Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[CH3:15].S(=O)(=O)(O)O.[I-:21].OO.[Cl-].[NH4+]>O.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[I:21][CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=1
Reactant: Cc1nc(-c2ccncn2)cc(=O)n1C
Reactant: [I-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(CI)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Yield: 112 %

Procedure:
To a suspension of 17 g (0.084 mol) of 1,2-Dimethyl-1H-[4,4]bipyrimidinyl-6-one in 45 mL of water, were added 8.5 mL of sulfuric acid, 25 mL of carbon tetrachloride and 9.6 g (0.037 mol) of iodide. The resulting mixture was refluxed and 16.38 mL of hydrogen peroxide (35% solution in water) was added dropwise. The mixture was stirred under reflux for 5 h and cooled at room temperature, 100 mL of saturated aqueous solution of ammonium chloride and 100 mL of chloroform were added. The resulting precipitate was filtered off, the filtrate extracted with chloroform, dried and evaporated to afford 13.6 g of product witch was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: CSc1ccc(O)cc1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-phenol (77 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-phenoxy)-nicotinamide (81 mg) as an off-white foam.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:29]([C:31]4([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32]4)=[O:30])=[CH:24][C:23]=3[F:43])[CH:13]=2)=[N:10][CH:11]=1.C1(C)C=CC=CC=1>CC(C)=O.O.C(O)(C(F)(F)F)=O>[F:43][C:23]1[CH:24]=[C:25]([N:28]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:29]([C:31]2([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32]2)=[O:30])[CH:26]=[CH:27][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(-c5ccc(C6OCCO6)cn5)sc34)c(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(-c5ccc(C=O)cn5)sc34)c(F)c2)CC1
Yield: 103 %

Procedure:
Intermediate 41 (0.22 g, 0.37 mmol) was dissolved in acetone (50 mL) to give a colorless solution. The reaction mixture was diluted with water (20 mL) and TFA (2 mL), heated to reflux for 2 h, then cooled and concentrated. The precipitated product was isolated by suction filtration. A small amount of toluene (5 mL) was added to the wet solid, the mixture was concentrated to remove water azeotropically, and dried in vacuum to afford intermediate 42 (0.21 g, 103% yield, presumably as tri-fluoroacetate salt). MS (m/z): 553.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[N:3]1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CCO.C1COCC1.O=[Pt]=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]=O
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ncc2ccc(N)cc21
Yield: 90 %

Procedure:
To a solution of 1-methyl-6-nitro-1H-indazole (1.2 g, 0.7 mmol) in EtOH (50 ml) and THF (15 ml) was added PtO2 (125 mg) at 26° C. The mixture was stirred for 1.5 h at 26° C. under a H2 atmosphere at 30 Psi. Once the reaction was complete by TLC analysis, the mixture was filtered and the filtrate concentrated to give the target crude product as a white solid which was used in the next step without further purification (1.0 g, Yield 90%). LCMS (m/z): 148.1 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.ClCC[I:33]>C(OCC)C>[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][C:18]=1[I:33])([CH3:9])([CH3:8])[CH3:7]
Reactant: ClCCI
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexanes, 100 mL, 240 mmol) was added dropwise over 1 h to a cooled (−78° C.) mixture of tert-butyl-6-methoxypyridin-3-ylcarbamate (16 g, 71 mmol) and N,N,N′,N′-tetramethylethylenediamine (34 mL, 221 mmol) in diethyl ether (100 mL). The reaction was stirred at −78° C. for 30 minutes, then warmed to −20° C. and left stirring for 3 h. The reaction mixture was transferred via cannula over fifteen minutes to a cold (−78° C.) solution of 1-chloro-2-iodoethane (48 g, 243 mmol) in diethyl ether (50 mL). On complete addition, the reaction mixture was allowed to warm to room temperature and left stirring at this temperature for 16 h. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and water (200 mL) then extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated sodium sulfite (50 mL), 1N hydrochloric acid (100 mL), water (100 mL), saturated sodium bicarbonate solution (100 mL) and brine (50 mL), dried over sodium sulfate, and evaporated to give a residue which was purified by flash chromatography (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a white cyrstaline solid (18 g, 72%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1.[F-:13].[Cs+].Cl>CS(C)=O>[F:13][CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: [F-]
Reactant: COC(=O)c1nccnc1CCl
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1nccnc1CF
Temperature: 140 °C
Yield: 9.2 %

Procedure:
Methyl 3-chloromethylpyrazine-2-carboxylate (1.55 g, 8.3 mmol) was dissolved in DMSO (30 ml), followed by adding cesium fluoride (2.52 g, 16.6 mmol) and hexamethyl triamidophosphate (0.3 ml) and heated at 140° C. for 40 minutes while stirring. The reaction solution was cooled, followed by pouring into a diluted HCl solution, extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 0.13 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Clc1ccc(Cc2cc(Br)ccc2I)s1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1ccc(Cc2cc(Br)ccc2-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of the above 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) in dimethoxyethane (10 ml) were added phenylboronic acid (310 mg), bis(triphenylphosphine)palladium (II) dichloride (85 mg) and 2M aqueous sodium carbonate solution (3.8 ml), and the mixture was stirred at 50° C. overnight. Added thereto was a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 11-2; 2.34 g, 7.19 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.69 g, 14.38 mmol) and ethyl bromoacetate (1.60 mL, 14.38 mmol). The mixture was heated to 60° C. under N2 with stirring for 3 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 1.78 g (60%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and Cul (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:2].Cl[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([CH:3]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:24]([O:26][CH3:27])=[O:25])#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1CC#N
Reactant: COC(=O)Cl
Product: COC(=O)C(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from tert-Butyl 4-(cyanomethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-B) using the same procedure as in Example 148-A using methyl chloroformate in the place of methyl bromoacetate. MS (ESI+) m/z 359.4 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:23])[N:10]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][CH:33]([O:36][CH3:37])[O:34][CH3:35]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C)C=O.CCOC(C)=O>[CH3:35][O:34][CH:33]([O:36][CH3:37])[CH2:32][CH2:31][N:12]1[CH:13]=[C:8]([C:4]2[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=2)[C:9](=[O:23])[N:10]([C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[C:11]1=[O:14]
Reactant: Cc1nc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)sc1C
Reactant: COC(CCBr)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2nc(C)c(C)s2)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Yield: 40.1 %

Procedure:
5-(4,5-dimethyl-1,3-thiazol-2-yl)-3-(phenylcarbonyl)-2,4(1H,3H)-pyrimidinedione (Prep 16, 80 mg, 0.244 mmol), K2CO3 (33.8 mg, 0.244 mmol), TBAI (9.03 mg, 0.024 mmol) and 3-bromo-1,1-bis(methyloxy)propane (0.033 mL, 0.244 mmol) in dry N,N-Dimethylformamide (DMF) (1.5 mL) were stirred in a closed vial at rt for 2 days then it was left standing at rt over the weekend. The mixture was diluted with EtOAc (20 mL) and washed with small portion of ice-water (3×1 mL). The organic was dried (Na2SO4, rotaevaporator) to afford a crude (95 mg) that was purified by silica chromatography, eluting with Cyclohexane:EtOAc 100:0 to 50:50 to afford the title compound as a white solid (42 mg).
Reaction SMILES: C(=O)C.[C:4](O)(=O)[C:5]1C=CC=C[CH:6]=1.C1(P(=C[C:33]2[CH2:34][S:35][C@@H:36]3[C@H:56]([NH:57][C:58](=[O:65])[CH2:59][C:60]4[S:61][CH:62]=[CH:63][CH:64]=4)[C:55](=[O:66])[N:37]3[C:38]=2[C:39]([O:41][CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:4]([C:33]1[CH2:34][S:35][C@@H:36]2[C@H:56]([NH:57][C:58](=[O:65])[CH2:59][C:60]3[S:61][CH:62]=[CH:63][CH:64]=3)[C:55](=[O:66])[N:37]2[C:38]=1[C:39]([O:41][CH:42]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[CH:5][CH3:6]
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CC=O
Solvent: ClCCl
Product: CC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 4 h
Yield: 55.9 %

Procedure:
A solution of acetaldehyde (20 ml., 354 mmole) and benzoic acid (73 mg., 0.6 mmole) in dry methylene chloride (50 ml.) as stirred at 23° and treated, over 30 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (1.528 g., 2 mmoles). After stirring for a further 4 hours, the solvent was removed in vacuo, the residue was extracted with ethyl acetate (50 ml.) and the insoluble material was filtered off; the filtrate was washed with saturated sodium bicarbonate (50 ml.), water (50 ml.) and brine (50 ml.), and dried and evaporated to a foam (1.58 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel with benzene: ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave pale-yellow crystals of the title compound (178 mg., 17%), Rf 0.58, m.p. 144° to 148° (decomp.), [α]D -25.9° (CHCl3), λmax. 286.5 nm. (ε 7,900), with an inflexion at 237 nm. (ε 13,200); the p.m.r. spectrum indicated that the compound was mainly the cis-isomer (with 5-10% trans) with signals at τ 3.96 (--CH=CHCH3, d, J 12 Hz.), 4.51 (=CHCH3, dd, J 12 and 7 Hz.) and 8.61 (CH=CHCH3, methyl dd, J 7 and 0.5 Hz.) [Found: C, 65.2; H, 5.0; N, 5.2; S, 11.9; C29H26N2O4S2 (530.7) requires C, 65.6; H, 4.9; N, 5.3; S, 12.1%].
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.28 g--see Preparation 3), 4-methylphenethyl bromide (0.2 g), anhydrous potassium carbonate (0.28 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.19 g.
Reaction SMILES: [C:1]([SiH:5]([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30])([CH3:18])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:15]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CC(C)(C)c1ccc(/C=C/CO)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(/C=C/CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
11.6 g (77 mmol) of t-butyldimethylsilane, 7.8 g (77 mmol) of triethylamine and 0.76 g (6.2 mmol) of 4-dimethylaminopyridine were added, in turn, and with ice-cooling, to a solution of 14.5 g (62 mmol) of 2-t-butyl-5-[(1E)-3-hydroxy-1-propenyl]-1-nitrobenzene [prepared as described in step (iii) above] in 140 ml of dimethylformamide, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was poured into ice-water and then extracted with diethyl ether. The extract was washed with a 10% w/w aqueous solution of hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:15 by volume mixture of ethyl acetate and hexane, to give 21 g of the title compound as crystals, melting at 33°-34° C. (from ethyl acetate-hexane).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[S:6])[NH:3][C:2]1=[S:7].[OH-].[Na+].Cl.[Cl:11][CH2:12][C:13]([NH2:15])=[NH:14]>C(O)C>[ClH:11].[C:13]([CH2:12][S:6][C:4]1[N:3]=[C:2]([SH:7])[S:1][CH:5]=1)(=[NH:14])[NH2:15]
Reactant: N=C(N)CCl
Reactant: S=C1CSC(=S)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)CSc1csc(S)n1
Yield: 19.9 %

Procedure:
In 20 ml of ethanol was suspended 1.49 g of thiazolidine -2,4-dithione, and 20 ml of 1N-sodium hydroxide solution was added under ice-cooling and stirring. To the mixture was added 1.29 g of α-chloroacetamidine hydrochloride, and the resultant was stirred at room temperature for 2.5 hours and concentrated. The precipitating crystals were collected by filtration, suspended to water, and hydrochloric acid was added to the suspension to dissolve the crystals. Thereafter this solution was subjected to a column chromatography on XAD-II (450 ml) being eluted with water. The eluate was evaporated to dryness and treated with ethanol. The resultant crystals were washed with a (1:2) mixture of ethanol and ethyl acetate to give 0.48 g of 4-amidinomethylthio-2-mercaptothiazole hydrochloride as colorless crystals. mp 178°-181° C. (decomp.)
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38])#[N:33]>C1COCC1>[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37]([N:6]1[CH2:7][CH2:8][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][C:11]21[CH2:12][CH2:13]2)(=[O:39])=[O:38])#[N:33]
Reactant: CN(CCC#N)S(=O)(=O)Cl
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCC#N)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
Intermediate 2 (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-cyanoethyl(methyl)sulfamoyl chloride (0.06 mmol) was added. The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13].C([O-])([O-])=[O:26].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].O.C(O)(=O)C>CO.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[CH3:1][C:2]1[C:3]([CH2:14][S+:15]([O-:26])[C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Temperature: 5 °C
Reaction time: 6 h
Yield: 200.8 %

Procedure:
2.3 g of 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol were dissolved in 11.5 ml of methanol and 90 mg of ammonium molybdate were added. The solution was cooled to 5° C. and 0.87 g of sodium percarbonate were added, then kept stirred at this temperature for 6 h. After the reaction finished 22 ml of water were added, then heating to 20° C. and adjusting the pH of the mixture to 7.5 with acetic acid. The mixture is extracted with 50 ml of dichloromethane and the organic phase was separated, which was then washed with 100 ml of water. The solvent was evaporated at a reduced pressure. 2.0 g of rabeprazol were obtained (yield: 81%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:17])=[CH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([CH:10]1[CH2:9][CH2:8][CH:7]([CH:6]=[C:5]([CH3:17])[CH2:4][OH:3])[CH2:12][CH2:11]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C(C)=CC1CCC(C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=CC1CCC(C(C)(C)C)CC1)CO
Temperature: 40 °C

Procedure:
46 g. of a 70% sodium dihydro-bis(2-methoxyethoxy)-aluminate solution in toluene are added dropwise at 25°-30° C. over a period of 90 minutes to a solution of 25.3 g of 3-(4-tert.butyl-cyclohexyl)-2-methyl-acrylic acid ethyl ester in 130 ml of absolute toluene and the mixture is subsequently warmed at 40° C. for 2 hours. The mixture is then cooled down to -10° C., treated dropwise with 130 ml of 2-N sodium hydroxide, the toluene phase is separated and the aqueous-alkaline phase is back-extracted twice with 200 ml of toluene. The combined toluene phases are washed neutral with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-(4-tert.butyl-cyclohexyl)-2-methyl-allyl alcohol of boiling point 112°-114° C./0.08 Torr.