c1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1O[C@@H](CO)CN1c1cc(F)c(N2CCSCC2)c(F)c1
Yield: 73.7 %

Procedure:
N-(3,5-Difluoro-4-thiomorpholin-4-yl-phenyl)-carbamic acid benzyl ester (WO 0232857 A1; WO 0198297 A2) (31.5 g, 86.4 mmol), lithium biS(trimethylsilyl)amide solution (95 ml, 1 M in THF) and (R)-(−)-glycidyl butyrate (14.5 g, 79.7 mmol) were reacted as described for Intermediate 25 to give the crude title compound (19.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][C:39]1[NH:40][CH2:41][CH2:42][N:43]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:43]3[CH2:42][CH2:41][N:40]=[C:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1=NCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC1=NCCN1c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methyl-4,5-dihydro-1H-imidazole according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 1.63-1.70 (m, 9 H), 3.29 (t, J=5.5 Hz, 4H), 3.67 (t, J=8.8 Hz, 2 H), 3.83 (t, J=8.8 Hz, 2 H), 6.25-6.53 (m, 1 H), 6.77 (d, J=11.7 Hz, 1 H), 6.99 (d, J=8.0 Hz, 1 H), 7.25-7.31 (m, 2 H), 7.49-7.60 (m, 2 H), 7.88-7.93 (m, 2 H), 8.01 (d, J=8.0 Hz, 1 H), 8.17 (s, 1 H), 8.34-8.36 (m, 1 H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[Si:22]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-methyl 4-(hydroxymethyl)cyclohexanecarboxylate was dissolved in dichloromethane (30 mL), then imidazole (1.0 g) and tert-butylchlorodimethylsilane (1.6 g) were added. The reaction was stirred at room temperature overnight. The reaction mixture was then concentrated, dissolved in ethyl acetate and washed with 1N aqueous HCl, water, and brine. The organic layer was dried over Na2SO4. The title compound was obtained after filtration and concentration.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11](N)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.C(OCC)(=[O:17])C>C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=[O:17])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: CC(N)Cc1ccc2occc2c1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Cc1ccc2occc2c1
Yield: 91 %

Procedure:
This amine was dissolved in 20 mL ethyl acetate and then a 1 N solution of hydrogen chloride in diethyl ether was added dropwise. The resulting slurry was filtered, the solid washed with 3 mL ethyl acetate, and the solid dried under vacuum to provide 0.548 gm (91%) of the title compound.