Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C=O)C.CCOC(C)=O.O>[CH3:28][C:26]1[O:25][N:24]=[C:23]([C:4]2[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=2)[N:27]=1
Reactant: Cc1nc(-c2nc(Br)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)no1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2nc(N3CCNCC3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)no1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (200 mg, 0.4383 mmol) in DMF (1.562 mL) was treated with piperazine (377.5 mg, 4.383 mmol) and the reaction mixture heated at 100° C. for 30 minutes. The reaction was allowed to cool to RT and diluted with EtOAc/Water and the layers separated. The organic layer was washed with water (3×), dried (MgSO4), filtered and concentrated in vacuo. The material was used crude in the next step (150 mg, 67% Yield). 1H NMR (400.0 MHz, CDCl3) d 1.37 (18H, s), 2.73 (3H, s), 3.14 (4H, m) ppm; MS (ES+) 462.14
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(-n2ccnc2)nn1
Yield: 37.5 %

Procedure:
A solution of 3,6-dichloropyridazine (Aldrich, 300 mg, 2.0 mmol), imidazole (Aldrich, 163 mg, 2.4 mmol), and diisopropylethylamine (620 mg, 4.8 mmol) in 1.5 mL 1,2-dichlorobenzene was heated in a sealed tube to 120° C. at 330 watts for 45 min in an Emry™ Creator microwave. The crude reaction mixture was purified by column chromatography (SiO2, 1% methanol-CH2Cl2) to give 135 mg of the title compound (0.75 mmol, 38% yield) as the major product. MS (DCl/NH3) m/z 181 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[ClH:20]>CCOCC>[ClH:20].[ClH:20].[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CCOCC
Product: C1CN(C2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 336A (3.92 g) in ether was added HCl (25 mL, 2M in ether) and the reaction mixture was stirred for 16 hours at room temperature. The solid product was filtered off, dried and used in next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[I:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[Cl-:26].[Na+]>O.C1(C)C=CC=CC=1.C(O)(=O)C>[Cl-:26].[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([I+:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(I)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc([I+]c2ccc(C)cc2)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A reaction vessel was fed with 6.35 g of ice and 20 g of sulfuric acid, and cooled to 20° C. Then, 30 g of glacial acetic acid was fed, 41 g of ammonium persulfate were added at 25° C. or lower. After cooling this mixture to 15° C., a mixture of 21.8 g of 4-iodo toluene and 36.8 g of toluene were added dropwise over 2 hours, while keeping the temperature of the solution at 20° C. After stirring at 20° C. for 15 hours, 135 g of water with 35% in mass of sodium chloride was added, the deposited solid product was filtered and washed with saturated sodium chloride water, followed by water washing. After further washing with toluene and hexane, the solid was dried under reduced pressure. By recrystallization from acetone, 15.9 g of di-p-tolyl iodonium chloride were obtained as pale yellow crystals (yield: 46%).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.3 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)phenyl)propanoate (131 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 ml), and the mixture was stirred at room temperature for 14 hr. 1N Hydrochloric acid (2.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (124 mg) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2cccc(N)c2)cc1-c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cc2cccc(NS(C)(=O)=O)c2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 4 mL vial was added P-255 (60 mg, 0.17 mmol), followed by pyridine (2 mL) then methanesulfonyl chloride (13 μL) at 0° C. The resulting solution was allowed to stir at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The combined organics were concentrated under vacuum, and the residue was purified by silica gel column chromatography with methanol/dichloromethane to yield 36.7 mg (55%) of P-271). 1H NMR (400 MHz, CDCl3) 2.98 (s, 3H), 3.79 (s, 3H), 3.94 (s, 2H), 6.53 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.99-7.17 (m, 5H), 7.22-7.35 (m, 3H), 7.34-7.41 (m, 1H), 7.48 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:63]=[C:62]4[C:58]([CH:59]=[N:60][NH:61]4)=[C:57]([NH:64][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=4[O:11][CH3:12])[CH:56]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
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: CN(C)C=O
Product: COc1cc(C)ccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 2 h
Yield: 16.3 %

Procedure:
To a solution of 4-methyl-2-(methyloxy)benzoic acid (67 mg, 0.40 mmol) in DMF (1 ml) were added HATU (248 mg, 0.40 mmol) and DIPEA (0.211 mL, 1.21 mmol). The mixture was stirred for 30 mins under nitrogen before addition of 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.201 mmol). The reaction was stirred for 2 h then it was loaded onto PS-aminopropyl cartridge (5 g) and left for 3 h. The cartridge was washed with 10% MeOH in DCM. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in MeOH: DMSO (1 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. Solvent was evaporated under a stream of nitrogen to give title compound (13 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:6].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[CH:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[C:14]([S:22][CH3:23])=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1=O
Reactant: CNC
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N(C)C

Procedure:
The title compound, brown gum, MS: m/e=377.3 [(M+H, was prepared in accordance with the general method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclopentyl)-4-trifluoromethyl-benzamide (intermediate M) and dimethylamine. The cis- and trans-isomer could be separated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]CC2C=CC(OC)=CC=2)[N:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1ccc(COc2cc(OC)nc(-c3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(O)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
4-Methoxy-6-(4-methoxybenzyloxy)-2-phenylpyrimidine was dissolved in a mixture of TFA:DCM (1:2, 30 ml). The mixture was stirred at RT for 2 h. NaHCO3 and DCM was added and the organic layer was separated off, dried, filtered and evaporated to give the title compound (1.04 g, 83%), MS (M+H)+203.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]1O)=S.C1(C)C=CC(S(Cl)(=O)=[O:28])=CC=1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[O:28]
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(C)C1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 67.3 %

Procedure:
A mixture of 0.42 g of N-methyl-6-nitro-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.58 g of p-toluenesulfonyl chloride, and 30 ml of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated, and 2N hydrochloric acid was added to the residue. The mixture was extracted with dichloromethane, and the extract was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH2Cl2) and then recrystalllzed from ethyl acetate to obtain 0.25 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=2)(=O)=O)=CC=1>>[CH3:41][O:40][C:39]1[C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1cccnc1CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Product: COc1cccnc1CCN1CCN(c2cccc3cc(C(=O)N(C)C)oc23)CC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 46 starting from N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.085 g, 0.31 mmol) (Example 39d) and 2-(3-methoxypyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.092 g, 0.31 mmol). The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=CC=[CH:5][C:4]=1C)[CH3:2].[C:10]1(=[O:20])[O:15][C:13](=O)[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C1(C)C=CC=CC=1>[C:3]1([CH3:8])[CH:4]=[CH:5][C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([OH:15])=[O:20])=[CH:2][CH:1]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 70 °C
Yield: 107.5 %

Procedure:
To a mixture of 108 g of the complex obtained in Example 1 and 92 g of toluene were added gradually 14.8 g of phthalic anhydride while stirring, and the mixture was maintained at 70°C for 2 hours after the addition. The reaction mixture was treated as usual to obtain 22.8 g of o-(p-toluyl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[CH2:23]([S:27](Cl)(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:27]([CH2:23][CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[C:4]=2[CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)Oc1cc(=O)oc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.455 mmol, 0.090 g) is suspended in 5 mL DCM. DIEA (1.37 mmol, 0.237 mL) is added and the reaction is cooled to 0° C. 1-Butanesulfonyl chloride (0.5 mmol, 64.8 μL) is dissolved in DCM is added and and the reaction is stirred at ambient temperature for 2 hrs. The DCM is removed under reduced pressure and the residue is redissolved in MeOH/H2O then is purified by HPLC to afford the title compound (36.2 mg, 25%) 1H NMR (DMSO-d6, 300 MHz) δ 7.81 (2H, m), 7.56 (1H, d, J=8.75 Hz), 6.59 (1H, s), 3.99 (2H, m), 1.83 (2H, m), 1.46 (2H, m), 0.92 (3H, t, J=7.25 Hz); MS (ESI, Pos.) calcd for C13H13ClO5S m/z [M+H]=317.0, found 317.1.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]2.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]#[N:20])=[CH:17][NH:16][C:11]=2[N:12]=[C:13]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]([CH3:42])[C:37](=[O:43])[CH2:36][CH2:35]3)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(NCc4ccccc4)c4c(C#N)c[nH]c4n3)ccc21

Procedure:
A solution of 4-(benzylamino)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg, 0.12 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (43 mg, 0.24 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2.5 mL) and dioxane (1.5 mL) was stirred at 116° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 424.3 (M+H); UV 207.7, 273.1 nm.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CN2CCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridin-2-ylcarbamate (96; 750 mg, 2.7 mmol) in dichloromethane (10 mL) was added TFA (4.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the resulting residue to adjust the pH=9. The mixture was then extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 6-(pyrrolidin-1-ylmethyl)pyridin-2-amine 97 (440 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:10][OH:11])=[CH:5][C:6]=1[I:9])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1c(I)cc(CO)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (7.14 g, 25.0 mmol) is dissolved in DMF (50 mL) in a dry flask under N2, sodium hydride (60% dispersion in mineral oil) (1.0 g, 25.0 mmol) is added, and the reaction is stirred for 1 h at rt. Allyl bromide (2.38 mL, 27.5 mmol) is added, and the reaction mixture is stirred 48 h at rt. The mixture is diluted with EtOAc (50 mL) and washed 4×25 mL of a 50% saturated solution of 1:1 NaCl/NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to a white solid. The solid is washed with hexane and dried to afford 3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodopyridine (C50) as a white solid (68% yield). MS (EI) for C9H9Cl/NO2, m/z: 325 (M)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH2:18][CH:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:20]=[N+:21]([O-:9])[CH:22]=[CH:23][CH:24]=3)[C:16]=2[CH:25]=1)#[N:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2cccnc2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2ccc[n+]([O-])c2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
The 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide used as the starting material was prepared as follows: (A) 10.25 g of 3-iodopyridine were added at room temperature to a solution of 44 mg of palladium(II) chloride, 131 mg of triphenylphosphine and 95 mg of copper(I) iodide in 200 mg of diethylamine. 9.25 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were then added and the mixture was stirred for 3 days. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (11:9) for the elution to give 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile in the form of an oil. (B) 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile were heated at reflux in 75 ml of 1,2-dichlorobenzene for 3.5 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. After recrystallization from cyclohexane there were obtained 6.7 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 98°-99° C. (C) 2.1 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 50 ml of ethyl acetate and shaken at room temperature under a hydrogen atmosphere with 50 mg of 10% palladium-on-charcoal for a total of 30 hours with several changes of catalyst. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. 910 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were obtained in the form of an oil. (D) 610 mg of m-chloroperbenzoic acid were added to a solution of 792 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane. After stirring at room temperature for one hour the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was crystallized from t-butyl methyl ether to give 710 mg of 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a solid of melting point 134°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH3:34]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][C:25]([NH2:34])=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(CCCC(N)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C

Procedure:
To a THF solution of 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]butanoic acid were added oxalyl chloride and one drop of DMF, followed by stirring at room temperature. The reaction mixture was added dropwise to an ice-cooled THF solution of concentrated aqueous ammonia and then, the whole was stirred for 30 minutes. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]butanamide. To a dichloroethane solution of the resulting compound were added pyridine, phosphorus oxychloride and one drop of DMF, followed by stirring at room temperature. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-3-(3-cyanopropyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 6.90 (1H, d, J=8.2 Hz), 4.67 (2H, q, J=7.1 Hz), 1.70-2.10 (2H, m).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@@H:10]([OH:12])[C@H:9]([N:13]([CH3:25])[C:14](=[O:24])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pt]=O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:13]([C@H:9]2[C@H:10]([OH:12])[CH2:11][N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8]2)[CH3:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Agent: O=[Pt]
Solvent: CCO
Product: CN(C(=O)c1ccc(N)cc1)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reaction time: 1 h

Procedure:
A solution of 44 g of trans-N-(1-cyclohexyl-4-hydroxy-3-pyrrolidinyl)-N-methyl-4-nitrobenzamide in 600 ml of absolute ethanol was treated with a catalytic amount of platinum oxide and shaken in the Parr apparatus under hydrogen for one hour. The suspension was filtered and the filtrate evaporated under vacuum. The residue crystallized from a benzene-cyclohexane mixture and was recrystallized from toluene. The yield was 39.6 g (99%); m.p. 180.0°-182.5° C.