Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4].[CH2:31](I)[CH2:32][CH3:33]>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C#N)cn3)ccc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Sodium hydride (0.08 9, 3.16 mmol) was added to a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 264) (0.6 g, 1.58 mmol) in DMF (15 mL). The heterogeneous mixture was stirred at rt for 30 min. Propyl iodide (0.62 mL, 6.32 mmol) was added, and the mixture was stirred at rt for 18 h. The excess NaH was quenched by the addition of water (5 mL) and the aqueous phase extracted with Et2O. The combined Et2O extracts were washed with water and brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.63 g, 99%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.35 (dd, 1H), 7.54 (dd, 1H), 7.06 (d, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 4.17 (q, 2H), 3.99 (t, 2H), 3.72 (t, 2H), 3.56-3.44 (m, 3H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.46-2.35 (m, 2H), 2.12-2.05 (m, 2H), 1.72-1.58 (m, 3H), 1.28 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:35](Cl)([Cl:37])=[O:36].C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:14]([CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:13][N:12]([C:35]([Cl:37])=[O:36])[CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 8, rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 16 (0.3 g, 0.74 mmol) was reacted with a toluene solution (Aldrich, 20%) of phosgene (0.7 mL, 1.3 mmol) and saturated aqueous NaHCO3 solution (5 mL) in dichloromethane (5 mL) to give rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride as a yellow oil (Yield, 0.34 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][C:5]([S:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:12][S:13]([O:11][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([S:8][CH2:9][CH3:10])[N:4]=1)(=[O:15])=[O:14]
Reactant: CCSc1ccc(Cl)c(O)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCSc1ccc(Cl)c(OS(C)(=O)=O)n1
Temperature: 40 °C
Yield: 93.5 %

Procedure:
5 g of 3-chloro-6-ethylthio-2-pyridinol and 3.7 g of methanesulfonyl chloride were dissolved in 50 ml of methylene chloride, followed by stirring. 4 g of triethylamine was added dropwise to the solution at 10° C. or below and the obtained mixture was allowed to stand to lower the temperature to room temperature. The mixture was heated to 40° C. and stirred for 2 hours. 50 ml of chilled water was poured into the reaction mixture to separate the methylene chloride layer. The water layer was further extracted with 50 ml of methylene chloride. The obtained methylene chloride layer was combined with the above methylene chloride layer. The combined layer was washed with water and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (with toluene and n-hexane) to obtain 6.6 g of objective 3-chloro-6-ethylthio-2-pyridyl methanesulfonate as a colorless crystal (yield: 93.4%). m.p. 40° to 41° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[C:18]([NH2:25])=[N:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:25][C:18]2[C:19]3=[N:24][CH:23]=[CH:22][N:21]=[C:20]3[NH:16][N:17]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1n[nH]c2nccnc12
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2nccnc12
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate 3) (0.10 g, 0.351 mmol), 1H-pyrazolo[3,4-b]pyrazin-3-amine (0.047 g, 0.702 mmol), HATU (0.133 g, 0.351 mmol) and N-methylmorpholine (0.069 ml, 0.702 mmol) in DMF (5 ml) was stirred at 75° C. for 90 minutes. After cooling to RT, the mixture was diluted with water (30 ml) and the resulting orange precipitate was filtered under vacuum and washed with water. Purification of the resulting solid by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100% EtOAc) to afforded the title compound as an orange solid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:14](OC)=[O:15])[C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1.[Cl-].[Ca+2].[Cl-].Cl.O1CCOCC1>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1cc(Br)cnc1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1COCCO1
Product: OCc1cc(Br)cnc1CO
Temperature: 23 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (15.9 g, 420 mmol) was added portionwise over 30 min to a solution of dimethyl 5-bromopyridine-2,3-dicarboxylate (20 g, 73 mmol) in ethanol (460 mL) precooled to 0° C. A solution of calcium chloride (23.3 g, 209 mmol) in 150 mL was added slowly at 0° C., and the reaction mixture was warmed to 23° C. and stirred overnight. Excess sodium borohydride was quenched by slow addition of aqueous 2 N HCl solution (230 mL, 460 mmol), followed by a stirring at 23° C. for 2 h. The mixture was concentrated to dryness. Saturated aqueous sodium bicarbonate solution was added to the residue until a pH of approximately 7 was reached. The aqueous mixture was extracted with 2-methyltetrahydrofuran (4×200 mL). The combined organic layers were dried over sodium sulfate then treated with a solution of 4 N HCl in dioxane (25 mL, 100 mmol). The resulting solid was filtered, washed with 2-methyltetrahydrofuran, and dried to give the title compound as a hydrochloride salt. MS: m/z=218.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1cc(C)nc(N2CCNCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (0.7 g, 3.66 mmol) and 1-chloro-4-nitro-benzene (0.69 g, 4.39 mmol) in toluene was added caesium carbonate (2.38 g, 7.32 mmol), then the mixture was stirred for 30 min. under an argon atmosphere. A solution of palladium(II) acetate (50 mg, 0.22 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (50 mg, 0.13 mmol) in THF was purged with argon for 30 min then added to the substrate mixture, and the resulting mixture was heated at 80° C. for 4 h. It was then allowed to cool and concentrated to dryness, and the resulting residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to a residue which was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate/petroleum ether as eluent. This afforded 1-(4,6-dimethyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine (0.4 g, 35%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:27][CH3:28])=[N:12][N:13]3[C:18](O)=[C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([CH3:26])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:31]>>[C:1]1([S:7]([C:10]2[C:11]([S:27][CH3:28])=[N:12][N:13]3[C:18]([Cl:31])=[C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([CH3:26])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)nc2c(S(=O)(=O)c3ccccc3)c(SC)nn2c1O
Product: CCOC(=O)Cc1c(C)nc2c(S(=O)(=O)c3ccccc3)c(SC)nn2c1Cl
Temperature: 25 °C
Yield: 94 %

Procedure:
A suspension of 1.5 g (3.56 mmol) of ethyl 2-(3-benzenesulphonyl-7-hydroxy-5-methyl -2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-6-yl)-acetate in 30 ml of POCl3 was heated at reflux for 4 hrs. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 70 ml of CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated.Chroma-tography (SiO2, CH2Cl220:1) of the residue yielded 1.0 g (94%) of ethyl 2-(3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-6-yl)-aceate as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:2]1.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[C:33]4[CH:36]=[C:37]([S:40]([N:1]5[CH2:4][CH:3]([N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)[CH2:2]5)(=[O:42])=[O:41])[CH:38]=[CH:39][C:32]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: C1CN(C2CNC2)CCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CC(N4CCOCC4)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-azetidin-3-ylmorpholine (52 mg, 0.36 mmol) and NEt3 (84 μL, 0.61 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (100 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-6% 2M NH3/MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 122 (40 mg, 65%). LCMS: RT 3.00 min [M+H]+ 500.3. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=2.40 Hz), 8.02 (1H, s), 7.94 (1H, d, J=0.62 Hz), 7.72 (1H, dd, J=8.62, 2.42 Hz), 7.32 (1H, d, J=8.62 Hz), 5.73-5.64 (1H, m), 4.64-4.63 (4H, m), 3.78 (2H, t, J=7.73 Hz), 3.58 (2H, dd, J=8.39, 5.80 Hz), 3.42 (4H, t, J=4.34 Hz), 3.03-3.01 (1H, m), 2.15-2.09 (4H, m), 1.49 (6H, d, J=6.62 Hz)
Reaction SMILES: [ClH:1].CCOC(C)=O.[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=1)=[O:10]>CCOC(C)=O>[ClH:1].[NH:23]1[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][C:14]2[CH:13]=[C:12]([NH:11][C:9]([NH2:8])=[O:10])[CH:17]=[CH:16][CH:15]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(NC(N)=O)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)Nc1cccc(CCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M hydrogen chloride/EtOAc (4 ml) was added to an EtOAc (9 ml) solution of tert-butyl 4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidinecarboxylate (227 mg), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain 1-{3-[2-(4-piperidyl)ethyl]phenyl}urea hydrochloride (185 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18][CH2:17]1)(=[O:15])=[O:14]>ClCCl>[CH3:12][S:13]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19](=[O:9])[CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N1CCSc2ccccc2C1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCS(=O)c2ccccc2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (1.4 g) in dichloromethane (200 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared as Example 17 above) in dichloromethane (50 ml). The reaction mixture was stirred for 15 minutes, washed with water, dried and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethanol. Yield 1.65 g (m.p. 195°-197° C.).
Reaction SMILES: [CH2:1]([C:5]1([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([C:14](C(OCC)=O)([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])C(OCC)=O)[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([C:5]1([CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:34])[C:9]([Cl:33])=[C:10]([CH2:14][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:11]=2)[C:6]1=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C2CCCC2)Cc2cc(C(CCCC(=O)OCC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CCCCC1(C2CCCC2)Cc2cc(CCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
The starting material, 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one, dissolved in dimethylformamide was treated with potassium carbonate and trifluoromethanesulfonyl chloride to form (2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate (Step 1). This material was subjected to triflate displacement by reaction with diethyl malonate to form diethyl-5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate (Step 2). The malonate of Step 2 was then alkylated with ethyl 4-bromobutyrate to form diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (Step 3). Upon hydrolysis the hexanedioic acid is formed (Step 4) which undergoes monodecarboxylation by treatment with copper in quinoline to form a compound of the present invention such as 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (Step 5). The starting materials used in these examples is obtained as shown in the Journal of Medicinal Chemistry, 20, 1400 (1977); and 21, 437 (1978). This synthetic route is illustrated below: ##STR3##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:14]([O:13][C:12](=[O:18])[N:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a suspension of 10% palladium-carbon (500 mg) in methanol (4 mL), tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(3-nitrophenyl)carbamate (B12, 500 mg) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and 30 minutes under a hydrogen atmosphere. To the reaction mixture, methanol was added, the insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 75 to 70% hexane in ethyl acetate) to obtain tert-butyl(3 -aminophenyl)(2-((tert-butoxycarbonyl)amino)ethyl)carbamate (B13, 140 mg).
Reaction SMILES: CC([O-])(C)C.[K+].C(C1C=CC=CC=1)(=O)C.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC(CCO)=CC=1.C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[C:53]([CH:57]1[CH2:62][CH2:61][C:60](=[O:63])[CH2:59][CH2:58]1)([CH3:56])([CH3:55])[CH3:54]>>[C:53]([C@@H:57]1[CH2:58][CH2:59][C@H:60]([OH:63])[CH2:61][CH2:62]1)([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: O=C(c1ccccc1)c1ccccc1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CC(=O)c1ccccc1
Solvent: OCCc1ccccc1
Product: CC(C)(C)[C@H]1CC[C@@H](O)CC1

Procedure:
The effectiveness of ruthenium-aryl-aminophosphine catalysts for the hydrogenation of ketones and aldehydes was investigated. The results are summarized in Tables 1-3. Table 1 shows the hydrogenation of a variety of ketones using complex 1 (FIG. 3) and KOtBu as the catalyst at room temperature. Acetophenone and benzophenone were readily converted to phenylethanol and benzhydrol, respectively. The hydrogenation of 4-tert-butylcyclohexanone was completed at room temperature and resulted in predominantly cis-4-tert-butylcyclohexanol (80%). Cis-4-tert-butylcyclohexanol is very valuable in the fragrance industry since it is used to prepare cis-4-tert-butylcyclohexyl acetate (woody acetate). The hydrogenation of the conjugated ketone benzalacetone resulted in the allyl alcohol as the only detectable product. Likewise, only the carbonyl group of 5-hexen-2-one was reduced to give the unsaturated alcohol. A 95% conversion of the ketone to the alcohol was observed in the reduction of norcamphor resulting in 75% endo-norborneol and 25% exo-norborneol. Benzaldehyde and acetyl ferrocene were converted to the respective alcohols.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH3:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][C:27]=1[CH3:32]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 ml) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (THF/diethyl ether) to yield the title compound as a white solid (0.24 g, 52%). MS (ISP) 445.9 [(M+H)+]; mp 267° C. (dec.).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])#[N:28].C(OCC)C.Cl>C(OCC)(=O)C.C(OCC)C>[ClH:25].[C:27]([C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1)#[N:28]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2c(Nc3cccc(C#N)c3)ncc(C(=O)N3CCCCC3)c12
Yield: 26.5 %

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-cyanoaniline (56 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether and then suspended in ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The mixture was evaporated and dried at 40° C. under vacuum to afford the title compound (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:15]([C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:20][N:19]=2)[N:14]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NNc1ccc(Cl)nn1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nnc3ccc(Cl)nn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-methoxyphenyl isocyanate and 3-chloro-6-hydrazinopyridazine in acetonitrile was stirred at room temperature for 30 minutes, and 1,2-dibromo-1,1,2,2-tetrachloroethane was added and the mixture was stirred at room temperature for further 2 hours. This reaction solution was combined with triethylamine and triphenylphosphine with cooling in ice, and stirred at room temperature for 3 days. Then, the reaction solution was concentrated under reduced pressure, purified by a standard method to obtain 6-chloro-N-(3-methoxyphenyl)-1,2,4-triazolo[4,3-b]pyridazin-3-amine. Dat (F:276).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[C:10]([C:12]3[S:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[C:14](=[O:22])[N:13]=3)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1cccc(-n2cccn2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-n3cccn3)n2)sc2ccccc12
Yield: 66.9 %

Procedure:
6-(Pyrazol-1-yl)-2-pyridinecarbonitrile (0.68 g, 4.0 mmol) and methyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (5 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.82 g, 67%) as pale yellow crystals.