Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(NCC(C)C)C(C)C.C1(C)C=CC=CC=1>[Cl:18][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(Oc2ccccc2)cc1Cl
Temperature: 70 °C
Yield: 121.2 %

Procedure:
To a 54 ml toluene solution of 4-phenoxyphenol (2 g, 10.7 mmol) and diisobutylamine (0.15 ml, 0.86 mmol) was added sulfuryl chloride (0.69 ml, 8.6 mmol). The mixture was heated to 70° C. for 3 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and aq sat. bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 15% AcOEt/hexanes gave the title compound 2.3 g as colorless syrup (97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].CS([C:14]1[N:19]=[C:18]([N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:16][N:15]=1)(=O)=O>C1COCC1>[C:25]1([C:21]2[N:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[N:19]=3)[CH:24]=[CH:23][N:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2nccn2-c2ccnc(Nc3ccccn3)n2)cc1

Procedure:
To a solution of 2-aminopyridine (31 mg, 0.33 mmol) in dry THF (0.5 mL) was added NaH (32 mg, 1.33 mmol) at room temperature. Once the resulting bubbling had ceased, 2-(methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (0.100 g, 0.33 mmol) was added all at once. After 1.5 hours the mixture was concentrated in vacuo, diluted with water and the pH of the resulting solution was adjusted to 7 with 1M HCl (aq). The resulting precipitate was filtered and purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA). 1H-NMR (300 MHz, CDCl3) δ 8.44 (d overlapping with s, J=5.4 Hz, 2H), 8.33 (d, J=4.1 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.55 (m, 4H), 7.40 (m, 3H), 7.33 (m, 1H), 6.95 (dd, J=4.9, 7.1 Hz, 1H), 6.45 (d, J=5.3 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[CH2:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
A solution of triphenylphosphine (212 mg, 0.81 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (144 mg, 0.81 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (250 mg, 0.73 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (279 mg, 1.61 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate), to afford N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (121 mg, 33%) as a white foam: mp 80-83° C. (foam to gel); FAB-HRMS m/e calcd for C20H22BrN3O5S (M+H)+ 496.0542, found 496.0543.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCOC(C)=O>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:34]2[C:33]2[CH:35]=[CH:36][C:30]([I:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(I)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(I)cc2)cc1
Temperature: 45 °C

Procedure:
The product from Example 42B (1.39 g, 2.499 mmol) in DMF (6.25 mL) was treated with 4-iodoaniline (Aldrich, 4.38 g, 19.99 mmol), heated at 40-50° C. for two hours, cooled and diluted into EtOAc. The EtOAc layer was washed 3×50 mL with 1 M HCl, with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on an ISCO 40 g silica cartridge eluting with 0-20% EtOAc in hexane afforded the title compound as a tan foam as a mixture of stereoisomers (0.96 g, 66%). MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: C1(S)C=CC=CC=1.[CH2:8]([S:20][CH2:21][CH2:22][C:23]([O:25][CH:26]([CH2:41][S:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]CCCCCC)[CH2:27][S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]CCCCCC)=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCC.C([O-])(=O)C=C.C(O)C>O>[C:23]([O:25][CH:26]([CH2:27][S:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:41][S:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)(=[O:24])[CH:22]=[CH2:21].[C:8]1([S:20][CH2:21][CH2:22][C:23]([O:25][CH:26]([CH2:27][S:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:41][S:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:24])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCCCCSCCC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC
Agent: C=CC(=O)[O-]
Agent: Sc1ccccc1
Solvent: CCO
Solvent: O
Product: C=CC(=O)OC(CSc1ccccc1)CSc1ccccc1
Product: O=C(CCSc1ccccc1)OC(CSc1ccccc1)CSc1ccccc1

Procedure:
1,3-bis(phenylthio)-2-propyl acrylate was prepared by using benzenethiol in place of dodecanethiol in the procedures described in Steps (1) and (2) of Example 1. A solution of 15 grams of the acrylate, 5 grams of benzenethiol, and 1 milliliter of "Triton B" in 75 millilters of ethanol was heated under reflux for 51/2 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with toluene. The toluene solution was stripped of solvent on a rotary evaporator leaving 19.8 grams of 1,3-bis-(phenylthio)-2-propyl 3-(phenylthio)propionate which was identified by means of its NMR spectrum.
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])[CH:11]([N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]2=[O:41])[C:12](=[CH2:14])C)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(O)[O-:46].[Na+].[I-].[K+]>C(OC)(=O)C.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])/[C:11](/[N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:16]2=[O:41])=[C:12](\[OH:46])/[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: O=S([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COC(C)=O
Product: C/C(O)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
(di) The crude 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid p-nitrobenzyl ester obtained according to Example 1.cvii) is dissolved in 20 ml of methyl acetate and ozonised at -70° C. until starting material is no longer present, according to a thin layer chromatogram. A stream of nitrogen is then passed through the solution and the latter is warmed to 0°-5° C. A solution of 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no further ozonide is detectable by means of potassium iodide/-starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off and the organic phase is washed with water, dried over magnesium sulphate and freed from the solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is recrystallised from methanol and gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid p-nitrobenzyl ester of melting point 159°-160° C. 155°-
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].O>C1(C)C(C)=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:16])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 150 g of water and heated at 100° C. for 1 hour. Then 600 g of xylene are added dropwise over 1 hour and a total of 260 ml of water are azeotropically distilled off with xylene. The reaction mixture is cooled and the precipitate is filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 164.7 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 97.7%; this corresponds to a yield of 95.6%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([CH2:19][CH3:20])(O)[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25]C=C[CH:22]=1.B(F)(F)F.[CH3:33][CH2:34]OCC>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([CH2:33][CH3:34])([C:19]3[CH:20]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=3)[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2cc(C(O)(CC)CC)ccc2o1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2o1
Yield: 87.7 %

Procedure:
5-(1-Ethyl-1-hydroxy-propyl)-benzofuran-2-carboxylic acid ethyl ester (5.70 g, 22.1 mmol) and o-cresol (2.86 g, 26.5 mmol) and BF3-Et2O (3.13 g, 22.1 mmol) are reacted analogous to Example 1D to give the title compound (7.10 g, 88%).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[N:8]=[C:9]([CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[NH:10][CH:11]=1)([O-])=O.C(OCC)C.C(Cl)[Cl:32]>[Pd]>[ClH:32].[ClH:32].[NH2:4][C:7]1[N:8]=[C:9]([CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:14])[NH:10][CH:11]=1
Reactant: O=C(C(c1ccccc1)c1nc([N+](=O)[O-])c[nH]1)N1CCCC1
Reactant: ClCCl
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: Cl
Product: Nc1c[nH]c(C(C(=O)N2CCCC2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Ethanol (200 mL) was added to a mixture of 2-(4-nitroimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one (3) (0.752 g, 2.8 mm) and 10% Pd on carbon (75 mg) in a Bradley hydrogenation apparatus. The stirred reaction mixture was subjected to a 60 psi H2 atmosphere and warmed to 60° C. After 2 hours, the reaction mixture was cooled to room temperature and the catalyst was removed by filtration. Anhydrous HCl gas was added to the filtered solution until saturation. The volatiles were then removed under vacuum to give a light yellow foam. Diethyl ether and methylene chloride (25:1) were added to the foam and the resulting mixture was stirred overnight to achieve crystallization. The resulting slurry was filtered and the cake was washed with diethyl ether. The cake was dried under vacuum to give 0.659 g (93%) of a yellow solid. LGD 208.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:23](=[O:24])[N:12]2[C@@H:13]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=O)[CH2:15][C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([SH:62])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]>C(#N)C>[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([S:62][C:14]2[CH2:15][C@@H:11]3[C@@H:10]([C@H:8]([O:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:9])[C:23](=[O:24])[N:12]3[C:13]=2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2[C@@H](C(=O)OCC=C)C(=O)C[C@H]12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CO)N(C(=O)OCC=C)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of allyl (3R,5R,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-2-oxo-1-carbapenam-3-carboxylate (1.01 g, 3 mmol) and N,N-diisopropylethylamine (0.73 ml, 4.2 mmol) in acetonitrile (20 ml) was dropwise added diphenyl chlorophosphate (0.75-3.6 mmol) under ice-cooling, and then the mixture stirred for 30 minutes. The reaction mixture under ice-cooling was treated successively with N,N-diisopropylethylamine (0.73 μl, 4.2 mmol) and (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-mercaptopyrrolidine (780 mg, 3.6 mmol) in acetonitrile (4 ml), stirred for 1 hour, and partitioned between ethyl acetate (60 ml) and water (40 ml). The organic layer was successively washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue purified by flash column chromatography on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate-hexane 1:1) to afford the title compound (1.20 g, 75% yield).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[CH2:36][C@@H:35]2[CH2:45][CH3:46])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1
Product: CCc1nc(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.21–1.34, 2.57, 2.73, 2.82, 3.00, 3.79, 4.41, 5.76, 6.82, 7.17; HRMS (FAB) calcd for C20H26BrN3O+H 404.1338, found 404.1317. Anal. Calcd for C20H26BrN3O: C, 59.41; H, 6.48; N, 10.39; Br, 19.76. Found: C, 59.05; H, 6.42; N, 10.13.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([C:18]1[C:19]([O:34][CH3:35])=[C:20]([O:32][CH3:33])[CH:21]=[C:22]2[C:27]=1[C:26]1=[CH:28][S:29][C:30](=[NH:31])[N:25]1[CH2:24][CH2:23]2)#N>O>[C:2]([C:28]1[S:29][C:30](=[N:31][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:25]2[CH2:24][CH2:23][C:22]3[C:27](=[CH:18][C:19]([O:34][CH3:35])=[C:20]([O:32][CH3:33])[CH:21]=3)[C:26]=12)#[N:1]
Reactant: COc1cc2c(c(C#N)c1OC)-c1csc(=N)n1CC2
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(C#N)sc(=NC(=O)c3ccccc3)n1CC2

Procedure:
5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of 10-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline, and the mixture is refluxed for 0.5 hours. After cooling, the mixture is diluted with water. 0.6 g. of 1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline is obtained in crystalline state; m.p.: 274°-276° C. (after crystallization from a mixture of dimethylformamide and butanol).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([Si:14]([CH3:16])([CH3:15])[O:4][CH2:1][C:2]#[CH:3])([CH3:13])([CH3:12])[CH3:10]
Reactant: C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of propargyl alcohol (15 g, 267 mmol) in DMF (60 mL), imidazole (21.85 g, 321 mmol) was added at 0° C. followed by the slow addition of a solution of TBDMS-Cl (47.2 mL, 272 mmol) in DMF (70 mL). Resulting reaction mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. On completion, water was added to the reaction mixture and the aqueous layer extracted with 20% ethyl acetate/hexane. The combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography over silica gel affording tert-butyldimethyl(prop-2-yn-1-yloxy)silane (45.5 g, 32.9%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=[C:8](Cl)Cl)[N:3]=1.[CH:11]([NH:14][CH:15]=[O:16])([CH3:13])[CH3:12].[OH2:17]>C(#N)C>[CH:15]([N:14]([CH:11]([CH3:13])[CH3:12])[C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=1)=[O:17])=[O:16]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: O
Reactant: CC(C)NC=O
Solvent: CC#N
Product: CC(C)N(C=O)C(=O)c1nc(Cl)c(Cl)[nH]1
Temperature: 0 °C
Yield: 84 %

Procedure:
654 g (3 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in a finely powdered form were added incrementally in the course of about one hour, to a mixture, which had been initially introduced, of 783 g (9 mol) of isopropyl-formamide, 162 g (9 mol) of water and 3 l of acetonitrile, while stirring and while cooling to about 0° C. The clear solution was then poured into about 15 kg of ice water. The white precipitate which had formed was filtered off, washed with water and dried. In this way, 630 g (84% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid N-formyl-isopropylamide with a melting point of 142° C. were obtained. The same result was also achieved without the addition of water.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:30])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A solution of 4-(dibenzylsulfamoyl)benzoic acid (24 g; 63 mmoles) in thionyl chloride (50 ml) was boiled under reflux for 2.5 hours and the excess of thionyl chloride removed under reduced pressure. 4-(dibenzylsulfamoyl)benzoyl chloride (25 g) was obtained as an oil which was used in the next step without purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[CH3:15].CC(O)=O>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19][CH2:20]2)[CH2:3][CH2:2]1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=CCC1CCOc2ccccc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NC1CCN(CCC2CCOc3ccccc32)CC1
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl]ethanal (2.50 g, 14.28 mmol) and 4-acetamidopiperidine AcOH (2.88 g, 14.28 mmol) (preparation described in U.S. Pat. No. 5,028,616) in ethanol (80 ml) under a nitrogen atmosphere, borane/pyridine complex (1.5 ml, 15 mmol) was added. The reaction mixture was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether and the diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of a 50% sodium hydroxide solution. The basic solution (>pH 12) was extracted with ethyl acetate. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (3.56 g). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (2.56 g) which was crystallized from diethyl ether to afford the title compound (2.40 g, 56%) mp=126-8°. Anal: C18H26N2O2Calc.: C 71.49; H 8.67; N 9.26; Found C 71.46; H 8.84; N 9.26.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1([CH3:36])O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.[OH:50][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:36][O:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:57]2=[O:81])=[CH:82][CH:83]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1(C)O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl) dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxy-methylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4-87.2° C.