Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C=O)cc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1sc(C2OCCO2)cc1Br
Yield: 93 %

Procedure:
A mixture of 4-bromo-5-methylthiophene-2-carbaldehyde (6.0 g), ethylene glycol (100 mL), p-toluenesulfonic acid (2 mL) and toluene (100 mL) was heated under reflux for 5 hr with a Dean-Stark trap. The reaction mixture was washed with water and saturated brine, and the obtained organic layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 2-(4-bromo-5-methyl-2-thienyl)-1,3-dioxolane (6.96 g, yield 93%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:20][CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(NC3CC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (151 mg, 0.674 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.046 mL, 0.857 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (200 mg, 0.423 mmol, 69.1% yield). LC-MS (M+H)+=473.10. 1H NMR (500 MHz, CDCl3) δ ppm 7.81 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.5 Hz), 7.44 (1H, s), 7.27-7.35 (2H, m), 7.19-7.25 (3H, m), 6.99-7.06 (2H, m), 6.95 (1H, d, J=8.2 Hz), 4.89 (1H, br. s.), 4.20 (1H, t, J=8.2 Hz), 3.45 (3H, s), 2.92 (1H, td, J=6.7, 3.1 Hz), 2.76-2.86 (1H, m), 2.59-2.75 (2H, m), 2.07-2.14 (1H, m), 0.85-0.91 (2H, m), 0.63-0.70 (2H, m).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>O1CCCC1.O>[Cl:41][C:42]1[CH:43]=[C:44]([S:48]([N:7]2[C:8]([C:9]3[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=3)=[C:4]([F:3])[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cncc(Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 78.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 52 mg) in tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (286 mg) and a solution of 5-chloropyridine-3-sulfonyl chloride (318 mg) in tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred for 20 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:117:3) to give the title compound as a colorless oil (yield 391 mg, 78%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:19]=[N:18][N:17]([CH3:20])[C:16]=1[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]([CH3:35])([N+:32]([O-])=O)[CH3:31])[NH2:24].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH2:32])([CH3:35])[CH3:31])=[C:21]([C:16]3[N:17]([CH3:20])[N:18]=[CH:19][C:15]=3[Br:14])[CH:22]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(OCC(C)(C)N)c(-c3c(Br)cnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
4-Acetamidobenzoyl chloride (11 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (5.6 mg, 22%) as a TFA-salt. LCMS m/z (%)=502.3 (M+H 81Br 42.9%), 500.4 (M+H 79Br 52.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 3H), 1.18 (s, 3H), 2.08 (s, 3H), 3.67 (s, 3H), 3.82 (d, J=9.60 Hz, 1H), 3.98 (d, J=9.85 Hz, 1H), 7.27 (d, J=9.09 Hz, 1H), 7.67 (s, 1H), 7.69 (d, J=2.78 Hz, 1H), 7.71 (d, J=8.84 Hz, 2H), 7.85-7.91 (m, 3H), 7.91 (d, J=8.84 Hz, 2H), 7.95 (dd, J=8.97, 2.65 Hz, 1H), 10.22 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:15][CH2:13][OH:14]
Reactant: NCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)c(CNCCO)c1
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To 2-fluoro-5-nitrobenzaldehyde (52.4 g, 0.31 mol) in absolute ethanol (500 ml) was added ethanolamine (18.93 g, 0.31 mol) and borane-pyridine complex (31.31 ml, 0.31 mol). The mixture was stirred for 48 h and then evaporated. The residue was acidified with 2.5N hydrochloric acid, extracted with methylene chloride (3×150 ml), and the extracts were discarded. The aqueous phase was basified with 25% aqueous sodium hydroxide and extracted with methylene chloride (4×200 ml). These extracts were washed with saturated brine solution, dried over magnesium sulfate and evaporated to give yellow crystals (37.67 g, 57%), m.p. 98.5-99.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:25]=[N:26][C:22]=2[CH:21]=1>CN(C=O)C>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([CH2:19][C:20]3[CH:35]=[CH:34][C:23]4[N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[N:25]=[N:26][C:22]=4[CH:21]=3)[C:8]=2[N:9]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(CBr)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nnc2cc(Cn3nnc4c(-c5ccco5)nc(N)nc43)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (404 mg, 2 mmol) in DMF (4 mL) was treated with NaH (60% dispersion, 80 mg, 2 mmol), stirred at room temperature for 10 min, treated with a solution of tert-butyl 5-(bromomethyl)-1H-benzotriazole-1-carboxylate (as a mixture with the 6-bromomethyl regioisomer) (624 mg, 2 mmol) in DMF (2 mL) and stirred overnight. The mixture was concentrated in vacuo and purified by chromatography [SiO2, isohexane:EtOAc (2:1)] to give tert-butyl 5-(5-amino-7-(2-furyl)-3H-triazolo[4,5-d]pyrimidin-3-yl)methyl-1H-benzotriazol-1-carboxylate (135 mg, 24%) (as a mixture with the 6-substituted regioisomer) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C([O-])(=O)C.[Na+].[CH3:17][O:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[CH:38]=O)[CH:22]=1.C([BH3-])#N.[Na+]>CO>[CH3:17][O:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][C:29]=2[CH2:38][NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)[CH:22]=1
Reactant: NC1Cc2ccccc2C1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 2-aminoindan hydrochloride (0.253 g, 1.49 mmol) in MeOH (2 mL) was added sodium acetate (0.122 g, 1.49 mmol), and the mixture was heated with a heating gun for 2 minutes. [3-(2-Formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.420 g, 1.24 mmol) in MeOH was added, followed by sodium cyanoborohydride (0.140 g, 2.23 mmol), and the reaction was stirred at room temperature for 2 hours and at 50° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and saturated aqueous NaHCO3, and the aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[O:21][C:22]1[C:36]([OH:37])=[CH:35][C:25]2[NH:26][C:27]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[N:28][C:24]=2[CH:23]=1>[Cu]=O.CN1CCCC1=O>[F:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[O:21][C:22]1[C:36]([O:37][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:35][C:25]2[NH:26][C:27]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[N:28][C:24]=2[CH:23]=1
Reactant: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Fc1ccccc1Oc1cc2nc(-c3cnccn3)[nH]c2cc1Oc1ccc(C(F)(F)F)nc1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
16 mg of 5-bromo-2-trifluoromethyl-pyridine, 50 mg of cesium carbonate and 10 mg of copper(II) oxide were added to an N-methylpyrrolidinone (1 ml) solution of 21 mg of 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 251 (step 1), and the reaction liquid was stirred at 130° C. for 5 hours. The deposit was separated through filtration, and the solution was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]Br)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])[CH2:21][CH2:22]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc3nccc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-iodo-1H-pyrazolo[4,3-b]pyridine (76 mg, 0.310 mmol) in DMF (4 ml) was cooled in an ice bath. Sodium hydride (16.13 mg, 0.403 mmol) was added and the reaction was stirred for 5 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (104 mg, 0.372 mmol) was added and the reaction was warmed to room temperature and then to 65° C. for 20 minutes. The reaction was then cooled, quenched with water and saturated NH4Cl solution and extracted with EtOAc. The organic layer were separated, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 4-((7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)methyl)piperidine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(I)cc1

Procedure:
A solution of 4-iodoacetophenone (6.15 g) in N,N-dimethylformamide dimethyl acetal (6.5 ml) was heated at reflux for 8 hours. The reaction mixture was evaporated and the solid residue was recrystallised from acetonitrile to give 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (4.38 g), as a solid, m.p. 117°-118° C.; NMR(CDCl3): 2.60-3.50(6H,br.d), 5.64(1H,d), 7.62(2H,d), 7.77(2H,d) and 7.80(1H,d), m/z 302(M+H). A mixture of 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (3.0 g) and hydroxylamine hydrochloride (0.73 g) in 1:1 dioxane/water (30 ml) was stirred at ambient temperature for 48 hours. Addition of water gave a solid which was collected by filtration, washed with water, and purified by flash column chromagatography on silica gel using 1:1 (v/v) ethyl acetate/pentane as eluent. There was thus obtained 5-(4-iodophenyl)-isoxazole (0.6 g); microanalysis found: C, 39.4; H, 2.3; N, 4.8%; C9H6INO requires: C, 39.9; H, 2.23; N, 5.17%; NMR(CDCl3): 6.54(1H,d), 7.52(2H,d), 7.83(2H,d) and 8.28(1H,d); m/e 272(M+H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[I-].[C:17]([CH2:19][CH2:20][N:21]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:18]>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][C@H:29]([N:21]([CH2:20][CH2:19][C:17]#[N:18])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: N#CCCN(Cc1ccccc1)[C@H]1CCNC1
Agent: [I-]
Product: CC(C)C(C#N)(CCCN1CC[C@H](N(CCC#N)Cc2ccccc2)C1)c1cccs1

Procedure:
Optically active body, 4-cyano-4-(2-thienyl)-5-methylhexyl iodide (iodide D (optically active body)) was synthesized from the alcohol A in accordance with Example 77 (1). The title compound was synthesized in accordance with Example 75 from the iodide D and (3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine of “Synthetic method A” (1) (1) of Example 175. The physico-chemical data of the title compound was as below.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Br:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2Br)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2Br)CC1)c1ccccc1
Yield: 70.8 %

Procedure:
0.108 g (0.0004 mol) of 1-(2-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.106 g (71%) of 1-(2-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>>[CH3:8][C:6]1[CH:5]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]([CH:27]=[C:33]4[S:29][C:30](=[O:35])[NH:31][C:32]4=[O:34])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)c1
Yield: 92.4 %

Procedure:
In a 100 mL round-bottomed flask equipped with a Dean-Stark apparatus, a mixture of 45 (1.55 g, 4.2 mmol), 2,4-thiazolidinedione (0.5 g, 4.2 mmol), benzoic acid (0.62 g, 5.0 mmol) and piperidine (0.62 mL, 6.3 mmol) was azeotroped in toluene (60 mL) for 45 min under vigorous reflux. The reaction mixture was cooled then poured over 10% citric acid (40 mL) and stirred until a bright yellow solid formed. The solid was filtered and washed with water and the wet solid was azeotroped and recrystallized from toluene to yield 1.83 g (93%) of 46. 1H NMR (400 MHz, DMSO-d6): δ 12.72 (br s, 1H), 12.57 (br s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.69 (s, 2H), 2.16 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][S:6][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][C:8]([C:7]2[S:6][CH2:5][CH2:4][O:3][C:2]=2[CH3:1])=[O:10])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cccc(C#N)c2)SCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
5,6-Dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.0 g, 0.031 mole) and thionyl chloride (4.1 g, 0.034 mole) were heated under reflux in methylene chloride for about 2 hours, then evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride and the chilled solution treated dropwise with a solution of 3-aminobenzonitrile (3.7 g, 0.031 mole) and triethylamine (3.2 g, 0.032 mole) in methylene chloride. The reaction mixture was stirred at room temperature for a further 3 hours and then worked up by washing with dilute hydrochloric acid and dilute sodium hydroxide. Evaporation of the solvent gave a solid residue, which was recrystallized from methanol to give a white solid, m.p. 119°-121° C. (5.5 g, 67% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=O)=[CH:9][N:8]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:10]3[CH:11]=[N:12][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[N:8][CH:9]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 17.4 %

Procedure:
Using methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyrimidine-5-carboxylate (100 mg) described in Preparation Example 231 and 1-(3,5-dimethylpyridin-2-yl)piperazine (74 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (28 mg) was obtained.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:42])[CH2:37][C:38]([F:41])([F:40])[F:39])[CH:29]=[CH:30][C:31]=1[Cl:32])(C)(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:32][C:31]1[CH:30]=[CH:29][C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:42])[CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CC(F)(F)F)NCCc1ccc(Cl)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
TBAF (1M in THF, 2.46 mL, 2.46 mmol) was added to a sol. of N-{2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-3,3,3-trifluoro-propionamide (500 mg, 1.22 mmol) in THF (15.8 mL) at 0° C. The mixture was stirred for 1 h at 0° C., and aq. sat. NH4Cl was added. The mixture was extracted with EtOAc (3×). The combined org. extracts were washed with water (4×), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 19:1) yielded the title compound (230 mg, 64%). LC-MS: tR=0.79 min.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:20]Cl>C(O)(=O)C>[NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCl
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of ethyl 2-amino-6-[(2,2-dimethylpropanoyl)amino]nicotinate (Example 1, METHOD A, Step 1, 805 mg, 3.03 mmol) in acetic acid (15 ml) was added a solution of chlorine in acetic acid (0.89 M, 8.5 mL, 7.6 mmol), and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo. The obtained residue was taken up in ethyl acetate (150 mL) and washed with saturated sodium bicarbonate, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/pentane (1:2) to give 685 mg (76%) of the title compound as a white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 72B) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.