Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([F:11])[CH:13]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: COc1cc(F)cc(B(O)O)c1
Product: COc1cc(F)cc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 59.8 %

Procedure:
The title compound (71 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-fluoro-5-methoxyphenylboronic acid (97 mg, 0.57 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51-7.45 (m, 2H), 7.05 (d, J 10.3, 1H), 7.00 (s, 1H), 6.73 (dd, J 2.1, 4.2, 1H), 5.60 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH2:45])([CH3:44])[CH3:43])[N:35]=2)[CH:30]=[C:31]([F:33])[CH:32]=1>>[F:33][C:31]1[CH:30]=[C:29]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH:45][CH2:20][CH:19]([C:16]3[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=3)[OH:25])([CH3:43])[CH3:44])[N:35]=2)[CH:28]=[C:27]([F:26])[CH:32]=1
Reactant: Cc1nc(-c2cc(F)cc(F)c2)nn1CCC(C)(C)N
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Product: Cc1nc(-c2cc(F)cc(F)c2)nn1CCC(C)(C)NCC(O)c1ccc(O)c(CO)c1

Procedure:
The compound is obtained according to general working method A from 121 mg (0.35 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 98 mg (0.35 mmol) of 3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine. Yield: 9 mg (6%); mass spectroscopy [M+H]+=447.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1.23 ml (6.22 mmol) of ethyl diethylphosphonoacetate were added dropwise, whilst ice-cooling, over a period of 3 minutes to a suspension of 271 mg (6.22 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 30 minutes. A solution of 1.37 g (3.11 mmol) of N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24), in 6 ml of dimethylformamide was ice-cooled and then added dropwise to the mixture over a period of 3 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. A solution of the residue in 20 ml of ethanol was stirred at room temperature for 8 hours in an atmosphere of hydrogen and in the presence of 400 mg of 10% palladiun-on-charcoal. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.56 g (yield 98%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24].[OH-].[Na+]>CN(C)C=O>[C:11]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: N#CCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCCCCCCC#N)cc(C(C)(C)C)c1
Temperature: 120 °C

Procedure:
A mixture containing 20.6 g (0.10 mole) of 3,5-di-t-butylphenol, 20.9 g (0.11 mole) of 7-bromoheptanenitrile, 4.0 g (0.10 mole) of sodium hydroxide and 250 ml of dimethylformamide was heated at 120° C. for about forty hours. The solvent was evaporated and the residue was added to 250 ml of water. The resulting oil was separated and dissolved in 250 ml of diethyl ether. The ether solution was washed twice with 250 ml portions of 10% sodium hydroxide, washed once with 250 ml water, dried over magnesium sulfate, and evaporated to give an oil which solidified on standing. The solid was recrystallized twice from methanol. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[CH:16]2.[BH4-].[Na+]>CO.O>[CH3:23][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]1=[O:24]
Reactant: Cn1c(=O)ccc2cc(OCCN)ccc21
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCNCc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
3-Pyridine carbaldehyde(0.99 ml) and 6-(2-Aminoethoxy)-1-methyl-1H-quinolin-2-one(2.18 g) were added to methanol (50 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride(0.757 g) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound(3.063 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:10]([C:11]3[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:21][N:22](C)C=O>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[CH:4]=[N:3][C:2]([C:21]#[N:22])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3c(Br)ncn23)c1
Reactant: CN(C)C=O
Product: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 1.0 g. of 8-bromo-4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine, 0.45 g. of cuprous cyanide and 25 ml. of N,N-dimethylformamide is refluxed for 16 hours. The solvent is removed under reduced pressure. The residue is extracted with methylene chloride and the solution passed through a column of hydrous magnesium silicate. The eluent is collected, concentrated and n-hexane added while heating. The product separates as crystals, m.p. 168°-169° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>C(Cl)Cl.Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)c1cncc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cncc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
The product from Example 15B (950 mg, 5.37 mmol) was dissolved in CH2Cl2 (20 mL). Triethylamine (1.10 mL, 7.89 mmol) and m-toluidine (0.70 mL, 6.46 mmol) were added, and the reaction stirred at ambient temperature for 2 h. The reaction mixture was diluted with 0.1M HCl (100 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (2.5% EtOAc in CH2Cl2, Rf=0.39) to afford the title compound as a white solid (1.11 g, 83%). MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[CH:35][CH:34]=2)=[O:31])=[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:14]=1>C(O)C>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[CH:35][CH:34]=2)=[O:31])=[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:14]=1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCC3CCCCN3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 198 %

Procedure:
4 M hydrogen chloride/ethyl acetate solution (5 mL) was added to an ethanol (5 mL) solution of tert-butyl 2-{[(5-chloro-2-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]carbonyl}phenyl)amino]methyl}piperidin-1-carboxylate (540 mg), followed by stirring at room temperature for 2 hours. By collecting the resulting precipitate by filtration, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-[(piperidin-2-ylmethyl)amino]benzamide hydrochloride (470 mg) was obtained as a solid.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[O:13])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 3.0 mL of ethanol were added to the obtained methyl 2-(4-methoxybenzamido)-4-phenylbenzoate and stirred at 40° C. for 2 hours. After the reaction mixture was cooled to room temperature, 8.0 mL of 0.38 mol/L hydrochloric acid and 10 mL of ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 55-100% acetonitrile /0.1% trifluoroacetic acid aqueous solution] to obtain 6.1 mg of 2-(4-methoxybenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(#N)C>[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: NCCN
Solvent: CC#N
Product: Cc1cc(NCCN)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-methyl-5-nitropyridine (2.0 g, 11.5 mmol) in acetonitrile (10 ml) was added dropwise to ethylenediamine (2.5 ml) in acetonitrile (10 ml). The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The aqueous layer was further extracted 4 times with dichloromethane. The combined organic layers were washed with a saturated sodium chloride solution, dried and concentrated in vacuo to give (2-aminoethyl)(4-methyl-5-nitro(2-pyridyl))amine as an orange solid (1.74 g).
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C@H:52]3[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:40][CH:39]=1)#[N:37]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:58][C@H:55]1[CH2:56][CH2:57][C@H:52]([C@H:49]2[CH2:50][CH2:51][C@H:46]([CH2:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=3)[CH2:47][CH2:48]2)[CH2:53][CH2:54]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=CCCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.1 g, 37.4 millimols) with THF (70 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.4 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(2-(4-cyanophenyl)ethyl)cyclohexyl)cyclohexanecarbaldehyde (11.0 g, 34.0 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate was made 500 ml, to obtain raw 4-(2-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)ethyl)benzonitrile (11.3 g).
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([N:14]3[CH2:21][CH2:20][C@:19]4([CH3:24])[C@@H:22]([CH3:23])[C@H:15]3[C:16](=[O:30])[C:17]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:18]=34)=[O:13])=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl>C(O)C>[N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([N:14]3[CH2:21][CH2:20][C@:19]4([CH3:24])[C@@H:22]([CH3:23])[C@H:15]3[CH:16]([OH:30])[C:17]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:18]=34)=[O:13])=[CH:11][C:6]=2[NH:5][CH:4]=1
Reactant: C[C@H]1[C@H]2C(=O)c3ccc(O)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1[C@H]2C(O)c3ccc(O)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (50 mg) is added to a solution of (2S,6R,11R)-3-(3H-benzoimidazole-5-carbonyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2H-2,6-methano-benzo[d]azocin-1-one (50 g) in ethanol (3 mL). The resulting mixture is stirred at ambient temperature overnight. Then, the solution is cooled in an ice bath and 1 M hydrochloric acid (0.5 mL) is added. After stirring for 5 min, the resulting mixture is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3).
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.[Na].O>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][CH:21]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=3)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCCCC(=O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C., 217 mg (1.15 mmol) of TiCl4 (1 M in CH2Cl2) were added to a solution of 500 mg (1.15 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-oxo-octanoate XIV and 190 mg (1.26 mmol) of methyl 4-aminobenzoate in 12.5 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min, and 383 mg (1.72 mmol) of sodium triacetoxyborhydride were then added. The progress of the reaction was monitored by thin-layer chromatography, and after the reaction had ended, water was added. The mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, gradient cyclohexane/ethyl acetate 10:1 to 0:100).
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH:15]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccsc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2ccsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-phenylsulfonylthiophene-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.[C:47](Cl)(Cl)([Cl:49])[Cl:48]>>[Cl:48][C:47]([Cl:49])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1ccc(C=C(Cl)Cl)cc1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
In 260 ml of carbon tetrachloride were dissolved 60 g of ethyl 2-(4-formylphenyl)propionate and 122 g of triphenylphosphine, followed by stirring in a stream of nitrogen gas at 50° C. for 4.5 hours. After cooling, the mixture was poured into 1 l of cold n-hexane and filtered. The filtrate was concentrated under reduced pressure to give an oily substance, which was subjected to silica gel column chromatography (eluent: n-hexane--ethyl acetate=40:1) to obtain 29 g of ethyl 2-[4-(2,2-dichlorovinyl)phenyl]propionate (ST-5) as an oily substance, b.p.0.2-0.3 128°-129° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:18]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1ccc(Br)nc1
Product: O=Cc1ccc(-c2cccc3ccccc23)nc1

Procedure:
Synthesized using compound 43c (720 mg, 3.87 mmol) and 1-naphthaleneboronic acid (1.00 g, 5.81 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. Orange solid. Yield: 733 mg, 81%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.50-7.62 (m, 3H), 7.65-7.69 (m, 1H), 7.77-7.81 (m, 1H), 7.92-8.00 (m, 2H), 8.10-8.14 (m, 1H), 8.31 (dd, J=7.9, 2.2 Hz, 1H), 9.25 (dd, J=2.2, 0.9 Hz, 1H), 10.22 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=125.1, 125.2, 125.4, 126.2, 127.0, 128.0, 128.5, 129.7, 130.0, 130.7, 134.0, 136.1, 137.2, 152.1, 164.6, 190.5; MS (ESI): m/z=234.29 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[O:21]1[CH2:20][CH:19]1[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: ClCC1CO1
Product: O=C(OCc1ccccc1)N1CCN(CC2CO2)CC1

Procedure:
By using 1-benzyloxycarbonylpiperazine (6 ml) and (±)-epichlorohydrin (2.4 ml) as starting materials, the title compound (7.80 g) was obtained in the same manner as that of Reference Example 33.
Reaction SMILES: [C:1]([C:6]1[CH:20]=[C:19]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([CH2:15][CH3:16])[C:10]([O:12]CC)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:20]=[C:19]([C:21]([CH2:24][CH3:25])([CH3:22])[CH3:23])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([CH2:15][CH3:16])[C:10]([OH:12])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)O
Reaction time: 6 h
Yield: 122.3 %

Procedure:
The above ethyl 2-(2,4-di-t-amylphenoxy)butyrate (317.9 g) and 27% aqueous sodium hydroxide (401.4 g) were placed in a 3-liter flask. The mixture was kept at 98° C. for 6 hours, and the hydrolysis reaction was completed. After completion of the reaction, the mixture was adjusted to pH 2 or lower by the addition of 40% aqueous sulfuric acid (349.9 g) and water (250 g), and toluene (317.9 g) was added thereto, followed by extraction. The water layer was separated with a separatory funnel, and the toluene layer was washed with water (317.9 g). Then, the toluene layer was concentrated by distillation under ordinary pressure for the removal of toluene, which afforded a concentrated solution (357.6 g) of the carboxylic acid compound in toluene. The analysis revealed that the concentrated solution contained the desired carboxylic acid compound in a yield of 99% on the basis of the raw material ester compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:43])[N:25]5[CH2:30][CH2:29][N:28]([C:31]6[CH:36]=[CH:35][C:34]([C:37]7[N:42]=[CH:41][CH:40]=[CH:39][N:38]=7)=[CH:33][CH:32]=6)[CH2:27][CH2:26]5)[CH2:19]4)=[O:17])[CH:13]=3)[N:8](COCC[Si](C)(C)C)[N:7]=2)=[N:4][N:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:4]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:43])[N:25]5[CH2:30][CH2:29][N:28]([C:31]6[CH:32]=[CH:33][C:34]([C:37]7[N:38]=[CH:39][CH:40]=[CH:41][N:42]=7)=[CH:35][CH:36]=6)[CH2:27][CH2:26]5)[CH2:19]4)=[O:17])[CH:13]=3)[NH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nnn[nH]2)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nnn[nH]3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a solution of 31 from Step 1 (31 mg, 0.054 mmol, 2 isomers) in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHCO3 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 13 mg of the product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].C[Si](Cl)(C)C.[CH2:15](O)[CH2:16][OH:17]>>[CH2:7]([C:6]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:17][CH2:16][CH2:15][O:9]1)[CH3:8]
Reactant: CCC(=O)c1cccs1
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Product: CCC1(c2cccs2)OCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30 g (214.3 mmol) of 1-2-thienyl-1-propanone are dissolved in 120 mL of ethylene glycol. 93 g (856 mmol) of trimethylsilyl chloride are then added. The reaction medium is stirred at room temperature for 24 hours. After treatment with water, the medium is extracted with ethyl acetate and the organic phases are then combined, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: 90 heptane/10 ethyl acetate). A yellow oil is obtained (m=15 g; Y=38%).