Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: Cc1cccc(CN)c1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-methylbenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 52 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[C:5](C)[N:6]=1.[CH3:18][O:19][CH2:20][CH2:21][Br:22]>>[BrH:22].[F:12][C:9]([F:10])([F:11])[C:8]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:21][CH2:20][O:19][CH3:18])[CH:5]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: COCCBr
Reactant: Cc1nc(N)sc1C(O)(C(F)(F)F)C(F)(F)F
Product: Br
Product: COCCn1cc(C(O)(C(F)(F)F)C(F)(F)F)sc1=N

Procedure:
A mixture of Example 186A and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 325 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH:23]=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:25](OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH:23]=[CH2:25]
Reactant: O=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5.19 g of methyl-triphenylphosphonium bromide in 80 ml of diethyl ether was treated with 1.55 g of potassium tert.butylate while gassing with nitrogen. The yellow suspension was stirred at room temperature for a further 45 minutes and then treated dropwise at 0° C. with a solution of 2.3 g of 4-[trans-4-[trans-4-(4-fluorophenyl)cyclohexyl]cyclohexyl]butyraldehyde. The reaction mixture was stirred at 0° C. for a further 2 hours and then diluted with 60 ml of water. The aqueous phase was separated and extracted twice with 60 ml of hexane each time. The combined organic phases were washed neutral with water, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane gave 1.89 g of crude product. After two-fold recrystallization from acetone at -20° C. there were obtained 1.22 g of 1-[trans-4-[trans-4-(4-pentenyl)-cyclohexyl]cyclohexyl]-4-fluorobenzene with m.p. (C-N) 65.7° C. and cl.p. (N-I) 129.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:14])[C:3]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)ccnc1CO
Solvent: ClCCl
Product: COc1c(Cl)ccnc1CCl
Product: [Cl-]

Procedure:
4-Chloro-2-hydroxymethyl-3-methoxypyridine (41.0 g) was dissolved in methylene chloride (150 mL), and thionyl chloride was added dropwise over 10 minutes with stirring under cooling with an ice bath. The ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure, and hexane (50 mL) was added to the residue, followed by distillation, whereby 4-chloro-2-chloromethyl-3-methoxypyridine chloride was obtained as a brown solid (54.1 g, yield: quantitative).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, white solid (22 mg, 74.9%), MS (ISP) m/z=469.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (24 mg, 0.0595 mmol) and 4-chlorobenzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23]Cl)[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C)C=O>[CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/CCl)c1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/Cn2ccnc2)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
50 mg of (E,E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-(4-chloro-2-butenyloxy)benzylamine was dissolved in 0.5 ml of dimethylformamide, and 30 mg of imidazole was added. The mixture was heated at 80° C. for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to extract it. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [ethyl acetate→ethyl acetate/methanol=10/1] to give 27 mg (yield 53 %) of the captioned compound as a pale yellow oil.
Reaction SMILES: Cl.[F:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([CH2:10][CH2:11][OH:12])[CH2:5]1
Reactant: FC[C@@H]1CCNC1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC[C@@H](CF)C1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
A mixture of (R)-3-(fluoromethyl)pyrrolidine hydrochloride (Intermediate 8, 4.26 g, 30.6 mmol), 2-bromoethanol (4.35 mL, 61.3 mmol), and potassium carbonate (12.7 g, 92 mmol) in acetonitrile (120 mL) was heated at 80° C. overnight. After cooling, solids were filtered off and washed with acetonitrile. The filtrate was concentrated on a rotary evaporator to give a residue that was purified by silica gel chromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine to afford 2.9 g of (R)-2-(3-(fluoromethyl)pyrrolidin-1-yl)ethanol as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 4.44 (t, 1H), 4.34 (dd, 1H), 4.22 (dd, 1H), 3.44 (q, 2H), 2.58-2.51 (m, 1H), 2.48-2.38 (m, 5H), 2.32-2.28 (m, 1H), 1.85-1.74 (m, 1H), 1.39-1.31 (m, 1H).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.C(N(CC)CC)C.CN1CCCC1=O>>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (5 mg, 0.00002 mol), 2-chloro-5-(trifluoromethyl)pyridine (6 mg, 0.00003 mol), and triethylamine (20 μL, 0.0001 mol) in N-methylpyrrolidinone (800 μL, 0.008 mol) was microwave irradiated at 180° C. for 10 min. After cooling, it was purified by prep.-HPLC to afford 1.7 mg of the desired product. LC-MS: 398.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[CH:7][N:6]=[C:5]([F:10])[C:4]=1[F:11].[Cl:12][C:13]([C:23]([F:26])([F:25])[F:24])=[CH:14][C@@H:15]1[C@H:17]([C:18](Cl)=[O:19])[C:16]1([CH3:22])[CH3:21]>>[Cl:12][C:13]([C:23]([F:24])([F:25])[F:26])=[CH:14][C@@H:15]1[C@H:17]([C:18]([O:1][CH2:2][C:3]2[C:8]([F:9])=[CH:7][N:6]=[C:5]([F:10])[C:4]=2[F:11])=[O:19])[C:16]1([CH3:22])[CH3:21]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1c(F)cnc(F)c1F
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cnc(F)c1F
Yield: 45.1 %

Procedure:
By the method of Example 2, 0.3 g (0.002 mole) of 4-hydroxymethyl-2,3,5-trifluoropyridine (from Example 9) was reacted with 0.5 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce 0.35 g of (2,3,5-trifluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as a clear, yellow oil, Compound 15 of the tables below.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])#[N:20]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting material and isolated (570 mg, 77%) as a yellow oil; MS (ESI, m/z): 444.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34]>>[ClH:29].[ClH:29].[CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:16][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]1[CH2:30][CH2:31][NH:32][C:33]1=[O:34]
Reactant: COc1c(N)cccc1CCN1CCN(c2cccc3nc(C)ccc23)CC1
Reactant: O=C=NCCCl
Product: COc1c(CCN2CCN(c3cccc4nc(C)ccc34)CC2)cccc1N1CCNC1=O
Product: Cl
Yield: 38 %

Procedure:
The title compound was prepared in 38% yield according to the general procedure for the synthesis of cyclic ureas and carbamates (Method G) starting from 2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and 1-chloro-2-isocyanatoethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.F[C:49](F)(F)S([O-])(=O)=O.[C:56](=[O:59])(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:23]([O:22][C:20](=[O:21])[O:19][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@@H:18]([O:59][CH2:56][CH3:49])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:11]=2[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCC1(CC)c2cc(OC(=O)OC(C)(C)C)ccc2CC2C1N2C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Yb+3]
Solvent: ClC(Cl)Cl
Product: CCO[C@@H]1Cc2ccc(OC(=O)OC(C)(C)C)cc2C(CC)(CC)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-tert-Butoxycarbonyloxy-7,7-diethyl-1a,2,7,7a-tetrahydro 1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (346.0 mg; 0.83 mmol) placed under Nitrogen was dissolved using anhydrous chloroform (15.0 mL) followed by 0.5 equivalents of Ytterbium trifluoromethanesulfonate (257.0 mg; 0.42 mmol) were then added. The reaction mixture was allowed to stir at room temperature overnight. The next day, it was poured into an aqueous solution of sodium bicarbonate and extracted using dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was removed by vacuo. The crude was purified by flash chromatography using; hexanes:ethyl acetate (9:1) then (8:2) as the eluent. The isolated product is a solid (275 mg, 71%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1.[CH3:14]O>CCOC(C)=O>[CH3:14][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)s1
Yield: 97 %

Procedure:
Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5-methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0° C. and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:23](COC)OC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[CH3:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>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>[CH3:23][C:43]1[CH:42]=[CH:41][CH:46]=[CH:45][C:44]=1[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: COCCOC
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: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.17 g, 3.2 mmol), Pd(PPh3)4 (0.39 g, 0.34 mmol), and dimethoxyethane (25 mL) were stirred at room temperature for 10 minutes then treated with 2-methylboronic acid (0.52 g, 3.8 mmol) and a 2 M solution of Na2CO3 (12 mL). The reaction was heated to reflux for 15.25 hours then cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown oil which was passed through a column of silica gel with 1:5 ethyl acetate/hexane to give 0.53 g (44%) of a brown oil as the title compound.
Reaction SMILES: C([C:3]1(CC)[C:7](=[O:8])[O:6][N:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:10])[C:4]1=[O:17])C.C(Cl)Cl.CCCCCC.O1C(=O)CC(=O)N1>C(Cl)(Cl)Cl.CCCCCC>[C:11]1([C:9]([N:5]2[C:4](=[O:17])[CH2:3][C:7](=[O:8])[O:6]2)=[CH2:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(c1ccccc1)N1OC(=O)C(CC)(CC)C1=O
Agent: O=C1CC(=O)ON1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: C=C(c1ccccc1)N1OC(=O)CC1=O

Procedure:
Analysis of crude 4,4-diethyl-2-(1phenylethenyl) isoxazolidine 3,5-dione was performed by thin layer chromatography (TLC) on Bakerflex Silica Plates using methylene chloride:-hexane (98:2) as the mobile phase. Components appeared at Rf 0.80, 0.78, 0.72, 0.60, 0.52, and 0.0. A sample of the crude isoxazolidine-3,5-dione weighing 3.50 g (38.4% purity by HPLC) was dissolved in 5.0 ml of chloroform:hexane (98:2), and applied to a 37×2 cm (O. D.) chromatography column containing 60-200 mesh silica gel as the adsorbant. The eluting solvent was chloroform:hexane (98:2) and the elution rate was 1 ml/min. Twenty 50 ml fractions were collected and analyzed by TLC as described above Fractions 11, 12, 13 and 14 showed a single component, Rf 0.60. These fractions were combined and concentrated to give 1.0 g of pure 4,4-diethyl-2-(1-phenylethenyl-isoxazolidine-3,5-dione as a viscous oil: IR(neat) 2976(w), 2938(w), 2882(w), 1816(s), 1721(s) and 1626 (s)cm-1 ; UV max (CH3OH) 245 nm (ε6800); 1H NMR (CDCl3) δ 7.72 (s, overlapping a small m, 5, aromatic CH) 5.47 (s, 1, vinyl CH), 5.34 (s, 1, vinyl CH), 1.83 (q, 4, CH2) and 0.91 (t, 6, CH3); high resolution MS, calc'd for: C15H17NO3 : 259.1208. Found: 259.1209; MS m/z (rel. intensity) 259 (44), 215 (48), 199 (85), 108 (89) and 106 (100). Elemental Analysis: Calc'd for: C15H17NO3 :C, 69.48; H, 6.61; N, 5.40.Found: C,69,64; H, 6.91; N, 5.04
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>[Zn]>[OH:9][C:7]([CH3:8])([CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)CC(CCc1ccccc1)OC(C)=O
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2-one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrochloric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>O1CCCC1>[CH2:11]1[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[CH:30]=[CH:29][C:27]([NH:26][C:24]=3[CH:25]=2)=[O:28])[CH2:13][CH2:14][N:9]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=2[Cl:8])[CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Temperature: 25 °C
Yield: 102.3 %

Procedure:
Aripiprazole (Formula VIA; 15 g, 0.03 mol) was dissolved in anhydrous tetrahydrofuran (360 mL). Trifluoroacetic acid (12 mL, 0.16 mol) was added to the clear solution. 1,2-Dichloro-4,5-dicyano quinone (24.3 g, 0.11 mol) was added and the mixture was stirred at room temperature under nitrogen atmosphere. The reaction was stirred for 40 minutes and TLC showed no starting material remaining Water (1.5 L) was added then reaction mixture basified with 50% aq NaOH until pH 12. The reaction mixture was extracted with dichloromethane (3×1 L) and the combined organics were dried (MgSO4) to give the crude product. This was purified by column chromatography on silica eluting with dichloromethane to 10% methanol/dichloromethane. The product was further purified by recrystallisation from 2-propanol to give the desired product (13.7 g, 92%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 12.33 (1H, br s), 7.72 (1H, d), 7.42 (1H, d), 7.16-7.11 (2H, m), 6.98-6.93 (1H, dd), 6.83-6.79 (2H, m), 6.53 (1H, d), 4.10 (2H, t), 3.09 (4H, br s), 2.67 (4H, br s), 2.52 (2H, t), 1.93-1.70 (4H, m). LCMS (acidic method) [M+H]+ 446.02, rt 14.246 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, yellow solid (39 mg, 35%), MS (ISP) m/z=455.4 [(M+H)+], mp 179° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.