Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:26][CH:23]2[CH2:25][CH2:24]2)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: NC1CC1
Product: COCCCOc1cc(CNC2CC2)ccc1OCc1ccccc1

Procedure:
4-(Benzyloxy)-3-(3-methoxypropoxy)benzaldehyde (945 mg) and cyclopropylamine (0.44 ml) were treated in the same manner as Reference Example 1 to give N-[4-(benzyloxy)-3-(3-methoxypropoxy)benzyl]cyclopropanamine (947 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(C2CC2)c(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(Br)c(C2CC2)nc1N
Reaction time: 5 h

Procedure:
Cuprous iodide (11.23 mg, 0.059 mmol) was added to a mixture of 5-bromo-6-cyclopropyl-3-iodopyridin-2-amine (1 g, 2.95 mmol), triethylamine (13.4 g, 132.75 mmol) and THF (4 mL) and the resultant mixture was purged with nitrogen gas. Ethynyltrimethylsilane (347.7 mg, 3.54 mmol) and Pd(PPh3)2Cl2 (41.36 mg, 0.059 mmol) were added and purged with argon. The resultant mixture was stirred under argon atmosphere for 5 hours. The mixture was concentrated to residue. Residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate and concentrated to get solid which was further purified on column (SiO2) using 15% ethyl acetate in hexane as eluent. This afforded 1.2 g (crude) of the pure compound.
Reaction SMILES: [C:1]([N:4]1[C@H:8]([C@H:9]([OH:12])[CH2:10][OH:11])[C@H:7]([OH:13])[CH:6]=[N:5]1)(=[O:3])[CH3:2]>[OH-].[OH-].[Pd+2].CO>[C:1]([N:4]1[C@H:8]([C@H:9]([OH:12])[CH2:10][OH:11])[C@@H:7]([OH:13])[CH2:6][NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C[C@@H](O)[C@H]1[C@H](O)CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1NC[C@H](O)[C@H]1[C@H](O)CO
Reaction time: 8 h
Yield: 40.3 %

Procedure:
Pearlmans catalyst (200 mg) was suspended in a solution of methanol with (3S,4S)-2-acetyl-1,5-dihydro-3-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-pyrazole (18) (200 mg, 1.11 mmol) and stirred overnight under an atmosphere of hydrogen. The reaction was filtered through celite and the filtrated concentrated in vacuo to afford a crude oil. The crude product was purified by chromatography to afford 19 (85 mg, 43%) as a colourless oil. 1H NMR δ 4.64 (dd, J=5.7, 3.4 Hz, 1H), 3.90 (m, 2H), 3.61 (m, 2H), 3.36 (dd, J=11.7, 6.5 Hz, 1H), 2.71 (dd, J=11.7, 6.0 Hz, 1H), 2.18 (s, 3H). 13C NMR δ 174.5, 75.4, 72.7, 68.2, 65.2, 56.4, 21.5. HRMS (M+) calc. for C7H14N2O4: 190.0953. Found 190.0951.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N+:10]([O-])[CH2:11][C:5]2=[N:4][NH:3]1>[Ni].CN(C)C=O>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1)=[N+]([O-])C2
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1)=NC2

Procedure:
33 grams of 1-keto-6-phenyl-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine-5-oxide were hydrogenated with 15 grams of Raney-nickel in 450 ml. of dimethyl formamide at 50 atmospheres absolute and 60°-70° C. After filtering off the catalyst with suction, the solution was concentrated to 100 ml., and then treated with water up to turbidity, whereupon the reaction product crystallized out. It was recrystallized from ethanol several times. Yield 15 grams; M.P. 222°-224° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:30]#[N:31].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:29][N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[C:18](=[C:30]([NH2:31])[C:10]([C:11]([N:16]=3)=[O:13])=[C:2]3[NH:1][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:3]3)[CH:19]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(c2)=C(N)C(=C2Nc4ccccc4N2)C(=O)N=3)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-benzimidazol-2-ylacetate (1.1 eq) and 2-amino-5-(4-methylpiperazinyl)benzenecarbonitrile (1.0 eq) were dissolved in 1,2-dichloroethane, and then SnCl4 (11 eq) was added. The mixture was heated at reflux overnight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3 M) was added to the solid, and the mixture heated at 80° C. for 0.5 hours. The solid was filtered and washed sequentially with H2O, CH2Cl2, and acetone. LC/MS indicated that the product was present in the acetone layer and the solid. These fractions were combined and purified by silica gel chromatography (5-10% MeOH in CH2Cl2 with 1% Et3N) to give the desired product. LC/MS m/z 375.4 (MH+), Rf 1.65 minutes.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(O)(O)=O>C(#N)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=1)=[N:3]2
Reactant: OB(O)c1cccc(F)c1
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Agent: [Pd]
Agent: O=C(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.0000 g, 4.424 mmol), 3-fluorophenylboronic acid (0.6808 g, 4.866 mmol), tetrakis(triphenylphosphine)-palladium (0.2556 g, 0.2212 mmol), and sodium carbonate anhydrous (2.344 g, 22.12 mmol) in acetonitrile-water (3:1) (0.04000 mL) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-2-(3-fluorophenyl)-quinoline-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.14 (1H, s), 9.06 (1H, d, J=0.8 Hz), 8.13-8.18 (1H, m), 7.92-8.00 (2H, m), 7.59-7.67 (2H, m), 7.53-7.58 (1H, m), 7.39-7.47 (1H, m); LC-MS (ESI) m/z 286.0 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-])=O)=[CH:45][CH:44]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:20][CH:21]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][C@H:25]([OH:34])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22])=[CH:15][CH:14]=2)=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:12]2[C:13]3[C:18](=[CH:17][C:16]([CH2:20][CH:21]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:24][CH:25]([OH:34])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:22])=[CH:15][CH:14]=3)[CH:19]=[C:11]2[C:9]([OH:10])=[O:8])=[CH:44][CH:45]=1
Reactant: CC(Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1)N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(Cc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(N)cc1)N(CC(O)COc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
To a solution of 5-{2-[tert-butoxycarbonyl-(2(S)-hydroxy-3-phenoxypropyl)-amino]-propyl}-1-(4-nitro-benzyl)-1H-indole-2-carboxylic acid benzyl ester (134 mg, 0.19 mmol) in THF (6 ml) was added 14 mg of 10% Pd/C catalyst. The reaction mixture was hydrogenated on a Parr shaker at 45 psi for about 4 hrs and then filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to afford a yellow foam (112 mg), AP-MS 572.
Reaction SMILES: [Cl-].[CH:2]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:59][O:60][CH3:61])[C:11]([NH:13][CH:14]2[C:57](=[O:58])[N:16]3[C:17]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])=[C:18]([CH2:21][P+:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=[O:3].[OH-].[Na+].C(OCC)C>CC(C)=O.O>[CH:2]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:59][O:60][CH3:61])[C:11]([NH:13][CH:14]2[C:57](=[O:58])[N:16]3[C:17]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])=[C:18]([CH:21]=[P:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=[O:3]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Yield: 72.4 %

Procedure:
[7-{2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido}-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyltriphenylphosphonium chloride (syn isomer)(5.33 g) was dissolved in a mixture of acetone (60 ml) and water (10 ml), and the solution was adjusted to pH 11 with 2 N aqueous solution of sodium hydroxide, followed by extraction three times with ethyl acetate (100 ml). The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was pulverized with diethyl ether to obtain benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (syn isomer)(3.7 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=O>>[SH:6][C:3]1[N:2]([CH3:1])[C:9]([C:8]([F:13])([F:12])[F:7])=[N:5][N:4]=1
Reactant: CNC(=S)NN
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(S)nnc1C(F)(F)F
Reaction time: 8 h

Procedure:
In a 500-ml flask, 100 g (0.95 mole) 4-methylthiosemicarbazide and 155 g [100 ml (1.36 mole)] trifluoroacetic acid were combined, refluxed 3 hours, and then allowed to stand overnight. Since the reaction mixture solidified overnight, it was heated to solution and then added to ice. The precipitated solid was filtered, washed with water and air-dried. The solid was dissolved in hot benzene and the water was separated. The benzene solution was concentrated cooled, and filtered to give the product as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:6]=[C:7]([O:12]C)[C:8]=1CCC.Cl.N1C=C[CH:29]=[CH:28][CH:27]=1>>[CH:28]([C:8]1[C:3]([OH:2])=[CH:4][C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:6][C:7]=1[OH:12])([CH3:29])[CH3:27]
Reactant: CCCc1c(OC)cc(C=Cc2c(F)cc(F)cc2F)cc1OC
Reactant: c1ccncc1
Agent: Cl
Product: CC(C)c1c(O)cc(C=Cc2c(F)cc(F)cc2F)cc1O
Yield: 14 %

Procedure:
This material was prepared from 1-(3,5-dimethoxy-4-1-propylphenyl)2-(2,4,6-trifluorophenyl)ethene and pyridine hydrochloride in 14% yield in the same way as described in Example 29. 1HNMR (CDCl3, ppm): δ 1.42 (d, J=7.1 Hz, 6H), 3.50 (qint, J=7.1 Hz, 1H), 4.77 (br, 2H), 6.55 (s, 2H), 6.59-7.24 (m, 4H).
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[S:49])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCCc1ccc(C(=O)Cl)cc1
Agent: CCCc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
4-Propyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-propyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-propyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 58%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:5][C:4]=1[O:23][CH3:24]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:5][C:4]=1[O:23][CH3:24])=[O:1]
Reactant: COc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1C=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
N-(4-Hydroxymethyl-3-methoxyphenyl)-2-(3-trifluoromethylphenyl)acetamide (0.7 g, 2 mmol) was dissolved in ethyl acetate (40 mL) and manganese dioxide (3 g, 34 mmol) was added. The reaction mixture was stirred at 20° C. for 3 hr and filtered. The organic phase was concentrated in vacuo to give crude N-(4-formyl-3-methoxyphenyl)-2-(3-trifluoromethylphenyl)acetamide that was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[OH:14][C:15]1[C:16]([C:25]([NH:27][NH2:28])=[O:26])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:28][NH:27][C:25]([C:16]1[C:15]([OH:14])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[O:26]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1c(O)ccc2ccccc12)c1cc2ccccc2cc1O
Yield: 97 %

Procedure:
Following the general procedure of Example 1, condensation of 2-Hydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide gave a white solid (97%): mp >300° C.; 1H NMR d 12.70 (s, 1 H), 12.25 (br s, 1 H), 11.37 (br s, 1 H); 9.58 (s, 1 H), 8.52 (s, 1 H), 8.33 (d, 1 H, J=8.7 Hz), 7.94 (d, 2 H, J=8.7 Hz), 7.89 (d, 1 H, J=8.1 Hz), 7.78 (d, 1 H, J=8.4 Hz), 7.58 (t, 1 H, J=7.6 Hz), 7.52 (t, 1 H, J=7.5 Hz), 7.41 (m, 2 H), 7.37 (s, 1 H), 7.25 (d, 1 H, J=9.0 Hz); 13C NMR d 163.05, 158.12, 153.88, 147.57, 135.94, 132.90, 131.68, 130.62, 128.90, 128.68, 128.33, 127.79, 127.73, 126.81, 125.85, 123.86, 123.54, 120.98, 119.84, 118.87, 110.62, 108.61; HRMS Calcd for C22H16N2O3 :356.1161, found 356.1151; Anal. (C22H16N2O3) C, H, N.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([O:14][CH:15]3[CH2:18][N:17]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:16]3)=[N:10][CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37].O.CC#N>C(Cl)Cl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:17]1[CH2:16][CH:15]([O:14][C:9]2[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([C:36](=[O:38])[CH3:37])[CH2:3][CH2:4]3)=[CH:13][N:12]=[CH:11][N:10]=2)[CH2:18]1
Reactant: CC(=O)Cl
Reactant: c1ccc2nc(N3CC(Oc4ncncc4C4CCNCC4)C3)ccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cncnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of 2-(3-((5-(piperidin-4-yl)pyrimidin-4-yl)oxy)azetidin-1-yl)quinoline hydrochloride in CH2Cl2 (10 mL) were added Et3N (100 mg, 0.99 mmol) and acetyl chloride (62 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with CH2Cl2 (20 mL), washed with water (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the crude product. Purified by column chromatography, and followed by prep. HPLC (10% to 80% water/MeCN) to give 1-(4-(4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)ethanone (34 mg, 0.08 mmol, yield 13%). M+1 IC50 (uM) 404 0.765 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.73 (s, 1H), 8.44 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.75-7.65 (m, 2H), 7.47-7.40 (m, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.71 (s, 1H), 5.04-4.98 (m, 2H), 4.79-4.71 (m, 2H), 4.68-4.63 (m, 1H), 3.97-3.93 (m, 1H), 3.26-3.19 (m, 1H), 3.11-3.04 (m, 1H), 2.71-2.64 (m, 1H), 2.14 (s, 3H), 2.03-1.89 (m, 2H), 1.69-1.63 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:19]O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>O>[Cl:34][CH2:19][C:5]1[C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([F:18])([F:17])[F:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c([C@H]2CCCC[C@@H]2C(F)(F)F)noc1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FC(F)(F)[C@@H]1CCCC[C@H]1c1noc(C2CC2)c1CCl
Reaction time: 6 h

Procedure:
A cold (0°C.) solution of (5-cyclopropyl-3-((1S,2S)-2-(trifluoromethyl)cyclohexyl) isoxazol-4-yl)methanol (1.8 g, 6.2 mmol) dichloromethane was treated with Hunig's base (953 μL, 6.8 mmol) followed by methane sulfonyl chloride (508 L, 6.5 mmol). Afte(6 hr of stirring, the reaction was treated with H2O and phases separated. The organic phase was collected, dried (MgSO4), filtered, concentrated, and chromatographed (SiO2, linear gradient, 0-80% EtOAc in Hex) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.48 (dd, J=36.5, 12.6 Hz, 2H), 3.48 (m, 1H), 2.44 (m, 1H), 2.15 (ddd, J=25.5, 12.8, 3.6 Hz, 1H), 2.04-1.87 (m, 4H), 1.82-1.68 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.14 (m, 2H), 1.09 (m, 2H), MS m/z 308.1 (M+1).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][N:25]=2)[C:5]1=[O:34])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[CH:26][N:25]=2)[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc([N+](=O)[O-])cc2C)C1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc(N)cc2C)C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-5-nitropyridin-2-yl)piperidin-2-one (Example 113, Step A) (120 mg, 0.23 mmol) and tin(II) chloride dihydrate (260 mg, 1.1 mmol) were dissolved in 2.3 mL of ethyl acetate. The reaction apparatus was outfitted with a reflux condenser and was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with 1M NaOH and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 90% EtOAc/Hex, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@H:8]1[CH2:21][CH2:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N:15]1[C:16]2[C:11](=[C:10]3[C:19](=[CH:18][CH:17]=2)[CH2:20][CH2:21][C@H:8]([CH2:7][OH:6])[O:9]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CCc2ccc3ncccc3c2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@H]1CCc2ccc3ncccc3c2O1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of (6R)-6-(tert-butyl-dimethyl-silanyloxymethyl)-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene (0.60 g, 1.82 mmole) in tetrahydrofuran (50 mL) was added tetra-n-butylammonium fluoride (2 mL, 1M in THF). The reaction mixture was stirred for 20 minutes, then diluted with ethyl acetate and washed with water, dried over sodium sulfate, and the solvent removed in vacuum. The residue was purified by column chromatography on silica gel (50% methylene chloride/hexane) to afford 0.38 g (98%) of the title compound as a white solid, mp 128° C., [α]25D=+113.81° (c=5.9, CHCl3).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8][C:7](=[O:15])[C:6]=1C(OC)=O>CO>[CH3:4][C:5]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8][C:7](=[O:15])[CH:6]=1
Reactant: COC(=O)C1=C(C)C(C(=O)OC)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(=O)C=C1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium methanolate (90 g, 1.67 mol) in methanol (300 mL) was added dimethyl 2-methyl-6-oxocyclohex-1-ene-1,3-dicarboxylate (150 g, 663.04 mmol) in methanol (150 mL) dropwise with stirring over 30 minutes. The resulting solution was heated to 80° C. for 30 minutes, and the mixture was concentrated in vacuo. The reaction mixture was diluted with H2O/ice (120 mL); then diluted furtherwith acetic acid (130 mL). The resulting solution was extracted with Et2O (3×), and the organic layers were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The final product was purified by distillation under reduced pressure (5 mm Hg), and the fraction was collected at 110˜120° C. Methyl 2-methyl-4-oxocyclohex-2-enecarboxylate was obtained as a yellow oil. MS ESI calcd. for C9H13O3 [M+H]+ 169. found 169.