Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:22]([NH:21][NH:20][C:18]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: [H][H]
Reactant: CCCC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 90.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N-butanoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 235 (0.31 g, 0.86 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-N′-butanoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 236 (0.21 g, 90%) as a brown foam.
Reaction SMILES: C(C1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:4]=1)#N.[C:21]([OH:24])(=[O:23])[CH3:22]>Cl>[CH3:9][C:7]1[CH:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:4]=[C:22]([C:21]([OH:24])=[O:23])[CH:8]=1
Reactant: Cc1cc(C#N)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1

Procedure:
2-cyano-4-methyl-6-[3-(trifluoromethyl)phenoxy] pyridine (2.055 g, 0.0074 mol) was heated and stirred in 10 ml of concentrated hydrochloric acid and 6 ml of acetic acid at 100° C. for 5 hours. Thereafter, the obtained reaction solution was concentrated under reduced pressure. The obtained residues were mixed with water. The precipitated solids were filtered out, washed with water, and then dried.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:2]1.[Si]([C:17]#[N:18])(C)(C)C>C(Cl)Cl>[C:17]([C:3]1([NH:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:4][CH2:5][O:1][CH2:2]1)#[N:18]
Reactant: CC(C)(C)S(=O)N=C1CCOC1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(C#N)CCOC1
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of Intermediate 334A (300 mg, 1.585 mmol) in DCM (10 mL) at RT was added TMSCN (198 μL, 1.477 mmol) dropwise, followed by Ti(OEt)4 (318 μL, 1.426 mmol). The resulting solution was stirred for 12 h. The reaction was quenched by pouring it into a vigorously stirred saturated aq. solution of NaHCO3 (20 mL). The precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude compound was triturated with diethyl ether to afford Intermediate 334B (150 mg, 44% yield) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.48-6.36 (m, 1H), 4.05 (d, J=9.0 Hz, 1H), 3.87 (d, J=8.5 Hz, 3H), 2.49-2.33 (m, 2H), 1.21-1.10 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([NH2:23])=[N:20][C:19]=2[CH:24]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([NH:23][CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])=[N:20][C:19]=2[CH:24]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: Nc1nc2cc(Cl)ccc2o1
Product: CC1(C)Oc2ccncc2C(Nc2nc3cc(Cl)ccc3o2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 5-chloro-benzooxazol-2-ylamine as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]3[C:17]([OH:18])=[N:16][CH:15]=[N:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2].[OH2:19]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]3[C:17]([OH:18])=[N:16][CH:15]=[N:14][C:13]=23)=[CH:7][CH:8]=1)(=[O:19])[CH3:2]
Reactant: O
Reactant: CCc1ccc(-c2cnn3c(O)ncnc23)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CC(=O)c1ccc(-c2cnn3c(O)ncnc23)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 8-(4-ethylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (240 mg) in acetic acid (5 ml) are added chromium trioxide (500 mg) and water (1 ml), and the mixture is stirred at room temperature for 14 hours. To the reaction mixture is added water, and the insoluble material is separated by filtration, washed with water and dried to give the title compound (150 mg).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].Cl[C:15]1[N:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[CH:12]=[O:13])[N:16]=[N:17][CH:18]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1cnnc(Oc2c(C=O)c(C(F)(F)F)nn2C)c1
Yield: 55.8 %

Procedure:
5-Hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (3.0 g, 0.015 mole), 3-chloro-5-methoxypyridazine (2.3 g, 0.015 mole), 2,6-lutidine (2.8 g, 0.025 mole), and toluene (80 mL) were heated in a flask equipped with a short Vigreux column until 5 mL of solvent had distilled. The mixture was then held at reflux for 4 hours, cooled, poured into 1% hydrochloric acid, and extracted with a mixture of ether and ethyl acetate. The combined extracts were washed with 1% hydrochloric acid, 1% sodium hydroxide, 5% sodium chloride, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/cyclohexane to give 5-[(5-methoxy-3-pyridazinyl)oxy]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (2.53 g, 55% yield) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1([CH3:22])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClC(Cl)C>[CH3:13][C:10]1([CH3:14])[N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C:8]([CH3:22])([C:6]2[O:3][C:1]([CH3:2])=[N:4][N:5]=2)[CH2:12][O:11]1
Reactant: CC(=O)NNC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CC(Cl)Cl
Product: Cc1nnc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 320 mg of tert-butyl 4-[(2-acetylhydrazino)carbonyl]-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate in 10 ml of dichloroethane was added 358 mg of a Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt), followed by stirring at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 84 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1c[nH]c(CC(NS(C)(=O)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methanesulfonamide in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.5 Hz, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.91 (dd, J=4.2, 8.7 Hz, 1H), 7.67 (td, J=3.0, 8.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 4.95 (t, J=8.1 Hz, 1H), 3.59 (dd, J=8.1, 14.8 Hz, 1H), 3.41 (dd, J=8.1, 14.8 Hz, 1H), 2.66 (s, 3H), 2.48 (dd, J=14.7, 19.7 Hz, 2H), 1.96 (s, 3H), 1.20 (q, J=7.2, 14.7 Hz, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.79 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CCCCCn1/c(=N/N=Cc2ccccc2)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of (2E)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (104 mg, 44 μmol), benzaldehyde (44.7 μl, 44 μmol) in ethanol (10 ml) was stirred at 70° C. for 3 hours. The reaction solution was concentrated in vacuo to give the desired product. LCMS calculated for C17H21N6O (M+H): 325.2. Found: 325.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]12(O)[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1>C1C=CC=CC=1>[Cl:3][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OC12CCCC(C1)C1CCC2C1
Solvent: c1ccccc1
Product: ClC12CCCC(C1)C1CCC2C1
Yield: 89 %

Procedure:
Five milliliters of thionyl chloride are added to a solution of 5.0 g (30 millimoles) tricyclo [4.3.1.12,5 ] undecane-1-ol in 30 ml dry anhydrous benzene and the entirety is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure and there is further added 20 ml of dry benzene. Reduced pressure concentration is repeated to distill out the excess thionyl chloride completely. The residue is distilled under reduced pressure to collect a fraction boiling at 95° C./3mmHg, to obtain 5.0 g (yield 89%) of 1-chlorotricyclo [4.3.1.12,5 ] undecane.
Reaction SMILES: [C:1]([Si:5]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][C:23]=3Cl)[NH:18][N:17]=2)[C:9]=1[F:26])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O>[Si:5]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[N:22][CH:23]=3)[NH:18][N:17]=2)[C:9]=1[F:26])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncnc(Cl)c23)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncncc23)c1F

Procedure:
A solution of tert-butyl-[2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,5,6-trifluoro-4-pyridyl]-dimethyl-silane (398 mg, 1.00 mmol), triethylamine (100.7 mg, 138.7 μL, 0.9953 mmol) in EtOAc (19 mL) was subjected to hydrogenation using H-cube apparatus. The following conditions were used to transform the starting material to subtitle product; 1×500 μL injection at 100 μL/min @ 70° C. followed by 4×4000 μL injection of reagent solution run at 150 μL/min @ 70° C. The product fractions were combined, diluted with EtOAc, washed with water (3×), brine, dried (MgSO4), filtered and concentrated in vacuo to give the sub title product as an orange solid (172 mg, 43.2% Yield). H1 NMR (400 MHz, DMSO) δ 14.59 (1H, s), 9.66 (1H, s), 9.10 (1H, m), 0.96 (9H, s) and 0.48 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-])=O)[C:7]=2[N:20]=1>[Ni].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][NH2:17])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCO1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(n1)c(CCN)c1n2CCCO1

Procedure:
Under a hydrogen pressure of 55 psi, 410 mg (1.48 mmol) of the compound obtained in Step I and 165 mg of Raney nickel are stirred in 20 ml of methanol at 60° C. for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to yield the title amine in the form of a brown oil.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)Cn1cncn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
9.2 g of sodium hydroxide are added to a solution of 16.8 g of 1,2,4-triazole in 150 ml of N-methylpyrrolidone and the mixture is heated at 50° C. for 30 minutes. After the reaction mixture has been cooled to room temperature, 73.1 g of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene, dissolved in 100 ml of N-methylpyrrolidone, are slowly added dropwise to the solution and stirring is carried out for 12 hours at room temperature. Thereafter, 200 ml of water are added and the mixture is extracted several times with methyl tert-butyl ether, and the organic phase is washed twice with water, dried over sodium sulfate and evaporated down. The remaining residue is chromatographed over silica gel using 9:1 n-hexane/ethyl acetate to give 38 g (71%) of Z-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-4,4-dimethylpent-1-ene, which can be crystallized from methyl tert-butyl ether/n-hexane (mp.: 81°-84° C., compound No. A1).
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccccc2)cc1)C(O)C(=O)OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccccc2)cc1
Yield: 61.3 %

Procedure:
To a solution of 0.3 g of metallic sodium in 30 ml of anhydrous methanol was added a solution of 3.1 g of methyl 2-hydroxy-3-(4-biphenylyl)-3-butenoate in 10 ml of anhydrous methanol. The resulting mixture was refluxed for 30 minutes and then cooled, and thereto was added 3 ml of glacial acetic acid. The mixture was distilled at a low temperature and under reduced pressure to remove the methanol therefrom. To the residue were added ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. 3.0 Grams of the crude crystals was recrystallized from isopropyl alcohol to obtain 1.9 g of methyl 3-methyl-3-(4-biphenylyl)-pyruvate, m.p. 84.5°-86.5° C. The yield was 61% (theoretical value).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1>CC(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reaction time: 16 h

Procedure:
A solution of Example 1 (14.1 g, 32.5 mmol) and the (S,S) catalyst described by Noyori in Angew. Chem. Int. Ed. Engl. 1997, 36, 285 (998 mg, 1.62 mmol) in IPA (20 mL) and CH2Cl2 (10 mL) was stirred at rt. After 16 h, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification: 1H NMR δ 1.43 (s, 3H), 1.56 (s, 3H), 1.96 (dd, J=9.7, 13.4, 1H), 2.06 (d, J=7.3, 1H), 2.28 (dd, J=6.2, 13.5, 1H), 5.00 (m, 1H), 7.03 (d, J=8.5, 2H), 7.18-7.26 (m, 5H), 7.90 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH:13]([CH3:15])[CH3:14].[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]12([CH2:26][C:27]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH:13]([CH3:15])[CH3:14])=[O:28])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.9 %

Procedure:
3-Amino-2-isopropyl-4(3H)-quinazolinone (Aldrich, 97.5 mg, 0.48 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (107.0 mg, 0.50 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (76.4 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21-1.26 (m, 6H), 1.60-1.75 (m, 12H), 1.94-1.99 (m, 3H), 2.09-2.20 (m, 2H), 3.09-3.18 (m, 1H), 7.50-7.55 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.82-7.88 (m, 1H), 8.12 (dd, J=7.9, 1.2 Hz, 1H), 10.80 (s, 1H) ppm; MS (DCI/NH3) m/z 380 (M+H)+; Elemental Analysis: Calculated for C23H29N3O2: C, 72.79; H, 7.70; N, 11.07. Found: C, 72.79; H, 7.81; N, 11.07.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH2:36]C5SC=CC=5)[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].S1[CH:49]=[CH:48][CH:47]=C1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][C:48]([CH3:47])([CH3:49])[CH2:36][NH:35][CH2:34][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:42]([NH2:44])=[O:43])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCc1cccs1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5cccs5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC(C)(C)C)c4)cc23)CC1
Yield: 59.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (30.6 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 30.4 mg of the title compound (59.5%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.[Br:30][C:31]1[C:39]2OC(C3C=CC(C([O-])=O)=CC=3)=[N:36][C:35]=2[CH:34]=[C:33]([C:49]#[N:50])[CH:32]=1>>[Br:30][C:31]1[C:39]2[O:25][C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:17]([NH:16][CH2:15][CH:12]4[CH2:13][CH2:14][N:9]([C:5]5[N:4]=[C:3]([C:2]([F:29])([F:1])[F:28])[CH:8]=[CH:7][N:6]=5)[CH2:10][CH2:11]4)=[O:18])=[CH:20][CH:21]=3)=[N:36][C:35]=2[CH:34]=[C:33]([C:49]#[N:50])[CH:32]=1
Reactant: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25) and 3-amino-5-bromo-4-hydroxybenzonitrile (INTERMEDIATE 1, Step B) by a procedure analogous to that described in Example 109. Mass spectrum (ESI) 587.0 (M+3).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:47][CH2:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][C:50]=1[C:57]([F:60])([F:59])[F:58]>ClCCl>[C:53]([C:52]1[CH:55]=[CH:56][C:49]([CH2:48][NH:47][C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:15][CH2:14]2)=[O:18])=[C:50]([C:57]([F:58])([F:60])[F:59])[CH:51]=1)#[N:54]
Reactant: N#Cc1ccc(CN)c(C(F)(F)F)c1
Reactant: CNc1nc(C)nc(N2CCC(C(=O)O)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNc1nc(C)nc(N2CCC(C(=O)NCc3ccc(C#N)cc3C(F)(F)F)CC2)n1
Yield: 3.1 %

Procedure:
1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (163 mg, 0.65 mmol) was dissolved in 10 mL of dichloromethane and treated with EDCI (150 mg, 0.72 mmol), HOBt (88 mg, 0.65 mmol), N-methylmorpholine (0.2 mL, 1.5 mmol), and 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (130 mg, 0.65 mmol) at room temperature for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC to provide N-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxamide (7 mg, 0.02 mmol, 2%) as a white solid. MS (ES+): m/e 434 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>N1C=CC=CC=1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OC(F)F)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
0.18 mL of 4-difluoromethoxybenzene sulfonyl chloride (1.13 mmol) were added to a solution of 0.25 g of (1.13 mmol) 4-methoxy-3-(4-methyl-piperazin-1-yl)-phenylamine in 10 mL of pyridine. The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated at reduced pressure. After addition of toluene and dichloromethane the mixture was again evaporated twice. The thus obtained residue was partitioned between dichloromethane and 5% aqueous ammoniumchloride. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was further purified via HPLC to yield 0.395 g of the desired title compound.