Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>CN(C)C=O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: OCCCCCCCl
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncn(CCCCCCO)c2cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.84 g of NaH, and further, 8.2 ml of 6-chloro-1-hexanol. After the reaction was carried out by stirring the mixture at room temperature for one day, the reaction was stopped by an addition of water. Subsequently, according to the same processes as in Example 1, crude 1-(6-hydroxyhexyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 95% or higher.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([OH:38])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12].[F:39][C:40]([F:44])([F:43])[CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl.C(N(CC)CC)C>[CH2:9]([C:13]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[N:16]=[C:15]([C:36]([O:38][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:37])[CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)OCC(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
N-Chlorosuccinimide (400 mg) was added to a stirred solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (682 mg), triethylamine (1.2 g), 2,2,2-trifluoroethanol (248 mg) and triphenylphosphine (891 mg) in dichloromethane (30 ml) by cooling with an ice-bath. After stirring for 15 minutes, triphenylphosphine (262 mg) and N-chlorosuccinimide (133 mg) were added and the mixture was stirred for 30 minutes. After addition of 2N-hydrochloric acid (15 ml) and stirring at room temperature for 30 minutes, the mixture was allowed to separate into layers. The organic layer was washed with water, dried, and concentrated to dryness to give a syrup, which was then purified by column chromatography on silica gel, to give a yellow syrup (460 mg, 58%).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]O.[C:6]([O:14]CC)([O:11][CH2:12][CH3:13])(OCC)[CH3:7].C(O)(=O)CC>CCCCCC.C(OCC)C>[CH3:3][C:2](=[CH2:1])[CH2:5][CH2:7][C:6]([O:11][CH2:12][CH3:13])=[O:14]
Reactant: C=C(C)CO
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCCC
Solvent: CCC(=O)O
Solvent: CCOCC
Product: C=C(C)CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (12.9 g, 0.18 mol), triethyl orthoacetate (230.0 mL, 1.3 mol) and propionic acid (0.9 mL, 0.12 mol) was heated to 170° C. (external). The reaction apparatus was equipped with a Vigreaux Claisen adapter with a collection flask to remove the ethanol produced. The reaction mixture was left under reflux overnight. The excess amount of triethyl orthoacetate was gently distilled off at 130 mm Hg until the temperature in the reaction flask began to increase. After the reaction was cool, the remaining liquid was treated with 300 mL of 10% monobasic potassium phosphate and the left reaction was stirred for 90 min at ambient temperature. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined organic phase was dried over Na2SO4 and concentrated in vacuo to give a yellow oil. Flash column chromatography of this oil (silica gel, 4:1 hexane/diethyl ether) afforded compound 7 as a colorless oil (17.0 g, 0.12 mmol, 67%) (Gen et al. (1973) J. Am. Chem. Soc. 95, 2656-2663).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23].Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23])[CH2:29][CH3:30]
Reactant: CCn1c(-c2ccc(N)c(F)c2)c(C#N)c2ccc(OC)cc21
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A biphasic mixture of 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (74 mg, 0.24 mmol), prepared as described in example 1Gb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Br>C(Cl)Cl>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[N:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:12]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)nc1
Reaction time: 66 h
Yield: 116.2 %

Procedure:
A solution of bromine (4 g, 25 mmol) in DCM (10 mL) was added drop wise over 5 min to a cooled (0° C.) solution of 1-(6-bromo-pyridin-3-yl)-ethanone (5 g, 25 mmol) and HBr (48%, 0.2 mL). The cooling bath was removed 40 min later and stirring was continued at RT for 66 h. The solid that formed was filtered, washed with DCM and dried at room temperature to give the impure title intermediate (8.1 g) as a yellow solid. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.96 (m, 1H), 8.28-8.25 (m, 1H), 7.82-7.79 (m, 1H), 4.7 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[ClH:31].[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:19]=2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: Cl
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1

Procedure:
Following general procedure F, (6-bromo-4-(3-(2-(pyrrolidin-1-yl)ethyl)phenylamino)quinolin-3-yl)(cyclopropyl)methanone (45 mg, 0.097 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.15 mmol) to obtain the desired product which was dissolved in methanol and HCl (2 mL, 1.25 M in methanol). The mixture was concentrated to obtain the desired product (46 mg, 79% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.44 (s, 1H), 8.23 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.65-7.57 (m, 1H), 7.56-7.47 (m, 2H), 7.41-7.35 (m, 1H), 7.16-7.10 (m, 1H), 6.97 (s, 1H), 3.71-3.65 (m, 2H), 3.46-3.39 (m, 2H), 3.19-3.06 (m, 4H), 2.91-2.87 (m, 1H), 2.19-2.09 (m, 2H), 2.06-2.00 (m, 2H), 1.26-1.15 (m, 4H); ESI MS m/z 530 [C31H29ClFN3O2+H]+; HPLC 98.4% (AUC), tR=10.81 min.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[N:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.Cl>>[Cl:5][C:6]1[N:11]=[C:10]([C:12](=[O:13])[C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[Cl:22])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc(Cl)n1
Reactant: Clc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccc(Cl)n1)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
40.9 g AlCl3 is added in portions to a mixture of 26.4 g 6-chloro-2-pyridinecarboxylic acid chloride and 112 g 1,3-dichlorobenzene. The mixture is slowly heated until 130°-40° C. After standing overnight, it is added to a mixture of diluted HCl and crushed ice, basified and extracted with ethyl ether. The ethereal extracts are washed with water, dried and solvent evaporated (water pump). The residual deep green oil is crystallised from ethanol:water in the presence of decolorizing carbon. Yield: 10 g title compound, m.p. 103°-4° C.; UV (ethanol): λmax. 281 nm; ε: 14,500; Cl 37.02 (37.12).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:27]#[N:28])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+].[I-].C(N(C(C)C)CC)(C)C>CC#N.O>[C:27]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([O:4][CH2:3][CH2:2][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:6][CH:7]=2)[N:11]([CH2:14][CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:28]
Reactant: C1COCCN1
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OCCCl)cc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OCCN3CCOCC3)cc21
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) is heated in a sealed tube at 100° C. for 25 h. The reaction mixture is cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are washed with saturated NaCl, dried and concentrated. The crude solid is triturated with EtOAc and filtered to give 41 mg (41%) of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)cn1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-3-pyridinecarboxaldehyde (50 mg, 0.36 mmol; prepared according to the method of Comins and Killpack, J. Org. Chem., 1990, 55, 69-73) in t-butanol (0.5 ml) was added a solution of potassium permanganate (81 mg) in water (1.0 ml). The mixture was stirred at room temperature for two hours, and then saturated sodium sulphite solution was added until the purple colour disappeared. Reaction mixture was extracted with chloroform several times as it was gradually acidified with dilute HCl (2N). Chloroform extracts were concentrated in vacuo to yield the title compound (42 mg) as a white solid.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([C:8]23[O:15][CH2:14][C:11]([CH2:16][CH2:17][CH3:18])([CH2:12][O:13]2)[CH2:10][O:9]3)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NCC)C>[CH2:16]([C:11]12[CH2:14][O:15][C:8]([C:5]3[CH:6]=[N:7][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:3][CH:4]=3)([O:13][CH2:12]1)[O:9][CH2:10]2)[CH2:17][CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC12COC(c3ccc(I)nc3)(OC1)OC2
Solvent: CCNCC
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C)nc3)(OC1)OC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bis-triphenylphosphine palladium dichloride (15 mg) and cuprous iodide (5 mg) were added to a stirred solution of 1-(6-iodo-3-pyridyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2] octane (430 mg.) and trimethylsilyl acetylene (252 μl) in dry diethylamine (10 ml) under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue extracted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on alumina (Alumina Woelm TSC), eluting with 1:6 dichloromethane:hexane, saturated with ammonia. 4-n-Propyl-1-[6-(2-trimethylsilylethynyl)-3-pyridyl]-2,6,7-trioxabicyclo[2.2.2]octane (282 mg) was obtained as a pale brown crystalline solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:7]=1[C:8]([O:10]CC=C)=[O:9])[CH3:2].N1CCCC1>C(#N)C>[CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:7]=1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: C=CCOC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NCC
Solvent: CC#N
Solvent: C1CCNC1
Product: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
The allyl 2-(3-ethylureido)-5-(trifluoromethyl)benzoate (1.8 g, ca. 5.7 mmol) was dissolved in acetonitrile (50 mL) The solution was charged with pyrrolidine (1.0 mL, 12 mmol) and Ph(PPh3)4 (140 mg, 0.17 mmol) and then stirred for 2 h at RT before being concentrated in vacuo. The residue was diluted with EtOAc and this was washed successively with 1N HCl (2×) and brine (1×) before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with methylene chloride to afford pure 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid (0.89 g). 1H-NMR (300 MHz, d4-MeOH): δ 8.59 (d, 1H, J=9.6 Hz), 8.26 (d, 1H, J=1.5 Hz), 7.72 (dd, 1H, J=9.2, 1.8 Hz), 3.23 (q, 2H, J=7.3 Hz), 1.17 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](=[O:29])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28](=[O:29])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=2[CH3:48])=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of hydroxylammonium chloride (2.49 g), sodium hydrogen carbonate (3.54 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (1.01 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.75 g, 66%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.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>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:22]=[CH2:23])[N:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (1000 mg, 2.92 mmol) was dissolved in 30 mL toluene. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Vinyltributyltin (952 mg, 3.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol) were added. The reaction mixture was refluxed overnight and evaporated. The residue was poured into 50 mL acetonitrile and extracted three times with heptane (50 mL each) to remove the tin products. The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (2-Methoxy-benzyl)-(5-vinyl-quinolin-2-yl)-amine was obtained as a light yellow gum (544 mg, 64%), MS: m/e=291.3 (M+H+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1.CO>C(Cl)Cl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: C1CC(N2CCCNCC2)C1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a stirred solution of tert-butyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (6.1 g, 23.98 mmol) in DCM (70 ml) at 20 to 25° C. was added a solution of 4M HCl in dioxane (30 ml, 120 mmol) dropwise. The resulting mixture was stirred at 20 to 25° C. for ca. 2 h. MeOH (6 ml) was added and the resulting mixture stirred at 20 to 25° C. for 1 to 2 days. The solvent was removed in vacuo and the resulting gummy residue slurried in ether (100 ml) for 0.5 h. The solvent was evaporated and the residue slurried in ether/MeOH (10:1, 66 ml). The resulting white solid was collected by filtration, suspended in DCM (150 ml) and treated with 2M NaOH. The aqueous phase was extracted with DCM until complete transfer of product in the organic layer, as monitored by TLC analysis (eluent, DCM/MeOH/conc.NH3 (90:10:1); stain, PMA) was achieved. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as orange oil (2.67 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH:32][C:14]([C@@H:9]3[CH2:10][CH2:11][CH2:13][CH2:33][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
The title compound was prepared by substituting (D)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.35-7.39 (m, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.21 (t, J=7.2 Hz, 2H), 4.86-4.88 (m, 1H), 4.25-4.30 (m, 1H), 4.08-4.12 (m, 1H), 3.58 (d, J=13.2 Hz, 1H), 3.47 (d, J=13.1 Hz, 1H), 3.29 (td, J=12.8, 3.1 Hz, 1H), 2.80 (d, J=6.1 Hz, 1H), 2.49-2.56 (m, 1H), 2.42-2.47 (m, 2H), 2.36 (dd, J=9.0, 3.2 Hz, 1H), 2.32 (d, J=7.7 Hz, 1H), 2.22-2.26 (m, 1H), 2.03-2.11 (m, 1H), 1.79-1.93 (m, 1H), 1.49-1.68 (m, 5H), 1.48 (s, 9H), 1.32-1.44 (m, 2H); MS (ESI+) m/z 428 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([CH2:14][OH:15])=[CH:11][CH:10]=[CH:9]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([CH:14]=[O:15])=[CH:11][CH:10]=[CH:9]2
Reactant: COCc1cccc2cccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCc1cccc2cccc(C=O)c12
Reaction time: 1 h

Procedure:
(8-Methoxymethyl-naphthalen-1-yl)-methanol (Tetrahedron Lett. 1997; 38, 8161-8164) (0.36 g, 1.8 mmol) was dissolved in dichloromethane (10 mL). To the solution was then added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, also known as Dess-Martin periodinane (1.5 g, 3.6 mmol). The reaction mixture was stirred for 1 hr, then partitioned with an aqueous saturated solution of thiosulfate and dichloromethane. The organic layer was washed with an aqueous saturated solution of thiosulfate, an aqueous saturated solution of sodium bicarbonate, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield crude 8-methoxymethyl-naphthalene-1-carbaldehyde which was used directly into the next step.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][C:34](=[O:35])[CH:33]=[CH:32][C:31]5[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:29]([O:28][CH3:27])[CH:30]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Oc2cc3c(cc2OC)CC2c4cc(OC)c(OC)cc4CCN2C3)cc1OC
Yield: 37.4 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4-dimethoxycinnamoyl chloride and 20 ml of anhydrous pyridine and there was obtained 1.0 g (38.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4'-dimethoxycinnamoyloxy)-8H-dibenzo[a, g] quinolizine as a pale brown powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 4 as determined from the melting point and IR spectrum.