Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CC2CCC(F)(F)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.66 g, 6.83 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.009 mL, 6.83 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.419 mL, 6.83 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.6 g, 65%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.10-2.12 (m, 15H), 2.96-3.05 (m, 1H), 3.08-3.19 (m, 1H), 3.71 (s, 3H), 3.87-4.00 (m, 1H), 4.14-4.24 (m, 1H), 5.72 (s, 1H). MS m/z 357 (M−H)−
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]1[C:40]([C:41]([C:43]([F:46])([F:45])[F:44])=O)=[CH:39][CH:38]=[C:37]([Cl:47])[CH:36]=1.CCCCCC>C1COCC1>[CH3:13][O:14][CH:15]=[C:41]([C:40]1[CH:39]=[CH:38][C:37]([Cl:47])=[CH:36][CH:35]=1)[C:43]([F:46])([F:45])[F:44]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(Cl)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C(c1ccc(Cl)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
Under a nitrogen atmosphere, 33.6 ml of n-butyllithium/hexane solution (1.2M solution) was added to a solution of 17.3 g of methoxymethyltriphenylphosphonium chloride in 150 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 30 minutes and at -20° C. for 30 minutes. A solution of 7.0 g of 4-chloro-α,α,α-trifluoroacetophenone in 10 ml of dry THF was slowly added to the reaction solution at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at room temperature for 12 hours. Thereafter, 200 ml of n-hexane was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with dilute HCl-ice water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residues was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (40:1) mixture] to obtain 4.17 g of the desired compound (E/Z=ca. 1/1).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1.FC(F)(F)S([O-])(=O)=O.[N:20]1([S:25](N2C=C[NH+](C)C2)(=[O:27])=[O:26])[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([S:25]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:2][O:3][CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:27])=[O:26])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: C1CC2(CCN1)CCOC2
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC2(CCOC2)CC1)n1ccnc1

Procedure:
8-(Imidazole-1-sulfonyl)-2-oxa-8-aza-spiro[4.5]decane was prepared in accordance with step A of the general method described in example 76 from 2-oxa-8-aza-spiro[4.5]decane hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=216.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O1CCCC1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc(Br)cc2)c1
Reaction time: 72 h
Yield: 80.5 %

Procedure:
A mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N′-(4-bromophenyl)urea (21 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:27][C:23]2[N:22]=[C:21]([C:19]([OH:20])=[O:18])[CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)n1

Procedure:
6-(2′-Nitro-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from 4-hydroxy-2′-nitrobiphenyl (available from TCI America. Portland, Oreg.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 2). Yield: 62 mg. Mass spectrum (ES) MH+=351.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C>CO.[Pd]>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[C:4]([NH:11][C@H:12]([C:14]1[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])[CH3:13])=[CH:3][CH:2]=[N:7]2
Reactant: C[C@H](Nc1cc(Cl)nn2ccnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](Nc1ccnn2ccnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (S)-3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-7 (50 mg, 0.104 mmol, 1.0 eq) in MeOH (20 mL), palladium on carbon (10%, 17 mg) and triethylamine (0.1 mL, 0.72 mmol, 6.9 eq) were added. The resulting mixture was degassed and back-filled with hydrogen (three cycles), and then stirred at RT under hydrogen overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% ethyl acetate-petroether) to afford the product, (S)-3-(1-(imidazo[1,2-b]pyridazin-8-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-8. ESI-MS m/z: 450.2 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1>CCOC(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)[CH3:11])[CH3:10]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)[C@H](C)NC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)N(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 41.6 %

Procedure:
(S)-ethyl 2-(isopropylamino)propanoate (2.83 g, 17.8 mmol) was added to methyl 6-chloro-5-nitronicotinate (1.72 g, 7.94 mmol) and the reaction mixture was stirred in a closed vial at 90° C. for 20 h. It was cooled and diluted with EtOAc (25 mL). The resulting precipitate was filtered off, the filtrate was concentrated in vacuo and purified using flash column chromatography on silica gel (220 g SiO2, hexanes:ethyl acetate 4:1) to afford the title compound as yellow oil (1.12 g, 42%). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm): 1.18 (t, J=7.07 Hz, 3H) 1.30 (d, J=6.32 Hz, 3H) 1.36 (d, J=6.57 Hz, 3H) 1.66 (d, J=6.82 Hz, 3H) 3.48-3.62 (m, 1H) 3.90 (s, 3H) 4.03 (q, J=6.65 Hz, 1H) 4.06-4.21 (m, 2H) 8.54 (d, J=2.02 Hz, 1H) 8.70 (d, J=2.02 Hz, 1H); [M+H] calc'd for C15H21N3O6, 340; found, 340.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:18](Br)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC=C(C)CCC=C(C)C)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.16 g, 20 mmol), geranyl bromide (4.2 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Cl>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1cccc(Cl)c1
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 3-chlorobenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]1)=O)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:40][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=2)[CH2:13][C@H:14]1[O:29][CH3:30])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Methyl cis(±)-2-acetyl-4-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-oxobutanoate obtained in Example (188b) (1.1 g) was dissolved in toluene. Lawesson's reagent (660 mg) was added, and the mixture was stirred at 110° C. for two hours. Further, Lawesson's reagent (330 mg) was added, and the mixture was stirred at 110° C. for two hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from methylene chloride/hexane, to obtain 50 mg of the title compound as crystals.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.C[O:24][B:25](OC)[O:26]C>CCOCC>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([B:25]([OH:26])[OH:24])[CH:14]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.4 ml, 11 mmol) was slowly added to a stirred solution of 3-bromoquinoline (2.08 g, 10 mmol) in anhydrous ether (20 ml), under nitrogen, at −75° C. After a further 20 minutes at −75° C., trimethylborate (1.46 ml, 13 mmol) was added, whereupon the red colour changed to yellow. The reaction mixture was allowed to warm to room temperature and quenched with water, followed by 1M aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for 30 minutes and then glacial acetic acid added until a pH ˜5-6 was attained, which generated a gummy precipitate. Diisopropyl ether was added to this mixture, stirring continued for 1 hour and then the clear aqueous and organic phases were decanted from the solid and discarded. The solid residue was dissolved in ethyl acetate and the solution washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a pale yellow solid (580 mg, 34%). Found: C, 62.74; H, 4.11; N, 7.92. C9H8BNO2 requires C, 62.49; H, 4.66; N, 8.10%. δ(DMSOd6): 7.59 (t,1H), 7.76 (t,1H), 7.98 (m,2H), 8.42 (brs,2H,exchangeable), 8.70 (s,1H), 9.18 (s,1H).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH2:6][N:5]2[N:9]=[CH:10][CH:11]=[C:4]12)=O.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[N+:12]([C:11]1[CH:10]=[N:9][N:5]2[CH2:6][CH2:7][CH2:8][NH:3][C:4]=12)([O-:14])=[O:13]
Reactant: O=CN1CCCn2nccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.5 %

Procedure:
To a solution of 4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (1.51 g) in sulfuric acid (7.5 ml) was added potassium nitrate (111 g) under ice-cooling. The mixture was stirred at room temperature for 17 hours. The reaction mixture was added to ice (100 g). The crystalline residue was collected by filtration and dried in vacuo to give 3-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.63 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(O)C.NN>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCCCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOP(=O)(CCCCCN)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
[5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid diethyl ester (0.300 g, 0.849 mmol) was dissolved in THF [2 mL], IPA [4 mL]. Hydrazine (0.081 g, 2.540 mmol) was added to this solution and stirred at room temperature for 18 hours. The white precipitate was filtered and washed with dichloromethane. Removal of the solvent in vacuo yielded the title compound (0.136 g, 72%) 1H-NMR (CDCl3): δ 4.07 (m, 4H), 2.68 (t, 2H, J=6.74 Hz), 1.72 (m, 2H), 1.60 (m, 2H), 1.43 (m, 4H), 1.31 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11](OCC)=[O:12])=O)=[CH:5][N:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:7]2[C:9]3[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:12])[NH:24][N:23]=2)=[CH:20][CH:21]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccc(OC)nc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-(6-methoxynicotinoyl)benzoate (0.496 g, 1.74 mmol) and hydrazine hydrate (0.39 mL, 6.9 mmol) in ethanol (6 mL) was stirred at 80° C. for 2 hours, concentrated, and azeotroped with PhMe to give crude 4-(6-methoxypyridin-3-yl)phthalazin-1(2H)-one, which was used without purification.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([F:15])[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)C>[C:21]([O:20][C:18]([NH:17][CH2:16][C:12]1([F:15])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCC1(F)CCN(C(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(F)CCNCC1
Yield: 58.2 %

Procedure:
A mixture of N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 3 of Example 15) (4.42 g, 13.1 mmol), NaOH (2.62 g, 65.5 mmol), H2O (9.00 mL) and ethanol (90.0 mL) was refluxed for 15 h and concentrated in vacuo. To the resulting residue were added water and chloroform. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the resulting solid with hexane-CH2Cl2 afforded a colorless solid 1.77 g (58%) as the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCN(CCO)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN(CCO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanol. MS (ESI): mass calcd. for C22H24FN5O3S, 457.16; m/z found, 458.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (m, 1H), 8.21 (d, J=1.5, 1H), 8.16-8.13 (m, 1H), 7.98 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.30 (m, 2H), 3.86-3.78 (m, 2H), 3.66-3.32 (m, 4H), 3.24-3.20 (m, 2H), 3.15-2.72 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a stirred suspension of 4-(5-bromo-2-chlorobenzyl)phenol (60 g, 0.202 mol) and tert-butylchlorodimethylsilane (37.9 g, 0.252 mol) in acetonitrile (300 mL) was added dropwise triethylamine (54.4 mL, 0.390 mol) so that the reaction temperature did not exceed 5° C. After the addition was completed, the reaction mixture was stirred for 2 hours at 10˜15° C. This reaction mixture was filtered, and the filter cake was washed with petroleum ether (2×50 mL). The combined organic layers were evaporated under reduced pressure (30° C.), and the residue was dissolved in petroleum ether (300 mL). The solution was washed with water (100 mL×2) and evaporated, and the residue was dissolved in ethanol (180 mL) at 35° C. with stirring. This solution was cooled to 5˜10° C. and kept for 4 h. The solids were filtered, the filter cake was washed with cold ethanol (0˜5° C., 60 mL) and then dried under vacuum at 25° C. overnight to give 22f as a white solid (72 g, 86.6% yield; HPLC purity 99%, retention time 6.6 min). 1H-NMR (CDCl3, 400 MHz): δ 7.21˜7.28 (m, 3H), 7.06 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 4.00 (s, 2H), 1.00 (s, 9H), 0.21 (s, 6H); MS ESI (m/z) 411 [M+1]+, calc. 410.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](N)C3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.0446 mmol; 23.8 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 117 (7.0 mg, 33%). 1H NMR (400 MHz, DMSO) δ 9.36-9.31 (s, 1H), 9.18-9.11 (m, 2H), 8.74-8.65 (s, 1H), 8.58-8.52 (d, J=1.9 Hz, 1H), 8.34-8.30 (s, 1H), 8.02-7.97 (d, J=8.4 Hz, 1H), 7.60-7.55 (d, J=8.4 Hz, 1H), 3.95-3.81 (dd, J=27.5, 10.2 Hz, 2H), 3.06-2.97 (t, J=10.2 Hz, 1H), 2.93-2.84 (t, J=9.5 Hz, 1H), 2.81-2.72 (m, 3H), 1.98-1.90 (d, J=12.6 Hz, 1H), 1.89-1.80 (d, J=13.3 Hz, 1H), 1.79-1.68 (d, J=12.9 Hz, 1H), 1.68-1.48 (s, 2H), 1.31-1.26 (t, J=7.6 Hz, 3H), 1.26-1.20 (m, 1H); MS (ESI) m/z: 434.2 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH:39][CH2:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCc1ccccc1
Temperature: 0 °C

Procedure:
Triethylamine (2.8 ml.) was added with stirring to a solution of N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) in tetrahydrofuran (50 ml.) maintained at 0° C. The temperature was lowered to -20° C., isobutyl chloroformate (2.7 ml.) was added, and stirring was continued for15 minutes. 2-Phenylethylamine (2.5 ml.) was then added with continued stirring, and the mixture was allowed to warm to room temperature and filtered. Concentration of the filtrate afforded a solid. Crystallization of the solid from ethyl acetate gave the product in two parts by filtration and in a third part from the filtrate, which was washed with water, aqueous citric acid (5%), saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, then dried and concentrated. High pressure liquid chromatography of the three parts on silica gel (350 g.) using hexane-ethyl acetate (7:3) as the eluant (200 ml./min.) afforded in fractions 7-8 1-(tert-butyloxycarbonyl)-N-(2-phenylethyl)-L-prolinamide (3.2 g., m.r. 153°-154° C.)