Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.[CH2:15]([OH:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[C:8]([C:4]1[CH:5]=[C:6]([CH2:17][CH2:16][CH2:15][OH:18])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: C=CCO
Reactant: Cc1cccc(C(C)(C)C)c1O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Yield: 82 %

Procedure:
To the solution obtained above after hydrogen gas evolution had ceased, 45 g (0.27 mol) of 2-methyl-6-t-butylphenol were added, and then heated under reduced pressure, thereby 15 g (0.47 mol) of methanol were removed from the reaction system. Then, 15.9 g (0.27 mol) of allyl alcohol and 13.5 g (0.15 mol) of toluene were added thereto. The resulting solution after the addition of toluene and allyl alcohol were transferred to a pressure container, and the atmosphere thereof was substituted with nitrogen gas, sealed and heated up to 210° C. and maintained at the same temperature for 4 hours. Thereafter the reaction mixture was cooled to room temperature and a sample thereof was analyzed by gas-chromatography. The desired product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 82%.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([C:12](=O)[CH2:13][CH2:14][CH2:15]Br)[CH:8]=[CH:9][C:10]=1[Cl:11])C(C)=O.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]2[C:19]3[N:18]([CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CC(=O)Nc1cc(C(=O)CCCBr)ccc1Cl
Reactant: c1c[nH]cn1
Product: Nc1cc(C2=CCCn3ccnc32)ccc1Cl
Temperature: 25 °C

Procedure:
Combine 5 g (15.7 mmol) of 3'-acetamino-4-bromo-4'-chlorobutyrophenone with 15 g (0.22 mol) of imidazole, and heat to 175° C. for 18 hr. Isolate the crude product by crystallization from ether, and add to a solution of 5 g of potassium hydroxide in 20 ml of 1:1 solution of methanol/water. Heat to reflux for 2 hr. Cool to room temperature, and pour the reaction mixture into 100 ml of water with rapid stirring. The resulting precipitate is recrystallized from ether to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N+:1]([C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
Dinitrobenzoyl chloride is caused to react with aniline so as to give dinitrobenzanilide. Thereafter, the resulting product is caused to react with Ar--N(R)2 and oxyphosphorous chloride and to the resulting product concentrated hydrochloric acid is added to prepare a compound having the formula: ##STR5##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C@H:18]([CH2:21][CH3:22])[CH:19]=[CH2:20])[C:15](O)=[O:16])=[CH:10][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([C@@H:18]([CH2:21][CH3:22])[CH:19]=[CH2:20])[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:16])=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: C=C[C@@H](CC)[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=C[C@H](CC)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1

Procedure:
Morpholine (0.107 ml, 1.23 mmol) and the intermediate I2 (239 mg, 1.12 mmol) were dissolved in 5 ml of DMF and cooled in an ice-bath. HOBT (188 mg, 1.23 mmol), triethylamine (0.309 ml, 2.24 mmol) and EDC (214 mg, 1.12 mmol) were added successively. The ice-bath was removed and stirring continued over night. The mixture was evaporated, redissolved in diethyl ether and extracted with 2N-HCl (twice), 5% sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give a pale yellow oil. Yield (crude): 320 mg (93%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][CH3:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[N:6]([CH2:15][CH3:16])[C:7](=[O:14])[CH:8]([N:11]([CH3:12])[CH3:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:19][CH3:20])=[N:23][CH:24]=1
Reactant: CCN1C(=O)C(N(C)C)CCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(N(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC
Yield: 15.9 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-3-dimethylamino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (78 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (89 mgs) were converted to the title compound as a tan solid (24 mgs). 1H-NMR (CDCl3, 400 MHz): 9.49 (s, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.31-7.28 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 4.32-4.26 (m, 1H), 3.83 (s, 3H), 3.54-3.48 (m, 2H), 3.15-3.08 (m, 1H), 3.00-2.95 (m, 1H), 2.78 (s, 6H), 2.65-2.10 (m, 8H), 1.27-1.24 (m, 2H), 1.15 (t, J=7.1 Hz, 3H). LC/MS found (M+H)+=588.21
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.C(=O)(O)[O-:27].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH:2]([OH:27])[CH3:3])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 11 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 24, 765 mg, 2.07 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was treated with a 1.0M borane solution in tetrahydrofuran (4.14 mL, 4.14 mmol). The reaction was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and treated with ethanol (15 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (45 mL) and hydrogen peroxide (15 mL). The resulting mixture was allowed to warm from 0° C. to 25° C. over 1 h. The reaction was then slowly quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (3×30 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-(2-hydroxy-propyl)-urea (103 mg, 11%) as a white foam: [α]23589=−33.0° (c=0.094, chloroform); EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1151.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reactant: O=Cc1cccnc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NCc2cccnc2)c1

Procedure:
A solution of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (prepared in Steps (a)-(d) of the procedure used for the synthesis of EXAMPLE I1, 70.2 mg, 0.205 mmol) and nicotinaldehyde (20 μL, 0.21 mmol) in DCM (1 mL) under N2 was treated with TFA (1 mL) and after 5 min was heated at reflux for 2 h. The cooled reaction mixture was then treated with Et3SiH (70 μL, 0.44 mmol) and the mixture re-heated to reflux for 19 h. After this time the solvents and excess reagents were removed by concentration in vacuo and the crude residue purified by column chromatography over silica gel eluting with 0.7-15% MeOH/DCM to provide the title compound; MS (ES+): m/z 435 [MH+]
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31]1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:36][CH2:35][CH:32]5[CH2:33][CH2:34][N:30]([CH3:29])[CH2:31]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CN1CCC(CN)C1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Solvent: C1COCCO1
Product: CN1CCC(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 120 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), C-(1-Methyl-pyrrolidin-3-yl)-methylamine (164 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol) tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 120 mg of 117 (yield=34%). 1H NMR (CDCl3, 400 MHz): δ8.67-8.52 (m, 1H), 8.11-8.06 (m, 1H), 7.58-7.50 (m, 1H), 7.16-7.02 (m, 3H), 6.96-6.90 (m, 1H), 6.42-6.31 (m, 1H), 4.28-4.21 (m, 2H), 3.50-2.84 (m, 8H), 2.72-2.64 (m, 3H), 2.38-2.22 (m, 1H), 1.94-1.82 (m, 1H). LC-MS (ESI): m/z=495 [M+H]+
Reaction SMILES: [CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13]([O:15]CC)=[O:14])[CH2:6]2)[N:3]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:11])[CH3:12])[CH2:9][CH:4]([CH:5]([C:13]([OH:15])=[O:14])[CH2:6]2)[N:3]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CC2C(C(C)C)CC1N(Cc1ccccc1)C2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1CC2C(C(=O)O)CC1C(C)N2Cc1ccccc1
Yield: 100.5 %

Procedure:
A mixture of ethyl 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylate (32.9 g, 100 mmol), ethanol (150 mL), water (150 mL) and NaOH (4.8 g, 120 mmol) were refluxed for 18 hours. The solvent was removed in vacuo and the residue was diluted with water and washed with ether (1×50 mL). The aqueous layer was acidified with acetic acid (6.9 mL, 120 mmol) and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford 30.3 g (100%) of 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10](O)[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C1C=CC(OP(OC2C=CC=CC=2)([N:22]=[N+:23]=[N-:24])=O)=CC=1.O>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>[N:22]([C@H:10]([C:4]1[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:11])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H](O)c1cc(F)c(F)c(F)c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(3,4,5-trifluorophenyl)ethanol (3.6 g) and diphenylphosphoric azide (6.0 ml) in toluene (70 ml), 1,8-diazabicyclo[5,4,0]undec-7-ene (4.1 ml) was added dropwise under ice-cooling. The reaction solution was stirred at the same temperature for one hour and at room temperature overnight. Water was added to the reaction solution, and the organic layer was separated. Then, the aqueous layer was subjected to extraction with toluene again. The organic layers were combined and sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layers were dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=49:1) to obtain 858 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>O>[Cl:26][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A mixture of 6-phenyl-2-(4-trifluoromethylphenyl)-4-(3H)-pyrimidinone (10 g) and phosphorus oxychloride (7.3 g) was stirred at 80° C. for 3 hours. To the reaction mixture is added water, and the mixture is neutralized with an aqueous sodium hydroxide solution (1 mol/L). The precipitates are collected by filtration, washed with water, and recrystallized from isopropyl alcohol to give the desired compound (9.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:29]3[CH:28]=[N:27][CH:26]=[N:25][C:24]=3[N:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1.CCCP(O)(O)=O.C(N(CC)CC)C>C1COCC1>[C:30]([N:23]1[C:24]2[N:25]=[CH:26][N:27]=[CH:28][C:29]=2[C:21]([C:19]([C:15]2[CH:14]=[C:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:18]=[N:17][CH:16]=2)=[O:20])=[CH:22]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1ccc(F)cn1
Agent: CCCP(=O)(O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(F)cn3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
2-(5-Fluoropyridin-2-yl)acetic acid (23.1 mg, 0.149 mmol) (see Preparation 92) was added to (5-aminopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (40 mg, 0.135 mmol) (see Preparation 31), 1-propylphosphonic acid cyclic anhydride (0.2 mL, 0.338 mmol, 50% in EtOAc) and triethylamine (0.65 mL, 0.474 mmol) in THF (3 mL). The mixture was stirred at 25° C. for 18 hours, evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and the residue was triturated with pentane:diethyl ether (3:1, 1 mL) to afford the title compound as an off white solid in 65% yield, 38 mg.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:14][C@@H:13]1[CH2:28][OH:29])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:14][C@@H:13]1[CH:28]=[O:29])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add sulfur trioxide pyridine complex (7.6 g, 47.8 mmol) in dimethylsulfoxide (27.0 mL, 382.4 mmol) to (2R, 5R)-5-Benzyloxymethoxy-2-hydroxymethyl-piperidine-1-carboxylic acid 1-tert-butyl ester (8.4 g, 23.90 mmol) in triethylamine (20.0 mL, 143.4 mmol) at 10° C. and stir at room temperature for 30 minutes. Add water and extract with diethyl ether. Combine the organic layers, wash with 5% citric acid followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate to provide the desired compound. (8.0 g crude)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH2:6]2)[CH3:2].[C:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:34])[CH2:28]2)(=[O:24])[CH3:23]>>[C:22]([C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH2:1][CH3:2])[CH2:6][C:7]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:12])[CH2:8]2)(=[O:24])[CH3:23].[CH2:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29]([NH:35][C:36](=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH3:34])[CH2:28]2)[CH3:23]
Reactant: CC(=O)c1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2
Product: CCc1cc2c(cc1C(C)=O)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
N-(5-Acetyl-6-ethyl-2-methyl-indan-2-yl)benzamide is prepared from N-(5-ethyl-2-methyl-indan-2-yl)-benzamide (2.6 g) following the procedure used to prepare N-(5-acetyl-2-methyl-indan-2-yl)-benzamide. The product is purified by chromatography (silica, hexane/ethyl acetate, 4:1) to give the title compound. ES+ MS m/e 322 (MH+)
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][C@H:9]([OH:10])[CH:2]12.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:14]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][C@H:9]([OH:10])[CH:2]4[CH2:1]3)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:14]=[C:13]([C:12]([F:46])([F:11])[F:45])[CH:18]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O[C@H]1CCN2CCNCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CC[C@H](O)C3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
To a solution of (8S)-octahydropyrrolo[1,2-a]pyrazin-8-ol (D71, 32 mg) in methyl sulfoxide (1.2 mL), 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (60 mg) and potassium carbonate (63 mg) were added. The resulting mixture was heated at 150° C. for 24 hours. The mixture was allowed to cool down to r.t. and diluted with water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2.5 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (DCM/MeOH from 100:0 to 95:5) to give the desired compound (18.8 mg) as yellow foam.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)=[O:5].CC(C[AlH]CC(C)C)C>C1COCC1>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([CH:4]=[O:5])=[CH:15][CH:14]=2)[N:9]=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)c1ccc2nccnc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc2nccnc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of N-methoxy-N-methylquinoxaline-6-carboxamide (4.34 g, 20 mmol, 1.0 eq.) in THF (40 mL) cooled at −78° C. was added DiBAl—H (40 mL, 40 mmol, 2.0 eq.) dropwise. The resulted mixture was stirred at −78° C. for 30 min, then quenched by the addition of aqueous NH4Cl solution. The mixture was adjusted to pH 7 with HCl (1N, 60 mL) and extracted with EA (50 mL×3). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified via flash column chromatography (PE/EA=4/1, v/v) to afford quinoxaline-6-carbaldehyde as yellow solid (2.96 g, 93.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:30])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CNCC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CN(C)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-isobutylmethylamine, TBTU, and triethylamine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=O)[N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH2:13][C:14]#[CH:15])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: C#CCN(C)c1nc(C(=O)N(C)C)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CCN(C)c1nc(CN(C)C)cs1
Temperature: 25 °C

Procedure:
2-(N-Methyl-2-propynylamino)-4-dimethylaminocarbonylthiazole (k) (474 mg) was dissolved in tetrahydrofuran (15 ml) and lithium aluminium hydride (250 mg) was added thereto at room temperature with stirring. The mixture was refluxed for 1 hour and, after decomposition of the excess lithium aluminium hydride with water, evaporated to remove the tetrahydrofuran. The residue was extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (10 g) to give 2-(N-methyl-2-propynylamino)-4-dimethylaminomethylthiazole (1) from chloroform-methanol (10:1) eluate as an oil (374 mg).