Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:23][C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[N:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])=[N:15][CH:14]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: C1CCNCC1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])nc2)cc1C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])nc2)cc1C
Temperature: 85 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitrobenzamide (500 mg, 1.31 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), and piperidine (330 mg, 3.88 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 85° C. in an oil bath. The reaction was then quenched with 100 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum to give 550 mg (98%) of product as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)#[CH:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:2]
Reactant: [H][H]
Reactant: C#Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Yield: 95.7 %

Procedure:
A mixture of 0.34 g of 2-(3-ethynylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of 5% palladium on carbon and 8 ml of ethyl acetate was stirred under about one atmosphere of hydrogen at room temperature for two hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.33 g of 2-(3-ethylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 35”).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:33])=[CH:7][C:8]([F:32])=[C:9]([CH:31]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23]CC3C=CC=CC=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]>CO.ClC(Cl)Cl.CN(C=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([Cl:33])=[CH:7][C:8]([F:32])=[C:9]([CH:31]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1O
Yield: 83.3 %

Procedure:
A solution of 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinazoline (250 mg, 0.54 mmol) in methanol (5 ml), trichloromethane (5 ml) and DMF (1 ml) was stirred under hydrogen at 1 atmosphere with 5% palladium-on-charcoal catalyst (100 mg) for 4 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was dissolved in ethyl acetate, washed with water and brine, and dried (MgSO4). Most of the solvent was removed by evaporation, the mixture was cooled and hexane added to obtain solid product which was collected by filtration, washed with hexane/ethyl acetate and dried to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (170 mg, 45%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH3:36])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH3:36])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OC(F)F
Temperature: 70 °C
Yield: 20 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 3-bromomethyl-3-methyl-oxetane (122 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 20%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1>>[Cl:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(Cl)c3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Yield: 81.8 %

Procedure:
As described for example 91a, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (734 mg, 2.1 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, to the title compound (592 mg, 84%) which was obtained as a white solid. MS: m/e=343.4 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[I:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[I:12])[CH2:6][CH2:7][C:8]2=[O:11])[CH3:20]
Reactant: O=C1CCc2cc(I)c(O)cc21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc2c(cc1I)CCC2=O

Procedure:
A mixture of 6-hydroxy-5-iodoindan-1-one (6.36 g, 23.2 mmol), caesium carbonate (15.12 g, 46.4 mmol) and ethyl4-bromobutyrate (9.05 g, 46.4 mmol) in acetone (60 ml) is heated at reflux pendant 1 hour 15 minutes.
Reaction SMILES: [C:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]1([C:38](N2C=CN=C2)=[S:39])C=CN=[CH:34]1.CN>C1COCC1.C(Cl)Cl>[C:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:27]=[CH:28][C:29]([NH:30][C:38]([NH:33][CH3:34])=[S:39])=[CH:31][CH:32]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of 4-[4-[2-(benzenesulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.091 g, 0.2 mmol) in THF (1.0 mL) was added to a solution of di(imidazol-1-yl)methanethione (0.050 g, 0.28 mmol) in DCM (1.0 mL) and the resulting solution was stirred at 40° C. for 30 minutes. A solution of methylamine (2.0M in THF, 0.5 mL, 1.0 mmol) was added and the reaction was stirred at 40° C. for 30 minutes and the solvent was evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (63 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1.[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][C:12]([O:15][CH3:23])=[CH:13][CH:14]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)N=C(Oc2ccc(O)nn2)c2cc(C#N)ccc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(OC2=NC(C)(C)Oc3ccc(C#N)cc32)nn1
Reaction time: 3 h

Procedure:
A mixture of 296 mg of 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-2H-1,3-benzoxazine, 1 g of K2CO3,0.65 ml of dimethyl sulfate and 16 ml of DMF is boiled for 3 hours and subjected to customary work-up. 2,2-Dimethyl-4-(6-methoxy-3-pyridazinyloxy)-6-cyano-2H-1,3-benzoxazine is obtained.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([OH:47])[CH:38]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([OH:47])[CH:38]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 108.9 %

Procedure:
Methyl 4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]-2-hydroxybenzoate (33 mg, 0.052 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 13 hours. The mixture was concentrated to afford the desired product (30 mg, 90%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 10.48 (s, 1H), 8.64-8.62 (m, 3H), 8.10 (dd, J=4.9 Hz and 1.4 Hz, 1H), 7.96 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.39-7.36 (m, 2H), 7.30 (dd, J=8.0 Hz and 1.1 Hz, 1H), 7.15-7.06 (m, 2H), 6.89 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.88 (s, 3H), 3.51-3.45 (m, 2H), 2.64-2.52 (m, 2H), 2.23-2.15 (m, 1H), 1.88-1.81 (m, 1H). LCMS: 530 [M+H].
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:29][C:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[CH:33]=3)=[O:31])[CH:25]=[C:26]([CH3:28])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:29][C:30]([C:32]4[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[CH:33]=4)=[O:31])[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc3nc(N)cn3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A mixture of N-{3-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (3.20 g, 5.82 mmol), trifluoroacetic anhydride (20 mL) and dichloromethane (30 mL) was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, ethanol (30 mL), water (15 mL) and 8N aqueous sodium hydroxide solution (15 mL) were added to the residue, and the mixture was stirred at room temperature for 60 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with diethyl ether to give the title compound (1.22 g, 56%) as a pale-brown solid.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(CCCCCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
2-isopropyl-7-phenylheptanoic acid (1.0 g; prepared as the intermediate for the compound of example 1 (b)) was dissolved in anhydrous acetic acid (5 ml). The solution was cooled in an ice-bath. Fuming nitric acid (0.4 ml) was dropped into the solution. The solution was stirred for 30 mins. Anhydrous acetic acid was quenched by adding potassium hydroxide to the reaction solution. The reaction solution adjusted to pH 6.0-7.0 was extracted with ethyl acetate. The ethyl acetate layer separated was washed with water, followed by saturated brine, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (850 mg) having the following physical data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12]CCO1.C([Li])(C)(C)C.[Li]C1C=CC=CC=1C1OCCO1.[S:30]1[CH:34]=[CH:33][C:32]2[CH2:35][CH2:36][C:37](=O)[C:31]1=2>>[S:30]1[CH:34]=[CH:33][C:32]2[CH2:35][CH:36]=[C:37]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH:8]=[O:12])[C:31]1=2
Reactant: Brc1ccccc1C1OCCO1
Reactant: O=C1CCc2ccsc21
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1C1OCCO1
Product: O=Cc1ccccc1C1=CCc2ccsc21

Procedure:
This scheme can be summarized as follows: 2-(2-bromophenyl)-1,3-dioxolane (A) is treated with 2 equivalents of tert-butyl lithium to effect halogen-methyl exchange. The 2-(2-lithiophenyl)-1,3-dioxolane (B) is then reacted in situ with 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one. After aqueous acid workup, 2-(4H-cyclopenta[b]thiophen-6-yl)benzaldehyde (C) is isolated by flash chromatography. This is treated with a Grignard reagent (R4MgBr) to provide the 6-[2-(1-hydroxyalkyl)phenyl]-4H-cyclopenta[b]thiophene (D) which is subsequently oxidized to the 6-[2-(alkylcarbonyl)phenyl]-4H-cyclopenta[b]thiophene (E). Reductive amination of E should then provide compounds of structure III.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([N+:21]([O-])=O)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(c1ncnc(Cl)c1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ncncc1N)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(6-chloro-5-nitro-4-pyrimidinyl)amino]piperidine (EXAMPLE 252, 3.00 g) is dissolved in 150 ml of ethanol and 0.75 g of palladium hydroxide is added. The reaction is placed on a Parr hydrogenator at 10 psi for 1 h, then filtered through diatemous earth and concentrated under reduced pressure. Purification by flash column chromatography (5% methanol/chloroform) gives the title compound.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:14])[N+:13]=1[O-:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(Oc2ccccc2)n1
Solvent: ClCCl
Product: Cc1cccc(Oc2ccccc2)[n+]1[O-]
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution containing 44.11 g of 6-phenoxy-2-picoline dissolved in 825 ml of methylene chloride under an atmosphere of nitrogen and at room temperature was added 96.82 g of 85% m-chloro-peroxybenzoic acid. The resulting mixture was stirred for 18 hrs. under an atmosphere of nitrogen and at room temperature. The reaction mixture was transferred to a separatory funnel and washed three times with 10% Na2CO3 twice with H2O and finally with saturated brine. After drying over anhydrous Na2SO4 removal of the solvents afforded 37.80 g of yellow oil. This material was used without purification in Part D.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14]C(=O)OCC(C)C)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[OH-].[K+]>C(O)CO.O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1
Reactant: CC(C)COC(=O)Nc1ccc(C2CCSCC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(C2CCSCC2)c(F)c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methylpropyl [3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]carbamate (Step 1, 2.12 g, 6.81 mmol) in ethylene glycol (25 mL) was treated with aqueous potassium hydroxide (45%, 25.5 g, 204 mmol) with vigorous stirring, and the mixture was heated to 95° C. and stirred at this temperature for 18 hrs. The reaction was then cooled to ambient temperature and diluted with water (50 mL) and CH2Cl2 (100 mL), the layers were separated, and the organic phase was washed with water (50 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on a Flash 40M 90 g silica gel cartridge with a gradient of EtOAc/heptane (15/85-25/75), and those fractions with an Rf=0.32 by TLC (EtOAc/hexanes, 25/75) were pooled and concentrated to give the title compound, mp 96-98° C.; MS (ESI+) for C11H14NFS m/z 212 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:11][CH2:10][C@@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[CH2:7]1)(=O)C.C[O-].[Na+].Cl.O1CCOCC1>ClCCl>[CH2:10]1[C@@H:9]2[CH2:12][CH2:13][CH2:14][N:8]2[CH2:7][C@@H:6]([CH2:5][OH:4])[O:11]1
Reactant: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: OC[C@@H]1CN2CCC[C@H]2CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.2 %

Procedure:
(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt % solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly. The mixture was stirred at room temperature for 5 minutes and then was concentrated in vacuo to afford a suspension which was diluted with dichloromethane, filtered and the filtrate was concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol as a brown oil (1.93 g, >100% yield). 1H NMR (400 MHz, CDCl3): 4.05 (dd, 1H), 3.73-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.39-3.34 (m, 1H), 3.10 (dt, 1H), 3.00-2.95 (m, 1H), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m, 1H); MS (EI) for C8H15NO2: 158 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:11]([C:32]2[S:33][C:34]([CH3:37])=[N:35][N:36]=2)[N:10]=1.Cl.CCOCC>CCOCC.C(Cl)Cl>[NH2:24][CH2:23][CH2:22][CH2:21][C:12]1([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]([C:32]2[S:33][C:34]([CH3:37])=[N:35][N:36]=2)[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:13]1
Reactant: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCNC(=O)OC(C)(C)C)c2cccc(O)c2)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCN)c2cccc(O)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
Tert-butyl 3-(5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (51 mg, 0.093 mmol) was weighed into a 25 mL flask, and dissolved in 7 mL of Et2O/DCM (1:1). HCl-Et2O (1.8 mL, 1.863 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. An additional 20 equivalents of HCl-Et2O was added and the reaction mixture was stirred an additional 2 hours. The crude reaction mixture was concentrated in vacuo to afford a yellow solid. The solid was then purified by flash column chromatography (10-40% MeOH/DCM), affording the desired product (31 mg, 74% yield) as a yellow foam. MS ESI (+) m/z 448 (M+1) detected; 1H NMR (400 MHz, DMSO-D6) δ 7.90 (m, 1H), 7.51 (m, 2H), 7.19 (m, 1H), 6.84 (m, 2H), 6.74 (m, 1H), 3.21 (m, 1H), 2.98 (m, 1H), 2.89 (m, 2H), 2.56 (m, 3H), 2.61 (m, 1H), 2.10 (m, 1H), 1.60 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:30][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:26]([F:28])([F:27])[F:29])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)[CH3:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2cn[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (±)-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole (35 mg, 0.087 mmol) and sodium cyanoborohydride (5.5 mg, 0.087 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 21 mg (58%). 1H-NMR (CDCl3, 500 MHz) δ 9.78 (bs, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.28-7.49 (m, 5H), 7.21 (s, 1H), 4.62 (q, J=6.7 Hz, 1H), 3.48 (s, 3H), 3.45-3.51 (m, 3H), 3.31 (d, J=8.9 Hz, 1H), 2.62 (m, 2H), 2.39 (m, 1H), 2.12-2.31 (m, 7H), 2.06 (m, 1H), 1.95 (m, 1H), 1.44 (d, J=6.7 Hz, 3H); 13C-NMR (CDCl3, 126 MHz) δ 138.1, 135.2, 128.9, 127.5, 127.1, 126.9, 124.7 (q, J=272 Hz), 123.3, 119.8 (q, J=2.9 Hz), 118.1 (q, J=3.8 Hz), 79.0 (br), 78.4, 52.0, 51.8, 50.8, 46.1, 40.7, 32.5, 32.3, 22.2. Mass spec.: 418.18 (MH)+. Accurate mass spec.: m/z 418.2101 [MH]+, Δ=1.2 ppm.
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24](OC(C)=O)=[O:25]>ClCCl>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:24](=[O:25])[CH3:23])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenyl(piperidin-4-yl)methanone hydrochloride (743 mg, 3.29 mmol) in dichloromethane (13.2 mL) and triethylamine (1.10 mL, 7.90 mmol) was treated with Ac2O (0.373 mL, 3.95 mmol) dropwise over 1 minute in an ice bath under argon, and the resulting translucent mixture was immediately removed from the ice bath and stirred at room temperature overnight. The reaction was then extracted with 1 M aqueous HCl (1×8 mL) and 1 M aqueous NaOH (1×8 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the title compound as a translucent beige oil that crystallized upon standing.