Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@H](NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1)c1ccccc1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CO
Product: C[C@H](NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1)c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-[(1S)-1-phenylethyl]-3-piperidinecarboxamide (186 mg, 0.406 mmol), EtOH (5 mL), Hunig's base (0.071 ml, 0.406 mmol), and hydrazine anhydrous (0.076 mL, 2.434 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (120 mg) as a light yellow solid. LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.14 (d, J=6.8 Hz, 3H), 1.36 (d, J=7.1 Hz, 3H), 1.66 (m, 1H), 1.68 (m, 1H), 1.77 (m, 2H), 2.34 (m, 1H), 4.94 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.56 (s, 1H), 7.19-7.30 (m, 1H), 7.36 (m, 4H), 7.56 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d, J=8.34 Hz, 1H), 7.94 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O1CCOCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:31]([NH:30][C:26]2[CH:25]=[C:24]([O:23][C:21]3[CH:20]=[CH:19][C:16]4[N:17]([CH3:18])[C:13]([NH:12][C:3]5[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=5[F:1])=[N:14][C:15]=4[CH:22]=3)[CH:29]=[CH:28][N:27]=2)=[O:32])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)C4CCNCC4)c3)ccc21
Solvent: C1COCCO1
Product: CC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide (1 eq) in dioxane and N,N-disopropylethylamine (2 eq) was added acetic anhydride (1 eq) and the resulting mixture was stirred for 1 h. 1-acetyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide thus formed was purified by preparative chromatography. MS: MH+=571.5.
Reaction SMILES: C([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)CCC.CC(C)([O-])C.[K+].BrC[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[NH:6]1[CH:7]=[CH:8][N:9]=[CH:5]1.[C:19]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: CCCCc1ncc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1c[nH]cn1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 4.07 g (32.8 mmol) of 2-butylimidazole (obtained from step 1) in 110 mL of DMF was added 44.3 mL (44.3 mmol) of potassium tert-butoxide (1M in THF), and the resulting solution was stirred at room temperature for 15 min. To the dark brown mixture was added 20.1 g (36.1 mmol) of the bromomethyl biphenyl. The reaction mixture was stirred at room temperature for 16 h, and concentrated in vacuo. The residue was dissolved in chloroform and washed with water. The aqueous layer was extracted with fresh chloroform, and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography to give 7.2 g (37%) of the biphenyl imidazole intermediate as a yellow oil which solidified as a glass: 1H NMR (CDCl3) δ 0.90 (t, J=7.31 Hz, 3H), 1.35 (septet, J=7.5 Hz, 2H), 1.71 (quintet, J=7.74 Hz, 2H), 2.61 (t, J=7.58 Hz, 2H), 4.93 (s, 2H), 6.65 (d, J=1.35 Hz, 1H), 6.79 (d, J=8.31 Hz, 2H), 6.92 (d, J=7.3 Hz, 6H), 6.97 (d, J=1.32 Hz, 1H), 7.11 (d, J=8.2 Hz, 2H), 7.2-7.4 (m, 10H), 7.4-7.55 (m, 2H), 7.95 (dd, J=6.85, 2.08 Hz, 1H); MS(FAB) m/e (relative intensity) 607 (100, M+Li), 601 (90, M+H).
Reaction SMILES: [Cl-:1].[NH4+].O.C(O)C.[N+:7]([C:10]1[CH:34]=[CH:33][C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH:17]=2)=[CH:12][CH:11]=1)([O-])=O>CN1C(=O)CCC1.[Zn]>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][CH2:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH2:15][NH:14][C:13]2[CH:33]=[CH:34][C:10]([NH2:7])=[CH:11][CH:12]=2)=[CH:29][CH:28]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc(NCc2cccc(CNc3ccc([N+](=O)[O-])cc3)c2)cc1
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: O
Product: Cl
Product: Nc1ccc(NCc2cccc(CNc3ccc(N)cc3)c2)cc1

Procedure:
The mixture of powdered zinc (30 g), ammonium chloride (3 g), water (5 ml) and absolute ethanol were brought to reflux with the oil bath. The 4-nitro-N-(3-{[(4-nitrophenyl)amino]methyl}benzyl)aniline (3 g) was dissolved in 50 ml of NMP and introduced dropwise until there was decoloration of the reaction medium, while at the same time the reflux was maintained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[OH-].[Na+].[C:15](#[N:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[OH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]=1[CH2:17][CH2:16][C:15]#[N:18]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCc1c(O)ccc2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To 44.8 g of 6-bromo-2-naphthol were added 120 ml of toluene and 8.8 g of sodium hydroxide, followed by stirring at 65° C. for 30 minutes. Then, thereto was added dropwise 11.4 g of acrylonitrile at 80° C., followed by stirring at the same temperature for 3.5 hours. After left for cooling, the toluene layer was decanted, and to the residue was added 240 ml of water. A small amount of insoluble matter was filtered off, and to the filtrate was added 140 ml of 5% hydrochloric acid. The precipitate was collected by filtration and sufficiently washed with water. The resulting crude product was recrystallized from ethanol to obtain 30.7 g of the desired product.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH3:24])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CC(=O)OCC>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:20][C@H:19]1[CH3:24])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1ncsc1Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ncsc1N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 120 °C
Reaction time: 7 h
Yield: 30.8 %

Procedure:
To a solution of methyl 5-bromo-1,3-thiazole-4-carboxylate (3 g) in NMP (30 mL) was added (R)-1-N-Boc-2-methylpiperazine (2.76 g) followed by DIPEA (10.1 mL). The resulting solution was stirred at 120° C. for 1.5 d, at RT over weekend and at 120° C. for 7 h. After cooling down, the reaction mixture was diluted with EA and washed with sat. aq. NaHCO3, 1M HCl and sat. aq NaCl. The aq. phases were extracted with EA. The combined org. layers were dried over Na2SO4, filtrated off and evaporated in vacuo. The crude was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 0 for 10CV, 0 to 10 over 5CV, 10 for 5CV, 10 to 20 over 5CV, 20 for 5CV, 20 to 30 over 5CV, 30 for 5CV) to afford 1.42 g of yellow oil. LC-MS (B): tR=0.84 min; [M+H]+: 342.08.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3C=CC=CC=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrCCBr>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][CH2:21][NH:27][C:15]=3[CH:14]=2)=[O:30])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
Steps 5 and 6. A solution of 4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester (26 g, 63 mmol) in DMF (2644 mL) was treated with 10% palladium on carbon (5.3 g). The reaction vessel was evacuated and filled with hydrogen. The mixture was stirred at room temperature for 4 hours, then the catalyst was filtered, washing with a small quantity of dimethylformamide. The resulting solution, containing crude 4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester, was concentrated to a volume of 300 mL, and treated with K2CO3 (34.1 g, 247 mmol) and 1,2-dibromoethane (46.4 g, 247 mmol). The resulting mixture was warmed at 70° C. and stirred for 18 hours. The mixture was then concentrated to a volume of 100 mL and diluted with ethyl acetate and water. The organic phase was separated, washed three times with water, dried over sodium sulfate and evaporated. The residue was taken up in methanol and sonicated. The white solid was filtered, yielding pure 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (8.6 g). The filtrate was evaporated and the residue purified by flash chromatography (toluene/acetonitrile gradient) providing further 2 g of material. 4-[(3,4-Dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester was thus obtained as a white solid, 10.6 g (52%), MS (ISP): m/e=327.0 (M+H+.); δH (300 MHz; d6-DMSO) 10.27 (1H, s), 7.92 (4H, s), 7.16-7.19 (2H, m), 6.75 (1H, d), 6.04 (1H, s), 4.29 (2H, q), 4.19 (2H, s), 3.32 (2H, s), 1.32 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[CH:4][N:3]=1.C([Li])CCC.[C:25]([Si:29]([O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]=[C:40]=[O:41])[CH2:35][CH2:34]1)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[F:19])[C:40]2=[O:41])[CH2:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(2-fluoro-4-methoxy-phenyl)amine (1.1 g, 3.64 mmol) (from Example 17a supra) in tetrahydrofuran (50 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.75 mL, 4.37 mmol) (Aldrich). After stirring at −78° C. for 40 minutes, tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane (1.12 g, 4.37 mmol) (from Example 17b supra) was added. The mixture was stirred at −70° C. for 1 hour and then at room temperature for 3 hours. It was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.60 g, 33%).
Reaction SMILES: [F:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)=O>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:13][C:2]2([F:1])[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:3]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(F)CN(CC=O)C(=O)OCC
Reactant: O=C(O)CNCc1ccccc1
Agent: O=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(Cc3ccccc3)CCC2(F)C1

Procedure:
20.8 g (0.11 mol) of ethyl N-(2-fluoroallyl)-N -(2-oxoethyl)-carbamate are heated under reflux with 19 g (0.115 mol) of N-benzylglycine in 300 ml of toluene until evolution of CO2 is complete. The mixture is concentrated and the residue is distilled.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a stirred mixture of 3-hydroxyazetidine hydrochloride (10.0 g, 91.3 mmol), benzoyl chloride (12.8 g, 91.3 mmol) in 3:2 water/ethyl acetate (500 mL) was added potassium carbonate (63.1 g, 456.5 mmol) at room temperature. After 16 h the organic layer was separated and concentrated under reduced pressure. The resulting residue was dissolved in 2:1 THF/methanol (150 mL) and stirred with 1.0 N sodium hydroxide (50.0 mL) at room temperature. After 1 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide (3-hydroxyazetidin-1-yl)(phenyl)methanone (13.5 g, 83%) as a colorless gum-like substance.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][NH:11][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirring solution of salicylic acid (2.0 g, 14.5 mmol) and t-butyl N-(2-aminoethyl)carbamate (2.32 g, 14.5 mmol) in dry THF (15 mL) was added a solution of 1,3-dicyclocarbodiimide (3.29 g, 16.0 mmol) in CH2Cl2 (5 mL) dropwise at 0° C. The reaction was stirred for 18 h and then filtered. The filtrate was conc in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 5% NaHCO3, dried with MgSO4, and conc in vacuo to a white solid. The solid purified by silica gel chromatography (gradient: 0–70% EtOAc in hexanes) to yield 2.88 grams (71%) of the product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].C1(S([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:27][N:26]=2)(=O)=O)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[CH:27][N:26]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To 4.08 g of 3,4-dichlorophenol dissolved in a 25 ml THF/25 ml DMSO mixture was added 2.9 g of t-BuOK and then 8.99 g of 2,5-bis(phenylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature, then added to 3 to 4 volumes of water and stirred. The brown precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the purified product, 2-(3,4-dichlorophenoxy)-5-(phenylsulfonyl)pyridine, (68% yield), as white shiny needles, m.p. 113°-114° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.[NH2:16][OH:17]>CO>[OH:17][N:16]=[CH:1][C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Reactant: NO
Solvent: CO
Product: CNc1nc(C=NO)c(-c2ccncc2)s1
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-methylamino-5-(4-pyridyl)thiazole (0.9 g) in methanol (15 ml) was added to a 1N-methanolic hydroxylamine solution (5.8 ml) at ambient temperature with stirring, which was continued under the same condition for 2 hours. The precipitate was collected by filtration and recrystallized from an aqueous tetrahydrofuran to afford 4-hydroxyiminomethyl-2-methylamino-5-(4-pyridyl)thiazole (1.02 g).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O:6][CH:7](OC)[CH2:8][CH2:9][CH2:10][CH:11]=O>CCOC(C)=O.CCCCCC>[N+:1](/[CH:4]=[CH:11]/[CH2:10][CH2:9][CH2:8][CH:7]=[O:6])([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C/[N+](=O)[O-]
Yield: 65.9 %

Procedure:
Prepared according to the general procedure A from nitromethane 112a (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 66% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A mixture of methyl 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetate (23.2 g), lithium hydroxide monohydrate (4.33 g), tetrahydrofuran (100 ml), water (60 ml) and methanol (40 ml) was stirred at room temperature for 1 hour. 1N hydrochloric acid (103 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from acetone to obtain 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetic acid (21.9 g, yield 98%). m.p. 181-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:50])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:50])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)OCc1ccc(OC(F)(F)F)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccc(OC(F)(F)F)cc3)C2)cc1

Procedure:
4-(Trifluoromethoxy)benzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 4-(trifluoromethoxy)benzyl carbonochloridate (65.8 mg, 0.18 mmol) according to General Procedure H to give 30 mg (34.7%) of light brown solid. Anal. Calcd. for C27H31F3N4O3 m/z 516.2, found: 517.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.04 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 5.05 (t, J=8.1 Hz, 2H), 3.89 (m, 1H), 3.8 (m, 1H), 3.10 (m, 1H), 2.77 (m, 1H), 2.39 (m, 2H), 1.92 (m, 1H), 1.81 (m, 2H), 1.66 (m, 3H), 1.47 (m, 1H), 1.18 (m, 7H), 1.04 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[N:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:20][C:19]3[C:18]([Cl:17])=[N:25][CH:24]=[CH:23][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cccnc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1cccnc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 2-chloronicotinaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C28 was scraped and collected. (100 mg)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1.[CH3:34][C:35](O)=O.[OH-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[N:3]=[C:4]([NH:17][C:18]4[CH:9]=[C:8]([CH:11]([CH3:16])[CH3:12])[CH:6]=[CH:5][C:35]=4[CH3:34])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:27][C:26]=2[O:32][CH3:33])[CH:24]=1
Reactant: CC(=O)O
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(Nc3cc(C(C)C)ccc3C)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Gp) (26.0 mg, 100 μmol) in Dioxane (Ratio: 1, Volume: 175 μl) was added 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (22.37 mg, 100 μmol) and AcOH (Ratio: 1.000, Volume: 175 μl). The resulting mixture was brought to 100° C. and stirred overnight. The reaction mixture was brought to pH 10 by the addition of 1 N aqueous NaOH. The resulting mixture was extracted with EtOAc (3×4 mL). The combined organic extracts were washed with brine (4 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was purified by Prep HPLC to yield the title compound. LC-MS (M+H)+=565.2.