Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:39]=[CH:38][C:30]2[C:31]([C:34](F)(F)F)=[N:32][O:33][C:29]=2[C:28]=1[CH2:40][CH2:41][CH3:42]>CN(C=O)C.O>[CH3:34][C:31]1[C:30]2[CH:38]=[CH:39][C:27]([O:26][CH2:25][CH2:24][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:16])[CH2:7][CH2:8]4)=[C:28]([CH2:40][CH2:41][CH3:42])[C:29]=2[O:33][N:32]=1
Reactant: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)ccc2c(C)noc12
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6) (62.4 mg, 0.28 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (111 mg, 0.34 mmol), and 3 drops of water were added. 6-(2-bromoethoxy)-7-propyl-3-(trifluoromethyl)1,2-benzisoxazole (100 mg, 0.28 mmol) was added and the reaction mixture was stirred for 10 h at 60° C. The solvent was removed under reduced pressure, and the crude product was taken up in EtOAc, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (2 mL), and LiOH (0.5 M aqueous solution, 0.9 mL) and MeOH (4 drops) were added. After stirring for 18 h at 50° C. the reaction mixture was concentrated under reduced pressure. Water and HCl (1 N aqueous solution) were added until the mixture was acidic which was followed by extraction using EtOAc. The product was purified by silica gel filtration (gradient 1:6 EtOAc/Hexane to 100% EtOAc), yielding 12 mg (9% over 2 steps) of the title compound as white crystals. 1H NMR (300 MHz, CD3OD): δ 0.91 (t, 3H), 1.70 (m, 3H), 2.33 (m, 2H), 2.68 (m, 2H), 2.87 (m, 3H), 3.46 (m, 1H), 4.33 (m, 2H), 4.48 (m, 2H), 6.73 (dd, 1H), 6.82 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:5][N:6]([CH3:8])[CH3:7].[Mg].[CH2:15]=[O:16]>>[CH3:7][N:6]([CH2:5][C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([CH:3]=1)[CH2:15][OH:16])[CH3:8]
Reactant: COc1ccc(CN(C)C)cc1Br
Reactant: C=O
Agent: [Mg]
Product: COc1ccc(CN(C)C)cc1CO

Procedure:
Successive reaction of 3-bromo-4-methoxy-N,N-dimethylbenzylamine with magnesium and formaldehyde (in a similar manner to Example 7) gave 5-dimethylaminomethyl-2-methoxybenzyl alcohol, m.p. 67°-69°, which was heated under reflux for 4 hours with cysteamine hydrochloride in acetic acid to give, after basification and chloroform extraction, 2-(5-dimethylaminomethyl-2-methoxybenzylthio)ethylamine, as an oil. This oil was heated under reflux with 1.1 molar equivalents of 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone in ethanol for 28 hours to give 2-[2-(5-dimethylaminomethyl-2-methoxybenzylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone which was treated with hydrogen chloride in ethanol and purified as the trihydrochloride salt m.p. 232°-235° (recrystallised from methanol-ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:22]1([O:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1)[C:3]([O:2][CH3:1])=[O:21])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
To a solution of Boc-L-Tyrosine methyl ester (2.37 g, 8.0 mmol), 4-phenyoxyphenylboronic acid (2.57 g, 12.0 mmol) and pyridine (3.16 g) in CH2Cl2 (200 mL) was added copper(II) acetate (1.46 g, 8.0 mmol). After stirring at rt for 24 h, the reaction mixture was concentrated in vacuo. The remaining material was dissolved in EtOAc (200 mL) and this solution was washed with water (2×100 mL). The organic layer was concentrated in vacuo and the crude product was purified by chromatography (7:3 hexane/ethyl acetate) to give 2.39 g of product (64%). 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.95-3.14 (m, 2H), 3.72 (s, 3H), 4.57 (q, J=7.2 Hz, 1H), 5.00 (br d, J=8.0 Hz, 1H), 6.90-7.11 (m, 11H), 7.30-7.36 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CNC=O.O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=1)=[O:9]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ncc(C(=O)O)c(O)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CNC=O
Product: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
The compound 20 (138 g, 0.596 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 g, 0.775 mol), and 1-hydroxybenzotriazole (100 g, 0.656 mol) were dissolved in methylformamide (970 ml), and 4-fluorobenzylamine (79 ml, 0.715 mol) was added. After the reaction solution was stirred at room temperature for 9 hours, water (2000 ml) was added, and crystals were collected by filtration, followed by washing with ether. 5-Bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 21 (156 g, 77%) was obtained as a colorless crystal.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[N:10]2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: OCc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round-bottomed flask was charged with (1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol 64 (0.703 g, 2.90 mmol) and 10 mL CH2Cl2. To this solution was added Dess-Martin periodinane (1.60 g, 3.77 mmol). After stirring at room temperature for 30 min, the reaction was quenched with saturated aqueous sodium thiosulfate. The layers were separated and the organics were dried and concentrated. The concentrate was passed through a short pad of silica gel rinsing with 7:1 hexanes/EtOAc to give 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 65.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:19]=2[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:26]([O:28][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:27][C:19]=2[CH2:18]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)CC1CCCc2ccc(O)cc2C1
Product: CCOC(=O)CC1CCCc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalene-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)(C(OCC)=O)C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:7]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Cc2ccccc2)nc1
Yield: 70.5 %

Procedure:
1.5 g of diethyl 2-phenyl-2-(5-nitropyridin-2-yl)malonate was dissolved in 50 ml of ethanol. After adding 10 ml of water and 10 ml of conc. sulfuric acid, the mixture was heated under reflux for 8 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n- hexane) to thereby give 632 mg of the title compound as reddish brown crystals.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Agent: Cl
Product: FC(F)CNCc1ccccc1
Yield: 41.1 %

Procedure:
An amount of 5 g (49.7 mmol) of 2,2-difluoro-1-chloroethane and 11.3 g (105 mmol) of benzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 50 ml of water and 50 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 3.5 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 41%, based on 2,2-difluoro-1-chloroethane used.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:25][CH:26]([C:31]([OH:33])=[O:32])[CH2:27][C:28]([OH:30])=O>>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:25][CH:26]([C:31]([O:33][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:32])[CH2:27][C:28]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:30]
Reactant: O=C(O)CC(CSc1nc2ccccc2s1)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cl
Product: CCCCCCCCCCCCOC(=O)CC(CSc1nc2ccccc2s1)C(=O)OCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
125 parts of dodecan-1-ol are saturated with dry hydrogen chloride gas at room temperature. 13.5 parts of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic acid are then added and the mixture heated to 85°. The resulting solution is stirred for 4 hours at 85°. Excess dodecan-1-ol is removed by heating at 90° under a vacuum of 0.01 mm Hg to give di-dodecyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[H-].[Na+].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20].O>CN(C)C=O>[S:19](=[O:22])(=[O:21])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:20]
Reactant: NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
108 mg of 2′-nitrobiphenyl-4-ol was dissolved in 1.5 ml of N,N-dimethyformamide, and a suspension of 120 mg of sodium hydride in 1.5 ml of N,N-dimethyformamide was added thereto under cooling with ice, followed by stirring for 10 minutes under cooling with ice. 367 mg of sulfamoyl chloride was added to this mixture, followed by stirring at room temperature for 3 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium. sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 106 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]1([C:20]2[C:28]([CH:29]=O)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:20]2[C:28]([CH:29]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 60 °C
Yield: 53.5 %

Procedure:
A solution of trimethyl phosphonoacetate (4.0 g) in toluene (10 ml) was added to a mixture of sodium hydride (63%, 880 mg) in toluene (45 ml) with stirring and cooling and then heated at 60° C. for 20 minutes. To the mixture 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g) was added and heated at 60° C for 8 hours. A saturated sodium bicarbonate solution (30 ml}was added to the reaction mixture and extracted with ethyl acetate (30 ml, 2 times). The extract was washed with brine (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isopropyl alcohol to give crystals of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (1.34 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[O:26]=[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]1[CH2:42][C:43]#[N:44].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:43]([CH2:42][N:28]1[C:27](=[O:26])[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:4][C:3]=2[CH3:25])=[CH:29]1)#[N:44]
Reactant: CC1(C)OB(c2ccc(=O)n(CC#N)c2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC#N)c1
Temperature: 80 °C
Yield: 6.1 %

Procedure:
N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (325.2 mg, 0.89 mmol), 2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetonitrile (0.300 g, 1.15 mmol), tetrakis(triphenylphosphine)palladium (0) (51 mg, 0.044 mmol) and potassium carbonate (1.71 g, 1.11 mL of 2 M, 2.21 mmol) were combined in a scintillation vial containing 1,2-dimethoxyethane (8 mL). The reaction mixture was then stirred and heated to 80° C. overnight. The crude reaction mixture was purified by reverse-phase preparative liquid chromatography to yield the product (25.3 mg, 6.1%) as a trifluoracetic acid salt. ESI-MS m/z calc. 464.1. found 465.1 (M+1)+. Retention time 2.00 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:47])[C:45]=1[OH:46])[CH2:5][CH:6]([CH:16]=[CH:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:47])[C:45]=1[OH:46])[CH2:5][CH:6]([CH:16]=[CH:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCCCC(C=Cc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCC(C=Cc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Cc1cc(F)c(O)c(F)c1

Procedure:
400 mg (0.61 mmol) of ethyl 6-(3,5-difluoro-4-hydroxybenzyl)-8-[5-fluoro-2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)phenyl]oct-7-enoate are stirred overnight at 50° C. with 73 mg (1.83 mmol) of sodium hydroxide in a mixture of 20 ml of THF and 10 ml of water. The cooled mixture is acidified with dilute hydrochloric acid and extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate and concentrated. 333 mg (86% of theory) of the title compound are obtained as E/Z mixture (2:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:49]2[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (150 mg, 0.49 mmol), HATU (282 mg, 0.74 mmol), 4-methylpiperazine (59 mg, 0.59 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (2 mL). MS (LC-MS): 386.0 [M]+; tR (HPLC conditions c): 3.77 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH2:10][CH2:11][NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8])#[N:12].[C:2](#[N:1])[CH:3]=[CH2:4]
Reactant: NC1CCCCC1N
Solvent: C=CC#N
Product: N#CCCNC1CCCCC1N

Procedure:
1,2-Diaminocyclohexane (1) is cyanoethylated with acrylonitrile in the presence of an acid catalyst (Equation 1). With one mole ##STR7## of acrylonitrile the monocyanoethylated product, N-(2-cyanoethyl)-1,2-diaminocyclohexane, (2) is formed, whereas two moles of acrylonitrile react to give the dicyanoethylated product, N,N'-di-(2-cyanoethyl)-1,2-diaminocyclohexane, (3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]([F:26])([F:25])[F:24])[CH:20]([CH2:27][OH:28])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.CCOCC>[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]([F:26])([F:24])[F:25])[CH:20]([CH:27]=[O:28])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCC1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
To a solution of 0.98 mL (11.2 mmol) of oxalyl chloride in 30 mL of CH2Cl2 at −78° C. was added 1.6 mL (22.4 mmol) of DMSO and the reaction mixture was stirred for 10 min. To this reaction mixture at −78° C. was added a solution of 1.46 g (5.6 mmol) of 1-benzyl-3-(RS)-hydroxymethyl-4-(RS)-trifluoromethylpyrrolidine in 10 mL of CH2Cl2. After stirring for 10 min. at −78° C., 3.9 mL (28 mmol) of Et3N was added and the reaction was allowed to warm to rt. The reaction mixture was poured into ether and extracted twice with sat'd NaHCO3 solution and once with sat'd NaCl solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 1.46 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a mixture of (5-chloro-pyridine-2-yl)-methanol (706 mg, 4.92 mmol) described in Manufacturing Example 63-1-1 and dichloromethane (70 mL) was added thionyl chloride (539 μL, 7.38 mmol), which was stirred for 1 hour at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (620.0 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[CH3:37]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.N#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH2:20][CH2:21][CH2:22]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 41.4 %

Procedure:
tert-Butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (50.3 mg, 0.1 mmol) was dissolved in 1,4-dioxane (5 mL). Methyl boronic acid (8.98 mg, 0.15 mmol) and potassium carbonate (41.5 mg, 0.3 mmol) were added. The solution was degassed, flushing with nitrogen tetrakis (11.56 mg, 0.01 mmol) was added and the solution was refluxed for 24 h. The reaction mixture was filtered, washed with ethyl acetate and evaporated. The crude product was purified by column chromatography using hex and ethyl acetate (0-65%) to give the title compound (20 mg, 42%). LCMS (Method I): RT=7.40 min, [M+H]+=483.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2.[CH3:14][CH:15](O)[CH:16]=[CH2:17].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: COc1cccc2c1C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CCc2cccc(OC)c2C1=O
Yield: 22 %

Procedure:
13.7 g of 8-methoxy-1-tetralone were dissolved in 140 ml of toluene under argon and added to 13.3 ml of 3-buten-2-ol, 14.2 ml of 2,2-dimethoxypropane and 300 mg of p-toluenesulfonic acid. The reaction solution was heated to reflux for 90 hours. The solvent was removed in a vacuum and the residue was chromatographed on 500 g of silica gel firstly with hexane/ethyl acetate 9:1, then with hexane/ethyl acetate 4:1 and finally with hexane/ethyl acetate 1:1. In addition to large amounts of unreacted educt (8.3 g) there were obtained 3.95 g (22%) of 2-(2-buten-1-yl)-8-methoxy-1-tetralone as a yellow oil.