Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(/C=C/c3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C=Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
Under an argon atmosphere, to a mixture of (E)-5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-styrylpyrazin-2-amine (7b) (500 mg, 1.24 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11b (563 mg, 864 mol, 69.7%) as a yellow solid. Rf=0.29 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.24 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.66 (s, 2H), 6.81-6.91 (m, 3H, includes AA′BB′), 6.99-7.04 (AA′BB′, 2H), 7.28-7.40 (m, 7H, includes AA′BB′), 7.82 (d, 1H, J=16 Hz), 8.11-8.19 (AA′BB′, 2H), 8.91 (s, 1H), 10.66 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.8, 17.9, 25.5 (6C), 42.0, 119.7 (2C), 120.3 (2C), 122.5, 127.1 (2C), 128.2 (2C), 128.5, 128.7 (2C), 128.9, 129.0, 130.3 (2C), 133.8, 136.0, 137.8, 142.8, 143.9, 148.0, 154.0, 156.7, 170.6; IR (KBr, cm−1) 471, 521, 638, 691, 746, 781, 806, 839, 914, 968, 1007, 1080, 1103, 1169, 1263, 1325, 1371, 1391, 1414, 1439, 1472, 1510, 1566, 1605, 1659, 2857, 2886, 2930, 2055, 3028, 3057, 3217; HRMS (ESI+) m/z 674.3203 ([M+Na]+, C38H49N3NaO3Si2+ requires 674.3205).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.[C:17]([O-])(O)=O.[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:17]=[N:16][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1cc(Br)ccc1NCCN1CCCC1
Agent: [Na+]
Solvent: O=CO
Product: Brc1ccc2c(c1)ncn2CCN1CCCC1

Procedure:
A solution of 904 mg (3.18 mmol) 4-bromo-N1-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 5 mL formic acid is refluxed for 1.5 h. It is made alkaline with semisaturated NaHCO3 solution and extracted twice with 70 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][SH:14])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([N:21]1[C:26](=[O:27])[C:25]([CH3:28])=[C:24](Cl)[CH:23]=[N:22]1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([N:21]1[C:26](=[O:27])[C:25]([CH3:28])=[C:24]([S:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:16][CH:15]=2)[CH:23]=[N:22]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: SCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(-c3ccccc3)cc2)cnn(C(C)(C)C)c1=O
Yield: 44.7 %

Procedure:
To 10 ml of dry N,N-dimethylformamide was added 0.75 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and added dropwise with a solution of 3.2 g of p-phenylbenzyl mercaptan dissolved in 15 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 3.2 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 15 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at 80° C. for one hour. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 4.8 g of crude product. The crude product was recrystallized from 5 ml of hexane to obtain 2.6 g of 2-t-butyl-4-methyl-5-(p-phenyl-benzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:5][C:4]=1[O:21][CH3:22])=[O:2].[OH-].[Na+]>CO>[CH:1]([C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][C:18]=1[O:19][CH3:20])=[O:2]
Reactant: CCOC(=O)CCCCOc1cc(OC)c(C=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OCCCCC(=O)O)cc(OC)c1C=O
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate (37 g, 119 mmol) in methanol (200 mL) was added 4 N sodium hydroxide (200 mL) and the mixture was stirred for 2 h. The methanol was removed in vacuo, water (100 mL) was added and the mixture was washed with ethyl acetate (100 mL) and dichloromethane (2×100 mL). The aqueous layer was acidified with 12 N hydrochloric acid until pH˜3 and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (2×50 mL), dried (magnesium sulfate) and concentrated in vacuo. The obtained product was recrystallized from ethanol to give 26 g of 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C@H:14]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:15]([NH:17][C:18]2[S:19][C:20]([F:23])=[CH:21][N:22]=2)=[O:16])[CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].O>O1CCCC1.CO>[CH:33]1([S:30]([C:27]2[CH:26]=[CH:25][C:24]([C@@H:14]([CH2:13][C@H:10]3[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9]3)[C:15]([NH:17][C:18]3[S:19][C:20]([F:23])=[CH:21][N:22]=3)=[O:16])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1
Reactant: CC(=O)OCC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCN(C(=O)CO)C1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
2-((S)-3-((R)-2-(4-(Cyclopropylsulfonyl)phenyl)-3-((5-fluorothiazol-2-yl)amino)-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl acetate (47.0 mg, 89.8 μmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and thereafter, an aqueous solution of sodium hydroxide (2 M, 0.36 mL) was added to the obtained solution under ice-cold condition. The obtained mixture was stirred for 30 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (38.2 mg, 88%) in the form of a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Agent: Cl
Solvent: CO
Product: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)n1
Yield: 85.8 %

Procedure:
A solution of the compound (425 mg, 0.82 mmol) obtained in Example 21-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (286 mg, 86%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:31][N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[C:20](=[O:22])[CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[N:17]=1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(CC(=O)OC(C)(C)C)C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 20 h
Yield: 68.3 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.35 g, 1.1 mmol) was dissolved in N,N-dimethylformamide (4 ml), and N-methylglycine tert-butyl ester (0.24 g, 1.3 mmol), WSC (0.43 g, 2.2 mmol) and HOBt (0.31 g, 2.3 mmol) were successively added thereto. The reaction mixture was stirred for 20 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol-hexane to give the titled compound (0.33 g, 67%) as white crystals.
Reaction SMILES: C([O:4][C:5]1[CH:34]=[CH:33][C:8]([C:9]([O:11][C:12]2[CH:32]=[CH:31][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C>O1CCCC1.CO.[OH-].[Li+].C(OCC)(=O)C>[OH:4][C:5]1[CH:34]=[CH:33][C:8]([C:9]([O:11][C:12]2[CH:32]=[CH:31][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In pyridine was dissolved 5 g of dodecyl p-hydroxybenzoate, and a solution of 5 g of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the solution and the mixture was stirred at room temperature for 4 hours. Water was added to the thus-obtained solution, the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 3.18 g dodecyl 4-(4-acetoxybenzoyloxy)benzoate. The obtained ester was dissolved in a mixed solvent of tetrahydrofuran and methanol at a volume ratio of 10/1, 7 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, and the obtained mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dried on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from a liquid mixture of n-hexane and ethyl acetate to obtain 2.22 g of dodecyl 4-(4-hydroxybenzoyloxy)benzoate.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[C:4]1(=[CH:36][C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:6][CH2:5]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C2CC2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.27 g) in tetrahydrofuran (40 mL) was added cyclopropyltriphenylphosphonium bromide (2.6 g), and the mixture was stirred at 70° C. for 2 hours. To the reaction mixture was added methyl terephthalaldehydate (1.0 g), and the mixture was stirred at 70° C. for 7 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=1/1) to give methyl 4-(cyclopropylidenemethyl)benzoate (0.80 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30])[C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[N:5][CH:4]=1.[Si:31]([O:38][C@@H:39]([CH2:43]Cl)[CH2:40][CH:41]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[BH4-].[Na+]>CO.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:11]3([C:9]([NH:8][C:6]4[S:7][C:3]([C@@H:2]([N:1]5[CH2:41][CH2:40][C@@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH2:43]5)[C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[Cl:30])=[CH:4][N:5]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Reactant: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:19]([CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:35][CH:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride (4.58 mmol) in ether (5 ml) is added to an ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmol) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×2 mm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band with Rf=0.55 is extracted with ether and evaporated to give the desired ester (0.85 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCCBr)cc1
Temperature: 60 °C
Yield: 39.4 %

Procedure:
As expressed in the following reaction scheme, hydroquinone (1) (4.5 g) and 1,6-dibromo hexane (2) (10 g) were dissolved in methanol (100 ml) at room temperature. Potassium hydroxide (2.3 g) was added to the mixture solution, and the resulting solution was then refluxed at 60° C. overnight. Then, the resulting reaction mixture is cooled to room temperature, and methanol was removed from the reaction mixture through evaporation, and the product was then extracted three times with water (100 ml) and ethyl acetate (100 ml)(200 ml×3). After removing water with magnesium sulfate and evaporating the solvent, the reaction product was refined by column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 4.4 g of 4-(6-bromohexyloxy)phenol (3).
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:40])[NH2:39])=[CH:33][CH:34]=4)[CH:29]=3)[S:20]([CH2:23][C:24]([OH:26])=[O:25])(=[O:22])=[O:21])=[CH:15][C:14]=2[F:41])[CH2:8][CH2:7]1)(=[NH:5])[CH3:4].Cl.O1CCO[CH2:45][CH2:44]1>C(O)C>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:39])[NH2:40])=[CH:33][CH:34]=4)[CH:29]=3)[S:20]([CH2:23][C:24]([O:26][CH2:44][CH3:45])=[O:25])(=[O:22])=[O:21])=[CH:15][C:14]=2[F:41])[CH2:8][CH2:7]1)(=[NH:5])[CH3:4]
Reactant: CC(=N)N1CCCN(c2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)S(=O)(=O)CC(=O)O)cc2F)CC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCN(C(C)=N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
300 mg of [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-fluorophenyl]-N-[(7-amidino-2-naphth-yl)methyl]sulfamoyl]acetic acid dihydrochloride obtained in Example 31 was dissolved in 10 ml of ethanol, to which was added 1 ml of a 4 N hydrochloric acid gas-dioxane solution, and stirred at room temperature for 22 hours. The reaction mixture was evaporated, and the resulting residue was dissolved in 20 ml of ethanol, to which was added 2 ml of a 4 N hydrochloric acid gas-dioxane solution, and stirred at room temperature for 7 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography using an eluent solvent of ethanol. A s mall amount of 1 N hydrochloric acid was added to the thus-purified product, which was then freeze-dried to obtain 238 mg of ethyl [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-fluorophenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetate dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][C:13]([O:15]CC)=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Li+].O1CCOCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([CH3:18])=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=C(C)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C=Cc1ccc(Cl)c(Cl)c1)=CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.4 %

Procedure:
A solution of ehtyl 5-(3,4-dichlorophenyl)-3-methyl-pentadienoate (0.120 g, 0.418 mmol) in tetrahydrofuran (0.5 mL) is treated with aqueous 1 M lithium hydroxide (0.5 mL, 0.5 mmol). The cloudy reaction mixture is treated with dioxane (1 mL). After stirring at room temperature for two days, the mixture is concentrated in vacuo. The residue is diluted with 1 M aqueous HCl and extracted several times with chloroform. The organic layers are combined, dried (sodium sulfate), and concentrated in vacuo to yield 0.110 g of a white solid, mp, 212-214° C.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][CH:24]([F:27])[CH2:25]I>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:25][CH:24]([F:27])[F:23])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: FC(F)CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
18 g (81.72 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 500 ml of abs. THF, and 39.22 ml (98.06 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 15 min. Subsequently, the reaction solution was warmed up to 0° C. 17.25 g (89.89 mmol) of 1,1-difluoro-2-iodoethane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed three times with semisaturated aqueous sodium chloride solution. The combined aqueous phases were reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:dichloromethane/cyclohexane 1/1). 13.57 g of the target compound were obtained (49% of theory, 84% purity).