Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2.Cl.[CH:18]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][NH:20][CH2:19]2.CCN(C(C)C)C(C)C>CO>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([N:20]3[CH2:19][CH:18]4[O:25][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2
Reactant: C1CC2CNCC1O2
Reactant: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Oc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Temperature: 140 °C
Yield: 41.6 %

Procedure:
In a 2-5 mL microwave vial was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 50 mg, 0.207 mmol) in MeOH (2.5 ml) to give a colorless solution. 8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 61.9 mg, 0.414 mmol) and DIPEA (0.217 ml, 1.241 mmol) were added. The reaction was heated under microwave irradiation at 140° C. for 30 min. Silica gel was added and the solvents were removed under reduced pressure. The mixture was purified by HPLC, using NH4OH buffers (Waters semi-prep LCMS) to give the title compound (27.4 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:5][C:2]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)([CH3:1])[CH2:3][NH:4][C:29](=[O:30])[C:28]1[CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=[N:26][CH:27]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccccc2)n[nH]1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccccc2)n[nH]1
Yield: 23 %

Procedure:
This compound was synthesized from 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (20 mg, yield 23%). 1H NMR (400 MHz, MeOD) δ 9.37 (m, 1H), 9.16 (m, 1H), 8.84-8.13 (m, 1H), 8.02-7.99 (m, 2H), 7.48-7.42 (m, 3H), 3.77 (s, 2H), 1.54 (m, 6H). MS (ESI) m/z: Calculated for C21H18F3N7O2: 457.15. found: 458.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].Br[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].C(O)(C)(C)C>O>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Br)C(=O)OC
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
In a preferred embodiment 2-(azidomethyl)-1,3- difluorobenzene is treated with methyl 2-bromoacrylate in mixture of t-butanol and water to produce methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-(quinolin-3-yl)-1H-inden-1-one (40 mg, 1.2 eq, 0.1 mmol) obtained in Step 3 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (53%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[CH:15]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=1.CN(C)[CH:44]=[O:45].Cl>C(OCC)C.O1CCCC1>[Si:25]([O:24][CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:14]=[CH:13]/[C:9]1[N:8]=[C:7]([CH:44]=[O:45])[CH:12]=[CH:11][CH:10]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/c1cccc(C=O)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
1.16 ml of n-butyllithium (1.6 molar in hexane) is instilled in a suspension of 500 mg of 2-bromo-6-[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine in 2 ml of diethyl ether and 1 ml of tetrahydrofuran at -80° C. under argon atmosphere. After completion of the addition, the reaction mixture is stirred for 15 minutes at -40° C., cooled to -80° C. and mixed by instillation at this temperature with 140 mg of dimethylformamide. After 4 hours at -80° C., the reaction mixture is hydrolyzed with 3 ml of 2 n hydrochloric acid, the organic phase is separated, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-10% ethyl acetate. 385 mg of 6-[(1E)-(3RS)-3-tert- butyldiphenylsilyloxy-1-undecenyl]-pyridine-2-carbaldehyde is obtained as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10].[OH-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1-c1ccccn1
Yield: 89.2 %

Procedure:
A mixture of 3.0 g of methyl 2-(2-pyridinyl)benzoate and 600 mg of sodium hydroxide in 50 ml of 9:1 methanol:water is refluxed for 4 hours. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution is neutralized with glacial acetic acid and the resulting product filtered, washed with water, and dried to give 2.5 g of the desired product:M+1=200.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:18])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:18])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[OH:8]
Reactant: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone (28 g, 1.00 equiv, Crude) in methanol (280 mL), NaBH4 (6.38 mg, 0.17 mmol, 2.00 equiv). The resulting solution was stirred for 0.5 h at 0° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of acetone. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:5). This resulted in 14 g of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanol as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].P([O-])(O)(O)=O.[Na+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Reactant: C=CC(=O)OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a stirred solution of 23° C. of 4-acetamidobenzenesulfinic acid (57.8 g., 290 mmol), sodium hydroxide (11.6 g, 290 mmol), and sodium dihydrogen phosphate (40.0 g, 290 mmol) was added a solution of methyl acrylate (31.2 g, 362 mmol) in 50 mL of tetrahydrofuran. The reaction vessel was stirred at 23° C. for 18 hours, and the resulting white precipitate was filtered and washed with water. The product was air dried, then recrystallized from 2-butanone to produce 59.4 g (71%) of a white powder, mp 156°-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 72.8 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 5-aminopyridin-2-ylcarbamate (313 mg, 1.5 mmol) to afford the desired product (352 mg, 72%) as a yellow solid: ESI MS m/z 483 [C23H23BrN4O3+H]+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22]N(C)C.[BH4-].[Na+].Cl>C(O)C>[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[C:6]([Cl:1])=[CH:5][C:4]=1[CH3:22]
Reactant: Cl
Reactant: COc1ccc(Cc2oc3ccc(CN(C)C)c(O)c3c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cc2oc3c(Cl)cc(C)c(O)c3c2C)cc1

Procedure:
To a solution of (177) (Example 45) (0.106 g, 0.3 mmol) in 5 mL ethanol was added sodium borohydride (0.111 g, 3 mmol). The mixture was refluxed for 1 h, cooled and poured into cold dilute HCl (1N). Extraction with ethyl acetate, followed by chromatography of the concentrated organic extract gave the title compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1O
Yield: 52.8 %

Procedure:
A mixture of 11.5 g of intermediate (2) and 150 ml of methanol was hydrogenated at normal pressure and at room temperature with 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3) 85/15). The pure fractions were collected and the eluent was evaporated, yielding 3.6 g (53%) of cis-3-methoxy-4-piperidinol as an oily residue (intermediate 3).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(O)=O>O>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[O:27])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: O=CNc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCN(CC)CCNc1ccc(CN(C=O)c2ccccc2)c2sc3ccccc3c(=O)c12
Temperature: 160 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.40 g, 9.59 mmol), formanilide (31g) and formic acid (3 mL) were heated to 160° C. for 2 hours. The mixture was cooled, poured into water (200 mL) and extracted with ether (3×150 mL). The aqueous layer was basified with 5N NaOH, extracted with CHCl3 (3×150 mL) and the combined organic extracts were dried over Na2SO4 and filtered through florisil eluting with CHCl3 (100%), then 5% isopropylamine/CHCl3. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 0.5% to 1% isopropylamine/CHCl3 and then by recrystallization from benzene/hexane (2x) to afford 1.88 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=O)[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:3]1.C(O)C.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>O>[C:8]1([CH:6]2[C:5](=[N:25][OH:26])[CH:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:3][C:2](=[O:1])[CH2:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)C(=O)C(c2ccccc2)N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)C(=NO)C(c2ccccc2)N1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
In a round-bottom flask were placed 15 g (50.6 mmol) of the nitro lactam 4,6-diphenyl-5-nitro-2-oxopiperidine and 85 mL of methylene chloride. Potassium tert-butoxide (5.72 g, 50.6 mmol) was added and the mixture was stirred for 15 min. To this system was added 85 mL of methanol. The mixture was stirred for 15 min and the system was cooled to -78° C. Ozone was bubbled through the reaction mixture for 4 hours, nitrogen was bubbled through the mixture, 10 mL of dimethyl sulfide was added and nitrogen was bubbled through the mixture overnight. A mixture of water and methylene chloride was added to the system and the resulting solid (8.8 g of a mixture of the nitro lactam 4,6-diphenyl-5-nitro-2-oxopiperidine and 2,5-dioxo-4,6-diphenyl-piperidine was collected by suction filtration. The filtrate was concentrated with a rotary evaporator and the residue was partitioned between methylene chloride and water. The layers were separated, and the aqueous phase was extracted with two portions of methylene chloride. The combined organic fractions were dried (sodium sulfate) and concentrated to afford 5.14 g of crude 2,5-dioxo-4,6-diphenylpiperidine which was used immediately without further purification. Under a nitrogen atmosphere in a round-bottom flask were placed 2,5-dioxo-4,6-diphenylpiperidine (5.14 g, 19 mmol) and 75 mL of ethanol. A solution of 3.96 g (57 mmol) of hydroxylamine hydrochloride and 7.74 g (95 mmol) of sodium acetate in 25 mL of water were added and the reaction mixture was stirred at room temperature. The reaction mixture was concentrated to ca. 1/2 its initial volume, and the resulting precipitate was collected by suction filtration. This precipitate (1.5 g) was washed with saturated aqueous sodium bicarbonate, water and ether to afford 722 mg of 4,6-diphenyl-5-oximino-2-oxopiperidine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1.[CH2:37](I)[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:37][CH3:38])[CH:26]=1
Reactant: CCI
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Product: CCN(c1cccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2C)c1)S(C)(=O)=O
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 61, N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-methanesulphonylaminobenzamide was reacted with ethyl iodide to give the title compound in 64% yield; m.p. 192-193° C.; NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.21 (s, 3H), 3.16 (t, 4H), 3.73 (m, 6H), 7.13 (m, 1H), 7.23 (d, 1H), 7.36 (m, 2H), 7.43 (d, 1H), 7.58 (m, 3H), 7.81 (d, 1H), 7.95 (m, 2H), 7.99 (d, 1H), 10.0 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 537.
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[C:3]([NH:5][C:6]1[N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:8]=[C:9]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1)=[O:4].[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:41])[CH:40]=1)[C@H:33]([OH:37])[C:34](O)=[O:35].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:24]([N:7]1[C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:34](=[O:35])[CH:33]([C:32]2[CH:38]=[C:39]([F:41])[CH:40]=[C:30]([F:29])[CH:31]=2)[OH:37])[CH3:28])=[CH:10][C:9]([C:11]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[N:8]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(N)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 0.14 g (0.4 mmol) of 2-amino-N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide and 0.08 g (0.4 mmol) of (S)-3,5-difluoromandelic acid (Garofalo, et al. Bioorg. Med. Chem. Lett. 2002, 12, 3051) in 5.0 mL of THF was stirred at rt as 0.06 g (0.4 mmol) of HOBT and 0.08 mL (0.7 mmol) of NMM was added followed by 0.90 g (0.5 mmol) of EDC.HCl. After 16 h, the reaction was quenched with 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]propionamide.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][C:24]([CH2:25][N:26]([CH3:27])[C:16]([C:11]1[C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[N:26]([CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])[CH3:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:18])=[O:28])[CH3:22]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1ccc(C(=O)c2cccnc2C(=O)O)cc1
Product: CCOC(=O)CN(C)C(=O)c1ccc(C(=O)c2cccnc2C(=O)N(C)CC(=O)OCC)cc1

Procedure:
Using the compound obtained in Step 1 (1.46 g) and N-methylglycine ethylester (3.0), substantially the same reaction and work-up as in Reference Example 2-Step 2 were conducted to give N-ethoxycarbonylmethyl-3-[4-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)benzoyl]-N-methyl-2-pyridinecarboxamide as a colorless oil (2.5 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH:5]=[CH:4][C:3]=1[OH:24].[CH2:25](C(CC)(CC)C([O-])([O-])[O-])[CH3:26]>>[CH:19]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=3[C:9](=[CH:8][C:6]3[CH:5]=[CH:4][C:3]4[O:24][C:25]([CH3:26])=[N:1][C:2]=4[CH:7]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Nc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1O
Product: Cc1nc2cc(C=C3c4ccccc4CCc4ccccc43)ccc2o1
Temperature: 25 °C
Yield: 79 %

Procedure:
Dissolve 2-amino-4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (60 mg, 0.191 mmol) in triethylorthoacetate (5 mL) and heat to reflux for 4 h. Cool to room temperature and concentrate in-vacuo to a brown oil. Chromatograph on 10 g silica gel eluting with 5% to 25% ethyl acetate/hexanes to afford S lmg (79%) of the title compound as a colorless oil. MS (ES) 338 (M+H); HPLC shows 98% purity.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1c(C)c[n+]([O-])c(C)c1C
Yield: 92 %

Procedure:
0.86 g (5 mmol) 4-chloro-2,3,5-trimethylpyridine N-oxide and 8.5 ml 2M sodium methoxide was heated in a closed vessel to 70° C. for 16 hrs. Gave after work up 92% yield of 4-methoxy-2,3,5-trimethylpyridine N-oxide. Addition of 20% dimethylsulfoxide to the solvent increases the reaction rate but complicates the work up. The product was obtained as a waxy solid. NMR: 2×3H, 2,25; 3H, 2,5(s); 3H, 3,80(s); 1H, 8,2(s). (CDCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22].Cl>CN1C(=O)CCC1>[N+:18]([C:3]1[CH:4]=[C:5]([C:14]([F:17])([F:16])[F:15])[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(OCC(F)(F)F)cc1Br
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 84.6 %

Procedure:
A mixture of 1-bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzene from step 2 (30.54 g, 83.0 mmol) and CuCN (7.80 g, 87.1 mmol) in NMP (83 mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl, extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a dark brown oil (33.9 g). Silica gel column chromatography with heptane/EtOAc 9:1->4:1 gave the title compound as a yellow solid (22.05 g, 85%). MS (EI) 314 [M].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]>C(Cl)Cl>[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:8]([C:4]2[NH:5][C:6]([CH3:7])=[C:2]([Br:1])[C:3]=2[CH3:11])=[O:10])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]
Reactant: CC(C)N1CCC(N)CC1
Reactant: Cc1[nH]c(C(=O)O)c(C)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(C(C)C)CC2)c(C)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.3 %

Procedure:
To 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (570 mg) in DCM (15 mL) was added DIEA (2.11 g), HATU (994 mg) and 1-isopropyl-piperidin-4-ylamine (372 mg). The mixture was stirred for 16 h at RT after which it was concentrated. The residue was purified by preparative HPLC to give 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (65 mg) which was directly used in the next step.