Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.C([Li])CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2([OH:17])[CH2:16][CH2:15][CH2:14]2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Br)ccc1I
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2C(F)(F)F)CCC1
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
To a solution of 5-bromo-2-iodobenzotrifluoride (5.00 g) in dehydrated tetrahydrofuran (140 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 5.30 mL) was added at −78° C. and the mixture was stirred at that temperature for 25 minutes. After adding a solution of cyclobutanone (999 mg) in tetrahydrofuran (5.00 mL), the mixture was brought to room temperature and stirred for 3 days. After adding a saturated aqueous solution of ammonium chloride under cooling with ice, two extractions were conducted with ethyl acetate. The combined organic layers were washed with water and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to give 1-[4-bromo-2-(trifluoromethyl)phenyl]cyclobutanol as a pale yellow oil (3.00 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.[Br-].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:27]/[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][N:19]=2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOc1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
A solution of 4-(2-methoxyethoxy)-2-nitrobenzaldehyde (27 mg, 0.12 mmol) obtained in Step 1 in methanol (1.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (57 mg, 0.12 mmol) and potassium carbonate (33 mg, 0.24 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (ethyl acetate) to obtain (E)-3-{2-[4-(2-methoxyethoxy)-2-nitrophenyl]vinyl}-1H-indazole (0.04 g, 100%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15][CH2:16][CH2:17][F:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([S:15][CH:16]([Cl:1])[CH2:17][F:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: FCCSc1ccccc1
Solvent: ClCCl
Product: FCC(Cl)Sc1ccccc1
Yield: 94.1 %

Procedure:
A solution of N-chlorosuccinimide (1.1 g; 8.25 mmol) and phenyl-(2-fluoroethyl)sulfide (1.28 g; 8.25 mmol) in 25 mL methylene chloride was stirred for 0.5 h at room temperature. Methylene chloride (25 mL) was added to the reaction mixture and washed with water (2×35 mL). The organic layer was dried and evaporated to yield 1.48 g phenyl-(1-chloro-2-fluoroethyl)sulfide as an oily material which was mixed with 6 (2.23 g; 9.9 mmol), triethylamine (1.0 g; 9.9 mmol) and dry acetonitrile (30 mL) and refluxed for 5 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (75 mL) and washed with water (50 mL), 5% aqueous sodium bicarbonate (50 mL) and 5% hydrochloric acid (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent removed, leaving a crude product (2.78 g). The crude product was purified by flash chromatography using hexane/methylene chloride as the eluting solvent, mp 73°-74° C. (1.92 g; 62% yield). 1H NMR: δ 2.80-2.98(m, 1H), 3.2-3.45(m,4H), 4.6-4.8(m, 1H), 4.82-5.10(m, 1H), 5.45(m, 1H), 7.1-7.35(m,3H), 7.5-7.65(m,2H).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]=[C:18]=[S:19]>O1CCOCC1>[C:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:18](=[S:19])[NH:17][CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN=C=S
Reactant: c1ccc(C2NCCc3[nH]cnc32)cc1
Solvent: C1COCCO1
Product: CNC(=S)N1CCc2[nH]cnc2C1c1ccccc1

Procedure:
A solution of 3.5 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci., 1967, 22, 821) and 3.5 g of methyl isothiocyanate in 55 ml of dioxane is refluxed for 4 h. The solution is cooled and filtered: 3.6 g of 4-phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine, m.p. 228°, are collected.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=O)[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=[S:41])[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 63.6 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 85 mg of N,N-dimethyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound B5) and 82 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-5 vol. % ethanol) affords 56 mg of the title compound as a light yellow, waxy solid. ESI-MS: 458.3 (MH+). TLC: Rf=0.46 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:32]([CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:33])[CH3:36]
Reactant: CCN(CC)C(=O)C(Cl)c1ccccc1
Reactant: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a solution of 4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (96 mg, 0.25 mmol) in MeOH (5 mL) was added HCl (2 mL, 1 M in Et2O). After 16 h at 25° C., the mixture was concentrated and the residue re-dissolved in DMF (2 mL). The solution was treated with 2-chloro-N,N-diethyl-2-phenyl-acetamide (225 mg, 0.32 mmol) and K2CO3 (138 mg, 1.0 mmol), and was stirred at 25° C. for 16 h. The resulting mixture was purified by PTLC to provide the title compound (25 mg, 21%). MS: 480.4. 1H NMR (CDCl3): 7.57-7.45 (m, 3H), 7.40-7.27 (m, 4H), 7.20-7.06 (m, 2H), 5.90 (s, 1H), 4.43 (s, 1H), 3.55-3.15 (m, 6H), 2.92-2.83 (m, 1H), 2.74-2.64 (m, 1H), 2.53-2.44 (m, 2H), 2.07-1.98 (m, 1H), 1.76-1.47 (m, 4H), 1.17-0.90 (m, 12H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.[CH3:29][O:30][CH2:31][C:32](O)=[O:33].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (150 mg, 0.391 mmol) in dichloromethane (15 mL), methoxy-acetic acid (142 mg, 1.56 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (112 mg, 0.587 mmol) and 1-Hydroxy-7-azabenzotriazole (HOAt) (106 mg, 0.78 mmol) and triethylamine were added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-3% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:13][N:12]=[C:11]([S:14][CH3:15])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[S:13][N:12]=[C:11]([S:14]([CH3:15])=[O:24])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nsc(OCc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nsc(OCc2ccccc2)n1
Reaction time: 1 h

Procedure:
Into 12 ml of chloroform was dissolved 1.39 g of 5-benzyloxy-3-methylthio-1,2,4-thiadiazole, and metachloroperbenzoic acid (>70%) was slowly added to the mixture under ice-cooling. After stirring for 1 hour, the compound of low-polarity from the reaction mixture was detected by thin layer chromatography. The reaction mixture was poured into a saturated sodium sulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogen carbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 1.4 g of 5-benzyloxy-3-methylsulfinyl-1,2,4-thiadiazole.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[CH:33][C:32]([C:35]([OH:1])=[O:36])=[CH:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (784 mg, 1.28 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (366 mg, 0.85 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=445.88
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8]C2C=CC=C(O)C=2)[C:5](F)=[CH:4][N:3]=1.[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22])[CH2:18][CH3:19]>>[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)=[O:22])[CH2:18][CH3:19]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCCNC(=O)c1cccc(N)c1
Product: CCCNC(=O)c1cccc(Nc2nccc(N)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-propylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, J=1.8 Hz), 7.69–7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16–7.05 (m, 3H), 6.67 (td, 1H, J=2.4 and 7.2 Hz), 3.34–3.29 (m, 2H), 1.65–1.56 (m, 2H), 0.96 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CD3OD): −46049; LCMS: purity: 94%; MS (m/e): 382(MH+).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:17]1([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cnc2cc(-c3ccccc3)ccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1

Procedure:
Tetrakis(triphenylphosphoine)palladium(0) (16 mg, 0.014 mmol, 0.050 equiv) was added to a deoxygenated mixture of 3-iodo-7-phenylimidazo[1,2-a]pyridine (1-5, 88 mg, 0.28 mmol, 1 equiv), phenyl boronic acid (50 mg, 0.41 mmol, 1.5 equiv), and aqueous saturated sodium carbonate solution (0.42 mL, 3.0 equiv) in dioxane (5 mL), and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled, then concentrated, and the residue was partitioned between half-saturated aqueous NaCl solution (50 mL) and EtOAc (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (dichloromethane, initially, grading to 40% EtOAc in dichloromethane) to give 3,7-diphenylimidazo[1,2-a]pyridine (1-6) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 8.41 (dd, 1H, J=7.2, 0.6 Hz), 7.90 (dd, 1H, J=1.8, 0.6 Hz), 7.74 (s, 1H), 7.69 (m, 2H), 7.62–7.39 (m, 8H), 7.12 (dd, 1H, J=7.0, 1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][Br:37])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Yield: 35.2 %

Procedure:
A refluxing solution of 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (7.19 g, 24.0 mmol) and dibenzoylperoxide (370 mg, 1.53 mmol) in benzene (247 ml) was treated in portions with N-bromosuccinimide (7.53 g, 42.3 mmol). The mixture was refluxed 24 hours, cooled, and filtered. The precipitate was washed once with benzene, and the combined filtrate and washings were evaporated under vacuum. The residue was triturated with diethyl ether and filtered, and the filtrate was evaporated under vacuum. The residue was chromatographed on silica gel (500 g) eluted with 7:3 (v/v) n-hexanedichloromethane using a preparative high-performance liquid chromatograph to provide 3.2 g (35%) of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide, m.p. 69°-73° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.CO.C1COCC1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 78.7 %

Procedure:
To a solution of 87B (3.648 g, 8.0 mmol) and 4-fluorobenzene boronic acid (2.24 g, 16.0 mmol) in a mixed solvent of MeOH-THF (80 mL, 1:1 ratio) was added K2CO3 (4.423 g, 32.0 mmol), followed by PXPd (215 mg, 0.40 mmol). The resulting suspension was vigorously stirred in a 70° oil bath for 35 min. After cooling down to RT, the dark brown solution was diluted with water (200 mL), and extracted with EtOAc (200 mL×2). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexane (0-30%) to afford the title compound (2.977 g, 79%) as a light brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Brc1ccccn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromopyridine (243 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (346 mg, 68%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N+:18]([O-])=[C:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH2:20][O:30][C:27](=[O:29])[CH3:28])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[NH:14][C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=[N+]([O-])C(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Reaction time: 96 h
Yield: 71.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (2.83 g,) and acetic anhydride (7.6 ml, 10 eq.mol) in methylene chloride (60 ml) was stirred for 4 days. From the reaction mixture methylene chloride was removed in vacuo. To the residue was added a mixture (60 ml) of diisopropyl ether and n-hexane (1:1). The resultant crystalline powder was collected by filtration and washed with diisopropyl ether to give (3RS)-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one (2.26 g, 71.1%) as a crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[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.[CH3:18][NH2:19]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH3:18])[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
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation G) (395 mg, 1.49 mmol) in THF (3700 μL), 2 M MeNH2 in THF (3700 μL, 7.45 mmol) was added. The reaction was allowed to stir at rt. When the reaction was complete, removed solvent and applied residue to silica gel. Eluted with EtOAc/Hex to afford the desired 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)+=260.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.07 (3H, dd, J=8.5, 5.5 Hz), 6.96 (2H, t, J=8.7 Hz), 4.72 (1H, br s), 4.23 (1H, t, J=7.2 Hz), 3.09 (3H, d, J=4.9 Hz), 2.67-2.77 (1H, m), 2.58-2.67 (2H, m), 2.01-2.11 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=O)[CH:13]3[CH2:18][CH2:17][NH:16]CC3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:22]1(C)C=CC(S(Cl)(=O)=O)=C[CH:23]=1.[OH-].[Na+]>CN(C)C=O>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([N:11]3[CH2:12][CH2:13][CH:18]([C:17]#[N:16])[CH2:23][CH2:22]3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CC1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Temperature: 110 °C
Yield: 85 %

Procedure:
75 g of the N-(6-nitrobenzothiazol-2-yl)isonipecotamide obtained in the Preparation Example 12 was dissolved in 700 ml of dimethylformamide. 50 g of p-toluenesulfonoyl chloride was added to the solution and the mixture was heated at 110° C. for 20 min, poured into ice/water and neutralized with sodium hydroxide. The formed precipitates were recovered by filtration, washed with water and then with ether, and dried to give 60 g of the titled compound.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.Cl[CH:13]([S:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([C:19]#[C:20][CH3:21])[CH3:18])=[O:15]>>[O:10]=[C:8]1[S:7][C:6]2[C:11]([CH2:21][C:20]#[C:19][C:17]([NH:16][C:14](=[O:15])[CH2:13][S:23][CH3:24])([CH3:18])[CH3:22])=[CH:2][CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Reactant: O=c1oc2ccc(O)cc2s1
Product: CSCC(=O)NC(C)(C)C#CCc1cccc2oc(=O)sc12

Procedure:
In a similar procedure, 5-hydroxy-1,3-benzoxathiol-2-one was reacted with 2-chloro-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide to give 5-(2-oxo-1,3-benzoxathiolyl)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 7).