Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]=[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[N:9]1[CH2:19][C:20]([O:22][CH2:23][CH2:24][OH:25])=[O:21].Cl>CS(C)=O>[OH:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[NH:9][C:19]=1[C:20]([O:22][CH2:23][CH2:24][OH:25])=[O:21]
Reactant: O=C(CN1C(=O)c2ccccc2S1(=O)=O)OCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCCO)C1=C(O)c2ccccc2S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a mixture, cooled at 18° C., of 19 g (0.17 mole) of potassium tert-butoxide in 100 ml of dimethylsulfoxide, 13.2 g (0.046 mole) of 2-hydroxyethyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide prepared in Example 1 are slowly added. The mixture is stirred for 10 minutes at room temperature and then rapidly dropped into 700 ml of 10% hydrochloric acid while cooling externally to 0°-5° C. The precipitate is kept under stirring at this temperature for 1-2 hours, then it is collected and washed with methylene chloride to give, after drying, 8.8 g (yield 67%) of 2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, m.p. 158°-159° C., Rf 0.57 (TLC as in Example 1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]2)[C:6]([F:28])=[CH:5][C:4]=1[Cl:29]>C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[C:6]([F:28])=[CH:5][C:4]=1[Cl:29]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(Cl)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1Cl
Yield: 93.3 %

Procedure:
To 2 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1:1) was added 430 mg of ethyl 1-(6-amino-5-chloro-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 6 hours with stirring and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 375 mg of the title compound as a colorless powder.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:41]1[CH2:43][CH2:42]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[CH:41]1([N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:43][CH2:42]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (450) (120 mg, 0.199 mmol) of in tetrahydrofuran (6 mL), was added 1N aqueous HCl (1.5 mL) and stirring was continued for 1 h at room temperature. After completion of the reaction, volatiles were removed and the residue was diluted with water (10 mL) and the pH was adjusted to pH 8 by using NaHCO3 and the mixture extracted with ethyl acetate (2×30 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 50-60% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacidcyclopropyl-(2-hydroxyethyl)-amide (451) (80 mg, 82%) as a colorless gummy liquid.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([NH2:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: NO
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 97.4 %

Procedure:
4-Amino-1,8-naphthalic anhydride (0.2 g, 0.9 mmol) and hydroxylamine hydrochloride (0.1 g, 1.4 mmol) were reacted in pyridine (20 mL) following the procedure of Example 1 to give 0.2 g of the title compound, mp>360° C.;
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+].[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]>>[NH2:10][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C([O-])/C=C\C(=O)O
Agent: NCCNCCN
Agent: [NH4+]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.67 h

Procedure:
Monoammonium maleate (2.993 g of 94% wet salt, 0.0212 mole) and diethylenetriamine(0,115 g, 0.0011 mole) were mixed together and reacted according to the procedure of Example 2 and 3 at 230° -255° C for 40 minutes. The resulting polysuccinimide-diethylenetriamine crosslinked copolymer weighed 1,970 g. Hydrolysis of this product produced an aspartic acid-diethylenetriamine copolymer having molecular weights by GPC of Mw 5207, Mn 1359, Mw/Mn 3.83.
Reaction SMILES: C(Cl)CCl.[CH2:5]([CH2:9][C@H:10]([N:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH2:6][CH2:7][NH2:8]>CS(C)=O>[NH2:8][CH2:7][CH2:6][CH2:5][CH2:9][CH:10]([N:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: NCCCC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: NCCCCC(C(=O)O)N(CC(=O)O)CC(=O)O

Procedure:
A solution was prepared by the addition of 1 mmol of EDC and 0.2 mmol of NHS to 1 ml of DMSO, and 50 μl of the thus prepared solution was added onto the CMD film. The solution was then allowed to undergo the reaction at the room temperature for 30 minutes. After the solution was removed, washing with DMSO was performed one time. Also, a solution prepared by the addition of 0.1 mmol of AB-NTA (supplied by Dojin Kagaku K.K.) to 1 ml of DMSO was allowed to undergo the reaction for 12 hours. The solution was removed, and washing with ultra pure water was performed one time.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Yield: 89.4 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (1.00 g, 4.21 mmol), THF (20 mL) and acetic acid (1.00 mL) was added methylpiperazine (561 μL, 5.05 mmol) at room temperature. The resultant mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added sodium triacetoxyborohydride (1.79 g, 8.42 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 2 hours and 15 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. An organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate-methanol) and then further purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to give the title compound (1.21 g, yield: 89%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11][CH2:10]3)=[N:7][N:6]=[C:5]2[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH2:3][CH2:2]1.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[CH:1]1([N:4]2[C:8]([C:9]3([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH2:10][CH2:11][CH2:12]3)=[N:7][N:6]=[C:5]2[C:18]2[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:25]=[CH:26][CH:27]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)c1
Reaction time: 12 h
Yield: 78.1 %

Procedure:
Methyl 3-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}benzoate (206 mg) was dissolved in dioxane (4 ml) and a 1M aqueous sodium hydroxide solution (1.1 ml) was added thereto at room temperature, followed by stirring at the same temperature for 12 hours. The solvent was removed by evaporation and pH was adjusted to 4 by adding an aqueous citric acid solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure to obtain an amorphous. Furthermore, ethyl acetate was added thereto and the whole was heated under stirring to obtain 155 mg of 3-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}benzenecarboxylic acid (white crystals).
Reaction SMILES: S1C(C2C3C=C(OCC)C(OCC)=CC=3CC(=O)NN=2)=CC2C=CC=C[C:2]1=2.[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH3:51])[C:36](=[O:52])[NH:35][N:34]=2)=[CH:31][C:30]2[CH:53]=[CH:54][CH:55]=[CH:56][C:29]1=2>>[S:28]1[C:32]([C:33]2[C:39]3[CH:40]=[C:41]([O:47][CH2:48][CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[CH:43][C:38]=3[CH:37]([CH2:50][CH3:51])[C:36](=[O:52])[N:35]([CH3:2])[N:34]=2)=[CH:31][C:30]2[CH:53]=[CH:54][CH:55]=[CH:56][C:29]1=2
Reactant: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NNC(=O)C2
Reactant: CCOc1cc2c(cc1OCC)C(CC)C(=O)NN=C2c1cc2ccccc2s1
Product: CCOc1cc2c(cc1OCC)C(CC)C(=O)N(C)N=C2c1cc2ccccc2s1
Yield: 70 %

Procedure:
By replacing 1-(2-benzo[b]thienyl)-7,8-diethoxy-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIab in example IIIba by 1-(benzo[b]thienyl)-7,8-diethoxy-5-ethyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIad and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. M: 79–81° C. 1H-NMR (200 MHz, CDCl3): d 1.07 (t, J=7.2, 3H, CH3), 1.42 (t, J=7.0, 3H, CH3), 1.52 (t, J=7.0, 3H, CH3), 1.92–2.47 (m, 2H, 5-CH2CH3), 2.96–3.04 (m, 1H, 5-H), 3.45 (s, 3H, 3-CH3), 3.99–4.25 (m, 4H, 3×OCH2CH3), 6.83 (s, 1H Ar), 7.13 (s, 1H Ar), 7.35–7.44 (m, 3H Ar), 7.72–7.90 (m, 2H Ar).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([CH:29]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:30][CH3:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCC(CC)OC(=O)OCI
Agent: [Na+]
Product: CCC(CC)OC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.4 %

Procedure:
In the same manner as in Example 81, 154 mg of the title compound was prepared from 149 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 120 mg of (1-ethylpropan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[B:12](OCC)([O:16]CC)[O:13]CC.[Li]CCCC.Cl>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([B:12]([OH:16])[OH:13])[CH:3]=[N:4][CH:5]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) solution of 3-bromo-5-(trifluoromethyl)pyridine (5 g, 22.1 mmol) in dry THF (50 ml), under an inert atmosphere of argon, is treated with triethyl borate (3.39 g, 23.21 mmol) followed by drop wise addition of 1.46M n-BuLi in hexanes (15.2 ml, 24.34 mmol). The reaction mixture is allowed to warm to room temperature overnight and treated with 5M HCl (100 ml). After stirring for 30 minutes, the THF is removed in vacuo and the aqueous layer is extracted with EtOAc (4×100 ml). The aqueous portion is concentrated in vacuo and dried under vacuum overnight to afford the title compound as the hydrochloride salt. [M+H]+ 168.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=CN=1.[CH2:29]=[C:30]1[O:34][C:32](=[O:33])[CH2:31]1>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:32](=[O:33])[CH2:31][C:30](=[O:34])[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: COc1ccc(CNCC(=O)OCc2ccccc2)cc1
Agent: Oc1ccccn1
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)OCc2ccccc2)C(=O)CC(C)=O)cc1
Yield: 78.9 %

Procedure:
Prepared according to the representative procedure (Method B) using (4-methoxy-benzylamino)-acetic acid benzyl ester (910 mg, 3.19 mmol), 2-hydroxypyridine (304 mg, 3.20 mmol) in THF (25 mL), and ketene dimer (1.0 mL, 16 mmol). Purification by flash chromatography on SiO2 (1:4 EtOAc/hexanes) gave keto ester 54e (930 mg, 78%) as a colorless oil. Due to the presence of enol tautomers and amide rotamers, the NMR spectra of this compound is extremely complex and so line listing is not provided. Rf=0.28 (33% EtOAc/hexanes); IR (neat) 1747, 1720, 1646 cm−1; LRMS (ESI) Calcd. for C21H23NO5 [M+H] 370, found 370; HRMS (ESI) Calcd. for C21H23NO5 [M+H] 370.1654, found 370.1655.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)[CH2:24][CH2:25]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and 1-(4-nitrophenyl)piperazine.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].N12CCCN=C1CCCCC2.Cl>C(O)C>[SH:24][C:23]1[N:22]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:8]=2)[N:25]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccnc(-c2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cn1c(S)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Yield: 92.9 %

Procedure:
A solution of 3-oxo-3-(2-phenyl-pyrimidin-4-yl)-propionic acid ethyl ester (2.74 g, 10.1 mmol), N-methylthiourea (1.39 g, 15.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-en (1.57 g, 10.3 mmol) in ethanol (30 ml) was heated under reflux for 18 hours. After the solution was acidified by addition of hydrochloric acid, ethanol was removed under reduced pressure, and the resulting solid was filtered, washed with water and dried to afford 2-mercapto-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.78 g, 93%).
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:35]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 12; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH (0.8 g in 1.5 ml water) was added to the solution and the mixture was stirred for 30 min at room temperature. Acetic acid (2 ml) was added. The solvent was evaporated under reduced pressure and the residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 2.0 g (95%). NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.5 (m, 12H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.7 (s, 2H), 7.0–7.3 (m, 6H), 7.4 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[CH:4]([NH2:21])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2.[NH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.Cl>[NH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=1[S:33]([NH:21][CH:4]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[C:3]([F:2])([F:22])[F:23])(=[O:35])=[O:34]
Reactant: Nc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cc(Cl)cc(Cl)c1S(=O)(=O)NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
A mixture of 60 mg (0.19 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethylamine hydrochloride and 51 mg (0.19 mmol) of 2-amino-4,6-dichlorobenzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 1 hour and then warmed at 65° C. for 4 hours. The mixture was cooled to room temperature and diluted with 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was first purified by Combiflash chromatography using EtOAc-hexanes (0-60% gradient) and then by preparative TLC using EtOAc-hexanes (2:8) to provide 20 mg (17%) of the title compound as a colorless foam. MS m/z 534 (MH+).
Reaction SMILES: C([S:5]([C:8]1[C:12]([CH:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:11][S:10][N:9]=1)(=O)=O)CCC.O.[SH-].[Na+]>CN(C=O)C>[SH:5][C:8]1[C:12]([C@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:11][S:10][N:9]=1
Reactant: CCCCS(=O)(=O)c1nsnc1C1CN2CCC1CC2
Agent: [Na+]
Agent: [SH-]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nsnc1[C@@H]1CN2CCC1CC2
Temperature: 95 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of (3S) 3-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane (Chirality, 1997, in press.) (1.90 g, 6.0 mmol) in dry DMF (15 ml) was added sodium hydrosulfide monohydrate (1.67 g, 18.0 mmol) and the mixture was stirred at 95° C. for 3 h. The reaction mixture was concentrated in vacuo, added ice water and made less basic with 4 N hydrochloride acid. The precipitate was isolated by filtration to give 1.05 g (77%) of (3S)3-(3-mercapto-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:22])[CH2:20]Cl)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CC(OC)(C)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]2[CH2:20][O:22]2)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H](O)CCl)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H]3CO3)c2s1
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of (R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-chloro-ethanol (140 g, 407.1 mmol) in TBME (420 ml) was added dropwise NaOH aqueous solution (2M, 420 ml) followed by tetrabutylammonium iodide (7.52 g, 20.36 mmol) added in one portion. After 4 h at 26° C., 400 ml TBME was added and the organic layer was separated. The aqueous layer was extracted with TBME (400 ml). The combined organic layers were washed with water (400 ml) and brine (400 ml) to give (R)-5-tert-butoxy-2-isopropoxy-7-oxiranyl-benzothiazole (122 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:19][N:20]=[C:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=1)[CH3:22]>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:19][N:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=2)[CH3:22])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)COc1ccc(C(C)=NO)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(C)=NOCc2ccc(C(F)(F)F)cc2)cn1
Reaction time: 12 h
Yield: 102.6 %

Procedure:
To a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.87 ml, 5.6 mmoles) in DMF (10 mL), cesium carbonate (3.35 gm, 10.2 mmoles) was added followed by addition of methyl 2-((5-(1-(hydroxyimino)ethyl)pyridin-2-yl)oxy)acetate (1.15 gm, 5.1 mmoles) at 25° C. under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 12 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 2.0 gm (94%) of product as thick liquid.