Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>CN1CCN(C)C1=O.O1CCCC1>[C:26]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: CCCC(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
Triethylamine (1.47 g) was added to 15 ml of a suspension containing 1.57 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 1,3-dimethyl-2-imidazolidinone, and the mixture was stirred at room temperature for 10 minutes. Then, 0.83 g of butyryl chloride dissolved in 8 ml of tetrahydrofuran was added dropwise to the mixture, and the resulting mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from ethyl acetate-methanol to obtain 1.47 g of 2-(butyrylamino)methyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)ccc(OC(C)C)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.30 g, 4.80 mmol) in DCM (5 mL) was added oxalyl chloride (810 mg, 6.19 mmol) followed by DMF (10 mL). The reaction mixture was stirred at 0° C. for 1.5 hours, then concentrated under vacuum. The residue was dissolved in MeOH (15 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (0-50%, EtOAc/heptane) to give the title compound (Cpd PP, 894 mg, 65%) as an amber oil. 1H NMR (400 MHz, chloroform-d) δ 1.33 (d, J=6.11 Hz, 6H) 2.16 (s, 3H) 3.95 (s, 3H) 4.50 (dt, J=12.04, 6.08 Hz, 1H) 6.75 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 1H); MS 287 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([CH2:31][CH2:32]O)=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:54][CH2:32][CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[C:19]3[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)=[N:23][CH:22]=[N:21][C:20]=3[S:24][C:25]=2[CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCBr)ccc5c34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) [1]benzothieno[2,3-d]pyrimidin-7-yl]ethanol (700 mg, 1.46 mmol, 1 equiv) in THF (10 mL) were added triphenylphosphine (0.82 g, 3.12 mmol, 3 equiv) and carbon tetrabromide (1.03 g, 3.12 mmol, 3 equiv). The resulting solution was stirred at rt for 14 h and the solvent was evaporated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with 9:1 CH2Cl2/EtOAc yielding a light yellow solid (688 mg, 1.27 mmol, 87%). 1H-NMR (CDCl3) δ 8.60 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.50-7.44 (m, 3H), 7.39-7.34 (m, 1H), 7.23 (m, 2H), 7.03 (td, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.12 (s, 2H), 3.68 (t, 2H), 3.36 (t, 2H); LCMS RT=4.26 min, [M+H]+=541/544
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:8]1[CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][C:7]1=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: CCCC[C@H]1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H]1CC(=O)N(CCCCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (R)-4-butylpyrrolidin-2-one (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of (R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one as a colorless oil: 1H NMR (CDCl3) δ 7.33 (m, 5 H), 4.51 (s, 2 H), 3.45 (m, 3 H), 3.27 (t, 2 H), 2.99 (dd, 1 H), 2.52 (dd, 1 H), 2.32 (m, 1 H), 2.06 (m, 1 H), 1.24-1.71 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e 318 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CN(C1C=CC=CN=1)C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis(+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0° C. was added dimethylaminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl acetate and washing with H2O (3×), 1N HCl, NaHCO3(sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis(+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)-piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of alcohol 103 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol, 1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one 104 (15.1 g, 88% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz). C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a suspension of 3-chloro-4-fluorobenzylamine (2.5 g, 15.66 mmol) and Rhodanine (2 g, 15 mmol) in acetonitrile (50 mL) was added DIPEA (5.57 mL, 32 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (4.34 g, 16 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (200 mL) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the partial solvent under the vacuum gave lot of solids. After cooling in the refrigerator, the solids were collected by filtration and washed with cold ethyl acetate. After drying in air, 2.5 g (64% yield) of 2-(3-chloro-4-fluorobenzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C10H8ClFN2OS (M+) 258.0030. found 258.0029.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].CO[C:12](OC)([CH3:14])[CH3:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:13][C:12]1([CH3:14])[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(C)(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a mixture of 3-hydroxy-2-hydroxymethyl-2-methylpropionic acid (6.71 g, 50 mmol), dimethoxypropane (7.99 mL, 65 mmol) and acetone (50 mL), p-toluenesulfonic acid hydrate (0.048 g, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, sodium bicarbonate (0.1 g) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 5 minutes and concentrated in vacuo. To the resulting residue was added water and the resulting mixture was extracted with ethyl ether. The extract was dried over anhydrous sodium sulphate and concentrated in vacuo to give 2,2,5-trimethyl-1,3-dioxane5-carboxylic acid (7.87 g, yield: 90%) as colorless oil.
Reaction SMILES: ClCl.[CH:3](=[N:5][OH:6])[CH3:4].C(=O)(O)[O-].[Na+].[Cl:12][C:13]1[C:14](=[O:21])[CH:15]=[CH:16][C:17](=[O:20])[C:18]=1[Cl:19]>O>[C:3](#[N+:5][O-:6])[CH3:4].[Cl:12][C:13]1[C:14](=[O:21])[C:15]2[C:3]([CH3:4])=[N:5][O:6][C:16]=2[C:17](=[O:20])[C:18]=1[Cl:19]
Reactant: O=C1C=CC(=O)C(Cl)=C1Cl
Reactant: CC=NO
Agent: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC#[N+][O-]
Product: Cc1noc2c1C(=O)C(Cl)=C(Cl)C2=O
Reaction time: 2 h

Procedure:
A solution of acetonitrile oxide was prepared by passing chlorine (10.8 grams) over 30 minutes into a stirred suspension of acetaldoxime (9 grams) and sodium bicarbonate (25.2 grams) in water at 0° C was added 2,3-dichlorobenzoquinone (17.7 grams) portionwise over 15 minutes. The mixture was stirred at 0°-5° C for 2 hours and then extracted with methylene chloride. The dried extracts were evaporated to dryness under reduced pressure and the residue recrystallized from ethanol to give the desired product as yellow crystals having a melting point of 214°-215° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].Cl[CH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:40][CH:41]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Reactant: O=C(NCc1ccccn1)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccn1)c1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
8-(2-nitrobenzenesulfonyl)amino-5,6,7,8-tetrahydroquinoline (402 mg, 1.20 mmol), 4-Chloromethyl-N-pyridin-2-ylmethyl-benzamide (314 mg, 1.20 mmol), and K2CO3 (498 mg, 3.60 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 50% ethyl acetate in CH2Cl2, afforded the title compound (603 mg, 90%) as white foam. 1H NMR (CDCl3) δ 1.56-1.61 (m, 1H), 1.74-2.05 (m, 2H), 2.32-2.36 (m, 1H), 2.58-2.64 (m, 2H), 3.95 (d, 1H, J=16.2 Hz), 4.74 (d, 2H, J=4.5 Hz), 4.85 (d, 1H, J=15.9 Hz), 5.30 (dd, 1H, J=11.1, 17.4 Hz), 7.05 (dd, 1H, J=4.5, 7.5 Hz), 7.22-7.29 (m, 2H), 7.34 (dd, 2H, J=7.5, 7.8 Hz), 7.48-7.73 (m, 8H), 8.12-8.15 (m, 1H), 8.20-8.24 (m, 1H), 8.45-8.59 (m, 1H); ES-MS m/z 558.2 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([CH3:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([C:3]#[N:4])[CH3:17])[N:7]=2
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Product: Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 27, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (233 mg, 64%). MS (ES): M/Z [M+H]=454. NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 2.47 (s, 3H), 5.44 (dd, J=57.5, 13.3 Hz, 2H), 7.27 (s, 1H), 7.79-7.99 (m, 5H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.01 (s, 3F).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C#N)cc1F
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline, (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-fluoro-4-methoxybenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 80–85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more hexane/ether (2/1). The pale yellow solid 3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (3.95 g, 74%) was used in the next reaction without further purification: mp (DSC) 195° C. Anal. Calc'd. for C15H15N2SO3F: C, 55.89; H, 4.69; N, 8.69. Found: C, 55.92; H, 4.74; N, 8.53.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.O=C1CCC([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])CC1>>[O:7]1[CH2:12][CH2:11][CH:10]([N:1]2[CH2:2][CH2:3][N:21]([C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:5][CH2:6]2)[CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCOCC2)CC1

Procedure:
The title compound was prepared by substituting tert-butyl piperazine-1-carboxylate for morpholine and dihydro-2H-pyran-4(3H)-one for tert-butyl 4-oxocyclohexylcarbamate in EXAMPLE 39A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)nc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00 equiv) in tetrahydrofuran (400 mL) under nitrogen at −78° C. was added dropwise n-BuLi (19 mL, 2.4 M in THF). After 1 h at −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.5 g, 47.74 mmol, 1.12 equiv) in tetrahydrofuran (100 mL) was added dropwise. The resulting mixture was stirred for an additional hour at −78° C. The reaction was then warmed to −30° C. and carefully quenched by the addition of 300 mL of water. The resulting mixture was extracted with 3×200 mL of ethyl acetate and the combined organic layers were washed with 1×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:3) as eluent to yield 5 g (33%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C=O.[C:14](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][N:3]1[C:8]2[C:9](=[CH:4][CH:5]=[CH:6][N:7]=2)[CH:10]=[CH:11][CH:2]1[Cl:1]
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2ncccc2C=CC1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 250 mg of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (U.S. Pat. No. 6,169,093) in methylene chloride (6.1 mL) was treated with 0.148 mL of a 37% formalin solution, followed by 0.388 g of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 60 hrs. and quenched by the addition of 2N sodium hydroxide (6 mL). After stirring for 1 hr., the mixture was diluted with water and extracted with methylene chloride (2×). The organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue using silica gel chromatography provided N-methylchloronaphthyridine.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(=O)CCCC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C(=O)C(Br)CCC
Yield: 121.2 %

Procedure:
The same operation as in Example (106a) was performed using butyl 2-oxohexanoate (Lapkin, I. I.; Dvinskikh, V. V.; J. Gen. Chem. USSR (Engl. Transl.); 48; 1978; 2278-2280; Zh. Obshch. Khim.; 48; 1978; 2509-2511, 3.41 g, 18.3 mmol), bromine (2.55 g, 16 mmol) and chloroform (30 mL), to obtain 5.14 g of the title compound as a colorless liquid (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41](=O)[CH2:42][CH3:43].CC#N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.O>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:41][CH2:42][CH3:43])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: CCC=O
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CCCN1CCC(N2Cc3cc4nc(-c5c(NCC(O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (27.1 mg, 0.05 mmol) and propionaldehyde (150 μL) in a mixed solvent of CH3CN (6 mL) and H2O (2 mL) was added HOAc (500 μL) at 0° C. and the resulting reaction mixture was stirred at 0° C. for 20 min and followed by addition of Na(OAc)3BH (254 mg, 1.2 mmol). The reaction mixture was stirred at 0° C. for 1 h and at the room temperature for 1 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (16.5 mg, 57%). 1H NMR (DMSO-d6) δ 0.87 (t, J=6 Hz, 3H, CH3), 1.45 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.97 (m, 2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH+).