Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[C:14]([O:16]C)=[O:15])[CH3:9])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[C:14]([OH:16])=[O:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 33.3 %

Procedure:
To 500 mg of methyl (S)-2-[1-(4-fluorophenyl)ethylamino](pyrazin-2-ylamino) isonicotinate (Example 134), was added 5 ml of methanol, and 2.7 ml of 2N sodium hydroxide aqueous solution was added subsequently, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate and water, and subjected to extraction, and 2N hydrochloric acid was added to the aqueous layer. The precipitated solid was filtered, and dried under reduced pressure to obtain 160 mg of the objective compound as white powder.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)C3C=CC=CC=3)[C@H:12]([O:25][CH3:26])[CH2:11]2)=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[C@H:12]([O:25][CH3:26])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(CCCOc2ccc(F)cc2)CC[C@H]1NC(=O)c1ccccc1
Agent: Cl
Product: CO[C@@H]1CN(CCCOc2ccc(F)cc2)CC[C@H]1N
Temperature: 140 °C
Yield: 79 %

Procedure:
A mixture of 5.1 parts of trans-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]benzamide and 84 parts of a concentrated hydrochloric acid solution was stirred and refluxed for 22 hours in an oil-bath at 140° C. The reaction mixture was cooled, filtered and the filter-cake was washed with water. The filtrate was evaporated. The residue was taken up in 35 parts of water and the whole was treated with sodium hydroxide solution. The product was extracted three times with methylbenzene. The combined extracts were washed with a small amount of water, dried, filtered and evaporated, yielding 2.9 parts (79%) of trans-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine as a residue (intermediate 121).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[C:23]([CH:30]=O)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:30][C:23]3[C:22]([Cl:21])=[CH:26][N:25]([CH:27]([F:29])[F:28])[N:24]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde using decaborane yielded (S)-2-amino-6-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one as colorless solid. MS (ESI): m/z=443.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])[CH3:18]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 4-(bromomethyl)-3-nitrobenzoate (100 mg) in THF (5 mL) was added dimethyl amine (2 mL, 2 M in THF) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then removed to afford methyl 4-((dimethylamino)methyl)-3-nitrobenzoate which was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[K+].[O:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]1=[O:30].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[O:29]=[C:28]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:23]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCCCCCCc1cc2ccccc2[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCc1cc2ccccc2n1C(=O)CCCC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-undecyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture was dihydro-pyran-2,6-dione and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[CH3:33][S:34]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15])=[O:12])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2N)c1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2NS(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (1.7 g, 5.1 mmol), triethylamine (5.2 g, 51.3 mmol), and dichloromethane (85 mL) was added methanesulfonylchloride (0.90 mL, 11.3 mmol) in dichloromethane (75 mL) dropwise over 3 min. The solution was maintained at room temperature for 1 h and concentrated to remove all solvent. The residue thus obtained was dissolved in THF (51 mL) and tetrabutylammoniumfluoride (24 mL, 1.0 M in THF) was added in a steady stream via syringe. The solution was maintained at 60° C. for 18 h, concentrated and dissolved in ethyl acetate (75 mL). The solution was washed with water (5×50 mL), washed with brine (50 mL), dried over MgSO4, filtered and concentrated. Purification on silica gel (0-8% methanol/dichloromethane, 60 min gradient) afforded 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a pale yellow foam. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.42 (s, 1H), 8.64 (s, 1H), 8.56 (d, J=4.88 Hz, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=7.63 Hz, 1H), 7.71 (d, J=7.63 Hz, 1H), 7.58 (t, J=7.78 Hz, 1H), 7.49 (d, J=4.88 Hz, 1H), 7.40 (d, J=7.93 Hz, 2H), 7.29 (t, J=7.63 Hz, 2H), 7.17 (t, J=7.17 Hz, 1H), 2.85 (s, 3H), 1.69 (s, 6H). LCMS: retention time: 1.277 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 410 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CC(O)=O.[BH3-]C#N.[Na+].[Br:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH2:39][CH2:40][O:41][CH:42]2[CH:47]=O>C(Cl)Cl.CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:47][CH:42]2[C:43]3[C:38](=[C:37]([Br:36])[CH:46]=[CH:45][CH:44]=3)[CH2:39][CH2:40][O:41]2)[CH2:17][CH2:18]1
Reactant: Brc1cccc2c1CCOC2CN1CCNCC1
Reactant: O=CC1OCCc2c(Br)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Brc1cccc2c1CCOC2CN1CCN(CC2OCCc3c(Br)cccc32)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine (160 mg, 0.52 mmol) in DCM/MeOH (1:1, 5 mL) was added DIEA (134 mg, 1.03 mmol), and then mixture was stirred at r.t for 10 min. Then AcOH (62 mg, 1.03 mmol), NaCNBH3 (65 mg, 1.03 mmol) and 5-bromo-3,4-dihydro-1H-isochromene-1-carbaldehyde (125 mg, 0.516 mmol) were added into the mixture. The reaction solution was stirred at ambient temperature overnight. The reaction mixture was added water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to give the product 1,4-bis[(5-bromo-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]3([CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]3O)[CH2:15]1)=[O:13])[CH2:8]2>C(O)C.[OH-].[OH-].[Pd+2]>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]3([CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15]1)=[O:13])[CH2:10]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCCC2(Cc3ccccc3C2O)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCCC2(Cc3ccccc3C2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
To a solution of N-(2-adamantyl)-1-hydroxy-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide (20 mg, 0.052 mmol) in ethanol (3 mL) was added Pd(OH)2 (10 mg), then the reaction mixture was stirred for 4 h at rt under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated to give a residue, which was purified by preparative HPLC to afford N-(2-adamantyl)-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide (5 mg, 29%): LC-MS Method 5 tR=3.057 min, m/z=365.2; 1H NMR (CD3OD, 400 MHz): δ=1.55 (m, 2H), 1.66 (m, 2H), 1.78 (m, 7H), 1.84 (m, 7H), 2.69-2.83 (m, 4H), 3.21 (s, 2H), 3.45 (m, 2H), 3.77 (s, 1H), 7.09 (m, 2H), 7.14 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:10]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:9]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:36][N:34]([CH3:35])[C:33]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[NH:14][C:15]([C:17]1[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:7][CH2:6][NH:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)CNCCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(CCNCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a mixed solution of ({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]benzyl}methylamino)acetic acid methyl ester (120 mg) in THF (1 mL)-methanol (3 mL) was added 4N aqueous sodium hydroxide (0.2 mL) The mixture was stirred at 50° C. for 2 hours under heating, allowed to stand for cooling down to room temperature, and concentrated in vacuo. After addition of water to the residue, 1N hydrochloric acid was added portionwise to the aqueous solution under ice-cooling to adjust the pH to 6 to 7, followed by extraction with ethyl acetate four times. The extract was dried over anhydrous sodium sulfate and concentrated to give the title compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1.[OH-].[Na+].[I:24]I>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[C:12][I:24])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1
Reactant: II
Reactant: C#CCOc1cc(-n2nnn(CCC)c2=O)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1nnn(-c2cc(OCC#CI)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a cold solution of 0.5 g (0.00153 mole) of 1-[2,4-dichloro-5-(2-propynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one in 20 mL of methanol was added 2 mL of a saturated aqueous solution of sodium hydroxide and an additional 10 mL of methanol. To this mixture was added a solution of 0.39 g (0.00153 mole) of iodine in 5 mL of methanol. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered and a solid collected. The solid was purified by column chromatography to yield 0.14 g of 1-[2,4-dichloro-5-(3-iodo-2-propynyloxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a solid, mp 134°-138° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]1[C:17]([N+:27]([O-:29])=[O:28])=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[C:38](F)=[CH:39][C:40]([F:63])=[C:41]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:48][CH:49]=[N:50][N:51]=2)(=[O:45])=[O:44])[CH:42]=1>CS(C)=O>[Cl:36][C:37]1[C:38]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)=[CH:4][C:3]=2[C:16]2[C:17]([N+:27]([O-:29])=[O:28])=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:20]=2)=[CH:39][C:40]([F:63])=[C:41]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:48][CH:49]=[N:50][N:51]=2)(=[O:44])=[O:45])[CH:42]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: N#Cc1cccc(-c2ccc(O)c(-c3cn(C4CCCCO4)nc3[N+](=O)[O-])c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
4′-Hydroxy-3′-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)biphenyl-3-carbonitrile (Preparation 64, 250 mg, 0.64 mmol) was dissolved in DMSO (3.5 mL) and potassium carbonate (177 mg, 1.28 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 310 mg, 0.67 mmol). The reaction was stirred at room temperature for 1 hour and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (10% to 80% EtOAc in heptane over 12 CV) to give the title compound (451 mg, 85%) as a light yellow foam.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:46]([C:42]3[S:41][CH:45]=[CH:44][CH:43]=3)(=[O:48])=[O:47])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccs1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2cccs2)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and thiophene-2-sulfonyl chloride (137 mg) were added-dropwise and the mixture was further stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a colorless oil (yield 195 mg, 89%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([CH2:18][OH:19])=[CH:13][CH:14]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2ccc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under N2, to a solution of 2-phenylquinoline-7-carboxylic acid hydrochloride (144 mg, 0.5 mmol) in THF (5 mL) was added LiAlH4 (95 mg, 2.5 mmol) in two portions. The mixture was stirred at rt for 15 h, quenched with water (1 mL), and filtered through a Celite pad, which was washed with EtOAc (30 mL). The combined filtrates were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the desired product. 1H-NMR (CDCl3, 400 MHz) δ 4.93 (s, 2H), 7.46-7.57 (m, 4H), 7.84 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.14-8.18 (m, 3H), 8.23 (d, J=8.4 Hz, 1H). MS (ES+): m/z 236 [MH+]. HPLC: tR=2.72 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]([C:7]1[S:8][C:9](=[S:22])[S:10][C:11]=1[C:12]([O:15]C1CCCCO1)([CH3:14])[CH3:13])=[O:6])[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[C:5]1([OH:6])[O:15][C:12]([CH3:14])([CH3:13])[C:11]2[S:10][C:9](=[S:22])[S:8][C:7]1=2)[CH3:2]
Reactant: CCOC(OCC)C(=O)c1sc(=S)sc1C(C)(C)OC1CCCCO1
Solvent: ClCCl
Product: CCOC(OCC)C1(O)OC(C)(C)c2sc(=S)sc21
Reaction time: 12 h

Procedure:
10 mg (0.024 mmol) of 2,2-diethoxy-1-(5-(2-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl)-2-thioxo-1,3-dithiol-4-yl)ethanone 5 was dissolved in 5 mL of CH2Cl2 containing 0.1 mL CF3COOH. The reaction mixture was stirred for 12 hours, washed with 20 mL of saturated solution of NaHCO3 and, the organic layer was separated and dried in vacuum to yield the target compound 4 as a solid material. Yield: 7.2 mg (0.02 mmol, 90%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:11]([CH3:29])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)=[C:11]([CH3:29])[CH:10]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)c(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h

Procedure:
A suspension of the product of Example 51B (2 g, 4.1 mmol) and 10% palladium on carbon (200 mg) in methanol (100 mL) was stirred under hydrogen for 18 hours. The catalyst was filtered and the filtrate was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 1/1 petroleum ether/ethyl acetate to give the title compound. MS: 310 (M+H+).
Reaction SMILES: C(OCC)C.[F:6][C:7]([F:31])([F:30])[C:8]1[CH:9]=[C:10]([C:14]2[CH2:15][CH2:16][N:17]([C:20](=O)[CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1.[ClH:32]>O>[ClH:32].[F:31][C:7]([F:6])([F:30])[C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCC1CCCCC1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1cccc(C2=CCN(CCCC3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.152 mole of LiAlH(OCH3)3 and 60 ml of anhydrous diethyl ether at room temperature 0.038 mole of 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropionyl)-1,2,3,6-tetrahydropyridine and 50 ml of anhydrous diethyl ether are added in 30 minutes. The product is left for 2 hours with stirring at room temperature, then water is added, the ethereal phase is decanted, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The oily residue constituted by 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridine base, is dissolved in isopropanol and the solution thus obtained is acidified with hydrogen chloride. In this way is obtained the 4-(3-trifluoromethylphenyl)-1-(3-cyclohexylpropyl)-1,2,3,6-tetrahydropyridine hydrochloride which, after crystallization from acetone, melts at 219°-222° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[N+:24]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)=[CH:7][CH:6]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Temperature: 10 °C
Yield: 85.9 %

Procedure:
A solution of 2-benzyl-4-(4-pyridyl)thiazole (4.50 g, 0.018 mol) in chloroform (25 mL) was added dropwise to concentrated sulfuric acid (15 mL). The resulting mixture was cooled to 10° C. and fuming nitric acid (1.45 g, 0.97 mL) carefully added dropwise such that the reaction temperature did not exceed 40° C. The mixture was allowed to stir for thirty minutes, carefully neutralized with saturated sodium carbonate and the layers separated. The aqueous layer was reextracted with chloroform (2×25 mL) and the combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, and concentrated to afford a crude product (4.6 g). Several recrystallizations from hexane/ethyl acetate afforded pure 2-(p-nitrobenzyl)-4-(4-pyridyl)thiazole. mp. 140°-142° C.