Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[C:15](Br)[CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[C:15]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH3:24])=[N:31][CH:30]=3)[CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(=O)Nc1cccc(-c2nc(Br)cc(N3CCOCC3)n2)c1
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: COCCOC
Product: COc1ncc(-c2cc(N3CCOCC3)nc(-c3cccc(NC(C)=O)c3)n2)cn1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
A mixture of 2-(3-acetamidophenyl)-4-bromo-6-morpholinopyrimidine (0.037 g), 2-methoxypyrimidin-5-ylboronic acid (0.019 g), tetrakis(triphenylphosphine)palladium(0) (3 mg), a saturated aqueous sodium bicarbonate solution (0.2 ml) and 1,2-dimethoxyethane (2 ml) was stirred and heated to 60° C. for 18 hours under an atmosphere of nitrogen. A second portion of each of 2-methoxypyrimidin-5-ylboronic acid (0.019 g), tetrakis(triphenylphosphine)palladium(0) (2 mg), a saturated aqueous sodium bicarbonate solution (0.2 ml) and 1,2-dimethoxyethane (1 ml) was added and the resultant mixture was heated to 60° C. for a further 18 hours. The resultant reaction mixture was evaporated and the residue was triturated under a 5:1 mixture (1 ml) of methylene chloride and methanol. The soluble material was purified by column chromatography on reversed-phase silica using an ‘Isolute SCX’ column (1 g; International Sorbent Technology Limited, Mid Glamorgan, UK) by initially washing the column with methanol (5 ml) followed by elution with a 5:3:2 mixture of methanol, methylene chloride and a 7M methanolic ammonia solution. The material so obtained was dried under vacuum. There was thus obtained the title compound as a solid (0.034 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 3.66-3.8 (m, 8H), 3.97 (s, 3H), 7.3-7.37 (m, 2H), 7.82 (d, 1H), 8.03-8.09 (m, 1H), 8.52 (s, 1H), 9.38 (s, 2H), 9.98 (s, 1H); Mass Spectrum: M+H+407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
3.12 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is dissolved in 50 ml of absolute dimethylformamide and combined with 0.3 g of sodium hydride (80% strength in white oil). The mixture is stirred for 30 minutes, and then 1.74 g of 2-bromopyridine in 25 ml of dimethylformamide is added dropwise thereto. The reaction mixture is stirred at room temperature under argon for 30 hours. Then the solution is poured into 300 ml of ice water, the product is extracted with ethyl acetate, the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from methylene chloride/ether, thus obtaining 2.94 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyridylthio)imidazole, mp 94°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[NH2:39].C(=O)([O-])O.[Na+].[Cl:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)(Cl)Cl>[Cl:45][CH2:46][C:47]([NH:39][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:7]=[C:6]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)=[O:48]
Reactant: Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
400 mg of 6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine synthesized in Production Example 182 was dissolved in 20 ml of chloroform, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 124 μl of chloroacetyl chloride were added thereto at 0° C., and then the resulting mixture was stirred at room temperature overnight. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated, to give 495 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:32]([N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:34]#[C:33][CH2:32][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl]allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 1-propargyl-1H-pyrazole (124 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (54 mg, 0.046 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 days, subsequently evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[I-:16].CN[C@@H]1CCCC[C@H]1NC.[I-].[Na+]>O1CCOCC1>[I:16][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: [I-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2cccc(I)c2)COCC(=O)N1
Temperature: 110 °C

Procedure:
A mixture of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (X-1) (2.0 g), cupper(I) iodide (72 mg), trans-N,N′-dimethyl-1,2-cyclohexandiamine (105 mg), and sodium iodide (2.22 g) in dioxane (20 ml) was heated at 110° C. over the weekend. The reaction mixture was evaporated at reduced pressure and the residue directly transferred to column chromatography on silica using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. The (RS)-5-(3-iodo-phenyl)-5-methyl-morpholin-3-one was obtained as a light green solid (2.26 g, 96% of theory). MS (ISP): m/z=318.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Br:1])[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Br
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.47 mmol) and 6-aminobenzothiazole (86 mg, 0.57 mmol, Lancaster) provided, after purification by silica gel chromatography (gradient: 0-30% EtOAc in hexane), the title product as an off-white solid. MP 214-215° C. MS (ESI, pos. ion) m/z: 427 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][NH:12][C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=C1NCc2cccnc2N1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1N(Cc2ccccc2)Cc2cccnc2N1c1cccc([N+](=O)[O-])c1
Yield: 26.3 %

Procedure:
1-(3-Nitrophenyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (300 mg, 1.1 mmole) was suspended in acetone (100 ml). To this suspension was added powdered K2CO3 (607 mg, 4.4 mmole) and benzyl bromide (282 mg, 1.65 mmole). The suspension was refluxed for 18 hours. The suspension was filtered, while still hot, to remove solid unreacted K2CO3, which was discarded. The solvents were removed from the filtrate and the residue was purified by preparative thin-layer chromatography (eluted with ethyl acetate) yielding 104 mg (0.289 mmole, 26% yield) of 1-(3-nitrophenyl)-3-benzylpyrido[2,3-d]pyrimidine-2(1H,3H)-one (mp 144°-145° C.), as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH3:26])[CH3:16]>C(Cl)CCl>[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:8]([C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[C:18]1[CH3:26])[CH3:16]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCn1c(C)cc2ccccc21
Solvent: ClCCCl
Product: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 67.2 g (0.4 mole) of 4-nitrophthalic anhydride and 63.0 g (0.32 mole) of 80.6 percent active 1-ethyl-2-methylindole in 50 ml of ethylene dichloride was heated at reflux for two hours. The reaction mixture was then allowed to cool to room temperature. The yellow precipitate which separated was collected by filtration, washed with fresh ethylene dichloride and dried to obtain 64.5 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid (Formula VIII: R°=R2 =R3 =Y1 =H; R1 =NO2 ; R5 =CH3 ; R6 =CH2CH3) having a meltingpoint of 203°-204° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][NH:21][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][C:8]([NH:12][C:13]2[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=2)=[CH:7]3)[CH2:25][CH2:26]1
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: NCCN1CCOCC1
Product: N#Cc1cnc(Nc2cc3cccc(NCCN4CCOCC4)c3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1, replacing 3,8-dichloroisoquinoline with 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile and replacing (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile with N-(2-aminoethyl)morpholine, and conducting the reaction at 140° C.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-:25]>CN(C=O)C>[Cl:25][CH:17]1[C:16](=[O:23])[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH2:19][CH2:18]1)[CH:11]=[CH:12][CH:13]=3
Reactant: [Cl-]
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1Cl
Temperature: 65 °C
Reaction time: 50 h
Yield: 71.3 %

Procedure:
A mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.441 g, 1.45 mmol), anhydrous CuCl12 (0.430 mmol, 3.20 mmol), anhydrous LiCl (0.308 g, 7.27 mmol), and DMF (3 mL) is stirred at 65° C. for 50 h. After cooling, the mixture is stored in the refrigerator overnight and then partitioned between CH2Cl2 and brine. The organic layers are dried over sodium sulfate and taken to dryness. Chromatography on silica gel gel (60 mL) using ethyl acetate/CH2Cl2/hexane (5:45:50) gave 0.349 g (71%) of 8-chloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (mixture of diastereomers).
Reaction SMILES: [C:1]([SiH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].Cl[C:13](C)(CC)CC.Cl[SiH](Cl)Cl>>[CH2:7]([SiH:6]([CH2:9][CH3:10])[C:1]([CH3:3])([CH2:2][CH3:13])[CH2:4][CH3:5])[CH3:8]
Reactant: CC[SiH](CC)C(C)(C)CC
Reactant: CCC(C)(Cl)CC
Agent: Cl[SiH](Cl)Cl
Agent: [Mg]
Product: CC[SiH](CC)C(C)(CC)CC

Procedure:
The procedure of synthesizing Compound 34a was repeated, except that 3-methylpentan-3-ylmaganesium chloride THF solution (100 mL), which had been prepared from magnesium (2.43 g, 100 mmol) and 3-chloro-3-methylpentane (13.6 mL, 100 mmol); trichlorosilane (10.0 mL, 99.1 mmol); and ethylmagnesium chloride THF solution (0.93M, 200 mL, 190 mmol) were employed, whereby the Compound 38a was obtained as a colorless liquid (boiling point; 39 to 42 mmHg, 94 to 97° C. fraction, 8.86 g, 51%).
Reaction SMILES: COCOC.B(F)(F)F.[CH3:10]COCC.[C:15]([N:18]1[CH2:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[NH:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16].[CH:29]1[CH2:33][CH2:32][CH2:31][CH:30]=1.[OH-].[Na+]>C(Cl)Cl>[C:15]([N:18]1[CH2:24][C:23]2=[C:22]3[C:28](=[CH:27][CH:26]=[CH:25]2)[CH:30]2[CH2:31][CH2:32][CH2:33][CH:29]2[CH2:10][N:21]3[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CCOCC
Reactant: CC(=O)N1CCNc2ccccc2C1
Reactant: C1=CCCC1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COCOC
Solvent: ClCCl
Product: CC(=O)N1CCN2CC3CCCC3c3cccc(c32)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Dimethoxymethane (34.9 mL, 394 mmol) was dissolved in methylene chloride (800 mL) and cooled to 0° C. in a ice bath. To this solution, boron trifluoride etherate (18.3 mL, 144 mmol) was added and the reaction was stirred for 30 minutes. Subsequently, a solution of 4-Acetyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (25 g, 131 mmol) in methylene chloride (500 mL) was added to the reaction through an addition funnel over several hours. During the course of this addition, cyclopentene (23.1 mL, 263 mmol) was added to the reaction. The reaction was allowed to warm to room temperature overnight. Additional portions of the dimethoxymethane, boron trifluoride etherate and cyclopentene were added as necessary to facilitate greater conversion. The reaction was neutralized with NaOH and extracted with methylene chloride and the organic layer was washed with saturated brine solution. After drying with MgSO4, the solvent was evaporated in vacuo and the product was purified by flash chromatography (silica gel, ethyl acetate:hexanes 55:45 with 1% triethylamine) to provide 7.4 grams of the title compound.
Reaction SMILES: [C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:16]([N:35]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=2)=[N:38][N:37]=[N:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>>[C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[N:9]([CH2:50][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[C:39]3[N:35]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:36]=[N:37][N:38]=3)=[CH:53][CH:52]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 74(a), but using 0.97 g of 4-isobutyryl-2-propylimidazole-5-carbonitrile (prepared as described in Preparation 39), 2.90 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.56 g of potassium t-butoxide, 1.90 g of the title compound was obtained as crystals, melting at 133°-134° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][C:14]2([CH3:23])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)C.ClCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([C:17]([C:4]3[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=3)=[CH:16][CH2:15][C:14]2([CH3:23])[CH3:22])=[CH:19][CH:20]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
p-Tolyl magnesium bromide (1 M solution in diethyl ether, 4.2 mL, 4.17 mmol) was added slowly to a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 3, 350 mg, 1.39 mmol) in 10 mL of diethyl ether at 0° C. After stirring and warming to room temperature for 2 h, the mixture was quenched with water at 0° C., extracted with diethyl ether (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure to give a light yellow oil. The crude oil was then dissolved in 10 mL of dichloromethane and stirred with 100 mg of para-toluenesulfonic acid at room temperature for 2 h. Water (10 mL) was then added and the organic layer was washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) gave the title compound (295 mg, 65% yield) as a colorless oil:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:28])[NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21]3)[CH2:10][C@@H:9]1[OH:29])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([NH:15][C:14]([C@@H:11]3[CH2:12][CH2:13][C@@H:8]([NH2:7])[C@@H:9]([OH:29])[CH2:10]3)=[O:28])[CH:17]=[CH:18][CH:19]=2)[N:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)Nc2cccc3ccc(C#N)nc23)C[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2cccc(NC(=O)[C@@H]3CC[C@@H](N)[C@@H](O)C3)c2n1
Yield: 67.1 %

Procedure:
A solution of carbamate (i) (2.4 g, 6 mmol) in dichloromethane (50 mL) was treated with trifluoroacetic acid (10 mL). After 18 hours the mixture was evaporated and partitioned between saturated aqueous sodium bicarbonate solution and 20% methanol/dichloromethane. The aqueous phase was twice more extracted and the combined extracts dried and evaporated giving a solid. This was triturated with ether/ethyl acetate (1/1) and filtered, washing with ether, to afford a light brown solid (1.25 g, 61%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:6][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: CNCC[C@@H](O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Product: CNCC[C@@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
A process according to claim 6 comprising the additional step, following all preceding steps, of reacting (R)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (R)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.
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@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2[C@H](O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Yield: 31.8 %

Procedure:
By carrying out the procedure as in Example 9, using 0.26 g of 2-dimethylaminophenylacetic acid and 0.50 g of (3aR,4R,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride, 0.21 g of (3aR,4R,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 204° C., [α]D20 =-212° (c=0.5, methanol).