Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[NH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:29][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethyl-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.70 (1H, s), 10.37 (1H, t, J=6 Hz), 8.47 (1H, d, J=1.5 Hz), 7.67 (1H, dd, J=9.3, 2.4 Hz), 7.59-7.51 (2H, m), 7.30 (1H, s), 4.72 (1H, t, J=5 Hz), 4.30 (2H, s), 3.23 (2H, d, J=6 Hz), 3.16 (2H, d, J=5 Hz), 0.83 (6H, s); HRMS calcd for C22H21F4N3O4+H+: 468.1546. Found: 468.1558.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=O)=O)C.S(=O)(=O)(O)O.O>C(O)C>[CH3:1][N:2]1[C:7](=[O:6])[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[CH:14]=[N:3]1
Reactant: CCOC(=O)c1cc[nH]c1C=O
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1ncc2[nH]ccc2c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of methylhydrazine (4.84 g) and 3-ethoxycarbonyl-2-formylpyrrole (3.34 g) in ethanol (30 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was further refluxed for 19 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=19:1) to provide the title compound as white powder (1.81 g; yield 61%). 1 H-NMR (DMSO-d6) δ: 3.68(3H,s), 6.65(1H,d,J=2.8Hz), 7.42(1H,t,J=2.8Hz), 8.17(1H,s), 12.02(1H,m).
Reaction SMILES: [H-].[Na+:2].[CH3:3][C:4]([CH3:33])([CH3:32])[C:5]#[C:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH:8]=1.[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42](Cl)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[OH-].[Na+]>CN(C=O)C>[N:34]1([C:38]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([O:31][CH:28]3[CH2:29][CH2:30][CH:25]([N:15]([C:9]4[CH:8]=[C:7]([C:6]#[C:5][C:4]([CH3:32])([CH3:3])[CH3:33])[S:11][C:10]=4[C:12]([O-:14])=[O:13])[C:16]([CH:18]4[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH2:26][CH2:27]3)[CH:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1.[Na+:2]
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(O)CC2)CC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(C(=O)N4CCC4)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 77 %

Procedure:
NaH (60 mg of a 60% oil dispersion, 1.50 mmol) was added in portions to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (130 mg, 0.291 mmol) and azetidin-1-yl-(2-chloro-pyridin-4-yl)-methanone from the previous step (290 mg, 1.47 mmol) in DMF (3.0 mL) at 0° C. After 30 min the reaction was warmed to room temperature and then heated at 85° C. for 3.5 h. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a solid residue. The solid was purified by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water). Fractions containing product were pooled and lyophilized to give the desired product as a colorless solid (140 mg, 77%). HPLC retention time: 6.41 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[C:15]([Br:20])[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Br:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[C:17]([Br:19])[N:16]=1
Reactant: O=C(NC(=S)Nc1cc(Br)nc(Br)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)nc(Br)c1
Temperature: 62.5 °C
Yield: 87.1 %

Procedure:
To a solution of 1-benzoyl-3-(2,6-dibromo-pyridin-4-yl)-thiourea (1.0 g, 2.14 mmol) in THF (50 mL) was added NaOH solution (0.48 in 20 mL H2O) at room temperature. The reaction mixture was heated up to 60-65° C. overnight. After completion of reaction (TLC monitoring) THF was distilled off followed by addition of water, and extraction with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was washed with mixture of ethyl acetate:hexane (30:70) and dried under high vacuum to get the desired product as a white solid (0.58 g, 78%).
Reaction SMILES: [OH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([O:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1c(Cl)cccc1C(=O)O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
To a mixture of 2-hydroxy-3-chloro-benzoic acid (5.0 g, 29.0 mmol) in acetic anhydride (9.0 mL, 95.6 mmol) was added conc. H2SO4 (0.44 mL) at rt. Resulting suspension was heated in a 100° C. oil bath for 40 min. After cooled to about 50° C., the reaction mixture was poured onto ice (100 g) with stirring. Liquid was decanted off and the gooey residue was dissolved in methylene chloride, washed with water and brine, and dried over MgSO4. It was then filtered, and concentrated to give the title compound (5.89 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.99 (dd, J=7.8, 1.6 Hz, 1H), 7.66 (dd, J=7.8, 1.6 Hz, 1H), 7.28 (m, 1H), 2.39 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][O:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].C(O)C>[N:5]1[N:6]2[C:7]([CH2:8][O:9][CH2:10][CH2:11]2)=[CH:12][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc2n(n1)CCOC2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCOC2
Reaction time: 2 h
Yield: 73 %

Procedure:
A 500-mL Parr hydrogenation bottle was purged with nitrogen and charged with 129a (1.01 g, 5.92 mmol), 10% palladium on carbon (50% wet, 125 mg dry weight) and ethanol (50 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 25 psi and shaken for 2 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The catalyst was removed by filtration through a pad of CELITE® 521 and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography using 400 cc of silica gel and eluting with 3% methanol in methylene chloride. The fractions containing 129b were collected to afford, after concentrating under reduced pressure, a 73% yield (601 mg) of 129b as a yellow solid: mp 74-76° C. 1H NMR (300 MHz, CDCl3 δ 5.37 (s, 1H), 4.72 (s, 2H), 4.07 (t, 2H, J=5.1 Hz), 3.98 (t, 2H, J=5.1 Hz), 3.57 (br s, 2H); MS (ESI+) m/z 140.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](/[CH:13]=C/C3C=CC=CC=3)=[N:10][O:11][CH:12]=2)=[CH:4][CH:3]=1.[O:21]=[O+][O-].CSC>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:13]=[O:21])=[N:10][O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: Clc1ccc(-c2conc2/C=C/c2ccccc2)cc1
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: O=Cc1nocc1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
(E)-4-(4-Chlorophenyl)-3-styrylisoxazole (2 g, 7.1 mmol) was dissolved in DCM/MeOH (20 mL/2 mL) and cooled to −78° C. The reaction was placed under ozonolysis conditions (O3 bubbling) until full disappearance of starting material. DMS (8 mL) was added and the reaction was let warm to ambient temperature. After 15 h, the reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 208.0 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1

Procedure:
A suspension of (S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was hydrogenated over 10% palladium on carbon (0.41 g) at 55 psi of hydrogen, at 50° C., for 5 hours. The mixture was cooled, and the catalyst was removed by filtration. The solvent was evaporated in vacuo. The residue was dissolved in hot ethanol (30 mL) and treated with a saturated solution of hydrogen chloride in ethanol (3 mL). The product crystallized as the hydrochloride salt, 1.27 g (32%), a colorless solid. MS m/z 207 (MH+). 1H NMR(DMSO-d6) δ 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H), 4.31 (m, 1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.28; H, 6.06; N, 11.66.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[C:12]2=[S:26])=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:40]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]([CH:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17]4)[C:12]3=[S:26])=[CH:7][CH:8]=2)=[N:2][N:42]=[N:41]1
Reactant: N#Cc1ccc(CCn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: S=c1n(CCc2ccc(-c3nnn[nH]3)cc2)ccn1C1CCc2ccccc2C1
Temperature: 120 °C
Yield: 0 %

Procedure:
A mixture 3-[2-(4-cyanophenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), prepared as in Example 15, and tributyltin azide (1.39 g, 4.2 mmol) in 3 mL of xylene was heated at 120° C. under nitrogen for approximately 16 hours. The mixture was purified by chromatography on silica gel eluting with methylene chloride/methanol and the purified product was recrystallized from ethyl acetate/methanol to give 3-[2-(4(1H)-tetrazol-5-ylphenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 nmol), m.p. 218°-220° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(O[CH2:14][C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)CCC.P(Cl)(OCC)([O:29][CH2:30][CH3:31])=O>O1CCCC1>[C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:29][CH2:30][CH3:31])#[CH:14]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCCCOCC(=O)c1cccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C#Cc1c(OCC)ccc2ccccc12
Reaction time: 2 h
Yield: 71.1 %

Procedure:
Under a nitrogen atmosphere, 9.19 ml of 2 mol/l tetrahydrofuran solution of lithium diisopropyl amide was added dropwise to 3.3 g of 2-butoxyacetonaphthone at −78° C., and the mixture was stirred for 2 hours. After addition of 3.17 g of diethyl chlorophosphate, the mixture was stirred at room temperature for 1 hour. 2.65 ml of 2 mol/l tetrahydrofuran solution of lithium diisopropyl amide was added dropwise thereto at −78° C., and the mixture was stirred for 18 hours. The compounds obtained were extracted with added ethyl ether. The ethyl ether layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours and filtered, and the solvent was evaporated. The residue was subjected to column purification by using chloroform/hexane (1/4) as the developing solvent, to give 1.9 g of 1-ethynyl-2-ethoxynaphthalene.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]3)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.CCOC(C)=O>C1COCC1.CO>[F:30][C:26]1([F:29])[CH2:27][CH2:28][CH:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([S:12]([C:9]3[CH:8]=[CH:7][C:6]([C:5]([OH:31])=[O:4])=[CH:11][CH:10]=3)(=[O:14])=[O:13])[CH:16]=2)[CH2:25]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 93.1 %

Procedure:
Add aqueous sodium hydroxide (5N, 0.72 ml, 3 eq) to a solution of 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methyl ester (500 mg, 1.20 mml, 1 eq) in 5 ml THF, 2.5 ml MeOH. Stir reaction at room temperature for 2 hours. Remove solvent on rotovap and add 1N HCl and EtOAc. Extract products into organics, separate organics, and then dry organics with MgSO4. Filter off drying agent, and remove organics on rotovap to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid (450 mg, 92% yield) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4](F)[CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a suspension of 2-(4-chloro-2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 112-1) (0.38 g, 1.3 mmol) in acetonitrile (8 mL) was added 4-aminotetrahydropyran (0.30 g, 2.9 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered. The crystals obtained were purified by silica gel column chromatography to yield the title compound (0.10 g, 21% yield) as brown crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)=[O:21])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:6][C@@H:5]1[CH3:41])(=[O:3])[CH3:2].Cl>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH2:24][NH2:25])=[O:21])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:6][C@@H:5]1[CH3:41])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A solution of 1,1-dimethylethyl (2-{[(4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}phenyl)carbonyl]amino}ethyl)carbamate (for a preparation see Intermediate 45) (57 mg, 0.099 mmol) in 1,4-dioxane (0.5 mL) at room temperature was treated with hydrogen chloride in 1,4-dioxane (2 mL, 8.0 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was co-evaporated with Et2O to give 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}-N-(2-aminoethyl)benzamide (32.5 mg, 0.063 mmol, 64.1% yield) hydrochloride as a pale yellow solid. LCMS (HpH, 2 min), Rt=1.01 min, MH+=477.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH2:16][OH:17])=[C:9]4[CH:18]=[CH:19][N:20]=[CH:21][C:8]4=[C:7]([CH3:22])[C:6]=3[C:5]=2[CH:4]=1.CC(C)=O.[CH3:27][N:28]=[C:29]=[O:30].OCC1C2NC3C=CC=CC=3C=2C(C)=C2C=NC=CC=12>N1C=CC=CC=1>[CH3:27][NH:28][C:29](=[O:2])[OH:30].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:10]([CH2:16][OH:17])=[C:9]4[CH:18]=[CH:19][N:20]=[CH:21][C:8]4=[C:7]([CH3:22])[C:6]=3[C:5]=2[CH:4]=1
Reactant: CN=C=O
Agent: COc1ccc2[nH]c3c(CO)c4ccncc4c(C)c3c2c1
Agent: Cc1c2cnccc2c(CO)c2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)O

Procedure:
The above alcohol 36 was dissolved in dry pyridine and dry acetone and treated with methyl isocyanate as in the case of the carbinol 25. The mixture was stirred until no further alcohol 36 could be detected on thin layer chromatography. The solvents were evaporated and the residual solid was crystallized from ethyl acetate-methanol to give the desired carbamate 37.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[C:17]1([C:16]2[N:3]3[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]4[C:11]([C:2]3=[N:25][N:24]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Reactant: NNC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-chloroisoquinoline-4-carboxylate, prepared essentially according to procedures described in Example 1, part 4, (293 mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C. overnight. The mixture is cooled and poured into water. The solid is then collected by filtration and dried to give the title compound as a solid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS (ES+) m/e 304 [M+H]+. (The HPLC retention time is obtained by the method of Example 1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(Cl)Cl>O>[C:28]([NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 8a (0.7 g, 1.79 mmol) was converted to the corresponding free base by partitioning between 0.1M aqueous NaOH (200 ml) and diethyl ether (200 ml). The phases were separated and the aqueous phase was extracted twice with ether. The combined ethereal phases were dried and evaporated. The residue was dissolved in dry methylene chloride (20 ml). Acetic anhydride (0.22 g, 2.15 mmol) was slowly added with ice cooling. After completed addition the mixture was stirred for one hour at room temperature. Methylene chloride (50 ml) and water (50 ml) was added and the aqueous phase was separated. The organic phase was dried and evaporated and the crude product purified by column chromatography, first with methylene chloride, then with methylene chloride/methanol (19:1 ), as eluent. Yield 400 mg, mp 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([OH:19])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.[CH3:36]I.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:15][CH:16]=[C:17]([O:19][CH3:36])[N:18]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:26])[F:27])[O:11][N:10]=1
Reactant: CI
Reactant: Oc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1csc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3cccc(F)c3)c2C(F)(F)F)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 52 mg (0.1 mmol) hydroxyl thiazole (example 9) in 5 ml dioxane were added alternately in small portions 0.140 g (1.0 mmol) of CH3I and a solution of 40 mg (1.0 mmol) NaOH in 1 mL water. The pH has to be kept at 8-9 and the temperature at 40-50° C. Then the reaction mixture was stirred for 1 hour at 40-50° C., diluted with 15 mL water, neutralized with HCl to pH 6-7. Thick oil was extracted with CCl4, dried with MgSO4 and purified by column chromatography on silica gel, using CCl4, then CHCl3/CCl4 (1:1, v/v) as eluents. Yield of glassy substance of example 10 is 20 mg (37%). Result of LC/MS MH+: 539.03; 1H NMR (DMSO-d6; CCl4): 3.73 (3H, s, CH3), 6.59 (1H, s, CH-thiazole), 7.52-7.78 (7H, m, CH-arom.), 8.62 (1H, s, CH-pyraz.)
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-]>[Pd]>[F:13][C:9]1[CH:8]=[CH:7][C:6]([CH:4]([NH2:1])[CH3:5])=[N:11][C:10]=1[CH3:12]
Reactant: Cc1nc(C(C)N=[N+]=[N-])ccc1F
Agent: [Pd]
Product: Cc1nc(C(C)N)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A 250 ml round bottom flask containing 6-(1-azidoethyl)-3-fluoro-2-methylpyridine (Method 20; 567 mg, 3.15 mmol) was charged with 10% Pd/C (242 mg) and was evacuated and backfilled with H2 via a filled balloon. MeOH (6 ml) was added, and the mixture was allowed to stir at room temperature. After 1 hour, the mixture was filtered through a plug of diatomaceous earth, which was subsequently washed well with MeOH. The filtrates were concentrated to give the title compound as a pale yellow oil (404 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 1.41 (d, J=6.6 Hz, 3H), 2.05 (s, 2H), 2.50 (s, 3H), 4.14 (q, J=6.6 Hz, 1H), 7.13 (d, J=3.8 Hz, 1H), 7.28 (d, J=6.6 Hz, 1H).