Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.[Br-].[Li+]>CN(C)C=O>[Si:15]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:9][OH:10])[CH2:2][CH2:3]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: OCC1CCC(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Br-]
Agent: [Li+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of cyclohexane-1,4-dimethanol (10.0 g) in N,N-dimethylformamide (100 mL) were added successively tert-butyldimethylchlorosilane (8.9 g) and imidazole (9.5 g), followed by stirring the reaction mixture at room temperature for 16 hours. To the reaction mixture were added ice and saturated aqueous lithium bromide solution, followed by extraction with diethyl ether. The organic layer was washed with saturated aqueous lithium bromide solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:9 to 2:3) to give [4-(tert-butyldimethylsilanyloxymethyl)-cyclohexyl]-methano 1 (8.7 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([O:11]C)=[O:10])=[CH:4]1.[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCCl>[C:13]([NH:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4]1)(=[O:15])[CH3:14]
Reactant: COC(=O)C1=CC(N)CC=C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1C=C(C(=O)O)C=CC1

Procedure:
A solution of 190 mg (1 m mole) of methyl 3-amino-1,5-cyclohexadienecarboxylate hydrochloride in 5 ml of dichloromethane is treated with 78 mg (1 m mole) of acetyl chloride and 202 mg (2 m mole) of triethylamine for 1 hour at 25° C. after which the solution is washed with water, dryed and concentrated. The residue is treated at 25° C. with 3 ml of methanol and 100 ml of sodium hydroxide in 200 ml of water for 3 hours then acidified and extracted with dichloromethane. The organic phase is dried and evaporated to afford 3-acetamido-1,5-cyclohexadiene carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Cl[C:33]([C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH3:36])=[O:34].CCN(CC)CC>C1COCC1>[CH3:36][C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C:33]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:34]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (131 mg, 0.31 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (45 μL, 0.31 mmol) and NEt3 (40 μL, 0.31 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a white solid (125 mg, 73%). LCMS (method H): RT 2.50 min [M+H]+ 547.5
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([CH3:26])[CH2:12][N:11]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)#[N:8].O1CC[CH2:29][CH2:28]1>>[C:14]1([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]2[CH2:10][C:9]([CH2:7][NH:8][CH2:28][CH3:29])([CH3:26])[CH2:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNCC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.1 g (161 mmol) of lithium aluminium hydride are suspended in 250 ml of tetrahydrofuran, and a solution of 21.1 g (80.5 mmol) of 3-cyano-1-diphenylmethyl-3-methylazetidine in 150 ml of tetrahydrofuran are added dropwise during 1 hour. The temperature is maintained during the addition at between 30° and 35° C. and the mixture is then stirred for 12 hours at room temperature. The excess lithium aluminium hydride is destroyed with ethanol, the insoluble inorganic fraction is filtered off, the tetrahydrofuran is removed, the residue is dissolved with chloroform, the organic phase is washed with water, dried with anhydrous sodium sulphate and evaporated to dryness and 16.1 g (75%) of 3-aminomethyl-1-diphenylmethyl-3-methylazetidine, melting point 46°-8° C., are obtained.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]O)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CCCC[C@@H](CO)NS(=O)(=O)c1ccc(C)cc1
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@@H](CP(=O)(OCC)OCC)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
Diethyl phosphite (8.9 ml., 69 mmole) is dissolved in dry tetrahydrofuran (125 ml.) under argon in a 250 ml. round-bottomed flask equipped with a condenser. Sodium hydride (2.4 g.) is added in small portions with frothing and bubbling. When the evolution of hydrogen ceases, the reaction mixture is heated to reflux for 45 minutes. It is then cooled to room temperature, and a solution of (S)-2-[[(4-methylphenyl)sulfonyl]amino]-1-hexanol, 4-methylbenzenesulfonate ester (18.1 mmole) is added dropwise over 5 minutes. A white solid precipitates. The mixture is then heated to reflux for 3.5 hours. It is cooled and partitioned between ethyl acetate and 5% potassium bisulfate. The ethyl acetate layer is washed with 5% potassium bisulfate, saturated sodium bicarbonate, and brine, and then concentrated in vacuo. The resulting gum is triturated with hexane to give 6.45 g. of beige solid (S)-[2-[[(4-methylphenl)sulfonyl]amino]hexyl]phosphonic acid, diethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1ccc(CCl)cc1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H), 6.98-6.94 (m, 2H), 5.26 (s, 2H), 2.89-2.86 (m, 4H), 2.80-2.78 (m, 2H), 2.73-2.70 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([NH:8][C:9]2[NH:13][CH2:12][CH2:11][N:10]=2)=[C:3]([Cl:14])[CH:2]=1.Br[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[N:8]([C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19]
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: C=C(C)CCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Temperature: 120 °C

Procedure:
A mixture of 6.9 gm (0.03 mol) of clonidine, 5.6 gm of 4-bromo-2-methyl-1-butene, and 5 ml of triethylamine in 25 ml of toluene was heated for 24 hours at 120° C. After cooling, the solvent was decanted, and the residue remaining was dissolved in 1 N hydrochloric acid. After extraction with ether several times (the ethereal extracts were abandoned), the solution was extracted with ether in fractions at stepwisely rising pH values (alkalizing with 2 N sodium hydroxide solution). The thin-layer chromatographically uniform ether extracts were united and dried over MgSO4, and the ether was evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)[NH:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(OCC)(=O)C>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 79 %

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After completed addition it was left to crystallize for another half an hour at a temperature below 5° C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1%) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][CH:24]([CH3:26])[N:23]([CH3:27])[C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][CH:24]([CH3:26])[N:23]([CH3:27])[C:20]5=4)[O:15][CH2:14]3)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)N(C)C(C)N4)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1Nc2ccc3c(c2N1C)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 95 °C
Yield: 12 %

Procedure:
A mixture of 0.69 g (1.8 mmole) of [(8R)-1,2-dimethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 90-100° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 0-3% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.090 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.025 g of fumaric acid gave the (S)-enantiomer of the title compound as a yellow solid, m.p. 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[O:30]=[C:31]1[C:35](=[CH:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[S:34][C:33](=[S:45])[NH:32]1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([CH:36]=[C:35]4[S:34][C:33](=[S:45])[NH:32][C:31]4=[O:30])=[CH:44][CH:43]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(C=C2SC(=S)NC2=O)cc1
Product: O=C1NC(=S)SC1=Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 623.8.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([N+:12]([O-:14])=[O:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)sc(Cl)c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 55.8-g (0.22 mol) sample of 2,5-dichloro-3-thienylsulfonyl chloride was added in small portions to a stirred solution of 150 ml concentrated nitric acid and 150 ml concentrated sulfuric acid. After the addition was completed, the reaction mixture was stirred at about 25° C overnight. The reaction mixture was then diluted with ice water and filtered to give the crude 2,5-dichloro-4-nitro-3-thienylsulfonyl chloride product. The product was washed with water and dried. Recrystallization from methylene chloride gave the product as a brown solid, m.p. 89° -91° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>>[C:9]([C:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)n2)CC1

Procedure:
2,6-Difluoropyridine (2 g, 17 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (2.4 g, 11 mmol) were reacted in the presence of potassium hexamethyldisilazide (14 mmol) using the method described in example 8-1 to afford the desired product: tert-butyl 4-cyano-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 7.86 (1 H, q, J=7.9 Hz), 7.54 (1 H, dd, J=2.3, 7.4 Hz), 6.93-6.91(1 H, m), 4.28 (21H, br s), 3.17 (2 H, br s), 2.25-2.17 (2 H, m), 2.02 (2 H, d, J=14.6 Hz), 1.48 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[NH:46])[NH2:45])=[CH:40][C:39]=1[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:38]2[CH:43]=[CH:42][C:41]([C:44](=[NH:45])[NH2:46])=[CH:40][C:39]=2[C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of 3.4 g of 4-benzyloxybenzoic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DCC. After having been stirred for 30 minutes, the mixture was admixed with 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate and stirred overnight at room temperature. The reaction mixture was freed from the insolubles by filtration and mixed with ethyl ether. The precipitated insoluble substance was recrystallized from a methanol-ethyl ether mixture to obtain 5.2 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-benzoyloxybenzoate methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]12([NH:35][C:27]([C:24]3[CH:25]=[CH:26][C:21]([S:18]([N:8]4[C:7]5[CH:32]=[CH:33][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]([CH:11]5[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]5)[C:9]4=[O:17])(=[O:19])=[O:20])=[C:22]([O:30][CH3:31])[CH:23]=3)=[O:29])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc1OC
Yield: 42.2 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.5 g of the compound obtained in EXAMPLE 13, 0.3 g of 1-aminoada- mantane hydrochloride, 0.5 g of BOP, 2 ml of DIPEA and 25 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.27 g of the expected product after crystallization from an EtOH/iso ether mixture (80/20; v/v). M.p.=228° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[C:10](/[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)=[C:11](/[F:20])\[C:12]([NH:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2].[OH-].[Li+]>CO>[C:1]([C:4]1[CH:5]=[C:6](/[C:10](/[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:36])(=[O:37])[NH2:35])=[CH:24][CH:23]=2)=[C:11](/[F:20])\[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)CNC(=O)/C(F)=C(/Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)c1cccc(/C(Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)=C(/F)C(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of methyl 2-{(2E)-3-(3-amidinophenyl)-2-fluoro-N-[4-(2-sulfamoylphenyl)phenyl]but-2-enoylamino}acetate (100 mg, 0.19 mmol) in 5 ml methanol was added a 0.5N lithium hydroxide solution (1 ml, 0.5 mmol). The reaction was stirred at room temperature for 4 hours then concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 2-{(2E)-3-(3-amidinophenyl)-2-fluoro-N-[4-(2-sulfamoylphenyl)phenyl]but-2-enoylamino}acetic acid (70 mg, 71%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 511.1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][CH:26]=1)([CH3:24])[CH2:22][OH:23]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:19])=[CH:30][CH:29]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C(C)(CO)CO)cc2)n(-c2cccc(Cl)c2)n1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (80 mg, 0.31 mmol, 1.0 eq) in MeCN (7 mL) was added TEA (0.17 mL, 1.2 mmol, 4 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (94 mg, 0.31 mmol, 1 eq) and the mixture was stirred for 16 h at reflux. The reaction mixture was concentrated under vacuum and the residue was purified by CC using EtOAc/n-hexane 1:1 as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)phenyl)urea (106 mg; 73%).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]=[CH:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])O>C(O)C>[CH2:1]([NH:19][CH:30]1[O:31][C@H:22]([CH2:21][OH:20])[C@@H:24]([OH:25])[C@H:26]([OH:27])[C@H:28]1[OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
20 g of octadecylamine are dissolved in 120 ml of ethanol and the solution is warmed to 70° C. 11 g of anhydrous D-glucose are added. After a clear solution has formed, stirring is continued at 70° C. for a further 15 minutes. The solution is cooled to 10° C. and left to stand for 15 minutes. The crystal sludge formed is filtered off with suction, washed twice with ethanol and dried in vacuo.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CC(C)NC(=O)OC(C)(C)C)cc1
Yield: 53.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.4 mmol) was reacted with tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate (2.6 g, 7.3 mmol) to afford the desired product (1.1 g, 50%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.