Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][N:51]=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 80 °C
Reaction time: 26.6 h
Yield: 44.3 %

Procedure:
To 100 mg (0.15 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 64 mg (0.44 mmol) of 2-chloro-5-methoxypyrimidine and 1 ml of 1,4-dioxane were added, and the reaction solution was stirred at 80° C. for 26.6 hours. After completion of the reaction, 0.5 ml of 6 N hydrochloric acid was added to the reaction solution and the mixture was stirred at 50° C. for 8 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=4/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 44 mg of the title compound as a white powder (yield: 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
Step 1 7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, intermediate 9), tert-butyl 2-bromoacetate (0.34 mL, 2.36 mmol), and potassium carbonate (0.45 g, 3.21 mmol) were combined in DMF (20 mL) and heated at 50° C. for 2 h. The reaction was cooled to room temperature diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to give tert-butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (1.24 g, 100% yield) as a clear oil. LCMS retention time=4.817 minutes and 97% purity, LCMS MH+ 581.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[O:11]1[CH2:35][CH:12]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]3[O:34][CH2:33]3)=[CH:26][CH:25]=2)([CH3:23])[CH3:22])=[CH:17][CH:16]=1>C(O)(C)(C)C>[OH:34][CH:32]([CH2:33][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1])[CH2:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([OH:11])[CH2:35][N:3]3[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]3([CH3:10])[CH3:1])=[CH:16][CH:17]=2)([CH3:22])[CH3:23])=[CH:29][CH:28]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CC(C)(C)O
Product: CC(C)(c1ccc(OCC(O)CN2C(C)(C)CCCC2(C)C)cc1)c1ccc(OCC(O)CN2C(C)(C)CCCC2(C)C)cc1

Procedure:
To 50 ml of t-butanol were added 14.1 g of 2,2,6,6-tetramethylpiperidine and 10.2 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane, and the mixture was reacted following the procedure described in Example 21 to give the desired Compound No. 1 in the form of white crystals melting at 110°-112° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](Cl)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[NH3:20]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([NH2:20])=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: N
Reactant: O=C(Cl)C1(CCCCl)CC=CCC1c1ccccc1
Solvent: ClCCl
Product: NC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Reaction time: 16 h
Yield: 85 %

Procedure:
1-(3-chloropropyl)-6-phenyl-3-cyclohexane-1-carboxylic acid (4.95 g, 17.6 mmol) was dissolved in methylene chloride and stirred under N2 at ambient temperature. Oxalyl chloride (2 equiv., 4.47 g) was added and the solution was allowed to stir for 16 hrs. The solution was concentrated to vacuo to afford the corresponding acid chloride (5.18 g, 100% yield) as a light yellow mobile oil. The infrared spectrum indicated the disappearance of the carboxyl carbonyl stretch of the starting material at 1700 cm-1 and the appearance of the acid chloride carbonyl stretch at 1790 cm-1. 1-(3-Chloropropyl)-6-phenyl-3-cyclohexene-1-carbonyl chloride (11.40 g, 38.6 mmol) was dissolved in methylene chloride (100 ml) into which ammonia is bubbled into the solution for 15 mins. via a gas dispersion tube. After stirring for 16 hrs. water was added to the solution and the organic fraction was dried over MgSO4, filtered and concentrated in vacuo to afford 9.05 g (85% yield) of 1-(3-chloro-propyl)-6-phenyl-3-cyclohexene-1-carboxamide as a viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Si:19]([O:18][CH2:17][CH2:16][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:14])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
7-Nitro-3,4-dihydroquinolin-2(1H)-one, (2-bromoethoxy)(tert-butyl)dimethylsilane, potassium carbonate, potassium iodide and water were added to DMF, followed by stirring at room temperature for 2 days and then stirred at 40° C. for 3 days. By post-treating the reaction liquid, 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-nitro-3,4-dihydroquinolin-2(1H)-one was obtained.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:48])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20][NH2:48])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)n1nnc(C)n1

Procedure:
3-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)propanol Vh1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])=[O:16])=[CH:11][CH:10]=1>S([O-])([O-])(=O)=O.[Cu+2].O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=2)=[O:16])=[O:18])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 27.5 g of copper sulfate (0.11 mol), 25 g of pyridine and 10 g of water was heated until the copper sulfate was completely dissolved. Then, 13.5 g of 2 (0.05 mol) was added, and the heating was continued for 2 hours.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[N:3]=[C:4]1[C@H:9](CCC)[CH2:8][C@H:7]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:5]12[CH3:6])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[CH:17][C:16]=1[CH2:15][CH2:14]3.BrCCC>>[CH3:27][N:2]([CH3:1])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:5]12[CH3:6])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH3:26])=[CH:17][C:16]=1[CH2:15][CH2:14]3
Reactant: CCC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=NN(C)C
Solvent: CCCBr
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NN(C)C)CC[C@@H]12

Procedure:
According to 1(b) 5.4 g of 3-methoxy-16α-propyl-1,3,5(10)-estratrien17-one N,N-dimethylhydrazone, m.p. 83°-85° C., is obtained from 5.0 g of 3-methoxy-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone with 1-bromopropane after crystallization from acetonitrile. By reaction with CuCl2.2H2O according to 1(c) 4.1 g of 3-methoxy-16α-propyl-1,3,5(10)-estratrien-17-one, m.p. 98°-100° C. (from acetonitrile), is obtained from 5.0 g of hydrazone, and 3.2 g of the 17-ketone yields with sodium borohydride according to 1(d) 2.1 g of 3-methoxy-16α-propyl-1,3,5(10)-estratrien-17β-ol, m.p. 54°-56° C. (from acetonitrile). By Birch reduction, acid hydrolysis, reaction with pyridine hydrobromide perbromide, acetylation in the 17-position, ketalization and deketalization in the 3-position 17β-acetoxy-16α-propyl-5(10)-9(11)-estradien-3-one is obtained as an oil.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([NH2:26])[CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1N
Product: Cc1ccc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)cc1N

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-amino-4-methyl-phenylboronic acid. Mass spectrum (ESI) 421.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(=O)O)cn1
Yield: 34.3 %

Procedure:
As described for example 283, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (250 mg, 0.7 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (83 mg, 35%) which was obtained as a white solid. MS: m/e=344.3 [M+H]−.
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[N:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[C:13]1([C:12]#[C:11][C:9]2[CH:10]=[C:5]([CH:4]=[O:19])[CH:6]=[N:7][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1cncc(C#Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
Charge an oven dried round bottom flask under nitrogen with a solution of N-methoxy-N-methyl-5-phenylethynylnicotinamide (2.00 g, 7.51 mmol), (prepared essentially as described in PREPARATION 2), in anhydrous toluene (20 mL) and cool to −78° C. Add a 1 M solution of diisobutylaluminum hydride in toluene (18 mL, 18 mmol) dropwise over 30 min and stir for an additional 30 min. Rapidly add methanol (15 mL) and warm to room temperature. Pour the reaction mixture into 100 mL of a saturated aqueous solution of Rochelle salt (potassium sodium tartrate) and stir vigorously for about 30 min. Upon standing, separate the organic layer, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 hexanes:ethyl acetate, to obtain the title compound as a white solid (1.2 g, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C@@H:4]1[NH:8][C:7](=[O:9])[CH2:6][C:5]1=[O:10].[H][H]>C(O)C.[Ni]>[OH:10][C@@H:5]1[C@H:4]([CH2:3][CH:2]([CH3:1])[CH3:11])[NH:8][C:7](=[O:9])[CH2:6]1
Reactant: CC(C)C[C@@H]1NC(=O)CC1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)C[C@@H]1NC(=O)C[C@@H]1O
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A solution of 5 g of (S)-5-(2-methylpropyl)-2,4-pyrrolidinedione in 250 ml of ethanol is treated with 2 g of Raney nickel (washed to neutral) and exposed to hydrogen gas at 50 pounds per square inch (psi). After 5 hours, hydrogen uptake ceases, the catalyst is filtered and the filtrate evaporated to a gum. The gum is taken up in chloroform and the chloroform is evaporated. The resulting gum is dissolved in chloroform, filtered through a 250 ml bed of silica gel in chloroform and eluted with chloroform-methanol (96:4) to afford 3.2 g of (4S-cis)-4-hydroxy-5-(2-methylpropyl)-2-pyrrolidinone after crystallization from 12 ml of hot ethyl acetate, 120 ml isopropyl ether and gradual cooling to 10° C.; mp 71°-73° C. [α]D23 =-19° (C=0.7% chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]1[CH:15]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:8].C(N(CC)CC)C.[CH2:47]([C:63]1([CH3:90])[CH2:72][CH2:71][C:70]2[C:65](=[C:66]([CH3:89])[C:67]([CH3:88])=[C:68]([O:74][CH2:75][CH2:76][O:77][C:78](=O)[O:79]N3C(=O)CCC3=O)[C:69]=2[CH3:73])[O:64]1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62].CO.C(Cl)(Cl)Cl>ClCCl>[CH2:47]([C:63]1([CH3:90])[CH2:72][CH2:71][C:70]2[C:65](=[C:66]([CH3:89])[C:67]([CH3:88])=[C:68]([O:74][CH2:75][CH2:76][O:77][C:78](=[O:79])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]3[CH:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:16][CH:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:8])[C:69]=2[CH3:73])[O:64]1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)ON3C(=O)CCC3=O)c(C)c(C)c2O1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCC1(C)CCc2c(C)c(OCCOC(=O)NCCCCCC(=O)N3CC(O)CC3C(OC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ccccc3)c(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
Amine 5 (8.7 g, 16.3 mmol) was dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. To the solution were added triethylamine (5.06 g, 6.73 mL, 50 mmol) and compound 18 (10 g, 16.2 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further for 6 h. The completion of the reaction was ascertained by TLC (10% MeOH/CHCl3). The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3, water followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude product. Compound 19 (14.5 g, 88%) was obtained as a white foamy solid after column chromatography over silica gel.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]1(/[CH:23]=[CH:22]/[CH2:21][C@H:15]([C@H:14]([OH:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)C[C@@H](C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](C/C=C/c1ccccc1)[C@@H](C)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of diisopropylamine (47.1 g, 466.1 mmol) in THF (500 mL) cooled to −50° C. is added n-butyllithium (466.1 mmol, 2.5M in hexanes) and the resulting solution is stirred at −50° C. for 0.5 h. The reaction mixture is cooled to −78° C. followed by slow addition of methyl (3R)-3-hydroxybutanoate (25 g, 211.9 mmol). After 0.5 h a solution of cinnamyl bromide (45.9 g, 233.0 mmol) in HMPA (10 mL) is added and the reaction mixture is allowed to warm to 0° C. and stirred for 16 h. The reaction mixture is quenched by addition 30 mL of saturated aqueous ammonium chloride solution, is poured into 400 mL of 1 M hydrochloric acid, and is extracted with two 500 mL portions of ethyl acetate. The combined organic layers are dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 25% ethyl acetate-hexanes) to afford methyl (2R,3R)-2-[(2E)-3-phenyl-2-propen-1-yl]-3-hydroxybutanoate as a yellow oil (42 g, 85% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[Na].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C2CCCN(C1)C2
Temperature: 100 °C

Procedure:
A solution of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (173.8 mg, 0.768 mmol; Example 201) in dimethyl sulfoxide (3 mL) was treated with sodium (30% dispersion in paraffin; 87.7 mg, 1.144 mmol; Aldrich), 2-methyl-5-vinylpyridine (204.6 mg, 1.717 mmol; prepared as described in International Publication No. WO 2001017968) and hydroquinone (28.6 mg, 0.260 mmol; Aldrich). The reaction was purged with nitrogen for 15 minutes, then heated to 100° C. for 17 hours. After cooling, the reaction was partitioned between 1 M K2CO3 (35 mL) and chloroform (3×35 mL). The combined organic layers were washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated. Methanol (10 mL) was added to the residue and the resulting suspension was filtered through diatomaceous earth, then purified by preparative HPLC (Phenomenex® Luna® Combi-HTS™ C8(2) 5 μm 100 Å AXIA™ 30×75 mm column, gradient of 10-100% acetonitrile in 0.1% trifluoroacetic acid, flow rate 50 mL/minute) to afford the title compound as the bis trifluoroacetic acid salt: 1H NMR (300 MHz, methanol-d4) δ ppm 1.54-1.78 (m, 3H), 1.95-2.05 (m, 1H), 2.41 (s, 3H), 2.67 (s, 3H), 3.42-3.55 (m, 4H), 3.68-3.72 (m, 1H), 4.34-4.41 (m, 1H), 4.48-4.57 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.27 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 8.03 (dd, J=8.3, 2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnn(Cc2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cnn(Cc2ccccc2)c1
Reaction time: 1.5 h
Yield: 46.2 %

Procedure:
(1-Benzyl-1H-pyrazol-4-yl)methanol (190 mg, 1.0 mmol) in DCM (8 mL) at rt was treated with Dess-Martin periodinane (670 mg, 1.58 mmol). After 1.5 h, the reaction was quenched with a mixture of saturated solution of sodium thiosulfate and 10% NaHCO3 (1:1) at rt, stirred for 30 min before extraction with DCM (3×30 mL). The combined extracts were washed with a saturated aqueous solution of NaHCO3, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-40% EtOAc/heptane provided 1-benzyl-1H-pyrazole-4-carbaldehyde (86 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (s, 2H), 7.27-7.30 (m, 2H), 7.36-7.43 (m, 3H), 7.88 (s, 1H), 8.01 (s, 1H), 9.85 (s, 1H); LCMS-MS (ESI+) 186.90 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)N(Cc2ccccc2)Cc2ccccc2)c(C)c1

Procedure:
A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 5.32 g. of dibenzylamine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,1-dibenzyl-3-(2,4-dimethylphenyl)urea, m.p. 124°-126° C.