Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([OH:32])=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([Cl:35])=[O:32])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
50 g (0.113 mol) of the previously obtained dicyclohexylamine salt of N-benzyloxycarbonyl-(L)-pyroglutamic acid are mixed to a paste with 1 liter of toluene, 110 ml of thionyl chloride are run in dropwise and the temperature is then raised to 60° C. for 2 hours. The mixture is cooled and filtered, the filtrate is evaporated and the residue is taken up several times with benzene. The acid chloride finally crystallizes from petroleum ether with a practically quantitative yield. Melting point=65°-70° C. (literature=71/72° C.).
Reaction SMILES: [Br:1][CH:2]([Br:23])[C:3](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].C1CCN2C(=NCCC2)CC1>CS(C)=O>[Br:23][C:2]([Br:1])=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CC(Br)(c1ccccc1)C(Br)Br
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CC(=C(Br)Br)c1ccccc1
Yield: 69.4 %

Procedure:
A solution of 1,1,2-tribromo-2-phenyl-3-phthalimidopropane (1.22 g) and DBU (0.50 g) in DMSO (50 ml) is heated at 85° for 4 hours. Work-up as described in Example 19 C gives 1,1-dibromo-2-phenyl-3-phthalimidopropene (0.71 g): colorless needles; m.p. 154°-155°;
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[OH:23][C@H:24]1[CH2:44][C@@:43]2([CH3:45])[C@@H:35]([CH2:36][C@@H:37]([OH:47])[C@:38]2([OH:46])[C:39](=[O:42])[CH2:40][OH:41])[C@H:34]2[C@H:25]1[C@:26]1([CH3:49])[C:31]([CH2:32][CH2:33]2)=[CH:30][C:29](=[O:48])[CH2:28][CH2:27]1>CCOCC.CCCCC.CO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][O:47][C@@H:37]1[CH2:36][C@@H:35]2[C@:43]([CH3:45])([CH2:44][C@H:24]([OH:23])[C@H:25]3[C@H:34]2[CH2:33][CH2:32][C:31]2[C@:26]3([CH3:49])[CH2:27][CH2:28][C:29](=[O:48])[CH:30]=2)[C@@:38]1([OH:46])[C:39](=[O:42])[CH2:40][OH:41])[CH3:2]
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Agent: CCOC(CNC(N)=O)OCC
Solvent: CO
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and B. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether pentane is diluted with 100 ml of methanol and cooled to 0°C. 11β,16α,17,21-Tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is recrystallized from methanol to yield the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:8](=[O:10])[C:7]5[CH:11]=[CH:12][CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=5)[CH:47]=[CH:46][CH:45]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)Oc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 66.9 %

Procedure:
Using 3-(isopropoxy)benzoic acid (56 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.39 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N,N-dimethylacetamide (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (82 mg, 67%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:20]=1)[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1.C([Li])CCC.[Cl-].C([Al+]CC(C)C)C(C)C.[C@@H:37]12[O:47][CH2:46][C@@H:44]([O:45]1)[C@@H:42]([OH:43])[C@H:40]([OH:41])[C@H:38]2[OH:39].[H-].C([Al+]CC(C)C)C(C)C.[Al]>CC1CCCO1.C1(OC)C=CC=CC=1>[CH3:21][C:5]1[CH:4]=[CH:3][C:2]([C@@H:37]2[O:45][C@H:44]([CH2:46][OH:47])[C@@H:42]([OH:43])[C@H:40]([OH:41])[C@H:38]2[OH:39])=[CH:20][C:6]=1[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Reactant: Cc1ccc(Br)cc1Cc1ccc(-c2ccc(F)cc2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Al]
Agent: [Cl-]
Solvent: CC1CCCO1
Solvent: COc1ccccc1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (796 mg, 2.2 mmol) in 2-methyltetrahydrofuran (20 mL) was added dropwise n-butyl lithium (1.63 mL, 2.6 mmol, 1.6 M in hexane) at −76° C. and was then stirred for 30 min. Diisobutylaluminum chloride (4.4 mL, 3.5 mmol, 0.8 M in n-heptane) was added and the mixture was stirred for 1 hour and then warmed to ambient temperature and was stirred overnight. To a suspension of 1,6-anhydro-β-D-glucopyranose (648 mg, 4.0 mmol) in anisole (10 mL) at 0° C. was added dropwise diisobutylaluminum hydride (12 mL, 12 mmol, 1.0 M in toluene) and was then stirred at ambient temperature overnight. This solution was then added to the above prepared aluminum mixture via syringe. The mixture was distilled (external bath temperature was 158° C.) to remove the low-boiling solvents. To the remaining mixture was added anisole (10 mL) and the mixture was heated (external bath temperature was 158° C.) for 22 hours at which time HPLC assay analysis indicated a 42% yield of 1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-β-D-glucopyranoside.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.CCOCC.[Cl-].[Na+].O.[O-]S([O-])(=O)=O.[Cu+2]>[I:41][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: II
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 0 °C

Procedure:
Combined 4-(2-hydroxy-1-ethyl)-1-tert-butoxycarbonyl-piperidine (37.4 g, 0.16 mol, from Step B), triphenylphosphine (55 g, 0.21 mol) and imidazole (14 g, 0.21 mol) in 800 mL of 33% acetonitrile in ether. Cooled to 0° C. and added iodine (56 g, 0.22 mol) portionwise. Diluted with 1 L of ether. Washed organic layer with 2×500 mL each of sat. aq. Na2S2O3, sat. aq. CuSO4 and brine. Dried over MgSO4, filtered and concentrated. Triphenylphosphine oxide precipitates. Added ether and filtered the slurry through a plug of silica gel. Purified a portion of the crude material by flash chromatography (5% ethyl acetate in hexane eluent) to afford the title compound. 1H-NMR (400 Mhz, CDCl3): δ 4.10 (br s, 2H), 3.23 (t, 2H, J=7.2 Hz), 2.72 (br t, 2H, 12.3 Hz), 1.79 (q, 2H, J=7 Hz), 1.67 (br d, 2H, 14 Hz), 1.61 (m, 1H), 1.47 (s, 9H), 1.14 (qd, 2H, J=4.3, 12 Hz); ESI-MS: 340 (M+H); HPLC A: 3.74 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:13]1[C:14]2[CH2:22][N:21]([C:23]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=3[C:25]#[N:26])[CH2:20][CH2:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:23]([N:21]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([NH:1][CH2:2][C:3]4[CH:8]=[N:7][C:6]([N:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=4)[C:14]=3[CH2:22]2)=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: CN(C)c1ccc(CN)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Br)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(CNc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A mixture of 5-(aminomethyl)-N,N-dimethylpyridin-2-amine (24 mg, 0.16 mmol), 2-(4-bromo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (50 mg, 0.14 mmol), and N,N-diisopropylethylamine (62 μL, 0.36 mmol) in acetonitrile (1.9 mL) was subjected to microwave irradiation at 180° C. for 6 hrs. The reaction mixture was concentrated to an oil which was purified by silica gel column (0-15% MeOH/CH2Cl2) to obtain a light yellow solid.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[C:13]1([C:19]2[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(I)C>CCCCCC.O1CCCC1.O.C(O)(=O)C.C(O)C.CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([CH:31]([CH2:30][CH2:29][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:28]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCc1cc(-c2ccccc2)nc2ccccc12
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC)CCc1cc(-c2ccccc2)nc2ccccc12
Temperature: -70 °C

Procedure:
Diisopropylamine (2.96 cc) is added to dry tetrahydrofuran (30 cc) placed under an atmosphere of nitrogen. The solution is stirred and cooled to -70° C. A 1.6 M solution (11.3 cc) of butyllithium in hexane is then introduced in the course of 15 minutes, and then, after stabilization of the temperature at -70° C., a solution of ethyl 2-phenyl-4-quinolinebutanoate (3.8 g) in tetrahydrofuran (30 cc) is introduced in the course of 5 minutes. The mixture is stirred for 30 minutes at -70° C. and ethyl iodide (1.15 cc) and hexamethylphosphoramide (0.8 cc) in tetrahydrofuran (20 cc) are introduced in the course of 5 minutes. The mixture is stirred for 7 hours at -70° C. Ethanol (7 cc) is added followed by acetic acid (2 cc). The temperature is allowed to rise to room temperature (approximately 20° C.), and the reaction medium is diluted with water (300 cc) and extracted with ethyl ether (2×100 cc). The ether phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel using a cyclohexane/ethyl acetate (90:10 by volume) mixture. Ethyl α-ethyl-2-phenyl-4-quinolinebutanoate (1.8 g), m.p. 76° C., is thereby isolated.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH:20]=[CH:21][C:22](OC)=[O:23])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].[I-].[Li+]>O1CCCC1.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][OH:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=CC(=O)OC
Agent: [BH4-]
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methoxy-3-oxo-1-propenyl)pyrrolidine (18.7 g) in tetrahydrofuran (190 ml) were added successively sodium borohydride (3.83 g) and lithium iodide (13.5 g) at room temperature and the mixture was refluxed for 4 hours. After cooling to room temperature, the mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×3). The combined extracts were washed with brine (400 ml), dried over magnesium sulfate and concentrated to give (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-hydroxypropyl)pyrrolidine (17.2 g) as a pale yellow paste.
Reaction SMILES: [N+]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-])=O.[H][H].O>CO.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][CH2:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: [H][H]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OCN1CCO[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)N(CCO)CO2
Yield: 97.4 %

Procedure:
A solution of 42 g (0.148 mole) of the compound of Example 1 in 6,300 ml of methanol was combined with 10% Pd/C, and the resulting mixture was placed in a hydrogen atmosphere having a head of water, at room temperature. At the end of the reaction, the suspension was filtered on celite and the solution obtained was evaporated under vacuum. The resulting crude product was taken up with ethyl ether and filtered under vacuum, thus yielding 30 g of 6-amino-2,3-dihydro-3-(2'-hydroxyethyl)-4H-1,3-benzoxazin-4-one. m.p. 94°-96° C. (ethyl ether).
Reaction SMILES: Cl[C:2]1[N:3]([C@H:24]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[S:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:36])(=[O:35])=[O:34]>CS(C)=O>[CH3:36][S:33]([N:37]1[CH2:42][CH2:41][N:40]([C:2]2[N:3]([C@H:24]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:5]=3)[CH2:39][CH2:38]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2[C@H]2CCN(S(C)(=O)=O)C2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to 5-{8-chloro-9-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (100 mg, 0.21 mmol) and N-mesylpiperazine (171 mg, 1.04 mmol) and the resulting mixture was stirred at 140° C. for 1 hour. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (105 mg, 83%) as a light brown solid.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:16][CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:4]([S:16][CH3:17])=[C:5]([Cl:27])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSC(SC)=C(Cl)c1ccc(CC(C)C)cc1
Yield: 83.8 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene (701 mg) was dissolved in 2 ml of chloroform, and 0.50 ml of triethylamine was added. With stirring under ice cooling, 5 ml of a chloroform solution of 380 mg of thionyl chloride was added over the course of 10 minutes. The mixture was further stirred for 30 minutes under ice cooling, and chloroform was added in an amount sufficient to adjust the total amount of the mixture to 30 ml. The mixture was then washed twice with 10 ml of water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a Florisil (chromatographic magnesium silicate) column using benzene as an eluent to afford 628 mg of 1,1-bis(methylthio)-2-chloro-2-(p-isobutylphenyl) ethylene as a colorless oil in a yield of 84%.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C>ClCCl.CS(C)=O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)c1ccc(C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the crude alcohol (1.0 g, 4.5 mmol) in dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL) and triethylamine (2.28 g, 22.5 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour. The reaction was then allowed to warm to room temperature and stir for 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate (Intermediate 1). 1H NMR (400 MHz, CDCl3) δ 8.05-8.17 (m, 2H), 8.04-7.92 (m, 2H), 4.40 (q, J=7.15 Hz, 2H), 2.96 (t, J=7.22 Hz, 2H), 1.86-1.69 (m, 2H), 1.40 (t, J=7.12 Hz, 3H), 1.00 (t, J=7.22 Hz, 3H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[H-].[Na+].Br[C:11]1[S:12][C:13]([Br:16])=[CH:14][N:15]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[Br:16][C:13]1[S:12][C:11]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:1]=[CH:2][N:15]2[CH:14]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: Brc1cnc(Br)s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncn2cc(Br)sc12
Reaction time: 2 h
Yield: 85 %

Procedure:
Methyl isocyanoacetate (0.63 ml, 6.9 mmol) was gradually added dropwise to a suspension of sodium hydride (60% in mineral oil, 346 mg, 8.6 mmol) in N,N-dimethylformamide (5 ml) in an argon atmosphere under ice cooling, and the mixture was stirred at the same temperature for 2 hr. This solution was added dropwise to a solution of 2,5-dibromothiazole (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) cooled to −20° C. (brine/ice water) through a cannula over a period of 15 min, and, while allowing the temperature to rise to about 0° C., the mixture was stirred for 2 hr. After the completion of the reaction, saturated brine was added thereto, and the mixture was extracted with dichloromethane (20 ml×5). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (910 mg, 85%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:39][C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cccs1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(Cc4cccs4)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (70.0 mg) and 2-thiophenecarbaldehyde (19.1 mg) in ethanol (1 ml) was added sodium cyanoborohydride (10.7 mg) and a drop of acetic acid at 0° C. The resulting mixture was stirred for 3 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate (1 ml), and the solvent was evaporated off. The residue was dissolved in ethyl acetate (20 ml), and washed with water, brine, dried over magnesium sulfate, and evaporated. Silica gel column chromatography [eluent: acetone/chloroform (10:1)] afforded N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-(2-thienylmethyl)-1,4-thiazepin-7-yl]acetamide (74.4 mg) as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:19]1=[S:20].N1CCCCC1>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:24]3[S:18][C:19](=[S:20])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:22]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=O)Nc3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture comprising 1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.85 g of rhodanine-3-acetic acid, 0.76 g of piperidine and 15 ml of ethanol was stirred at room temperature for 2 hours, and the resulting mixture was left to stand overnight. The crystals which precipitated out were collected by filtration dispersed in dilute aqueous hydrochloric acid, and washed with stirring for 30 minutes. The resulting crystalline product was recrystallized from a mixture of acetic acid and ethyl acetate, giving 0.78 g of the desired compound as an orange powder.
Reaction SMILES: CS(C)=O.FC(F)(F)[C:7](OC(=O)C(F)(F)F)=[O:8].[O:18]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1CO.C(N(CC)CC)C>C(Cl)Cl>[O:18]([C:25]1[N:30]=[C:29]([CH:7]=[O:8])[CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Oc2ccccn2)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 141 %

Procedure:
A solution containing 21.0 ml of dry DMSO in 150 ml of dry CH2Cl2 under an atmosphere of nitrogen was cooled to -75° (internal). To this reaction mixture was then added 31.0 g of trifluoroactic anhydride at such a rate to maintain the temperature below -60° (internal). After the addition was complete the reaction mixture was stirred at -75° for 20 min. To the resulting mixture was added a solution containing 29.25 g of 6-phenoxypyridine-2-pyridinemethanol in 150 ml CH2Cl2. During this addition the internal temperature was not allowed to rise above -60° C. After stirring this reaction mixture for 1 hr. at -75° C., 90 ml of triethylamine was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with 1 L of ether and washed four times with H2O. After drying over anhydrous Na 2 SO4, removal of the solvents afforded 29.31 g of dark oil. This material was treated with decolorizing carbon and recrystallized from hexane-ethyl acetate to afford 21.50 g of the desired crystalline aldehyde.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH3:7].CN(C)C1C=CC=CC=1>>[CH:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:6]([CH3:7])[CH3:5])[C:13]=1[O:14][C:1]([Cl:4])=[O:2])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Phosgene (13 mL, 20% in toluene) was added to propofol (3.6 g, 20 mmol) under a nitrogen atmosphere. The mixture was cooled to 0° C. and N,N-dimethylaniline (3.3 mL, 26 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature slowly and stirred for 14 h. The solvent was removed in vacuo. The crude product was carried to next step without further purification.