Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28](=[O:39])[C:29]3[CH:34]=[C:33](F)[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28]([C:29]3[CH:34]=[C:33]([N:5]4[CH2:6][C@@H:1]5[CH2:7][C@H:4]4[CH2:3][N:2]5[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])=[O:39])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1, which is concerned with the preparation of starting materials, and tert-butyl(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give of tert-butyl(1S,4S)-5-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.70 (m, 2H), 1.39 (d, 9H), 2.00 (m, 2H), 2.32 (s, 3H), 2.54 (s, 2H), 2.86 (m, 1H), 3.40 (m, 1H), 3.66 (t, 1H), 4.53 (d, 1H), 4.87 (s, 1H), 6.80 (s, 2H), 7.30 (d, 1H), 7.58 (m, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.38 (d, 1H), 9.90 (s, 1H); Mass Spectrum: M+H+ 536.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.[H][H]>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ncccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ncccc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a suspension of N5-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (5 g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as an oil.
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([NH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[CH3:12].[Na].O>C(Cl)Cl>[N:1]1([CH2:5][C@@H:6]([NH:10][CH2:11][CH3:12])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[C@H](N)CN1CCC1
Reactant: CC=O
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CCN[C@H](CN1CCC1)C(C)C
Yield: 19.9 %

Procedure:
(S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine (Compound U) (0.420 g, 2.95 mmol) and acetaldehyde (0.166 mL, 2.95 mmol) was mixed in DCM (10 mL). Sodium triacetoxyhydroborate (0.813 g, 3.84 mmol) was added in small portions and the resultant mixture was stirred at rt for 5 h. Water was added and the pH was adjusted to pH9. The water phase was extracted with DCM (4×50 mL). The combined organic layers were combined and washed with brine, passed through phase separator and evaporated under reduced pressure to give the title compound (0.1 g, 20%). The obtained crude product was used without further purification. LCMS (M+H)+: 171.
Reaction SMILES: [NH2-].[Li+].N.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[CH:12].Br[CH2:16][CH2:17][CH2:18][Cl:19]>O1CCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][C:12]#[C:11][CH2:10][CH:9]([C:5]1[O:4][CH:8]=[CH:7][CH:6]=1)[O:13][CH3:14]
Reactant: ClCCCBr
Reactant: C#CCC(OC)c1ccco1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC(CC#CCCCCl)c1ccco1
Yield: 67.8 %

Procedure:
To a stirred mixture of 0.51 g of lithium amide and 25 ml of liquid ammonia was added a solution of 3.0 g of 4-(2-furyl)-4-methoxy-1-butyne in 2.5 ml of tetrahydrofuran. The mixture was stirred under reflux for 30 minutes and then treated with a solution of 3.94 g of 1-bromo-3-chloropropane in 5 ml of tetrahydrofuran. This mixture was stirred under reflux for one hour, then the ammonia was allowed to evaporate and the residue partitioned with ether and water. The ether layer was separated and evaporated. The residue was distilled at 0.06 mm on a Kugelrohr, giving 3.07 g of the desired compound as an oil, bp 110°-120° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:13]([NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCN
Product: CCCCCCC/C=C/C(=O)NCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and amylamine as starting materials to give the aimed compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:5]=1.[OH-].[Na+].Cl>CO.O>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:12][O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])=[O:28])=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid methyl ester (see example 402, 89 mg) in methanol (3 ml) was added 2M sodium hydroxide (1 ml). The reaction mixture was stirred at room temperature for 7 hours. The mixture was diluted with water (12 ml) and acidified with 4M HCl aq. The resulting precipitated material was isolated by filtration and dried under vacuum, affording the title compound. 13C-NMR (DMSO-d6) δ 167.2, 167.1, 149.5, 149.0, 148.3, 136.4, 133.1, 132.5, 130.8, 129.7, 129.1, 128.5, 128.0, 121.9, 114.8, 113.3, 111.4, 76.3, 44.7.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-:11].[K+].CCOCC>CN(C=O)C>[F:11][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(CF)c1ccccc1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
A mixture of 2-bromoacetophenone (20.00 gm, 100 mmol) and KF (8.82 gm, 152 mmol) in dry DMF (35 ml) was heated at 100° C. for 1 hour. Additional KF (2.26 gm) was added and heating of the mixture continued for 4 more hours. The dark-red solution was cooled, poured into Et2O and washed with H2O (twice) and brine. The ethereal solution was dried (Na2SO4), filtered, and stripped to yield a dark red oil. The oil was distilled to collect a fraction boiling between 62°-64° C. at 1 mm Hg which was 91 molar percent the title compound and 9 molar percent acetophenone (6.00 gm). Flash chromatography (Merck SiO2, 10% EtOAc in hexane) afforded the pure title compound (5.50 gm, 45%) as a liquid that solidifies near room temperature.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=2[O:17]C)=[CH:5][N:4]=1.C([O-])(O)=O.[Na+]>Br.O>[OH:17][C:10]1[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ccc(OC)c(-c2ccc(OC)nc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1ccc(-c2cc(O)ccc2O)c[nH]1
Temperature: 25 °C

Procedure:
A solution of 502 mg (2.05 mmol) of 2-methoxy-5-(2,5-dimethoxyphenyl)pyridine in 20 mL of 48% hydrobromic acid (aqueous) is refluxed for 6 hours, cooled to ca. 25° C. and diluted with 150 mL of water. The mixture is neutralized with solid NaHCO3, cooled to 0° C. and the resulting solid product collected by filtration. The solid is washed well with water, collected by centrifugation, then further purified by recrystallization in methanol to obtain 5-(2,5-dihydroxyphenyl)-2(1H)-pyridone m.p. 303-306° C. dec).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:14]=1[C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:15][C:14]=1[C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Cc1ccn2c(Br)cnc2n1
Product: Cc1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-methylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-methylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile. Purification by high performance liquid chromatography afforded the trifluoroacetate salt as a white powder: δH (400 MHz, DMSO) 2.60 (3H, s), 7.11 (1H, d, J 7), 7.59-7.70 (2H, m), 7.76 (1H, d, J 8), 7.84-7.89 (3H, m), 8.00-8.04 (2H, m), 9.00 (1H, d, J 7); m/z (ES+) 329 (M++H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[OH:25].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[F:26][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3[nH]c2=O)c1OC(F)F
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)[nH]c2nccnc12

Procedure:
7-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 2.6) (0.34 g), isobutyryl chloride (0.11 ml), and pyridine (0.10 ml) were stirred in dichloromethane (10 ml) at ambient temperature for 2 hours. The reaction mixture was washed successively with aqueous hydrochloric acid (1M), aqueous sodium hydrogen carbonate (saturated) and water. The organic fraction was dried over sodium sulfate and concentrated to give Compound No. B23 of Table B (0.335 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=O.O=P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2nnc(-c3cccs3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To 250 mL round bottom flask was added 2.0 g (11.7 mmol, 1 eq) of 4-chlorobenzhydrazide (1) in 100 mL of amelene stabilized chloroform, followed by addition of 4 mL (29.25 mmol, 2.5 eq) of TEA. Then, 1.4 mL (12.87 mmol, 1.1 eq) of 2-thiophenecarbonyl chloride (2) was added drop-wise and the mixture was stirred at ambient temperature for 1 h. Reaction progress was monitored by LCMS on a twelve minute gradient. The formed white precipitate was filtered, washed with chloroform and then dried on the high vacuum for two hours. The resulting material was confirmed to be the desired diacylhydrazide and was used in the next step without further purification. The crude diacyl-hydrazide was dissolved in 60 mL of POCl3 under heating. The resulting mixture was then heated under reflux in oil bath (100-110° C.) for 5-7 h. The reaction progress was monitored by LCMS on a twelve minute gradient. Once the cyclization reaction was completed as determined by LCMS, POCl3 was carefully evaporated in vacuum and the reaction was then neutralized with a 1 N solution of ammonium hydroxide. The product was extracted with ethyl acetate (300 mL) from saturated solution of NaHCO3 (200 mL), washed with a brine (2×200 mL), then dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by flash column chromatography (hexane→12% ethyl acetate/hexane), and then recrystallized from mixture of hexane/ethyl acetate (5:1) to give 1.3 g of the desired compound 2-(4-Chloro-phenyl)-5-thiophen-2-yl-[1,3,4]oxadiazole (42%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:3]=1[CH:4]=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C:27]#[N:28]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:26]([CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH3:17])[C:27]([NH2:28])=[N:1]2)=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1cc(F)c(N2CCOCC2)cc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cc(N3CCOCC3)c(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluoro-5-morpholin-4-ylbenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=4)=[O:24])[NH:12][C@H:11]3[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:5]2=[CH:4][CH:3]=1.CC[N:42]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:31]([C:29]1[N:30]=[C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:34][C:35]([CH3:37])([CH3:38])[CH3:36])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:39])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])[S:27][CH:28]=1)(=[O:33])[NH2:42]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2nc(C(=O)O)cs2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2nc(C(N)=O)cs2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a solution of rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-thiazole-4-carboxylic acid (40 mg, 0.07 mmol) prepared in Example 197 in anhydrous DMF (2 mL) were added EDCI (26 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol), NH4Cl (36 mg, 0.67 mmol), and triethylamine (14 mg, 0.13 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-thiazol-2-yl)-amide as a off white solid (12 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]([CH2:12]Br)[CH2:10]Br)=[CH:5][CH:4]=1.[CH3:16][NH2:17]>O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]2[CH2:12][N:17]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(COC(CBr)CBr)cc1
Solvent: O
Product: COc1ccc(COC2CN(C)C2)cc1
Temperature: 90 °C

Procedure:
33.7 Parts of 2-(p-methoxybenzyloxy)-1,3-dibromo-propane, 70 parts of monomethylamine and 70 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 11.7 parts of 3-(p-methoxybenzyloxy)-1-methylazetidine boiling at 85°-87° C. under 2 mm Hg were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:29]
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2c(F)ccc(F)c2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(Cl)=[O:9]>>[CH:1]1([CH2:6][NH:7][C:8]([NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: NCC1CCCC1
Product: O=C(NCC1CCCC1)NCC1CCCC1
Yield: 81 %

Procedure:
In the manner of step (a) of Example 1, cyclopentanemethylamine (K. Jewers and J. McKenna, J. Chem. Soc. 1958, 2209-2217; 23.0 g, 0.158 mole) was reacted with phosgene to give 1,3-bis(cyclopentylmethyl)urea as white powder (14.41 g, 81%), m.p. 162°-164° C.;
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[NH:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[O:18])=[CH:4][CH:3]=1.[C:26]1(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[NH:23][CH:22]=[C:21]([C:24]#[N:25])[N:20]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:7]=2)=[CH:9][CH2:10]1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: O=C1CCCC1
Product: CC1(C)CC=C(c2nc(C3(O)CCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) and cyclopentanone according to the procedure in Example 1, step (h).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:36]1([Mg]Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[OH:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (244 mg, 0.48 mmoles) in THF (3 mL) at 0° C. was added cyclohexylmagnesium bromide (18% solution in THF, 0.6 mL, 0.57 mmoles) and the reaction was allow to warm to room temperature and stirred overnight. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in hexane) to yield 110 mg (39%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.6 (m, 3H) 1.8 (m, 1H) 1.9 (d, J=12.4 Hz, 1H) 2.2 (s, 1H) 4.2 (s, 3H) 4.6 (d, J=7.5 Hz, 1H) 4.8 (m, 4H) 7.3 (s, 1H) 7.5 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H)). MS (ES+) Calc: 595.2, Found: 596.4 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[C-]#N.[Na+].CCO.[CH3:23][N:24](C=O)[CH3:25]>CCOC(C)=O>[CH3:23][N:24]([CH3:25])[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Temperature: 130 °C
Yield: 27 %

Procedure:
To a solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (294 mg, 1.31 mmol, as prepared in the previous step) in 8 mL EtOH-DMF (v/v) was added NaCN (128 mg, 2.6 mmol). The reaction was heated to 130° C. in a sealed tube for 24 h. The reaction was diluted with EtOAc (50 mL) and washed with water (2×50 mL). Chromatography (50% EtOAc-hexane) of the crude product afforded 88 mg (27%) the title compound as well as 78 mg (24%) (1-(5-ethoxy-2-nitro-phenyl)-piperidine as yellow solids. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O2, 250.1 (M+H), found 250.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.CC1C=CC(S([C:36]#[N:37])(=O)=O)=CC=1>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([C:36]#[N:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C#N)cnc21
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo-[2,3-b]pyridine (1.22 g) in tetrahydrofuran (12.2 mL) was added 0.95M sec-butyl lithium in n-hexane (8.3 mL) dropwise at −78° C. The mixture was stirred at the same temperature for 1 hour. To the solution was added 4-methylbenzenesulfonyl cyanide (1.43 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (444 mg) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:8](=[O:9])[C:7]([O:10][CH3:11])=[CH:6][C:5]([C:12]#[N:13])=[CH:4]1.C[O-].[Na+].CO.CS(O)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@:31]([C:36]2[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=2)(N)[C@@H:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1>CO>[CH2:2]([N:3]1[CH:4]=[C:5]([C:12]2[NH:34][C@@H:32]([CH3:33])[C@:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)([C:36]3[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:13]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]1=[O:9])[CH3:1]
Reactant: C[C@H](N)[C@](N)(c1ccc(F)cc1)c1ccc(F)nc1
Reactant: CCn1cc(C#N)cc(OC)c1=O
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(C2=N[C@@](c3ccc(F)cc3)(c3ccc(F)nc3)[C@H](C)N2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 2.5 %

Procedure:
1-ethyl-3-methoxy-2-pyridone-5-carbonitrile (30 mg) was dissolved in methanol (1 mL), and 25% sodium methoxide-methanol solution (6.6 mL) was added thereto. The mixture was stirred at room temperature for 17 hours, and methanesulfonic acid (11 μL) and a solution of (1S,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (44.5 mg) in methanol (1 mL) were successively added. The mixture was stirred at room temperature for two days and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel (chloroform:methanol=10:1) to give the title compound (1.8 mg) as a brown solid.