Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (10.1 g, 65.95 mmol) and cesium carbonate (42.9 g, 131.9 mmol) in DMF (1 L) is added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.96 g, 98.93 mmol) in 20 ml of DMF over 2 hours. The reaction is stirred 4 hours at room temperature and then poured over water (1 L) and stirred for additional 1 hour. A brown solid is collected by filtration and washed with additional water. The solid is dried to a constant weight to give the intermediate compound (10.3 g 66%) of methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate which is used without further purification. To a solution of methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate (4.5 g, 19.1 mmol) in methanol (45 mL) is added sodium hydroxide 1 M solution (38.2 ml, 38.2 mmol) and the reaction is stirred for 2 hours at room temperature. The pH of the reaction mixture is adjusted with HCl 35% w/w to adjust pH=1 and then the resulting solid is isolated by filtration. The solid is washed with water and then dried under vacuum to give the title compound (3 g, 70%). ES/MS (m/z): 222.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH:15]=[C:16]([C:24](=O)[CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(O)C>[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH:15]1[N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]2[NH:1][C:24]([CH3:25])=[C:16]1[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18].[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH:15]1[N:6]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][N:3]=[C:2]2[NH:1][C:24]([CH3:25])=[C:16]1[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: CCOC(=O)c1c[nH]c(N)n1
Reactant: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)NC(C)=C(C(=O)OC(C)(C)C)C2c1ccc(Cl)cc1Cl
Product: CCOC(=O)c1cnc2n1C(c1ccc(Cl)cc1Cl)C(C(=O)OC(C)(C)C)=C(C)N2
Temperature: 75 °C
Yield: 212.1 %

Procedure:
Ethyl 2-amino-1H-imidazole-4-carboxylate (980 mg, 6.8 mmol) and tert-butyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate (2.03 g, 6.4 mmol) were dissolved in ethanol (15 mL) and the reaction was heated to 75° C. for 16 h. The reaction was concentrated under reduced pressure to obtain a 10:1 mixture (by HPLC) of 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2,6-dicarboxylate and 6-tert-butyl 3-ethyl 5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-3,6-dicarboxylate (3.07 g, 100% crude yield) as a yellow foam. A small amount of this mixture (350 mg) was purified by silica gel chromatography to obtain 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (190 mg, 54%) and 6-tert-butyl 3-ethyl 5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-3,6-dicarboxylate (19 mg, 5.4%) as white solids.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1ccoc2cc(O)ccc12
Solvent: O
Solvent: c1ccncc1
Product: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, 0.24 ml of trifluoromethansulfonic anhydride was added at 0° C. to 4 ml of pyridine solution with 180 g of 7-hydroxy-4H-chromen-4-one, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 83 mg of the above compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12]/[C:13](/[CH3:17])=[CH:14]\[C:15]#[N:16]>C(O)(=O)C>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[NH:12][C:2]([CH3:9])=[C:3]2[C:4]#[N:5])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 160.4 %

Procedure:
2-Fluoro-5-formylbenzonitrile (30 g, 201.17 mmol) and 3-aminocrotononitrile (35.01 g, 431.63 mmol) were dissolved in acetic acid and heated to 90° C. After 4 hr, the reaction mixture was cooled to rt, concentrated, neutralized with a saturated solution of sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The solid were dissolved into ethyl acetate, and hexane was added. The solid precipitated, and was filtered to afford 4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (44.9 g, 80.2%) as a pale yellow solid. 1H-NMR (400 MHZ, DMSO-D6): δ=9.61 (br. s, 1H), 7.97 (dd, 1H), 7.48 (dd, 1H), 7.35 (dd, 1H), 4.64 (s, 1H), 2.01 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:30][O:29][C:26]1[N:25]=[CH:24][C:23]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][OH:22])=[CH:28][CH:27]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: COc1ccc([C@H](N)CO)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(C)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (55 mg, 0.21 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (35 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC (100×20.2 mm, C18 column; 25-50% CH3CN-water [10 mM Et2NH]) to give a light yellow solid.
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][CH:21]2[S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][CH2:23][S:22]2(=[O:30])=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:33]I>C1COCC1.CCCCCC.CCOCC>[C:1]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C:21]2([CH3:33])[S:26](=[O:27])(=[O:28])[CH2:25][CH2:24][CH2:23][S:22]2(=[O:30])=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CC2S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CC2(C)S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Reaction time: 1 h

Procedure:
A solution of 0.98 g of 2-[(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl-methyl]-1,3-dithiane 1,1,3,3-tetroxide in 300 ml of THF is mixed at -30° with 1.3 ml of a 1.6 molar solution of butyl-Li in hexane. The mixture is stirred for 1 h and then 0.56 g of methyl iodide is added and the mixture is stirred for 24 h in a thawing cooled bath, diluted with 50 ml of ether, and worked up as usual to give 2-[(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl-methyl]-2-methyl-l,3-dithiane 1,1,3,3-tetroxide, m.p. 176°-177°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.0 g) and commercially available 5-hydroxyindole (1.19 g) were mixed and stirred at 150° C. for 1.5 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting in sequence with hexane/ethyl acetate, chloroform and chloroform/methanol, to obtain 898 mg of the title compound (yield: 63%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]4[CH2:36][CH2:35]4)=[O:33])[N:30]=3)[CH:27]=2)[CH:37]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
3-(1-Cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (2.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (75 mg, 0.233 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and diisopropyl ether to give the title compound (40.8 mg, 35%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)n1
Yield: 51.1 %

Procedure:
To 26.8 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml anhydrous methylene chloride was added 67.0 g of 2-isopropoxycarbonylbenzenesulfonyl isocyanate in 100 ml anhydrous methylene chloride. The resultant suspension was stirred at ambient temperature for 72 hours, and filtered to yield 40.0 g of the desired product as a white solid, m.p. 193°-196° C. The solid showed infrared absorption peaks at 1700 and 1710 cm-1 consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(isopropoxycarbonyl)-benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[C:8]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:9]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CCC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.56 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (6.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.14 g, 78%) of 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([NH:16][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: NC1CCCCc2c1[nH]c1ccc(Br)cc21
Reactant: Clc1ncccn1
Product: Brc1ccc2[nH]c3c(c2c1)CCCCC3Nc1ncccn1

Procedure:
2-Bromo-N-pyrimidin-2-yl-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-6-amine was prepared from 2-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-6-amine (150 mg, 0.54 mmol) and 2-chloropyrimidine (123 mg, 1.07 mmol) in a similar manner as described in Example 22 to give 18 mg (9%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.80 (s, 1H), 8.31 (d, 2H), 7.57 (s, 1H), 7.49 (d, 1H), 7.20 (d, 1H), 7.07-7.04 (m, 1H), 6.60 (t, 1H), 5.36-533 (m, 1H), 2.94-2.89 (m, 1H), 2.70-2.63 (m, 1H), 2.05-1.94 (m, 2H), 1.89-1.59 (m, 4H); MS m/z (M+1) 357, 359; (M−1) 355, 357.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[C:20]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:43]([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:44][CH3:45].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)(=O)C>[CH:28]1([O:27][C:20]2[CH:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][N:8]([CH2:34][C@H:35]([OH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:13][CH:14]=3)[CH:23]=[CH:22][C:21]=2[C:24]([NH:49][S:46]([CH2:43][CH2:44][CH3:45])(=[O:48])=[O:47])=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reactant: CCCS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a solution of 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (133 mg) in N,N-dimethylformamide (1.3 ml) was added N,N′-carbonyldiimidazole (41.3 mg) and the mixture was stirred at room temperature for 5 hours. To the mixture were added 1-propanesulfonamide (31.4 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (41.6 μl) and the mixture was stirred at 50° C. for 14 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml×2) and brine (10 ml). The solution was dried over magnesium sulfate then concentrated in vacuo to give a crude solid which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [3-[3′-(cyclohexyloxy)-4′-[[(propylsulfonyl)amino]carbonyl]-4-biphenylyl]propyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (63.5 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH:13]=[C:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(Cl)(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: N=C1CCCN1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.8 g (29.7 mmoles) of 2-bromo-4'-methoxyacetophenone in 50 ml of CHCl3 was added a solution of 5 g (59.4 mmoles) of 2-iminopyrrolidine in 30 ml of CHCl3 with chilling. After 4 hours of stirring at 25° C., the solvent was removed in vacuo. The residue was dissolved in water, the pH adjusted to 2.5 and the solution heated on a steam bath under argon atmosphere for 8 hours. The cooled solution was adjusted to pH 6. The resulting precipitate was filtered, washed with water and dried in vacuo to afford the titled compound, mp 116°-117.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].B(F)(F)F.[CH3:16][C:17]1[S:18][C:19]([CH3:27])=[CH:20][C:21]=1[C:22](O)([CH:24]=[CH2:25])[CH3:23].C(O)=C>O1CCOCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]2[C:3]=1[O:11][C:22]([C:21]1[CH:20]=[C:19]([CH3:27])[S:18][C:17]=1[CH3:16])([CH3:23])[CH2:24][CH2:25]2
Reactant: Cc1cc(O)c(Cl)c(C)c1O
Reactant: C=CC(C)(O)c1cc(C)sc1C
Agent: C=CO
Agent: FB(F)F
Solvent: C1COCCO1
Product: Cc1cc(C2(C)CCc3c(C)c(O)c(C)c(Cl)c3O2)c(C)s1
Temperature: 120 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
To a solution of 2-chloro-3,5-dimethyl-benzene-1,4-diol (520 mg) and BF3 etherate (1.28 g) in dioxane (10 mL) at 120° C. was added slowly a solution of the vinyl alcohol 2-(2,5-dimethyl-thiophen-3-yl)-but-3-en-2-ol (600 mg) in 2 mL of dioxane in 30 min. After completion, the solution was stirred at 120° C. for 3 h. Workup and purification by silica gel column chromatography eluting with 10% EtOAc in hexane gave 50 mg off-white solid 4-Chloro-6-(2,5-dimethyl-thiophen-3-yl)-1,3,6-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol. 1H NMR (300 MHz, CDCl3) 8:6.52 (s, 1H), 4.29 (s, 1H, OH), 2.63-2.33 (3s+m, 12H), 2.06-2.01 (s+m, 4H), 1.62 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 δ:145.40, 143.98, 139.90, 134.97, 132.28, 125.68, 121.24, 120.34, 119.97, 119.57, 78.05, 32.85, 28.52, 21.74, 15.49, 14.96, 13.49, 11.77 ppm. MS m/z: 337 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:20])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:40]=1)#[N:24]
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.30 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=601 ([M+H]+, 7), 76 (100); IR (KBr): 2169 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from ethanol/petroleum ether; m.p.: 106° C. (ethanol/petroleum ether).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH3:4])[CH2:3][C:13]1[C:12]2[C:16](=[CH:17][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)[NH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.4 %

Procedure:
A solution of dimethylamine (25 g, 0.17 mol) and formaldehyde (14.4 mL, 0.15 mol) in acetic acid (100 mL) was stirred at 0° C. for 30 min. To this solution was added 6-nitro-1H-indole (20 g, 0.12 mol). After stirring for 3 days at room temperature, the mixture was poured into 15% aq. NaOH solution (500 mL) at 0° C. The precipitate was collected via filtration and washed with water to give dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 87%).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]1([CH3:28])[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])=[CH:10][CH:9]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>C(O)C>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([CH2:33][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:28])=[CH:9][CH:10]=2)=[O:15])[CH:31]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Reactant: BrCc1cccc(Br)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Br)c1)(NC(=O)c1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
To 100 ml of dry ethanol, 21.45 g of 20% sodium ethoxide-ethanol solution and 17.61 g of diethyl p-toluoylaminomalonate were added and stirred for 30 minutes at room temperature under argon atmosphere. After 15.00 g of 3-bromobenzyl bromide was added dropwise, the reaction solution was stirred for 8 hours at 55° C. and then concentrated. To the residue was added water, and extracted with ethyl acetate. The organic.layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 29.82 g of the objective compound as yellow oil.