Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH3:19]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:19])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: CO
Reactant: Cc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Product: COc1ccc(C(=O)Cc2ccc(C)cc2)c(O)c1
Yield: 92.9 %

Procedure:
Using the previous procedure and starling from 1-(2,4-dihydroxyphenyl)-2-(4-methylphenyl)ethanone (7.51 g, 31.0 mmol) and methanol (1.32 mL, 32.55 mmol), 7.38 g (93%) of the title compound was obtained as a white solid: mp (EtOAc/hexane) 71-72° C.; IR (KBr) 1639, 1623, 1590, 1516, 1508, 1439, 1388, 1355, 1268, 1231, 1205, 1131, 10.33, 1010, 957, 800, 780, 571, 504, 491 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.72 (br s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.24-7.14 (m, 4H), 6.43-6.40 (m, 2H), 4.1.5 (s, 2H), 3.81 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDC3) δ 202.63, 166.56, 166.28, 137.14, 132.47, 131.71, 129.87, 129.61, 113.60, 108.20, 101.43, 55.98, 44.89, 21.48; HRMS calculated for C16H16NaO1(M+Na)+ 279.0997; found 279.0989.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>[N+](C)([O-])=O>[C:17]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc2ccccc2c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, 2-methoxynaphthalene (64 g, 0.41 mol) easily available from a reagent manufacturer was dissolved in nitromethane (150 ml) dried with a molecular sieve 3A. Under an ice bath, aluminum chloride (80 g, 0.60 mol) was added. Subsequently, decanoyl chloride (92 ml, 0.45 mol) was dropped into the solution under the ice bath. The solution was stirred under room temperature for 5 hours, and water (100 ml) was dropped into the solution under the ice bath. The reaction solution was extracted with methylene chloride (200 ml×4), and the obtained organic layer was washed with water (100 ml×3). The organic layer was dried with anhydrous magnesium sulfate, and filtered. Then, the solvent was distilled away under reduced pressure. The obtained yellow solid was recrystallized from hexane to obtain 2-decanoyl-6-methoxynaphthalene (102 g, 82%) as a white solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[ClH:18].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:18][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)c(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/c1ccc(C(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
4.67 g of ethyl (E)-3-(3-amino-4-isopropylphenyl)acrylate was dissolved in 46.7 ml of acetic acid. To the solution was added 46.7 ml of 2N hydrochloric acid with ice-cooling. To the mixture was dropwise added 10 ml of an aqueous solution containing 1.52 g of sodium nitrite. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to 30 ml of 6N hydrochloric acid solution containing 2.18 g of cuprous chloride, with ice-cooling. The mixture was stirred for 1 hour at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added 100 ml of ethyl acetate. The organic layer was separated and washed with water. Thereto was added 50 ml of water. The mixture was adjusted to about pH 7 with sodium hydrogencarbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=20/1) to obtain 3.57 g of colorless oily ethyl (E)-3-(3-chloro-4-isopropylphenyl)acrylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:37])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N(C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a tetrahydrofuran (1 mL) solution of Compound 56 (72 mg), potassium bis(trimethylsilyl)amide (0.5M toluene solution: 273 μL) was added at −78° C. The mixture was stirred at −78° C. for 30 min and methyl iodide (9 μL) was added portionwise. The mixture was then stirred overnight as it was allowed to be slowly warmed to room temperature (20 to 30° C.). Subsequently, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (ethyl acetate:hexane=1:19 to 1:1) to give 7.7 mg (10% yield) of tert-butyl 2-(1-((l-benzylpiperidine-4-yl)(methyl)amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)carbamate. 2.6 mg (42% yield) of the title compound was synthesized from tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)-amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)-carbamate in the same manner as in Example 71.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14][CH:15]([CH3:17])[CH3:16])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N:14]([CH:15]([CH3:17])[CH3:16])[CH3:20])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)Nc1cc([N+](=O)[O-])ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1N(C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
2-Isopropoxy-N-isopropyl-5-nitrobenzenamine 29 (218 mg, 0.915 mmol, 1 equiv) in DMF (4 mL) under nitrogen gas, was cooled to 0° C. Sodium hydride (60% oil, 168 mg, 3.84 mmol, 4.2 equiv) was added in one portion, and the reaction mixture was stirred for 10 minutes at 0° C. Methyl iodide (525 uL, 7.68 mmol, 8.4 equiv) was added at 0° C., then the reaction mixture was stirred at ambient temperature for 2 hours, and heated at 80° C. overnight. The reaction mixture was concentrated to dryness and directly loaded into a silica gel flash column and eluted with dichloromethane to provide 2-isopropoxy-N-isopropyl-N-methyl-5-nitrobenzenamine 30 (205 mg, 89%) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:31])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine in 40 ml of DMSO 3.7 g of 4-tert.butylbenzene sulfonamide potassium salt was added. The resulting solution was stirred for 20 h at room temperature. Eventually, the mixture was poured onto 400 ml of water and washed twice with 200 ml of diethyl ether. The organic layers were extracted with 200 ml of water. The combinded aqueous layers were acidified with conc. hydrochloric acid. The mixture was cooled to 0° C. and 100 ml of brine was added. The precipitate that formed was collected and dried to yield 2.7 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.80 min, [M+1]+=448.17, [M−1]−=446.21.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:32]([C:29]3[N:26]4[C:25]([S:24][CH:28]=[CH:27]4)=[N:31][CH:30]=3)=[O:33])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cnc2sccn12
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cnc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=482.1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>>[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: BrCc1ccccc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccccc2Br)cc1

Procedure:
Analogously to Method D, 0.953 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.510 g of 2-bromobenzylbromide are reacted. The title compound is obtained as a beige oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14](Br)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:46]2[CH2:47][CH2:48][N:43]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:44][CH2:45]2)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 120 °C
Yield: 62.3 %

Procedure:
{(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (45 mg, 0.082 mmol), 1-benzyl-piperazine (216 mg, 1.23 mmol), and acetonitrile (500 μl) were placed in a microwave vessel and heated at 120° C. for 1 hr by microwave irradiation with stirring. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford the 33 mg of the compound as a colorless oil (yield 62%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8](N(OC)C)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>O1CCCC1>[Br:1][C:2]1[C:3]([C:8]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CON(C)C(=O)c1nn(C)cc1Br
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cn1cc(Br)c(C(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of compound 4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide (1.0 g, 4 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere was added (4-chlorophenyl)magnesium bromide (8 mL) in tetrahydrofuran (1 M) at 0° C., The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by saturated solution of ammonium chloride, and dichloromethane (100 mL) was added, the separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give the titled product as a white solid (1.0 g, 84%). LC/MS m/z 298 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=9 Hz, 2H), 7.53 (s, 1H), 7.43 (d, J=9 Hz, 2H), 3.99 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:25]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:25][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2

Procedure:
tert-Butyl 1-benzyl-7-(ethylsulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.652 g, 1.422 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>C(O)(=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][C:17]2[NH:2][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][C:12]=3[C:16]=2[CH2:15]1
Reactant: NNc1ccccc1C(=O)O
Reactant: CC1CCC(=O)CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2[nH]c3c(C(=O)O)cccc3c2C1
Yield: 87.2 %

Procedure:
A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (20 ml) was slowly boiled under stirring and 1.2 ml (9.8 mmol) of 4-methylcyclohexanone was dropped thereinto. The obtained mixture was heated under reflux for 8 hours and then allowed to cool. After adding water, the precipitate thus formed was recovered by filtration, washed with water and dried to thereby give 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylic acid. This product was dissolved in acetone (50 ml) and 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added thereto. The reaction mixture was heated under reflux under stirring for 2 hours, then allowed to cool and extracted with water and ethyl acetate. The organic layer was taken up, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus 1.49 g of methyl 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate was obtained. This product was suspended in diphenyl ether (10 ml) and 890 mg of 10% palladium-carbon was added thereto. The obtained mixture was heated under reflux under stirring in a nitrogen atmosphere for 1 hour. After allowing to cool, It was dissolved by adding tetrahydrofuran. Then the catalyst was filtered off and the filtrate was concentrated. After adding n-hexane, the crystals thus formed were recovered by filtration to thereby give 1.26 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH2:21]=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(C)CC2

Procedure:
The title compound (113 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and paraformaldehyde as in Example 35. MS (ESI): exact mass calculated for C17H22FN3, 287.18; found, m/z 288.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.40 (m, 2H), 7.34-7.30 (m, 2H), 4.42 (m, 1H), 3.77-3.74 (m, 1H), 3.67-3.62 (m, 2H), 3.36-3.34 (m, 1H), 3.27-3.21 (m, 3H), 3.03 (s, 3H), 2.92-2.89 (m, 1H), 2.80-2.76 (m, 1H), 1.49-1.29 (m, 6H).
Reaction SMILES: [Br-].[C:2]1([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([Br:54])[C:48]1C=CC=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[Br:54][CH2:47][CH2:48][CH2:49][CH2:50][CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCc1ccccc1
Reaction time: 24 h
Yield: 94 %

Procedure:
Phenylmethyl-triphenylphosphonium bromide (51 a) (PAA 59). Triphenylphosphine (2.364 g, 9.00 mmol) was added to benzyl bromide (1.348 g, 8.00 mmol) in 35 mL toluene in a 100-mL round-bottom flask. The mixture was heated to reflux under argon and stirred 24 h, then concentrated in vacuo. The resulting white amorphous solid was triturated with ether (3×20 mL) to yield 3.268 g (94%) white powder. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.78 (m, 15H), 7.10-7.26 (m, 5H), 5.34-5.42 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41N4O2Cl2 [(M+H)+] 607.2601, observed 607.2603.
Reaction SMILES: [C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1([C:4]2[C:14]3[CH2:13][CH2:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[O:22][CH2:21][CH2:20][O:3]1
Reactant: CC(=O)c1cccc2c1CCc1ccccc1C2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1

Procedure:
7.4 g. of 1-acetyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, 9.5 g. of ethylene glycol, 30 ml. of toluene and 60 mg. of p-toluenesulfonic acid are heated in a water separator at reflux for 8 hours. Thereafter, the mixture is concentrated under reduced pressure, taken up in ethyl acetate, washed with sodium carbonate solution and water, dried and evaporated, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is obtained as yellow crystals having a melting point of 144°-145°C. (from ethyl acetate/petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(c(C(=O)O)c1OC)CCCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(c(C(=O)Cl)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[I:40]I.[I-]>C1C=CC=CC=1>[CH2:6]([I:40])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCCC=CCCCCCCCCCCCCCCCC
Reactant: II
Agent: [I-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 44.8 g. (0.15 mole) of Cp2ZrCl2 in 800 ml. tetrahydrofuran under Argon was added 24.7 g. (0.086 mole) of NaAlH2 (OCH2CH2OCH3)2 in benzene via syringe. After stirring 2 hours at room temperature, 36.8 g. (0.077 mole) of the olefin, 17-tetratriacontene, was added and the mixture kept at 40° C. for 7 days. After cooling in an ice bath, solid iodine (34.0 g., 0.134 mole) was added. The mixture was filtered and the solvent removed in vacuum. NMR analysis indicated an olefin:iodide ratio of 25:75. The residue was dissolved in hexane and percolated through dry silica gel to remove impurities. Recrystallization from hexane gave 13.0 g. pure iodide, m.p. 75°-6° C. and 14.4 g. of a 58:42 olefin:iodide mixture.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].BrCC=C>C(Cl)Cl>[CH2:1]([O:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h

Procedure:
(S)-methyl 3-(allyloxy)-2-(tert-butoxycarbonylamino)propanoate (200 mg, 0.91 mmol) and 3-bromoprop-1-ene (552 mg, 4.56 mmol) were dissolved in DCM (10 mL). Then Ag2O (654 mg, 2.74 mmol) was added at the room temperature. After stirring for 3 hours, the mixture was filtered, concentrated and purified by flash column chromatography to give the title compound A6-1 (149 mg, 63.1%) as light yellow oil.