Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH2:39](OC(OCC)OCC)C>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]7[O:35][CH:39]=[N:37][N:36]=7)=[CH:30][C:29]=6[CH3:38])=[CH:26][CH:27]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(C(=O)NN)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Product: Cc1cc(-c2nnco2)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Yield: 58 %

Procedure:
A suspension of 2,3,5,6,7,8-hexahydro-1'-methyl-5-(4'-hydrazinocarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E49) (794 mg) in triethylorthoformate (25 ml) was heated at reflux overnight. The mixture was concentrated in vacuo and the residue refluxed overnight in xylene (40 ml) to complete cyclisation. The xylene was evaporated under reduced pressure and the residue purified by chromatography on silica gel, eluting with chloroform and methanol, to afford the title compound (470 mg, 58%). The hydrochloride salt precipitated from acetone as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:23][C:24](=[O:48])[CH:25]([CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[C:7]([NH:9][CH:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[O:8].[CH3:49][N:50]=[C:51]=[S:52]>C(Cl)(Cl)Cl>[OH:18][CH:11]([CH:10]([NH:9][C:7](=[O:8])[CH:6]([NH:23][C:24](=[O:48])[CH:25]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([NH:50][CH3:49])=[S:52])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CC(C)CC(NC(=O)C(CCCCN)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reactant: CN=C=S
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCCCC(NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)NC(CC(C)C)C(O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
[2R-[2R*,3S*(S*)]]-3-[[6-amino-2-[[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]amino]-1-oxohexyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester (Example K), 3.44 g (5.3 mmol), is dissolved in 65 ml of chloroform, 0.42 g (5.7 mmol) of methyl isothiocyanate is added, and the reaction mixture is stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture is concentrated and 2.05 g (53% yield) of the title compound is obtained after flash chromatography over silica gel 60 (230-400 mesh) and elution with hexane-ethyl acetate (1:4); mp softens at 89° C., melts at 93°-95° C.
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[N:5]1[C:22](=[O:41])[CH2:23]/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:40])[O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])([CH3:3])[CH3:2].[Cl-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:54]=[C:55]([CH2:63][CH2:64][CH3:65])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57].C(O)(=O)C>O1CCCC1>[OH:54][C@@:55]([CH2:63][CH2:64][CH3:65])([C@@H:23]([C:22]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:7][C:6]1=[S:21])=[O:41])/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])=[O:40])[C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57]
Reactant: CC(C)[C@@H]1N(C(=O)C/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=S)OC1(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
2-Trimethylsilanyl-ethyl [(E)-9-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-9-oxo-non-6-enyl]-carbamate (400 mg, 0.672 mmol) and dried lithium chloride (114 mg, 2.69 mmol) were dissolved in tetrahydrofuran (3.2 mL), and the mixture was then cooled to −78° C. in a dry ice-acetone bath. Lithium hexamethyldisilazide (a solution of 1 M tetrahydrofuran, 1.51 mL, 1.51 mmol) was added in order, and the mixture was then stirred for 1 hour. A solution of tert-butyl 2-oxo-pentanoate (130 mg, 0.755 mmol) in tetrahydrofuran (2.4 mL) was added, and the mixture was then stirred at −78° C. for further 6 hours, and quenched with acetic acid (0.160 mL, 2.80 mmol). The dry ice-acetone bath was then removed. Ethyl acetate (30 mL) and water (10 mL) were added and the mixture was then separated. The organic layer was washed with a saturated aqueous solution (20 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 270 mg (0.352 mmol, 52% yield) of tert-butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate.
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH4-].[Na+].O>O1CCCC1.C(O)C>[N:1]1([C:10]2[O:11][C:12]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)c1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Ethyl 2-[2-(1H-benzimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-2-oxoacetate (3.50 g) was dissolved in a mixed solvent of tetrahydrofuran (60 mL)-ethanol (20 mL), sodium borohydride (100 mg) was added at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the precipitated solid was collected by filtration and dried. The obtained solid was added to thionyl chloride (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated and poured into 10% aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in acetic acid (50 mL) and zinc powder (10 g) was added. The mixture was stirred with heating under reflux for 30 min. Insoluble material was removed by filtration, and the filtrate was concentrated and poured into 10% aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and ethyl 2-[2-(1H-benzimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]acetate (2.07 g, 61%) was obtained as crystals from a fraction eluted with acetone-hexane (1:2, volume ratio). Recrystallization from acetone-isopropyl ether gave colorless needle crystals. melting point: 152–153° C.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][CH:25]([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH:25]([F:24])[F:36])=[CH:28][CH:29]=3)[C:34]2=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(OC(F)F)cc3)c(=O)n(C3CCCC3)c12
Yield: 41.9 %

Procedure:
1-Cyclopentyl-3-(4-difluoromethoxy-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-difluoromethoxy-4-isocyanato-benzene (0.5 mmol) following general procedure C. LCMS: m/z 454 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[N:16]=2)=[CH:12]\[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[N:16]=[C:17]([O:22][CH3:23])[C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:12]\[CH2:13][O:14][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1nc(/C(=C/COc2ccccc2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
N,N,N′,N′-Tetramethylazodicarbodiimide (104 mg) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol obtained in Reference Example 4-4 (199 mg), phenol (63 mg) and tributylphosphine (189 mg) in tetrahydrofuran (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give 6-[(1E)-1-(4-tert-butylphenyl)-3-phenoxyprop-1-en-1-yl]-3-chloro-2-methoxypyridine as a yellow oil (212 mg, 87%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[CH:7]=[O:8].Cl>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][C:11]=1[S:12][CH3:13]
Reactant: CSc1ccc(C=O)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(CO)cc1C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.40 g, 0.037 mol) was added to an ice-bath cooled solution of the product of example 28 step a) (6.16 g, 0.037 mol) in ethanol (50 ml). After 1 hour, the reaction mixture was neutralised by careful addition of aqueous hydrochloric acid (2 molar) and concentrated in vacuo to remove the organic solvent. The remaining aqueous solution was then extracted with ethyl acetate (×3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield the sub-title compound as a brown oil (6 g) in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[C:25]1([C:35](O)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:35]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:36]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1cccc2ccccc12
Yield: 77 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1-naphthyl)carbonyl]-L-phenylalanine methyl ester was prepared in 77% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-naphthoic acid using the general procedure described in example 3. HR MS: Obs. mass, 521.1024. Calcd. mass. 521.1053 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:7]([Cl:19])=[N:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:10][C:11]=1Cl.[K+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([NH-:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>CS(C)=O>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:11]2[C:6]([O:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[O:2][CH3:1])=[C:7]([Cl:19])[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:10]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: Cc1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
2 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-(4-pyridyl)-pyrimidine was dissolved in 30 ml dry DMSO. 2.40 g p-toluene-sulfonamide potassium salt was added and stirring continued for 20 h. The reaction mixture was poured onto 200 ml water and extracted twice with 200 ml diethylether. The combined organic layers were extracted twice with 50 ml water. The combined water layers were acidified by acetic acid to pH=4. The precipitated product was filtered off, washed with ether and dried under reduced pressure. 1.9 g p-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide was obtained as a slightly colored solid. Rf (EA/Hex=1/1)=0.15.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[CH2:7]([O:9][SiH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH3:8]>CC1C=CC(C)=CC=1>[N:4]([CH2:1][CH2:2][CH2:3][Si:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:9][CH2:7][CH3:8])=[C:5]=[O:6]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCN=C=O
Solvent: Cc1ccc(C)cc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 71.8 %

Procedure:
In analogy to Example 6, a reaction mixture consisting of 640 g of p-xylene, 680 g (8.17 mol) of allyl isocyanate and 1250 g (7.6 mol) of triethoxysilane was reacted at from 76° to 92° C. over the course of 150 minutes. Working up by distillation gave 1350 g of 3-isocyanatopropyltriethoxysilane in addition to the trimer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].I[C:15]1[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[N:17]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:15]2[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:16]=2)=[O:6])[CH:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: Ic1cn(CCOC2CCCCO2)c2ccncc12
Product: O=C(c1ccnc(Br)c1)c1cn(CCOC2CCCCO2)c2ccncc12

Procedure:
Prepared according to the method described for Preparation 37 using 2-bromo-N-methoxy-N-methylisonicotinamide and 3-iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrrolo[3,2-c]pyridine (Preparation 50).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].CC[O-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[N:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:12]=1>CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24]([NH:26][CH2:27][CH2:28][CH2:29][O:30][CH2:3][CH2:2][C:1]#[N:4])=[N:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCO)c23)cc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCC#N)c23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Add 47 mg (0.89 mmol) acrylonitrile and 57 mg (0.83 mmol) sodium ethylate to 300 mg (0.80 mmol) of the compound from Stage 1. Stir the mixture overnight at 80° C. After cooling, take up the mixture in DMSO and purify directly by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). 160 mg (47% of theor.) of the title compound is obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([N:7]([CH2:18][CH3:19])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nn1cnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)n1cnc(Br)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
tert-Butyl (4-bromo-1H-imidazol-1-yl)carbamate (1.16 g, 4.43 mmol) was dissolved in N,N-dimethylformamide (DMF, 12 mL) and treated with sodium hydride (0.310 g, 7.75 mmol, 60% dispersion in oil). After 45 minutes, the mixture was cooled on an ice bath and was treated with iodoethane (0.828 g, 5.31 mmol). The ice bath was removed after five minutes of stirring and the reaction was stirred for an additional 90 minutes. The reaction mixture was diluted with aqueous potassium carbonate (50 mL, 5% w/w) and the product was extracted with ethyl acetate. The organics were washed with 5% aqueous potassium carbonate and brine and dried over sodium sulfate. The organic layer was concentrated and the residue was purified using silica gel chromatography (0-10% methanol/dichloromethane) to afford the title compound (1.023 g, 3.53 mmol, 80%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=1.5 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 3.71 (q, J=7.2 Hz, 2H), 1.44 (s, 9H), 1.16 (t, J=7.2 Hz, 3H); ESIMS m/z 290 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CC=CC=1.C1(C(=O)C(=O)C)C=CC=CC=1>>[CH3:1][C:7]1[N:8]=[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1c(CCC(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Agent: CC(=O)C(=O)c1ccccc1
Product: Cc1nc(CCC(=O)O)n(COCC[Si](C)(C)C)c1-c1ccccc1

Procedure:
Prepared in analogy to the methods described for 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid replacing benzil with 1-phenyl-propane-1,2-dione.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][N:13](C(OC=C)=O)[CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(O)C>[N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C=COC(=O)N1CCN(c2cccc3nsnc23)CC1
Agent: Cl
Solvent: CCO
Product: c1cc(N2CCNCC2)c2nsnc2c1

Procedure:
To a 50 ml round-bottomed flask equipped with condenser and N2 inlet were added 530 mg (1.83 mmol) 4-(2,1,3-benzothiadiazolyl)-N-vinyloxycarbonylpiperazine and 25 ml ethanol, and the suspension saturated with HCl gas. The reaction was refluxed 2.75 hours, cooled, and evaporated. The residue was triturated with acetone to give a yellow solid N-(2,1,3-benzothiadiazolyl)-piperazine, m.p. 240°-244° C., 365 mg (62%).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>O.C(N(CC)CC)C>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
47.6 g of trityl chloride were added in small portions over 30 minutes to a mixture (cooled at -30° C.) of 32.2 g of the anti isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetate of Step A of Example 1, 90 ml of dry dimethylformamide and 24 ml of triethylamine and the mixture was left to spontaneous heating for 21/2 hours. Then, 150 ml of 2 N hydrochloric acid and 600 ml of water were added thereto and the mixture was stirred for 15 minutes, then vacuum filtered. The recovered precipitate was empasted 3 times with ether and was then taken up in a mixtue of methanol, water and triethylamine. The mixture was stirred and then vacuum filtered. The recovered product was rinsed with aqueous methanol and dried to obtain 60.2 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate 3.4 g of the said product were recrystallized from a methylene chloride-methanol mixture to obtain 3 g of pure product melting at 260° C.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:15]>ClCCl.C(N(CC)CC)C>[NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(N)c1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)c1ccc(CCNS(=O)(=O)c2ccc(C#N)cc2)cc1

Procedure:
4-(1-Amino-1-methylethyl)phenethylamine (A18, 2.132 g) was treated with 4-cyanophenylsulphonyl chloride (2.63 g) in dichloromethane (35 ml) and triethylamine (1.8 ml) to give N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-cyanobenzenesulphonamide, as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N+:11]([O-])=[CH:10][C:9]=2[C:8]([CH3:21])=[CH:7]1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:9]2[C:8]([CH3:21])=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1
Reactant: CCOC(=O)c1cc2c(c[n+]1[O-])c(C)cn2CCCOC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(c(C)cn2CCCOC)c(Cl)n1

Procedure:
A solution of ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 5-oxide (40 mg) in phosphorus oxychloride (2 mL) was stirred at 100° C. for 1 hours. The reaction solution was concentrated, and the resulting residue was dissolved in ethyl acetate. It was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=1/1) to give ethyl 4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-6)] (23 mg) as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: C=CCCCBr
Product: CCCC=CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and 5-bromopentene, reacted at 60° C. for 3 hours, the title compound was obtained as a white powder. δC (CDCl3, 62.9 MHz): 25.4, 28.0, 29.6, 30.9, 48.0, 48.3, 62.4, 115.4, 127.3, 127.7, 128.5, 129.1, 137.5, 138.4, 139.4 and 145.3. δH (CDCl3, 250 MHz): 1.56-1.67 (8H, m), 2.03 (2H, m), 3.16 (4H, m), 3.65 (2H, t, J 7.1), 4.94 (2H, m), 5.74 (1H, m), 7.43 (3H, m), 7.59 (2H, d, J 7.0), 7.69 (2H, d, J 8.2) and 7.84 (2H, d, J 8.2).