Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11]Cl)[N:8]=[C:5]2[S:6][CH:7]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O-:19])=[CH:15][CH:14]=1.[Na+]>C1COCC1>[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11][O:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)[N:8]=[C:5]2[S:6][CH:7]=1
Reactant: Cc1csc2nc(CCl)cn12
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc2nc(COc3ccccc3)cn12

Procedure:
g of 3-methyl-6-chloromethyl-imidazo-(2,1-b)thiazole hydrochloride, prepared as described in Example 27, is introduced with stirring into a cooled solution of 3.5 g of sodium phenate in 100 ml of THF. After about 1 hour the sodium chloride which precipitates is filtered off, the solvent is evaporated and acidic water is added to the residue. The aqueous solution is extracted, at pH 3-6, with chloroform. The pH is then raised to 7-7.5 and the aqueous solution is again extracted with chloroform. This extract is dried and the solvent is then evaporated to yield 4 g of 3-methyl-6-phenoxymethylimidazo-(2,1-b)thiazole; m.p. 190°-192° (methyl-ethyl-ketone).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[O:4][CH2:5][S:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10].[OH-].C[Sn+](C)C>ClCCCl>[CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[O:4][CH2:5][S:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)CCSCOc1c(C)cccc1C
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cccc(C)c1OCSCCC(=O)O
Yield: 83.2 %

Procedure:
A 50-mL flask equipped with reflux condenser and a magnetic stirring bar was charged with 0.254 g (1 mmol) of methyl 3-[(2,6-dimethylphenoxy)methylthio]propanoate and 0.362 g (2 mmol) of trimethyltin hydroxide dissolved in 25 mL of 1,2-dichloroethane and was refluxed overnight under an argon atmosphere. The solvent was removed under reduced pressure, the organic residue was dissolved in 40 mL of ethyl acetate, extracted 3 times with 10 mL 5% HCl, then with 10 mL brine, and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the reddish residue was purified by normal-phase (COMBIFLASH) chromatography with a hexane/ethyl acetate (95:5, 7 minutes; 95:40, 15 minutes) to afford 0.2 g (83%) of 3-[(2,6-dimethylphenoxy)methylthio]propanoic acid 29. 1H NMR (400 MHz, CDCl3): 2.33 (s, 6H), 2.78-2.82 (t, 2H, J=7.2 Hz), 3.03-3.07 (t, 2H, J=7.2H), 4.99 (s, 2H), 6.94-7.04 (m, 3H), 10.98 (b, OH). MS (ESI): 241 [M+H]+; 263 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:17]([NH:16][N:15]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=[C:14]1[CH2:20][CH2:21][CH3:22])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A solution of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 2.76 mmol) in 20 mL 1-propanol was treated with phenylboronic acid (0.371 g, 3.04 mmol) giving a suspension. The headspace of the flask was purged and back-filled with nitrogen (3×). The reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H2O), H2O (2 mL), and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the flask was purged and back-filled with nitrogen (3×). The reaction mixture was heated to 100° C. After 16 h, the reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was partitioned between CHCl3 (45 mL) and H2O (15 mL) and separated. The organic portion was washed again with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan solid. The solid was recrystallized from MeCN to yield N1-isopropyl-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.401 g) as light yellow crystals. mp 217–220° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=8.5 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.78–7.76 (m, 2H), 7.55 (dd, J=7.5, 1.9 Hz, 1H), 7.52–7.47 (m, 2H), 7.40–7.35 (m, 1H), 7.01 (s, 1H), 6.53 (s, 2H), 3.57–3.49 (m, 1H), 2.92 (bs, 2H), 1.94–1.81 (m, 2H), 1.06–1.01 (m, 9H); 13C NMR (75 MHz, DMSO-d6) δ 154.2, 151.9, 144.9, 140.3, 138.1, 132.1, 128.9, 127.2, 126.7, 123.9, 123.2, 121.4, 119.4, 113.8, 50.8, 27.8, 20.7, 20.2, 13.9; MS (ESI) m/z 360 (M+H)+; Anal. Calcd for C22H25N5: C, 73.51; H, 7.01; N, 19.48; Found: C, 73.39; H, 7.20; N, 19.36.
Reaction SMILES: CS(O[C@@:6]1(C)[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C@@H:6]2[CH2:10][C@H:9]([S:11][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][N:7]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH2:48][CH2:47]1
Reactant: CN1CCNCC1
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CN1CCN([C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.37 g) in dimethylformamide (100 ml) was added N-methylpiperazine (5.45 ml) and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fraction containing the desired compound were collected and evaporated in vacuo to give (2S ,4S) 2-(4-methylpiperazin-1-yl)-1-(4-nitrobenzyloxy carbonyl)-4-(triphenylmethylthio)pyrrolidine (6.87 g).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[C@@H:14]([OH:17])[C@H:13]2[C@@H:9]1[CH2:10][CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.O>[CH2:1]([N:8]1[C:15](=[O:16])[C@@H:14]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])[C@H:13]2[C@@H:9]1[CH2:10][CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@@H](O)[C@@H]2OCC[C@@H]2N1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C(=O)N(Cc2ccccc2)[C@H]2CCO[C@@H]12
Reaction time: 8 h

Procedure:
15 g of the (1R*,5S*,8S*)-6-benzyl-8-hydroxy-7-oxo-2-oxa-6-azabicyclo[3.3.0]octane obtained in the step 2 of Example A was added to 300 ml of methylene chloride, and cooled with ice. To this mixture was added 16.3 ml of triethylamine. Then, 7.5 ml of methanesulfonyl chloride was added dropwise thereto, followed by stirring overnight. Thereafter, water and methylene chloride were added to the reaction mixture so as to extract the desired product in an organic layer. After this organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 20.6 g of (1R*,5S*,8S*)-6-benzyl-8-mesyloxy-7-oxo-2-oxa-6-azabicyclo[3.3.0]octane.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:14][NH2:15].C1COCC1>>[Cl:9][C:6]1[N:5]=[C:4]2[C:10](=[O:12])[N:15]([CH3:14])[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1nc(Cl)ccc1CBr
Solvent: C1CCOC1
Product: CN1Cc2ccc(Cl)nc2C1=O

Procedure:
2-Chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one was prepared according to the general procedure in Example 7 Step 1 using methyl 3-(bromomethyl)-6-chloropyridine-2-carboxylate (0.40 g, 1.49 mmol) and methylamine, 2 M in THF (10 mL, 20 mmol) as the starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13](=[O:35])[NH:14][C:15]3[N:20]=[C:19]([O:21][CH2:22][CH:23]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:8][CH:9]=[C:10]([NH:12][C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([O:21][CH2:22][CH:23]4[CH2:27][CH2:26][NH:25][CH2:24]4)[N:20]=3)=[O:35])[N:11]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OCC2CCNC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C

Procedure:
To a slurry of tert-butyl 3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate (1.291 g, 2.603 mmol) in CH2Cl2 (25 mL) was added TFA (5 mL) under N2. The reaction mixture was heated to reflux for 3 h, then cooled to rt. Saturated NaHCO3 solution (40 mL) was added and the precipitate was washed with EtOAc (3×40 mL) and H2O (2×10 mL), filtered and dried under high vacuum to give a white solid. MS m/z: 397.0 (M+H). Calc'd. for C19H21N6O2S-397.1.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:14]([N:16]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:20]=2[C:19](=[O:29])[C:18]2[C:30](=[O:37])[C:31]3[C:36]([C:17]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:15].Cl>C(Cl)Cl>[CH2:14]([N:16]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:20]=2[C:19](=[O:29])[C:18]2[C:30]([OH:37])([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]3[C:36]([C:17]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:15]
Reactant: Br[Mg]c1ccccc1
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(O)(c1ccccc1)c1ccccc1-2

Procedure:
2M solution of phenyl magnesium bromide in THF (1.07 mL, 1.87 mmol) was dissolved in anhydrous methylene chloride. To this solution was added dropwise a solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1.58 mmol) in anhydrous methylene chloride with ice cooling and stirring followed by stirring at room temperature overnight. The reaction mixture was treated with 10% hydrochloric acid. The organic layer was separated, washed sequentially with diluted hydrochloric acid and saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove methylene chloride. The title compound was isolated by subjecting the residue to silica gel-chromatography (chloroform) and crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.30 (6H, d, CH(CH3)2), 1,79 (3H, t, NCH2CH3), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH2), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:36]2[CH2:35][CH2:34][N:33]([S:30]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=4)[CH:26]=3)(=[O:32])=[O:31])[CH2:38][CH2:37]2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
In the same manner as in referential Example 12, a reaction was conducted using (1-tert-butoxycarbonylpiperidin -4-yl)acetic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [OH-].[Na+].[C:3](#[N:6])[CH:4]=[CH2:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([O-:9])=[O:8]>[Cl-].C([N+](CCCC)(CCCC)C)CCC>[C:3](#[N:6])[CH:4]=[CH2:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:5][CH2:4][C:3]#[N:6])([O-:9])=[O:8]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C=CC#N
Product: N#CCCCc1ccccc1[N+](=O)[O-]
Yield: 40 %

Procedure:
0.75 ml of 45% sodium hydroxide solution and 175 mg of tributylmethylammonium chloride are placed in a 100 ml three-neck flask with a dropping funnel, reflux condenser and internal thermometer, stirring. At 40° C., a mixture of 1.4 ml acrylonitrile (21.15 mmol) and 25 ml ortho-nitrotoluene is added dropwise and maintained at this temperature for 3 h. The phases are separated, and the organic phase is dried and filtered off. With quantitative conversion of acrylonitrile, 1.61 g of 4-(2-nitro-phenyl)butyronitrile (8.5 mmol, 40%) are obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[C:25]([CH3:29])([CH3:28])[CH2:24][O:23]5)[C:9]2=[O:30])C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:28][C:25]1([CH3:29])[CH2:24][O:23][C:22]2=[CH:21][C:18]3[O:19][CH2:20][C:10]4([C:17]=3[CH:27]=[C:26]12)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]4=[O:30]
Reactant: [H][H]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Yield: 66.4 %

Procedure:
To a solution of 1′-(diphenylmethyl)-5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.23 g, 0.49 mmol) in methanol (50.0 mL) was added palladium on carbon (0.10 g). The mixture was hydrogenated under 120 psi of hydrogen at ambient temperature overnight. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give the title compound (0.10 g, 68%): mp 95-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.28-7.20 (m, 1H), 7.15 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.94 (d, 1H), 4.66 (d, 1H), 4.19 (s, 2H), 1.20 (s, 3H), 1.16 (3H); 13C NMR (75 MHz, CDCl3) δ 180.4, 161.3, 161.0, 140.3, 133.0, 130.1, 128.8, 124.2, 123.4, 120.0, 116.6, 110.1, 93.4, 85.5, 80.6, 58.3, 41.4, 27.7, 27.6; MS (ES+) m/z 308.6 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:20]=1)(=[O:10])[CH3:9].Br[CH:38]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])[C:39]([CH:41]1[CH2:43][CH2:42]1)=[O:40]>>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:38]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[C:39]([CH:41]2[CH2:42][CH2:43]2)=[O:40])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[CH:23]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[N:20]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)Cc1cc(/C=C2\CNCCC2SC(C)=O)nn1C(=O)OC(C)(C)C
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1C(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 132-(g), (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-5-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrogen trifluoroacetate (1.23 g) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone. The product was purified by silica gel chromatography to afford the title compound (1.11 g, yield: 81%) as a pale yellow amorphous solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:5]([CH3:13])[CH:4]=1.BrCCBr.[N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:18]=[CH:19][CH:20]=[CH:21]3)[OH:29])=[CH:4][C:5]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(Br)cc1C
Reactant: O=Cc1ccc2ncccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCc1ccc(C(O)c2ccc3ncccc3c2)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Magnesium (83 mg, 3.40 mmol), 4-bromo-1-butyl-2-methylbenzene (722 mg, 3.18 mmol) and, as an initiator, catalytic amount of 1,2-dibromoethane were added to tetrahydrofuran (2.5 mL) under nitrogen atmosphere, and the mixture was stirred for 10 minutes under reflux. This mixture was cooled to 0° C., a solution of quinoline-6-carbaldehyde (100 mg, 6.36 mmol) in tetrahydrofuran (12 mL) was added thereto, followed by stirring for 1 hour at this temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (152 mg, 78%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](O)=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[NH:14][N:15]=[CH:16]3)=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]ncc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
1-Benzylpiperazine (256 mg) and 1H-5-indazolecarboxylic acid (intermediate 2) (243 mg) were dissolved in dimethylformamide (3 ml), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (263 mg), 1-hydroxybenzotriazole (225 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (30 mg).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[C:24]([Cl:29])=[N:23][CH:22]=1)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][C:21]([C:20]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([O:7][C:6]([F:15])([F:16])[F:5])=[CH:9][CH:10]=2)=[O:19])=[CH:22][N:23]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C#N)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution trimethylaluminium 2 M in toluene (20.77 mL, 41.5 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (2.247 mL, 16.62 mmol) in toluene (150 mL) under an argon atmosphere. After 30 min, a solution of 6-chloro-5-cyanonicotinic acid ethyl ester (3.5 g, 16.62 mmol) in toluene (10 mL) was added and the RM was stirred at 25° C. for 1 h. After cooling to 5° C., the RM was treated dropwise with a solution of sat. aq. NH4Cl (50 mL) and EtOAc (50 mL) was added. The mixture was stirred for 60 min, filtered over Hyflo® and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 30% EtOAc) and recrystallized from n-hexane/DCM to afford the title compound as a yellow crystalline solid. m.p. 198-200° C., HPLC (Condition 4) tR=6.24 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=340.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.34 (m, 2H), 7.67 (d, J=8.99 Hz, 2H), 8.02 (br. s, 1H), 8.53 (d, J=2.35 Hz, 1H), 9.05 (d, J=2.35 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=O)[N:8]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccc(Br)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 14.5 %

Procedure:
To a solution of 3-(7-bromo-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide (1.13 g) in methanol (19 ml) and methylene chloride (45 ml) under an atmosphere of argon was added NaBH4 (114 mg) portionwise and the reaction stirred at room temperature for 17 hours. Concentrated hydrochloric acid (0.2 ml) was added and the reaction stirred for a further 1 hour. The reaction mixture was concentrated and the residue resuspended in methylene chloride, washed 2N HCl, dried (magnesium sulfate) and concentrated to give 3-(7-bromo-1-oxoisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a brown solid (157 mg); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.10 (s, 3H), 2.85 (m, 1H), 6.80 (d, 1H), 7.42 (d, 1H), 7.51 (d, 1H), 7.78 (d, 1H), 7.79 (s, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]([N+:16]([O-])=O)[C:10]2([CH2:13][O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].CO>[Fe].O>[CH2:1]([N:8]1[CH2:15][CH:14]([NH2:16])[C:10]2([CH2:13][O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC12COC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC1CN(Cc2ccccc2)CC12COC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of 6-benzyl-8-nitro-2-oxa-6-aza-spiro[3.4]octane (2 g, 8.1 mmol), iron powder (2.3 g, 40.5 mmol), ammonium chloride (4.3 g, 81 mmol), methanol (40 mL) and 8 mL of water was heated with stirring for 2 hours at 80° C. The reaction mixture was filtered by a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Reactant: C1CCNC1
Product: O=C(CSc1nc(-c2ccc(F)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 52.8 mg (0.74 mmol) of pyrrolidine. Yield: 17 mg.