Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[C:17]=1[N:27]=[C:28]=[O:29]>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([Cl:26])[C:17]=1[N:27]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:28]1=[O:29]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 28.5 %

Procedure:
A 20 ml dimethylformamide solution of 2.7 g of ethyl 3-amino-4,4,4-trifluorocrotonate was added dropwise to a 20 ml dimethylformamide solution of 0.78 g of sodium hydride (purity: 55%) with stirring at 0° C. After heated to room temperature under stirring for 15 minutes, the mixed solution was cooled to -30° C. and then added dropwise with 20 ml of a dimethylformamide solution of 3.8 g of 2,6-dichloro-4-trifluoromethylphenyl isocyanate. The resulting solution was again heated to room temperature and stirred at 80° C. for 30 minutes. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 100 ml of water. This aqueous solution was washed twice with diethyl ether, then added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with water and dried, and the solvent was distilled away under reduced pressure to obtain 3.75 g of a crude product. This crude product was recrystallized from a mixed solvent of diisopropyl ether and isopropyl alcohol to obtain 1.65 g of the objective compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CC[O:19]CC1.ClC(OCC(C)C)=O.C(N1[C:40]([NH2:41])=[C:39]([NH2:42])[C:37](=[O:38])N(CC=C)C1=O)C=C>O1CCCC1.C(OCC)C>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:1]([CH:7]1[C:11](=[O:19])[CH:10]([CH2:9][CH:8]=[CH2:12])[C:37](=[O:38])[C:39]([NH-:42])=[C:40]1[NH2:41])[CH:2]=[CH2:3]
Reactant: CN1CCOCC1
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)[C@@H]1CCC[C@H]1c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1C(=O)C([NH-])=C(N)C(CC=C)C1=O
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Dissolve trans-2-phenyl-cyclopentanecarboxylic acid (1.0 g, 5.3 mmol), prepared according to F. G. Bordwell and J. Almy, J. Org. Chem., 38, 571 (1973), in tetrahydrofuran (20 ml) and add N-methylmorpholine (0.58 ml, 5.3 mmol). Cool the reaction to -20° C. and add isobutyl chloroformate (0.69 ml, 5.3 mmol). Stir the reaction for 30 minutes, add 1,3-diallyl-5,6-diaminouracil (1.2 g, 5.3 mmol, in 4 ml dimethylformamide) and stir at -20° C. for 3 hours. Warm to room temperature and dilute the reaction with diethyl ether (400 ml). Separate the layers and rinse the organic layer with saturated sodium bicarbonate (2×200 ml), 50% aqueous sodium chloride (2×300 ml), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by radial chromatography (2% to 5% methanol/chloroform, 2 mm plate) to provide trans-2-phenyl-cyclo-pentanecarboxylic acid (3,5-diallyl-2-amino-4,6-dioxo-cyclohex-1-enylamide (0.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10](=O)(O)[O-:11].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:10]=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=Nc1ccc(Cl)c(F)c1
Temperature: 0 °C

Procedure:
4-Chloro-3-fluoroaniline (2 g, 13.7 mmol) was dissolved in 60 mL of dichloromethane. Under ice bath, saturated sodium bicarbonate solution (60 mL) was added. The mixture was stirred at 0° C. and triphosgene (1.36 g, 4.58 mmol) was added. The mixture was stirred at 0° C. for 1 h and then extracted with dichloromethane and water. The organic layer was dried with sodium sulfate and filtered. The filtrate solution was concentrated and the residue was treated with 50 mL of hexanes. The hexane solution was concentrated to remove all solvents. The residue was taken up in 12 mL of hexanes and filtered. The solution was concentrated and dried to give 1-chloro-2-fluoro-4-isocyanatobenzene as an off white solid (1.69 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.82-6.90 (m, 1H) 6.93 (dd, J=9.22, 2.65 Hz, 1H) 7.31-7.41 (m, 1H).
Reaction SMILES: [CH:1]12[NH:10][CH:5]([CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:4][O:3][CH2:2]2.CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:10]2[CH:5]3[CH2:6][C:7](=[O:9])[CH2:8][CH:1]2[CH2:2][O:3][CH2:4]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1CC2COCC(C1)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirring mixture of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (408 mg, 2.3 mmol) in dichloromethane (8 mL) was added Et3N (1.2 mL, 9.2 mmol) and 4-chlorobenzenesulfonyl chloride (582 mg, 2.76 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with a saturated aqueous NaHCO3 solution (15 mL). The aqueous phase was separated and extracted twice with EtOAc (2×25 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum, and the residue was purified on a silica gel column (eluant hexane/EtOAc, 50/50 to 100) to give 510 mg (70%) of 9-(4-chloro-benzenesulfonyl)-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a white solid; Retention time (min)=1.687 min, Method [1], MS(ESI) 316.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.84-7.81 (m, 2H), 7.56-7.51 (m, 2H), 4.28-4.27 (m, 2H), 3.76 (d, J=12.1 Hz, 2H), 3.61 (d, J=11.5 Hz, 2H), 2.65 (dd, J=15.93, 5.49 Hz, 2H), 2.46 (d, J=15.93 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ 204.3, 140.1, 139.1, 130.1, 128.7, 71.7, 51.7, 44.4 ppm.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]([CH3:32])[CH3:31])=[C:27]([SH:29])[CH:28]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:27]1[CH:28]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[CH:30]([CH3:32])[CH3:31]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(C(C)C)c(S)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 183°-184° C.). 1H NMR (DMSO-d6) δ 1.15 (d, 6 H), 1.85 (s, 3 H), 3.22 (m, 1 H), 3.80 (bs, 2 H), 5.88 (bs, 1 H), 6.77 (d, 1 H), 7.03 (d, 1 H), 7.32-7.47 (m, 10 H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1.O1CCOCC1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:15]=[C:5]=[O:11])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 1 h
Yield: 144.1 %

Procedure:
21.16 g of triphosgene are dissolved in 100 mL of anhydrous toluene in a 500 mL four-neck bottle equipped with a nitrogen intake, a magnetic stirrer, a condenser and a guard filled with 2 N sodium hydroxide. A solution of 20 g of 4-amino-2-trifluoromethylbenzonitrile in 125 mL of anhydrous dioxan is added dropwise at ambient temperature in 1 hour 30 min. The mixture is heated to 110° C. Pronounced release of gas for 1 hour then appearance of an insoluble brown substance. After 2 hours under reflux, stirring is maintained overnight at AT. The insoluble matter is filtered and rinsed with toluene. The filtrate is concentrated in order to obtain 21.8 g of expected product (Yd=96%). The product is stored in solution in THF (2 M) in a refrigerator.
Reaction SMILES: Cl.[C:2]([C:4]([CH3:24])([CH3:23])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19]COC)[CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3]>CO.C(OCC)(=O)C.O>[C:2]([C:4]([CH3:23])([CH3:24])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3]
Reactant: CCOC(=O)CC(c1cccc(COCOC)c1)C(C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(c1cccc(CO)c1)C(C)(C)C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Conc. hydrochloric acid (1.10 mL) was added to a solution of ethyl 4-cyano-3-(3-((methoxymethoxy)methyl)phenyl)-4-methylpentanoate (210 mg) in methanol (2 mL) at room temperature, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, water was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (147 mg) of the title compound and methyl ester thereof. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]Cl)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][CH:28]([NH:35][CH3:36])[CH2:27][CH2:26]2>>[CH2:1]1[CH2:20][O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:35]([CH3:36])[CH:28]4[CH2:27][CH2:26][C:25]5[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=5)[CH2:29]4)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Reactant: O=C1Cc2cc3c(cc2CCN1CCCCl)OCCO3
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc4c(cc3CC1=O)OCCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-ethylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dimethoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 152°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[OH:19])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:11]2[C:12]([O:19][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[C:13]([F:18])[C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(F)c(F)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Oc1c(C(=O)Cc2ccc(Cl)cc2)ccc(F)c1F
Reaction time: 5 h

Procedure:
A solution of 2-(4-chlorophenyl)-1-(3,4-difluoro-2-hydroxy-phenyl)-ethanone (4.5 g, 87% pure, 13.85 mmol) and triethylamine (1.7 g, 2.35 ml, 16.8 mmol, 1.2 eq.) in methylene chloride (100 ml) is treated dropwise at ambient temperature with isobutyryl chloride (1.79 g, 1.76 ml, 16.8 mmol, 1.2 eq.). After stirring for 5 h, the solution is washed successively with 2M HCl solution and saturated sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness in vacuo to afford a black residue. This is triturated with methanol at room temperature overnight to afford a brown solid, which is filtered and washed with methanol. The solid is purified twice by flash chromatography (ethyl acetate/cyclohexane=1:9) to furnish the title compound.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:18][C:14]=3[CH2:13]2)=[CH:4][CH:3]=1.FC1C=CC(CC2C=CC=CC=2COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=CC=1.Cl.C(OCC)(=O)C>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH2:13]2)=[CH:44][CH:45]=1
Reactant: Fc1ccc(Cc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Cl
Agent: Fc1ccc(Cc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc(Cc2ccccc2COCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A solution of a mixture of 5-[2-(4-fluorobenzyl)benzyloxymethyl]1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-[2-(4-fluorobenzyl)benzyloxymethyl]-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (0.62 g, 1.0 mmol) in water (0.6 ml) and glacial acetic acid (5 ml) was heated to 90° C. for 2.5 h. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 ml). A 3.5 M solution of hydrogen chloride in ethyl acetate (0.6 ml, 2.1 mmol) was added. The solvent was removed in vauco. The residue was dissolved in ethyl acetate (30 ml). A precipitation appeared, which was isolated to give 235 mg of the hydrochloride salt of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.O1CCCC1.[NH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromobenzaldehyde (150 mg, 0.811 mmol) was placed in a flask that was subsequently evacuated and backfilled with nitrogen (3×). Tetrahydrofuran (8107 μl) and thiomorpholine 1,1-dioxide (110 mg, 0.811 mmol) were then added and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (258 mg, 1.216 mmol) was weighed and quickly added to the solution (flask was uncapped during addition). The reaction was stirred at room temperature overnight. The reaction was diluted in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was extracted and the aqueous layer was extracted 3× with ethyl acetate. All organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified via HPLC to yield the title compound. LRMS (APCI) calc'd for C11H15BrNO2S [M+H]+: 304. Found: 304.
Reaction SMILES: [Mg].II.[CH3:4]I.[N:6]1([CH2:11][CH:12]2[C:21](=O)[C:20]3[CH:19]=[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])[CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13]2)[CH:10]=[CH:9][N:8]=[CH:7]1.Cl>C(OCC)C.O1CCCC1.O>[N:6]1([CH2:11][C:12]2[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:23]([OH:25])=[O:24])=[CH:19][C:20]=3[C:21]=2[CH3:4])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C(=O)C(Cn1ccnc1)CC2
Reactant: CI
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1=C(Cn2ccnc2)CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a suspension of anhydrous magnesium (0.23 g) and a small crystal of iodine in anhydrous diethyl ether (3 ml) a solution of methyl iodide (1.3 g) in anhydrous diethyl ether (6 ml) is added dropwise. The mixture is refluxed for 1 hour then cooled to room temperature. To this mixture a solution of tert-butyl 5,6,7,8-tetrahydro-7-(1H-imidazol-1-ylmethyl)-8-oxo-2-naphthalenecaboxylate (1.0 g) in anhydrous tetrahydrofuran (25 ml) is added dropwise. The reaction mixture, after stirring at room temperature for 2 hours, is poured into water, neutralized with diluited hydrochloric acid and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue is taken up with trifluoracetic acid and refluxed for 45 minutes. The resulting solution is evaporated under reduced pressure and the residue is purified by silica gel column chromatography, eluiting with methylene chloride-methanol-acetic acid (180:20:2), to give 0.6 g of 5,6-dihydro-7-(1H-imidazol-1-ylmethyl)-8-methyl-2-naphthalenecarboxylic acid
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
N,N'-carbonyldiimidazole (2.43 g) is added to a solution, cooled to +5° C., of 2-dimethylaminophenylacetic acid (2.68 g) in dry dichloromethane (50 cc). The mixture is stirred for 90 minutes at +5° C. and a solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (4.9 g) and triethylamine (4.2 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting 125-cc fractions. Fractions 5 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of acetonitrile (40 cc) and isopropyl ether (200 cc). The crystals are drained, washed with isopropyl ether and dried. (3aR, 7aR)-7,7-Diphenyl-2-[2(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (2.58 g) is obtained in the form of white crystals, m.p. 190° C.; [α]D20 =-242° (c=1.18, chloroform).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([CH:35]1[CH2:40][CH2:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([CH:35]1[CH2:40][CH2:39][C:38]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=2)=[CH:37][CH2:36]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: CC(C)(C)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)C1CC=C(c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)CC1

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (250 mg, 0.5 mmol, Example 7) and 2-(4-tert-butyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane from step (b) above (200 mg, 0.76 mmol) reacted under the conditions of Example 10 to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 552 (M+1). M.p. 96-97.7° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].[C-]#N.[Na+].O.CC(C)=O>CS(C)=O>[CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 182.5 °C

Procedure:
5.0 g Venlafaxine was dissolved in 50 ml dimethylsulfoxide at 25-30° C. Sodium cyanide 9.0 g was added and reaction mass was heated to 180-185° C. for 4 hours. The reaction mass was cooled and 25 ml water was added. The resulting solution was extracted with 2×50 ml ethyl acetate, combined organic layer was dried over anhydrous sodium sulfate, followed by distillation to give residue. The residue was treated with 25 ml acetone then cooled to 0-5° C. to give O-desmethylvenlafaxine.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][Cl:13])[O:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:19])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][Cl:13])[O:10][C:4]=2[CH:3]=1
Reactant: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=S
Yield: 73.2 %

Procedure:
To a solution of 43 g (0.16 mole) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 400 ml of dry toluene was added a mixture of 23 g (0.12 mole) of phosphorus pentasulfide and 23 g of potassium sulfide which had been ground together. The reaction mixture was stirred and heated at reflux for 24 hr. The mixture was filtered hot and the filtrate concentrated under reduced pressure to give 25.5 g (55%) of orange oil which solidified on standing at room temperature. The solid was recrystallized from ethanol, m.p. 105°-106° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[CH:7]([Si:9]([CH3:12])([CH3:11])Cl)=[CH2:8].C(N(CC)CC)C>O1CCCC1>[CH:4]([N:3]1[CH:7]([SiH:9]([CH3:12])[CH3:11])[CH2:8][O:6][C:2]1=[O:1])=[CH2:5]
Reactant: O=C1NCCO1
Reactant: C=C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CN1C(=O)OCC1[SiH](C)C

Procedure:
A 3-vinyldimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. A mixture of 34.8 grams of 2-oxazolidinone and 48.17 grams of vinyldimethylchlorosilane was prepared in 750 ml of tetrahydrofuran solvent. 40.26 grams of triethylamine was added dropwise. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes.