Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.O>CS(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100° C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL×3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate. The solid was filtered and the filtrate, 10% Pd/C (100 mg) was added and the mixture was stirred under hydrogen atmosphere at ambient temperature overnight. The catalyst was filtered, and the filtrate was concentrated to afford tan solid 3.7 g. MS (m/z): 193 (M+H)+
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:8]([O:10][C:11]([N:13]=[C:14]=[S:15])=[O:12])[CH3:9].[O:16]1CCCC1>>[CH2:8]([O:10][C:11](=[O:12])[NH:13][C:14]([N:4]1[CH2:5][CH2:6][CH:7]([OH:16])[CH2:2][CH2:3]1)=[S:15])[CH3:9]
Reactant: CCOC(=O)N=C=S
Reactant: OC1CCCNC1
Reactant: C1CCOC1
Product: CCOC(=O)NC(=S)N1CCC(O)CC1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxypiperidine (1.0 g, 9.89 mmol) in tetrahydrofuran (50 ml) was added ethoxycarbonyl isothiocyanate (1.4 ml, 11.9 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes and then stirred overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:2) as the eluant to afford (4-hydroxypiperidine-1-carbothioyl)carbamic acid ethyl ester (2.3 g, yield 100%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC>O1CCOCC1>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([CH:26]=[CH2:27])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.5 g, 1.44 mmol) in 1,4-dioxane (10 mL) was added Pd(TPP)2Cl2 (0.101 g, 0.144 mmol) and tributylvinyltin (2.285 g, 7.20 mmol) under a nitrogen stream. Upon completion of addition, the reaction mixture was heated to reflux at 90° C. for 16 h. After this time, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% ethyl acetate, hexane) to yield 5-phenyl-N-(pyridin-2-ylmethyl)-2-vinylquinazolin-4-amine (0.38 g, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.22 (dd, 1H, J=4.8 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.75 (s, 1H), 7.70 (dt, 1H, J=2 Hz, 8 Hz), 7.45-7.56 (m, 5H), 7.20-7.28 (m, 3H), 6.72 (dd, 1H, J=10.4 Hz, 17.2 Hz), 6.64 (t, 1H, J=3.6 Hz), 6.56 (dd, 1H, J=1.6 Hz, 17.2 Hz), 5.67 (d, 1H, J=10.4 Hz), 4.62 (d, 2H, J=4.0 Hz). LCMS Method T: retention time 1.500 min; [M+1]=339.2; HPLC Method A2: purity 98.1%, retention time=8.74 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([CH2:10][N+:11]([O-])=O)[CH2:7][CH2:8][CH3:9])C.[H][H]>CO>[CH2:7]([CH:6]1[CH2:10][NH:11][C:4](=[O:3])[CH2:5]1)[CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Solvent: CO
Product: CCCC1CNC(=O)C1
Yield: 78.7 %

Procedure:
300 g (1.476 mol) of 3-nitromethyl-hexanoic acid ethyl ester (B) are diluted in methanol (500 ml). The mixture is transferred to an autoclave of 1 L. The reaction mixture is allowed to react at 55° C. under 50 bars of hydrogen pressure for 28 h. The catalyst is filtered on celite and washed with methanol. The filtrate is recovered with 500 ml of dichloromethane. Then, the solution is extracted with water (2×400 ml). The organic layers are dried with MgSO4, filtered and concentrated to afford an oil residue (177.12 g, HPLC purity=82.6%) which is purified by distillation (110° C., 7.10−2 mbar). 147.82 g of (C) are obtained (Yield=78.7%).
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27](S(C)(=O)=O)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)(=O)C.O.CN(C=O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:2]([NH:1][C:27]2[N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]([O:24][CH3:23])[N:26]=2)[C:3]([OH:5])=[O:4])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C(c2cccc(OC)c2)C(N)C(=O)O)c1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(C(c2cccc(OC)c2)C(Nc2nc(OC)cc(OC)n2)C(=O)O)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 34.1 %

Procedure:
2.20 g (7.3 mmol) of 2-amino-3,3-di(3-methoxyphenyl)propionic acid, 0.66 g (3.04 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.39 g (3.65 mmol) of sodium carbonate were introduced into a mixture of 16 ml of DMF and 16 ml of water and stirred at 80° C. for 10 hours. Water and ethyl acetate were then added to the reaction mixture. The aqueous phase was acidified with 6 normal hydrochloric acid and extracted three times with ethyl acetate. Drying with MgSO4 and concentration resulted in the crude product, which was chromatographed on silica gel with dichloromethane/methanol (50:1). 0.455 g (34.1%) of a white powder of melting point 58-66° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)CC=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:25]CC1.CCCCCC.[CH2:35]1C[O:38][CH2:37][CH2:36]1>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:35][CH:36]([OH:25])[CH2:37][OH:38])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(c1ccccc1)S(=O)(=O)c1ccc(Cl)nc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)c1ccccc1
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 1.3 g (4.2 mmol) of 6-chloro-N-phenyl-N-(prop-2-en-1-yl)pyridine-3-sulfonamide in 17 mL of a mixture (1/1) of tBuOH and water are added, at room temperature, 1.37 g (11.7 mmol) of NMO and 0.52 mL (0.04 mmol) of 2.5% OsO4 in tBuOH. Stirring is continued for 12 hours. The medium is then diluted with 200 mL of water and extracted with Et2O (2×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.14 g of 6-chloro-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-sulfonamide are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.C(OCC)(=O)C>CN(C=O)C.CCCCCC>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1cc(I)cn1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
To a stirred solution 4-iodo-1H-pyrazole (1.5 g, 7.7 mmol) in DMF (15 ml) was added potassium carbonate (3.2 g, 23.2 mmol) followed by drop wise addition of 2-fluoro benzyl bromide (2.56 g, 8.5 mmol) and stirred the reaction at RT for 15 h. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was diluted with ice water (150 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 2.25 g (96.56% yield) of 1-(2-fluorobenzyl)-4-iodo-1H-pyrazole.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[O:4].[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][N:21]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Reactant: C1=Cc2ccccc2NCc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C=Cc2ccccc21
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
6-(trifluoroacetamido)hexanoyl chloride (Clark et al., Chem. Soc. Perkin Trans. 1 2001:3312-3324) (0.984 g, 4.52 mmol) was added to a solution of 2 (0.75 g, 3.62 mmol) and pyridine (0.859 g, 10.86 mmol) in CH2Cl2 (approximately 10 ml) at room temperature, and stirred for 30 minutes. The reaction mixture was diluted with CH2Cl2 (approximately 20 mL), washed with water (2×30 mL), dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography (hexanes:ethyl acetate 2:3) to provide 1.064 g (2.56 mmol, 71%) of 3 as yellowish oil. 1H: δ 7.32-7.22 (m, 4H), 7.19-7.11 (m, 4H), 6.77 (d, J=13.2 Hz, 1H), 6.58 (d, J=13.2 Hz, 1H), 5.46 (d, J=14.8 Hz, 1H), 4.20 (d, J=14.8 Hz, 1H), 3.29-3.15 (m, 2H), 2.09-2.02 (m, 1H), 1.93-1.85 (m, 1H), 1.51-1.32 (m, 4H), 1.25-1.04 (m, 2H); 13C: 172.7, 157.5, 141.1, 136.1, 135.8, 134.8, 132.4, 131.8, 130.5, 128.5, 128.2, 128.1, 128.0, 127.3, 127.2, 117.5, 114.6, 54.8, 39.6, 34.3, 28.2, 25.9, 24.3; FIRMS (ESI+) m/z calcd for C23H24F3N2O2 [M+H]+ 417.1790. found 417.1783.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].[CH3:17]I>C(O)C.O>[CH3:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: CI
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cc3ccccc3cc2[nH]1
Yield: 122.3 %

Procedure:
20.0 g of 1H-naphth[2,3-d]imidazole-2-thiol and 4.0 g of sodium hydroxide were heated for 1 hour under reflux and in 150 ml of ethanol with 6.5 g of methyl iodide. The reaction solution was diluted with 500 ml of water and the precipitated product was suction filtered. Crystallisation from dioxane provided 12.0 g of 2-methylthio-1H-naphth[2,3-d]imidazole having a m.p. of 242°-244°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].Cl.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)CCC>[ClH:34].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:4][C:3]3[CH:5]=[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])[C:7]([CH3:9])=[CH:8][C:2]=3[F:1])=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CCCC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Yield: 94.9 %

Procedure:
2-Fluoro-5-methoxycarbonyloxy-4-methylaniline (883 mg, 4.4 mmol), (prepared as described for the starting material in Example 26), was added to a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (1 g, 3.7 mmol) in 2-pentanol (15 ml) at 120° C. and the mixture was then heated at reflux for 4 hours. The precipitate was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.65 g, 97%/) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[N:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:53][CH2:52][CH2:51][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: NCCN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN4CCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (56 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 40%).
Reaction SMILES: [CH2:1]([O:7][C:8]([CH:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCCCCCI)OCc1ccccc1
Reactant: CCCCCCOC(=O)C1CCCN1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)C1CCCN1CCCCCCC(=O)OCc1ccccc1

Procedure:
A solution of 1.99 g. (0.01 mol.) of 2-[(hexyloxy)-carbonyl]pyrrolidine obtained in Example 1, 3.45 g. (0.01 mol.) of benzyl 7-iodoheptanoate and 1.21 g. (0.012 mol.) of triethylamine in 10 ml. of benzene is heated at 50° for 16 hours. The cooled reaction mixture is washed with 5% aqueous sodium bicarbonate, saturated aqueous chloride, dried, and concentrated in vacuo to give an oil, 2-[(hexyloxy)carbonyl]-1-pyrrolidineheptanoic acid benzyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([N:18]=[C:19]=[O:20])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:19]([NH:18][CH:16]([CH3:17])[CH3:15])=[O:20])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 25 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 648 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 15 minutes and then 2-propylisocyanate (1.48 ml) was introduced dropwise via syringe. The reaction mixture was then stirred at 0° C. overnight. The reaction mixture was diluted with 300 ml of ethyl acetate. The reaction mixture was washed with 10% citric acid solution and brine. The organic extracts were dried and then concentrated in vacuo to yield 3.9 g of the title compound in sufficient purity to be used in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]([C@@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:28])[C:22]=3[C:23]([O:25]CC)=[O:24])=[CH:14][CH:13]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O>C1COCC1>[Cl:2][C:3]1[C:4]([N:9]([C@@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:28])[C:22]=3[C:23]([OH:25])=[O:24])=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCNC3)cc2)cnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCNC3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
EXAMPLE 6 Ethyl 4-(4-{(3-chloropyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1-methyl-1H-pyrazole-5-carboxylate hydrochloride salt (7.65 g, 15.2 mmol) was slurried in 50 mL THF followed by the addition of aqueous NaOH (1 mol/L, 50 mL, 50 mmol). Another 23 mL of water was added and the reaction stirred at room temperature for 1.5 h. THF solvent was removed in vacuo, then pH of residual aqueous phase was adjusted to pH 7 with 1 M aqueous HCl, resulting in precipitation of solids. The solids were collected via filtration and after drying afforded the hydrochloride salt of the title compound as an off-white solid (6.49 g, 97%).
Reaction SMILES: O.C([O-])(=O)C.[Na+].[CH3:7][N:8]([CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:9].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>C(OCC)(=O)C.C(O)(=O)C>[CH3:9][N:8]([CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: C=C(C)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(CN(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 5 l three-necked flask were placed 1 l of water and 225.5 g. of sodium acetate. After dissolution of the sodium acetate with stirring, the resulting solution was cooled on an ice bath and 375 g. of p-dimethylaminomethylaniline and 400 ml of acetic acid were added thereto. The resulting mixture was cooled until the temperature became below 10° C. To the cooled mixture was added dropwise 287.4 g. of methacrylic acid chloride gradually to the extent that the temperature in the flask might not exceed 10° C. After completion of the dropwise addition, the stirring was continued for 30 minutes at the same temperature, followed by further stirring for 2 hours without the ice bath. To the reaction mixture thus obtained were added 500 ml of ethyl acetate and a solution of 400 g. of sodium hydroxide in 600 ml of water and the resulting mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the ethyl acetate was removed by distillation. The residue was dissolved in 300 ml of benzene and poured into 3.2 l of cooled n-hexane to precipitate the desired product. White crystal mp.(melting point): 65.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:28][CH2:29][S:30](=[O:41])[CH2:31][CH2:32]3)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(c3nc(OCCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCc1ccc(C2CC(c3nc(OCCOC)no3)CN(C(=O)N3CCS(=O)CC3)C2)cc1
Yield: 25.6 %

Procedure:
60.0 mg (0.122 mmol) of the compound from Example 59 were reacted according to General Method 2 with 38.0 mg (0.110 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 33.9 mg of the racemate according to Method 7D gave 15.6 mg of the title compound from Example 60 (enantiomer 1) and 13.4 mg of the title compound from Example 61 (enantiomer 2).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C@H:9]1[CH2:29][C@@:28]2([CH3:30])[C@@H:20]([CH2:21][C@H:22]([CH3:37])[C@:23]2([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:24](=[O:27])[CH2:25][OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:39])[C:16]([CH2:17][CH2:18]2)=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]1.O.Cl>N1C=CC=CC=1>[C:1]([O:26][CH2:25][C:24](=[O:27])[C@:23]1([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C@:28]2([CH3:30])[C@H:20]([C@H:19]3[C@H:10]([C@@H:9]([Cl:8])[CH2:29]2)[C@:11]2([CH3:39])[C:16](=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]2)[CH2:17][CH2:18]3)[CH2:21][C@@H:22]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 3.5 h

Procedure:
Acetic anhydride (0.22 ml.) was added to a solution of 11β-chloro-21-hydroxy-17-isobutyryloxy-16β-methylpregna-1,4-diene-3,20 dione (71 mg.) in pyridine (1 ml.) at room temperature. After 3.5 hours, a little water was added and the solution was poured into dilute hydrochloric acid. Filtration of the precipitated solid and crystallization from methanol afforded the title compound, m.p. 204°-205° (K), [α]D + 95.2 (c 0.6 chloroform) λmax 240 nm (ε 15,450) (Found: C, 67.05; H, 7.4; Cl, 7.05, C28H37Cl O6 requires C, 66.6; H, 7.4; Cl, 7.0%).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cc(F)ccn2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cc(F)ccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-4-[(4-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 78) (36 mg, 0.069 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 2.5 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.06 mmol, 0.09 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-N-(4-fluoro-2-pyridinyl)-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (23 mg, 0.043 mmol, 62%) as a pale brown solid.