Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)Cl.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>O.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)OCc2ccccc2)n2oc(=O)nc2n1

Procedure:
4.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 50 ml. of methylene chloride and 5 ml. of triethylamine and cooled to 0° C. 5 ml. of benzyl chloroformate are slowly added dropwise while stirring. The mixture is then stirred at 0° C. for 1 hour, subsequently treated with water and adjusted to pH 4 with 2-N hydrochloric acid. The aqueous phase is extracted twice with methylene chloride and the combined organic extracts are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure benzyl 5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate, having a melting point of 171°-173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:45][CH2:44][CH2:43][C:42]1=[O:46]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][N:41]4[CH2:45][CH2:44][CH2:43][C:42]4=[O:46])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCCN3CCCC3=O)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-{[4-(methylsulfonyl)phenyl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.25 (t, J=5.3 Hz, 1 H), 8.57 (s, 1 H), 7.84 (d, J=8.2 Hz, 2 H), 7.20 (d, J=8.1 Hz, 2 H), 7.02-6.97 (m, 5 H), 5.45 (br, 2 H), 4.02 (s, 2 H), 3.50-3.38 (m, 6 H), 3.03 (s, 3 H), 2.39 (t, J=7.9 Hz, 2 H), 2.04 (m, 2 H), 1.88 (m, 2 H); HRMS C31H31FN4O6S (M+H)+ calcd 607.1948, found 607.2043.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])(C)C)=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2].[CH3:24][CH:25]([CH3:37])[CH2:26]CCC1C=CC(C#C)=CC=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:22][CH2:24][CH:25]([CH3:37])[CH3:26])=[CH:17][CH:18]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Reactant: C#Cc1ccc(CCCC(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc(CCCC(C)C)cc2)nc1

Procedure:
Using the same general procedure as described for Compound 3, but using instead 4-(4-methylpentyl)phenylethyne (Compound 26), the title compound was synthesized as a yellow solid. PMR (CDCl3): & 0.91 (6H, d, J~6.6 Hz), 1.20-1.30 (1H, m)., 1.47 (3H, t, J~7.2 Hz), 1.51-1.72 (3H, m), 2.63 (2H, t, J~7.8 Hz), 4.45 (2H, q, J~7.2 Hz), 7.22 (2H, d, J~8.4 Hz), 7.53-7.64 (3H, m), 8.30 (1H, dd, J~8.1 Hz, 2.1 Hz), 9.23 (1H, d, J~2.1 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O>[N:1]1([C:11]2[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCc1cccc(I)c1
Reactant: c1ccc2[nH]ncc2c1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1cccc(-n2ncc3ccccc32)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a round bottom flask was added 1H-indazole (0.47 g, 4.0 mmol), (3-iodophenyl)methanol (1.4 g, 6.0 mmol), ferric chloride (0.13 g, 0.8 mmol), and tri-potassium phosphate monohydrate (1.84 g, 8.0 mmol). Degassed water (2 mL) was then added followed by (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.25 mL, 1.6 mmol). The reaction mixture was then heated to 135° C. and stirred overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford [3-(1H-indazol-1-yl)phenyl]methanol (0.67 g, 74%). LC-MS: (FA) ES+ 225.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Fe]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iron powder (10 g) was added to a solution of the product from step (ii) (20 g) in acetic acid (200 mL) and MeOH (100 mL). The mixture was stirred at rt for 30 min then evaporated under reduced pressure. The residue was partitioned between DCM and water, the organics separated, washed with aq NaHCO3 solution, water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 3-5% MeOH in DCM to give a brown oil, 10.1 g.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[N:13][CH:14]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(5-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.92 g, 3.6 mmol) and hydrazine hydrate (0.80 ml, 16 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.55 g, 67%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](C(O)=O)=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.C(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(Cl)ccc1-2
Agent: O=C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(Cl)ccc2-n2cncc2[C@@H]2CCCN12

Procedure:
5.8 g (18.2 mmol) of (S)-7-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid are heated to 230°. After completion of the carbon dioxide evolution, the melt is treated with ethyl acetate. The solid material is filtered off under suction and dried. There is obtained (S)-7-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 216°-217°.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:9]=[C:10]1[NH:16][C:15]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=2[NH:13][CH2:12][CH:11]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O=C1NC2C=CC=CC=2NCC1NC(OC(C)(C)C)=O>>[O:9]=[C:10]1[NH:16][C:15]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=2[N:13]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:12][CH:11]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Agent: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCC1

Procedure:
Step 1 of Example 1 was repeated except that cyclopentylcarbonyl chloride was used instead of pivaloyl chloride, and that 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 4 was used instead of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: CN(C=O)C.[CH3:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=23)[CH2:8]1.[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40]([N:12]2[CH2:11][CH2:10][N:9]([C:13]3[N:14]=[N:15][C:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[CH2:8][C@@H:7]2[CH3:6])=[O:41])[CH2:36][CH2:35]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1C(=O)N1CCC(F)(F)CC1
Temperature: 75 °C

Procedure:
DMF (3 mL) was added to (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (150 mg, 402 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (230 mg, 803 μmol), potassium carbonate (167 mg, 1.2 mmol), 4-dimethylaminopyridine (9.8 mg, 80 μmol). The reaction was heated to 75° C. for 72 h. The reaction was diluted with ethyl acetate (70 mL) and washed with 1×10 mL water, 1×10 mL NaHCO3, and 1×10 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 48. MS 520.2 (calc'd) 521.2 (M+H, found).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([CH3:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])[CH:18]=3)=[CH:13][CH:12]=2)=[N:8][N:7]=1>CO>[CH:28]1([NH:27][C:25]([C:19]2[CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:9]4[O:10][C:6]([CH2:5][O:2][CH3:1])=[N:7][N:8]=4)=[CH:12][CH:13]=3)[C:22]([CH3:23])=[C:21]([F:24])[CH:20]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Freshly prepared sodium methoxide in methanol (0.2M, 0.8 ml) was added to a solution of (4′-[5-chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (50 mg) in methanol (1 ml) and the reaction stirred at room temperature for 18 hours. Further sodium methoxide in methanol (0.2M, 1.6 ml) was added and the reaction continued for 72 hours. The reaction was reduced to dryness under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was reduced to dryness and loaded onto a bond-elut (silica, 10 g). Eluted with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-5-fluoro4′-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([N+:34]([O-])=O)=[CH:18][N:17]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([NH2:34])=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc(N)c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-4-(2,4-dimethoxybenzylamino)-3-(4-(6-fluorochroman-4-ylamino)-5-nitropyrimidin-2-ylamino)benzonitrile (prepared as described below in example 26, paragraph [0157]) (12 mg) in THF (5 mL) was added a premixed solution of sodium hydrosulfite (100 mg) and sodium bicarbonate (50 mg) in water (10 mL). MeOH (1 mL) was also added to aid solution of the mixture, which was stirred at room temperature for 30 min, when sodium chloride was added to saturate the solution. The resultant mixture was extracted with EtOAc (2×), the combined organics were dried, filtered and evaporated to yield (R)-4-(2,4-dimethoxybenzylamino)-3-(5-amino-4-(6-fluorochroman-4-ylamino)pyrimidin-2-ylamino)benzonitrile that was used as such for the next step, MH+=542.
Reaction SMILES: C([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][CH2:11][CH2:12][NH:13]C(C(F)(F)F)=O)(OC(C)(C)C)=O.N[C@H](C(C(OC)=O)=O)CCCNC(C(F)(F)F)=O.CN1CCOCC1>>[NH2:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)C(F)(F)F)C(=O)O
Agent: COC(=O)C(=O)[C@@H](N)CCCNC(=O)C(F)(F)F
Solvent: CN1CCOCC1
Product: NCCC[C@H](N)C(=O)O
Yield: 97 %

Procedure:
Bi-directional synthesis was then initiated by the coupling of acid 6 with amine 7 using isobutyl chloroformate for activation of 6 and NMM as a base, as shown in Scheme 2. This reaction proceeded smoothly to give the fully protected ornithine dimer 9 in 97% yield with sufficient purity after extractive work-up to be utilized directly in subsequent reactions. Ornithine dimer 9 was divided into two equal portions. The first part was hydrogenated giving 11 in quantitative yield, while the second part was treated with HCl giving the amine hydrochloride salt 10 in 83% yield. Both compounds were of sufficient purity after work-up to be utilized directly in the subsequent coupling.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:13]([CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:20])=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Yield: 92 %

Procedure:
To a solution of 3.4 g of 2-benzyl-3-phenylpropionic acid ethyl ester in 170 ml of ethanol was added 34 ml of a 2N-aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was washed with diethyl ether to remove neutral materials, then the aqueous solution was acidified by adding concentrated hydrochloric acid. The aqueous solution was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.8 g of 2-benzyl-3-phenylpropionic acid as colorless crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:20][C:19]3=[CH:21][N:22]=[C:23]([CH3:24])[N:18]3[C:17]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>[C].[Pd].CO>[CH3:24][C:23]1[N:18]2[C:17](=[O:25])[N:16]([CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:20][C:19]2=[CH:21][N:22]=1
Reactant: Cc1ncc2n1C(=O)N(CCC1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd]
Solvent: CO
Product: Cc1ncc2n1C(=O)N(CCC1CCNCC1)C2
Yield: 47.7 %

Procedure:
2-(2-(1-Benzyl-4-piperidinyl)ethyl)-5-methyl-1,2-dihydroimidazo[1,5-c]imidazol-3-one (4.0 g) obtained in Example 96a) and 10% palladium carbon (0.8 g) were added to methanol (100 ml), and mixed under hydrogen atmosphere at room temperature for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate, ethyl acetate/methanol=20/1). The product was recrystallized from ethyl acetate-hexane to obtain the title compound (1.4 g, 48%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][N:4]=1.[H][H]>[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CNc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CO
Product: CNc1nccc(-c2ccccc2Oc2ccc(N)cc2)n1
Reaction time: 24 h

Procedure:
To N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.667 g, 2.1 mmol) and palladium, 10 wt. % on activated carbon, wet (0.44 g, 0.41 mmol) in a 100 mL round bottom flask was added MeOH under nitrogen via syringe. The atmosphere was replaced with hydrogen from a balloon and the mixture stirred rapidly for 24 h. The reaction was flushed with nitrogen, and filtered through celite rinsing with 100 mL MeOH. The filtrate was concentrated in vacuo to give 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine as a light yellow solid. MS m/z=293 [M+1]+. Calc'd for C17H16N4O: 292.34.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
2,3-Dichloropyrazine (1.0 g, 0.0067 mol), tert-butyl-4-(aminomethyl)-piperidine-1-carboxylate (1.6 g, 0.0075 mol) (Astatech) and cesium carbonate (2.4 g, 0.0075 mol) in acetonitrile (10 mL)were heated to 90° C. under nitrogen for 18 h. The reaction was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic extract was dried over sodium sulfate, filtered and chromatographed on silica using a gradient of 10 to 30% ethyl acetate/hexane to give the title compound as a foam. M.S. (M+1): 327
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[C:40]([NH:43][NH2:44])(=[O:42])[CH3:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[C:40]([NH:43][NH:44][C:36](=[O:37])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1)(=[O:42])[CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.50 g), acetohydrazide (0.085 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole (0.15 g) and N,N-dimethylformaldehyde (5 mL) was stirred at room temperature for 22 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.42 g, 76%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:11]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C@@H:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][C@H:18]2[CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]=1[C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=O)=O>[Pd].C(OCC)(=O)C>[CH2:27]([O:26][CH2:25][C@@H:18]1[CH2:19][C:20]([F:23])([F:24])[CH2:21][CH2:22][C@H:17]1[C:9]1[C:8]([C:34]2[CH:35]=[CH:36][C:37]([S:40]([CH3:43])(=[O:41])=[O:42])=[CH:38][CH:39]=2)=[CH:7][N:11]([CH2:12][C:13]([F:15])([F:16])[F:14])[N:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2c([C@@H]3CCC(F)(F)C[C@H]3COCc3ccccc3)nn(CC(F)(F)F)c2OS(=O)(=O)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2COCc2ccccc2)cc1

Procedure:
A mixture of 3-{(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate (4.54 g, 6.58 mmol) and 10% palladium on charcoal (2.20 g) were stirred together in ethyl acetate (60 mL) under an atmosphere of hydrogen gas at rt for 16 h. Filtration through Celite®, concentration of the filtrate and flash chromatography on silica gel eluting with 45/55 ethyl acetate/hexanes yielded 3-{(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole as a colorless, thick syrup.