Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)=[O:37])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Yield: 79.8 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.353 g, 0.826 mmol), 4-iodo-4′-fluorobutyrophenone (0.27 g, 0.826 mmol), and potassium carbonate (0.17 g, 1.24 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.39 g, 80%); MS for C35H46FN3O4 m/z 592 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].C(OCC)(=O)C>CN(C)C=O>[O:18]=[C:16]([CH3:17])[CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 25.0 g of diethyl malonate in 5 ml of dimethylformamide was added dropwise under ice-cooling over 20 minutes to a suspension of 6.55 g of sodium hydride in 90 ml of dimethylformamide. The reaction fluid was stirred for an hour under ice-cooling, to which a solution of 17.3 g of chloroacetone in 5 ml of dimethylformamide was added, and the mixture was stirred for an hour under ice-cooling and for 6 hours at room temperature. Ethyl acetate was added to the reaction fluid and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate. An oily matter obtained by concentrating the organic layer under a reduced pressure was distilled under vacuum to obtain 14.8 g of diethyl 2-oxopropylmalonate as a yellow oily matter.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:25]=1>>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:17])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by chromatography on silica gel to give 7(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]heptanamide, the title compound, mp 57°-59° (from acetone-hexane) in 75% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-])=O)=[CH:28][CH:27]=2)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH2:1])=[CH:12][CH:13]=2)([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:21])[F:19])=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(C(c2ccc(Nc3ccccc3[N+](=O)[O-])cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ccc(C(c2ccc(Nc3ccccc3N)cc2)(C(F)(F)F)C(F)(F)F)cc1
Yield: 94.9 %

Procedure:
20 g (34.7 mmol) of 2,2-bis[N-(2-nitrophenyl)-(4-aminophenyl)]hexafluoropropane synthesized above were dissolved in 200 ml of ethyl acetate. Thereto was added 1 g of 10% palladium carbon as a catalyst, and replacement with hydrogen was then carried out. After that, reaction was conducted at room temperature under a hydrogen pressure of 1.01 MPa (10 atm) for 18 hours with stirring vigorously. The obtained reaction solution was filtered with cerite to remove the catalyst, and ethyl acetate was removed under reduced pressure. The residue was re-crystallized by using a chloroform-hexane mixed solution, and ethanol-water mixed solution to obtain 17 g of 2,2-bis[N-(2-aminophenyl)-(4-aminophenyl)]hexafluoropropane (hereinafter pNPN-AF) in white solid (yeild: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxolan-4-one (15 g; 55 mmol) is dissolved in 50 ml of methanol. 4-(2-Aminoethyl)-2-methoxyphenol hydrochloride (14 g; 69 mmol) and triethylamine (7 g; 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. The remaining 2-(4-bromophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide is purified by chromatography on silica gel.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C(O)C>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][C:7](=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])[CH2:12]1
Reactant: CS(=O)(=O)CC#N
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CC(N2CCCC2)=CC(=C(C#N)S(C)(=O)=O)C1

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (4.7 g., 0.015 mol.), methylsulfonylacetonitrile (1.8 g., 0.015 mol.) and triethylamine (4.6 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 5 minutes. After chilling, the crude dye is collected on a filter, washed with methanol and dried. After one recrystallization from pyridine/methanol, the yield of purified dye is 1.2 g. (27%), m.p. 260°-261°C. with decomposition. The above dye compound has excellent absorption characteristics in the ultraviolet region of the spectrum as shown in Table 1 below.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][O:28][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:21][CH:20]=1
Reactant: OCCCc1ccncc1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCc1ccncc1

Procedure:
The title compound, brown solid, m.p. 147-50° C. and MS: m/e=374.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-pyridin-4-yl-propan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH:20]([OH:23])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[O:23][CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3ccc(Br)cc3c(Cl)n2)n[nH]1
Reactant: CC(C)O
Product: Cc1cc(Nc2cc3ccc(Br)cc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 376 was used, starting from (7-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropanol to give (7-Bromo-1-isopropoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 361 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 45 h
Yield: 53.1 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg) and acetone (5.0 ml) was stirred in a sealed tube at 60° C. for 45 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added thereto. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound (360 mg, 53%). In this chromatographic separation, some of the starting compound was recovered.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]1([CH:30]2[O:35][CH2:34][CH:33](O)[CH2:32][O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:33]3[CH2:32][O:31][CH:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:35][CH2:34]3)=[CH:23][C:6]1=2
Reactant: OC1COC(c2ccccc2)OC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OC3COC(c4ccccc4)OC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-phenyl-[1,3]dioxan-5-ol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[OH:21])[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH2:27]1[O:29][CH:28]1[CH2:30][OH:31]>CS(C)=O>[CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[O:21][CH2:27][CH:28]([CH2:30][OH:31])[OH:29])[CH2:2][CH2:3][CH3:4]
Reactant: OCC1CO1
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCC(O)CO)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
Under an argon atmosphere, 3-O-butylglyceryl ascorbic acid (4.98 g) obtained in Example 6 was stirred in DMSO(10 mL), and further, sodium hydrogen carbonate (0.33 g) was added. Thereafter, glycidol (1.46 g) was added and the mixture was heated up to 80° C. and stirred for 18 hours, followed by extraction with n-butnol. The extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.23 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-butylglyceryl-2-O-glyceryl ascorbic acid (1.23 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7](F)=[CH:6][C:5]=1[F:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[F:12]
Reactant: COC(=O)c1c(F)cc(F)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(F)cc(N(C)C)cc1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
To a stirred solution of 4.28 g (22.5 mmol) 2,4,6-Trifluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 6a was obtained in 74% yield (3.59 g, 16.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([O-:19])=[O:18].[OH-].[Na+]>CO>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: Nc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Yield: 72.6 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), 5-amino-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylate (6.0 g, 20.96 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (4.14 g, 15.21 mmol, 73%) was obtained.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[O:30][CH3:31]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([O:30][CH3:31])[CH:25]=3)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(N)ccc1Cl
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc(C(=O)NCC3CCCCC3)c(C(F)(F)F)n2)ccc1Cl
Yield: 47.9 %

Procedure:
In a manner similar to Example 243, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) and 4-chloro-3-methoxy-phenylamine (Wychem) (122 mg) were reacted to give the title compound (33 mg)
Reaction SMILES: [N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)/[CH:7]=[CH:8]/[C:9]2[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](=O)([O-])O.[Na+]>CO>[CH3:27][O:18][C:17](=[O:19])/[CH:16]=[CH:15]/[C:13]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[CH:6]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:14]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(/C=C/c2cccc(/C=C/C(=O)O)n2)N2CCCC2)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1cccc(/C=C/C(c2ccc(C)cc2)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 93 %

Procedure:
A solution of (E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-acrylic acid (2.04 g, 5.9 mmol) in methanol (50 ml) was treated with concentrated HCI (10 ml) and stirred at room temperature for 6 days. The reaction was neutralised with a saturated solution of sodium hydrogen carbonate and solvent removed under reduced pressure. DCM was added to the residue and inorganic solids removed by filtration. Concentration of the filtrate under reduced pressure yielded methyl-(E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-acrylate as a pink foam (1.98 g, 93%). 1H-NMR; δ (CDCl3), 7.70 (1H, d, J=15.7 Hz), 7.57 (1H, t, J=7.7 Hz), 7.30 (1H, t, J=7.6 Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=7.2 Hz), 7.10 (2H, dt, J=8.2, 1.8 Hz), 6.96 (1H, d, J=15.6 Hz), 6.93 (1H, d, J=7.9 Hz), 3.83 (3H, s), 3.65 (2H, bs), 2.85 (4H, bm), 2.41 (3H, s) and 2.04 (4H, bm).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCc1ccccc1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCc1ccccc1CC2

Procedure:
A mixture of 6-bromo-indan-1-one (300 mg, 1.43 mmol), 1,2-bis(2-bromoethyl)-benzene (414.3 mg, 1.43 mmol) in THF (10 mL) was added NaH (114 mg, 2.86 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-1′(3′H)-one (20 mg, 5%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23](O)=[O:24].[N:26]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23]([N:34]1[CH2:35][CH2:36][CH:31]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:32][CH2:33]1)=[O:24]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Yield: 12 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a light yellow oil (12%). MS: 484.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1.Cl>CN(C)C=O>[CH:50]1([NH:53][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[CH:21]=[C:17]([C:15]([NH:14][CH:3]([C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[CH:5]=4)[C:2]([F:30])([F:1])[F:29])=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:27])[CH2:52][CH2:51]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-({2,2,2-trifluoro-1-[3-(trifluormethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylic acid (100 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (100 mg, 0.46 mmol) and cyclopropylamine (36 mg, 0.63 mmol), and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat, sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10%, acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:33][CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1([N:16]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a solution of the crude 1-[[3-(tert-butyl-dimethylsilanyloxy)propyl]-(4'-fluorobiphenyl-4-sulfonyl)amino]cyclopentanecarboxylic acid benzyl ester (27.35 grams) in methylene chloride (450 mL) at room temperature was added boron trifluoride etherate (11 mL, 89.4 mmol). After 45 minutes, the reaction was quenched by sequential addition of saturated ammonium chloride solution and water. The organic phase was separated, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum provided crude 1-[(4'-fluorobiphenyl-4-sulfonyl)-(3-hydroxypropyl)amino]cyclopentane carboxylic acid benzyl ester as an amber oil (22.1 grams).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)(O)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:10](=[O:37])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2C3C(=CC=C(C(C4C=NC(Cl)=CC=4)(O)C4N(C)C=NC=4)C=3)[N:48](C)C(=O)C=2)C=CC=1>>[NH2:48][C:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:33][CH:34]1[CH2:36][CH2:35]1)[C:10](=[O:37])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)c1ccc(Cl)cn1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Product: Cn1cncc1C(N)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)c1ccc(Cl)cn1
Yield: 43 %

Procedure:
The same procedure was used as that in example 3, except that 4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (258 mg, 0.486 mmol was used in the place of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one, to give the title compound as a white solid, 112 mg (0.21 mmol, 43% yield).