Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([OH:17])[CH:9]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>COCCOC.O.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>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:30])=[O:31])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:10]([OH:17])[CH:9]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)cc1O
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Temperature: 125 °C
Yield: 92.4 %

Procedure:
A vial containing a suspension of Cs2CO3 (0.292 g, 0.897 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (0.045 g, 0.292 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.1 g, 0.224 mmol) in DME (2.5 ml) and water (0.375 ml) was degassed with nitrogen and tetrakis(triphenylphosphine)palladium (0.026 g, 0.022 mmol) was added. The vial was sealed and heated under microwave irradiation at 125° C. for 30 min. The aqueous layer was discarded using a pipette and the organic layer was concentrated and purified by silica gel chromatography (25 g column, eluting with Hex:EtOAc (0 to 50%)). Pure fractions were combined and concentrated to obtain 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.108 g, 0.207 mmol, 92% yield) as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J4) (303 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (252 mg, 1.1 mmol) according to the general procedure M. Obtained as an off-white solid (257 mg).
Reaction SMILES: [C:1]1([S:7][CH2:8][F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:15])C1>O>[C:1]1([S:7]([CH2:8][F:9])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FCSc1ccccc1
Solvent: CO
Solvent: O
Product: O=S(CF)c1ccccc1
Yield: 89.5 %

Procedure:
Fluoromethyl phenyl sulphide (85 g, 351.63 mmol) was added to a mixture of methanol (250 ml) and water (50 mL) The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (75.10 g, 1.2 eq) was added in small portions maintaining the same temperature range. The reaction mixture was stirred until the reaction was complete, and then, was quenched with Na2SO3 solution (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8 with NaHCO3 saturated solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 300 mL). The combined organic layer was washed with water (2×300 mL) and concentrated to 1/3 of the volume. Heptane (50 mL) was added and the resulting mixture was concentrated again. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 49.8 g (89.6%) of the desired product as colourless oil at rt, which is a white solid at −20° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[CH:1]1([C:7]2[CH:12]=[C:11]([CH2:27][CH2:26][C:25]([O:29][CH3:30])=[O:28])[CH:10]=[C:9]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:8]=2[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1c(C2CCCCC2)cccc1C1CCCCC1
Reactant: C=CC(=O)OC
Agent: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1

Procedure:
The yield of crude product is 1217 g. The crude product contains 800 g of product, 120 g of 2,6-dicyclohexylphenol, 27 g of potassium acetate and also oligomerised methyl acrylate.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:27])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[N:21]=3)[CH:18]=2)=[C:9]([C:28](O)=[O:29])[CH:8]=[N:7]1>>[N:1]1([C:28]([C:9]2[CH:8]=[N:7][N:6]([CH3:5])[C:10]=2[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[N:21]=3)[CH:18]=2)=[O:27])=[O:29])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cscn3)nn2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccc2nc(-c3cscn3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light brown solid (25 mg, 18%). MS: m/z=409.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:4].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.CCOC(C)=O>[O:21]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)COc2ccccc2)c(OC)c1
Yield: 84.6 %

Procedure:
A solution of 2-bromo-2′,4′-dimethoxyacetophenone (5 g, 19.1 mmols) in 25 mL of 2-butanone was added to a suspension of phenol (1.8 g, 19.1 mmols), K2CO3 (2.6 g, 19.1 mmols) and KI (41.5 mg, 0.25 mmols) in 20.0 mL of the same solvent. The solution was then refluxed for 20 hours. The mixture was filtered and the solvent was evaporated off under vacuum. The residue obtained was dissolved in EtOAc and washed with a 10% aqueous solution of NaOH and then with water. The organic extract was dried over Na2SO4, filtered and evaporated under vacuum. Finally, the crude residue was washed with Et2O and dried under low pressure to provide 4.4 g (yield: 84%) of the title compound.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=O>O1CCCC1.CCCCCC>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCCCCCCCBr
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCCCCCCCCCCBr
Temperature: -40 °C

Procedure:
Isopropyltriphenylphosphonium iodide (6 g, 14 mmoles) was suspended in tetrahydrofuran (120 ml), stirred at -40° C. and treated with n-butyllithium (14 mmoles) dissolved in hexane (2.5M). The mixture was stirred at -40° C. for 15 minutes, cooled to -75° C. and treated with a solution of 1-bromo-11-oxoundecane (2.8 g, 11.5 mmoles) in tetrahydrofuran (30 ml). The mixture was stirred at -75° C. for 15 minutes, allowed to warm to 25° C. and concentrated in vacuo. The residue was triturated with hexane, filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluted with hexane to afford 1-bromo-12-methyl-11-tridecene.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (0.55 mmol) and cyclohexyl isocyanate (0.55 mmol) using the procedure described for compound (10) (146 mg, 59%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCc1ccccc1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 28.9 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 5 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 4.8 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 1.2 g of the subject compound as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O>[NH:8]([C:6]1[CH:7]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH2:15][CH2:16]2)[N:3]=[CH:4][N:5]=1)[NH2:9]
Reactant: COCCN1CCNCC1
Reactant: NNc1cc(Cl)ncn1
Solvent: O
Product: COCCN1CCN(c2cc(NN)ncn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g (6.9 mmol) of the compound from Example 7A and 1.1 g (7.6 mmol) 1-(2-methoxyethyl)piperazine in 10 ml water is stirred at 100° C. for 2 h. A further 0.9 g (6.2 mmol) 1-(2-methoxyethyl)piperazine is added and the reaction mixture is stirred further at 100° C. for 16 h. After concentration in vacuo, the residue is stirred in acetonitrile. The solid which has precipitated out is filtered off, washed first with ethanol and then with diethyl ether and dried in vacuo.
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[NH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH:11]=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:15]([NH:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH:13]=1)=[O:24]
Reactant: CC(C)N=C=O
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)NC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 2-isocyanatopropane (0.050 g, 0.59 mmol), N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (0.047 g, 0.17 mmol) and diisopropylethylamine (50 mg, 0.39 mmol) in 1,2-dichloroethane (3.0 mL) was stirred at 60° C. for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product as a white solid (0.025 g, yield: 41%). 1H NMR (DMSO-d6, 500 MHz): δ 8.02 (d, J=5.5 Hz, 1H). 7.51 (s, 1H), 7.40-7.34 (m, 3H), 7.05 (m, 1H), 3.87 (m, 1H), 1.14 (t, J=6.5 Hz, 6H). LCMS (ESI) m/z: 367.1 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[C:1]1([C:7]2[CH:12]=[C:11]([B:25]([OH:26])[OH:24])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1-c1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a mixture of 2-phenyl-4-bromoanisole (26.00 g, 0.0988 mol) in THF (240 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (68 mL, 1.6 M, 0.109 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was warmed to 0° C. over 1 hour and 1.0 N HCl (190 mL) was slowly added and allowed to warm to RT overnight. The mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting reddish residue solidified overnight. The solid was collected and washed with hexane and dried under high vacuum to afford 17.29 g of 3-phenyl-4-methoxyphenyl boronic acid (77%). 1H NMR (300 MHz; DMSO-d6): δ 3.78 (s, 3H), 7.07 (d, J=8.1 Hz, 1H), 7.28–7.50 (m, 5H), 7.72–7.80 (m, 2H), 7.92 (brs, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:8]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[CH2:35]Br>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][C:28]3[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:8]1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccco1
Product: COc1ccc(C(=O)O)c(CN2CCC(c3cn(Cc4ccco4)c4ccc(OC)cc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.17 mmol) of 1-furan-2-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole and 0.057 g (0.22 mmol) of 2-bromomethyl-4-methoxy-benzoic acid methyl ester. After standard work-up and purification by chromatography using a C18 column, 0.029 g (36% of yield) of the expected acid were obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[CH:15][CH:14]=2)=[C:7]([NH2:23])[CH:6]=1)(=O)C.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](Cl)=O>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:29][NH:23][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][C:8]=1[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(C=Cc2ccc(OC(C)=O)cc2N)cc1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Product: Oc1ccc(C=Cc2ccc(O)cc2NCc2ccc(OCCN3CCCCC3)c(F)c2)cc1
Yield: 20 %

Procedure:
Synthesized from acetic acid 4-[2-(4-acetoxy-2-aminophenyl)vinyl]phenyl ester (300 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (370 mg) according to an analogous synthetic method to Example 152, the title compound (89 mg) was obtained.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C>[F:14][C:9]1[CH:8]=[C:7]([B:15]([OH:18])[OH:16])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: OB(O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
91.5 ml of tert-butyllithium are added at −78° C. to 20 g of 1-bromo-3,5-difluorobenzene in 300 ml of diethyl ether. The reaction mixture is stirred for 1 hour at −78° C. and 14.2 ml of trimethyl borate are then added. The reaction mixture is stirred for 1 hour at −78° C. and then for 12 hours at room temperature. 200 ml of aqueous 1 N hydrochloric acid solution are added. The resulting mixture is extracted with diethyl ether, the organic phase is washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. The residue is taken up in cyclohexane and the precipitate obtained is isolated by filtration.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]([CH2:9][C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cccnc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: OCCN(Cc1ccccc1)Cc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of the compound (11.8 g) obtained in step 1 in THF (30 mL) was added 1M BH3.THF complex/THF solution (134 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (20 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 6N hydrochloric acid (43 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give 2-{benzyl[(2-chloropyridin-3-yl)methyl]amino}ethanol (6.92 g, 86%) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([CH2:18][C:19]#[N:20])[CH2:17][CH2:16]1>C1COCC1>[C:19]([C:18]([CH:15]1[CH2:17][CH2:16]1)=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)#[N:20]
Reactant: N#CCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) and cyclopropylacetonitrile (0.97 g, 12 mmol) were dissolved in THF (20 mL), heated to reflux, and allowed to stir for 3 hours. The mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was purified by MPLC on silica gel to afford the title compound as a white solid. LRMS (ESI) calc'd for C15H23N2O2 [M+H]+ 263. Found 263.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9]1)=O)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].Cl>CO>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:33][C:31]([F:32])([F:34])[C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1)[O:20][CH2:19][C@H:10]1[C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(OC[C@@H]2CNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
The mixture of trans-tert-butyl-3-((3,5-bis(trifluoromethyl)phenoxy)methyl)-4-phenylpyrrolidine-1-carboxylate as trifluoroacetic acid salt (31 mg) and HCl (1.0 M diethyl ether solution, 0.5 mL) in methanol (0.2 mL) was stirred at room temperature over night. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to yield a white solid as the title compound (18 mg, 90% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][CH:18]=[CH:19]2)(=[O:5])=[O:4]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][CH2:17][C:18](OC)=[O:19].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:15][CH2:16][CH2:17][C:18]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:19]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.62 g (3.5 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (16 mL). After addition of 1.0 g (3.5 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[NH4+:9].[OH-].[Na+]>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:8])=[O:5].[NH4+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following the examples of U.S. Pat. No. 4,839,461, a slurry of 9.8 g (0.1 mole) maleic anhydride was dissolved in 20 ml water at 80°-95° C. and stirred for 30 minutes while allowing the mixture to cool to 25° C. To this colorless solution at 25° C. was added 13 g of 30% aqueous solution of ammonium hydroxide (0.11 mol NH3) to give a colorless solution. This solution was boiled to dryness over a period of 30 minutes at approximately 100°-115° C. to give a white crystalline solid. The solid was tumbled under nitrogen at 100 Torr, at 145°-150° C. for 4 hours to give a water insoluble, pinkish-tan brittle glasslike solid weighing 11.4 g. This solid was dissolved in 26.2 g of an aqueous solution containing 1.36 g of sodium hydroxide to form a clear red-brown solution, pH 7.0, containing 25% solids.