Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:31]
Reactant: NC1(c2ccccc2)CCC2CCCN2C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCCN2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 55 mg (0.254 mmol) 6-phenyl-octahydro-indolizin-6-ylamine (example A.3) and 130 ul (0.762 mmol) N-ethyldiisopropylamine in dichloromethane (0.9 ml) was added drop-wise a solution of 63 mg (0.22 mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (example B.1) in dichloromethane (0.6 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 50%) to provide 26 mg (y: 22%) of example 3 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 1, first running compound) as a light yellow gum, MS (m/e): 465.2 (M+H+) and 49 mg (y: 41.5%) of example 4 (2-methoxy-6-methylsulfanyl-N-(6-phenyl-octahydro-indolizin-6-yl)-4-trifluoromethyl-benzamide, diastereoisomer 2, second running compound) as a white solid, MS (m/e): 465.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4](=[S:12])[S:5][C:6]=1[C:7]([O:9]CC)=O.Cl.[C:15](N)(=[NH:17])[CH3:16].C[O-].[Na+]>C(O)C.CO>[CH3:13][N:3]1[C:2]2[N:1]=[C:15]([CH3:16])[NH:17][C:7](=[O:9])[C:6]=2[S:5][C:4]1=[S:12]
Reactant: CC(=N)N
Reactant: CCOC(=O)c1sc(=S)n(C)c1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1nc2c(sc(=S)n2C)c(=O)[nH]1

Procedure:
Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4 mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966), was suspended in approximately 40ml of ethanol. Acetamidine hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a 25% solution of sodium methoxide in methanol were added to the suspension and the resultant mixture refluxed for approximately 20 hours. The ethanol was removed in vacuo and the residue was suspended in water and neutralized with concentrated hydrochloric acid. The resultant precipitate was filtered and dried to provide 1g of 3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11].C1CCN2C(=NCCC2)CC1.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[C:28]([S:34][CH3:35])[N:27]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]([OH:12])=[O:11])=[N:25][C:26]2[N:27]=[C:28]([S:34][CH3:35])[N:29]=[CH:30][C:31]=2[CH:32]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: O=C(O)C(=O)Cc1ccccc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
3.372 g 3-(2-bromophenyl)2-oxopropionic acid in 20 ml DMF were treated with 4.434 g DBU under cooling and stirred for 10 min at RT. 2.728 g 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde were added and the mixture was stirred at 85° C. for 4.5 hrs. Stirring was continued over night at RT, then the solvent was evaporated and the residue dispensed in aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate, then acidified to pH 2 and again extracted with chloroform. The chloroform extracts were dried and evaporated and the residue triturated with hot ethyl acetate. 2.786 g of the title product were thus obtained after filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[SH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.BrC1C=C(C(F)(F)F)C=CC=1SC1C=CC(Cl)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:32])=[CH:26][CH:27]=2)([OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2S)CC1
Agent: FC(F)(F)c1ccc(Sc2ccc(Cl)cc2)c(Br)c1
Product: COC(=O)c1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-tert-Butoxycarbonyl-4-[2-(4-methoxycarbonyl-phenylsulfanyl)-phenyl]-piperidine-4-ol (intermediate for 4a) was prepared from 4-hydroxy-4-(2-mercapto-phenyl)-piperidine-1-carboxylic acid tert-butyl ester, and 4-iodo-benzoic acid methyl ester by the palladium-catalysed coupling procedure described for 1-bromo-2-(4-chloro-phenylsulfanyl)-5-(trifluoromethyl)-benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6]([CH3:9])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24]C(S)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6][C:9]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: COC(=O)C(CS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CSc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Solution of 2-tert-Butoxycarbonylamino-3-methylsulfonylpropanoic acid methyl ester (0.86 g, 2.89 mmol) and 4-bromobenzenthiol (0.56 g, 2.89 mmol) in DMF (10 mL) was cooled to at 0° C. and treated with Cs2CO3 (1.1 g, 3.2 mmol). After stirring at room temperature for 2 h, the reaction was acidified with 5% HCl (15 mL) and diluted with ethyl acetate (25 mL). After separation, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with sat. aq NaCl, dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave the desired product (857 mg, 76%) as a white solid. 1H NMR (CDCl3), δ 7.40 (d, J=9 Hz, 2H), 7.27 (d, J=9, 2H), 5.30 (d, J=7 Hz, 1H), 4.56 (m, 1H), 3.59 (s, 3H), 3.35 (ddd, J=7, 7, 12 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: B.[CH2:2]([N:9]1[C@H:14]([CH3:15])[C:13](=O)[NH:12][C@@H:11]([CH2:17][CH3:18])[C:10]1=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>C1COCC1>[CH2:2]([N:9]1[CH2:10][C@H:11]([CH2:17][CH3:18])[NH:12][CH2:13][C@H:14]1[CH3:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC[C@@H]1NC(=O)[C@@H](C)N(Cc2ccccc2)C1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1
Temperature: 70 °C
Reaction time: 72 h
Yield: 81.4 %

Procedure:
A solution of borane in THF (1 M, 197 mL) was slowly added to (3S,6R)-1-benzyl-3-ethyl-6-methyl-piperazine-2,5-dione (4.9 g, 19.7 mmol) over 15 min under nitrogen. The reaction mixture was then stirred at 70° C. for 72 h. The resulting solution was cooled to 0° C. and MeOH (60 mL) and 5 M hydrochloric acid (16 mL) were slowly added, then the solution was heated at 70° C. with stirring for 2 h. The solvent was removed in vacuo, and the residue was partitioned between water and Et2O. 1 M aqueous NaOH was added to give pH 12 and the product was extracted with EtOAc (3×). The organic phase was dried (MgSO4), filtered and concentrated to give (2R,5S)-1-benzyl-5-ethyl-2-methyl-piperazine (3.5 g) as a yellow liquid. MS: [M+H]+=219.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.O[C@H:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[O:23]=[C:19]1[C@H:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=3)=[N:6][CH:7]=2)[CH2:22][CH2:21][NH:20]1
Reactant: COC(=O)c1cnc(-c2ccc(O)cn2)s1
Reactant: O=C1NCC[C@@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(-c2ccc(O[C@@H]3CCNC3=O)cn2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a round-bottomed flask was added methyl 2-(5-hydroxypyridin-2-yl)thiazole-5-carboxylate (400 mg), (S)-3-hydroxy-pyrrolidin-2-one (188 mg), PPh3 (443 mg), and THF (10 mL). DEAD (299 mg) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After being diluted with ethyl acetate (50 mL), the organic layer was washed with water (20 mL×2) and brine (10 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to 1:3) to afford the subtitle compound. MS ESI+: m/z=320 [M-FH]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>C(O)CCC>[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NCCCCN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NCCCCNc1nc(Cl)nc2[nH]ccc12
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol), 1,4-diaminobutane (0.125 mL, 1.25 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N-(4-aminobutyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (63 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([CH2:14][S:15][C:16](=S)[S:17]CC(O)=O)(O)=[O:12].[OH-].[Na+]>>[O:12]=[C:11]1[CH2:14][S:15][C:16](=[S:17])[N:1]1[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(N2C(=O)CSC2=S)c1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
3-amino-benzoic acid (6.00 g, 43.77 mmol), bis(carboxymethyl)trithiocarbonate (10.2 g, 45.09 mmol) in 1.029 N aqueous sodium hydroxide (44.5 g, 44.06 mmol) was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature. The precipitated solid was filtered, washed successively with 3N aqueous HCl (3×20 mL), water (3×20 mL), ethanol (2×20 mL) and dried in vacuum oven at 60° C. for 2 h to obtain 3-(4-oxo-2-thioxo-thiazolidin-3-yl)-benzoic acid (9.10 g, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.34 (2H, s), 7.52-7.55 (1H, m), 7.67 (1H, t, J=8 Hz), 7.87 (1H, t, J=2 Hz), 8.02-8.05 (1H, dt, J=1.2 & 2.8 Hz); ESI-MS: 253.30.
Reaction SMILES: CN1CCN(C)C1[C:8]1[S:9]C=[CH:11][CH:12]=1.CN(C)CCN(C)C.C([Li])CCC.ICC.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:12]([C:8]1[S:9][C:31]([CH:30]=[O:29])=[CH:32][CH:33]=1)[CH3:11]
Reactant: CN1CCN(C)C1c1cccs1
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCI
Product: CCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-2-(2-thienyl)imidazolidine (5.46 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) and N,N,N',N'-tetramethylethylenediamine (4.7 ml) were dissolved in tetrahydrofuran (150 ml). The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 19.5 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and iodoethane (2.4 ml) was added. The mixture was slowly heated to room temperature and then stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid (200 ml) was added to the residue. The mixture was stirred for 24 hours and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-ethyl-2-thiophenecarbaldehyde (1.68 g) as oil. 5-ethyl-2-thiophenecarbaldehyde (1.68 g) was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.54 g) in water (10 ml) and 30% hydrogen peroxide (2.0 ml) were added. Sodium chlorite (3.0 g) in water (20 ml) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-ethyl-2-thiophenecarboxylic acid (1.48 g) as crystals.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1C(O)=O)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26].C(N(CC)CC)C>ClC(Cl)C>[C:24]1([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:1][N:3]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=CN1CCCCC1C(=O)O
Reactant: C=C(Cl)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccn2c1CCCC2

Procedure:
To a solution of 10 g of the carboxylic acid obtained in Step A (63.6 mmol) in 65 mL of dichloroethane there are successively added 13.4 g of tosyl chloride (70.4 mmol), 11.5 mL of methyl 2-chloroacrylate (113.5 mmol) and then, dropwise, 17.8 mL of N,N,N-triethylamine (127.2 mmol). The reaction mixture is then refluxed for 1 hour 30 minutes. It is then placed at ambient temperature, and there are then added 5 mL of methyl 2-chloroacrylate (48.9 mmol) and, dropwise, 9 mL of N,N,N-triethylamine (64 mmol). The batch is refluxed overnight.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].[I-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.4 mmol of 2-(t-butyloxycarbonylamino)-3-methylpent-4-eneoic acid (2R,3S; 3S,2R) prepared by the method of P. A. Bartlett et al., J. Org. Chem., 1982, 47, 3933, in 10 ml. of dry DMF containing 4.4 mmol of benzyl bromide, 4.4 mmol of sodium bicarbonate and 10 mg. of sodium iodide was stirred for 15 minutes at 20° C. The mixture was dissolved in ethyl acetate, the solution washed three times with water, was dried over sodium sulfate, filtered and evaporated. The ester product was purified by flash chromatography on silica gel. The ester was obtained in an 80% yield as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:14]3[S:18][C:17]([CH3:19])=[N:16][C:15]=3[C:20]([F:23])([F:22])[F:21])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:24])[CH2:3]1.C[S:27]P1(=S)SP(=S)(SC)S1>O1CCCC1>[CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:14]3[S:18][C:17]([CH3:19])=[N:16][C:15]=3[C:20]([F:23])([F:22])[F:21])=[S:27])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:24])[CH2:3]1
Reactant: CSP1(=S)SP(=S)(SC)S1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Nc2cccc3c2C(C)CC3(C)C)s1
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)c(C(=S)Nc2cccc3c2C(C)CC3(C)C)s1
Reaction time: 10 h
Yield: 67.1 %

Procedure:
0.20 g of N-(1,1,3-trimethyl-4-indanyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide and 0.18 g of 2,4-bis(methylthio)-1,3,2,4-dithiadiphosphetan-2,4-disulfide were dissolved in 5 ml of tetrahydrofuran and reaction was effected for 10 hours under reflux. The reaction mixture was concentrated and the residue was chromatographed on silica gel (eluent; n-hexane:chloroform:tetrahydrofuran=6:2:1) to obtain 0.14 g of N-(1,1,3-trimethyl-4-indanyl)-2-methyl-4-trifluoromethylthiazole-5-carbothioamide (yield 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(CC)C(C)C)(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>C(Cl)Cl.[Cl-].C[N+](CCCC)(CCCC)CCCC>[C:48]([O:47][C:45]([CH2:44][N:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:24]2[N:25]=[CH:26][C:21]([C:19]([NH:18][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])=[O:20])=[N:22][CH:23]=2)[CH2:28][CH2:29]1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(N2CCCNCC2)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzamide (Example 1, 0.3 g, 0.64 mmol) in methylene chloride was added methyltributylammonium chloride (1 mL), N,N-diisopropylethylamine (2.2 mL) and tert-butyl bromoacetate (2.496 g). The mixture was stirred at room temperature until a clear solution was obtained (24–48 h), diluted with methylene chloride (50 mL), washed with water (2×10 mL) and brine, dried over sodium sulfate, evaporated, and dried. Yield=0.079 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26](Cl)=[O:27].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[N:15]1[CH:24]=[CH:25][C:26]([OH:27])=[N:16]1
Reactant: O=C(Cl)CCBr
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2ccc(O)n2)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.2 %

Procedure:
12 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 200 mL of tetrahydrofuran, and 100 mL of water was added. To this solution, 16 g of potassium carbonate and 8.1 g of 3-bromopropionyl chloride were added, followed by stirring at room temperature for 5 hours. The aqueous layer was neutralized to the vicinity of pH 2 with 6N hydrochloric acid. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid, which was washed with hexane. Then, this solid was dissolved in 200 mL of toluene, and 100mL of water was added. Then, 3.7 g of potassium permanganate and tetra n-butyl ammonium bromide in a catalytic amount were added, followed by stirring at room temperature for 10 minutes. Then, an insoluble solid was removed by filtration, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the solid was washed with hexane to obtain 8.7 g of pale yellow crystals (melting point: 166-168° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Reactant: Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(COc2nc(Oc3ccccc3)nc(Oc3ccccc3)n2)cc1
Yield: 98.5 %

Procedure:
Next, a synthesis method of the hydroxy group-protecting agent 2 will be explained. To a 30 mL eggplant flask, 470.6 mg (1.50 m mol) of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine, 3.00 mL of dichloromethane, 178.8 mg (1.90 m mol) of phenol and 0.390 mL (1.90 m mol) of N,N-diisopropylethylamine were added, and reacted at 0 degree under a nitrogen atmosphere for 4 hours. After the reaction, 50 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away to obtain 548.5 mg of 6-benzyloxy-2,4-diphenoxy-1,3,5-triazine (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]1[O:27][CH2:26]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:25][CH2:26][O:27][C:7]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: C1CO1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 15 g. (51.9 mmole) of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was added dropwise. After 18 hours of stirring at room temperature, the reaction mixture was heated to 40° for 1 hour and then cooled to room temperature and treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hours at 45°-50° and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by filtration. The filtrate was separated and the organic phase reduced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid and the pH of the solution adjusted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave the above-titled product as colorless rods, m.p. 183°-184°.