Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(c2ccncc2)CC1
Temperature: 145 °C
Yield: 41.5 %

Procedure:
A stirred mixture of 4-(4-fluorobenzoyl)piperidine, hydrochloride salt (3.90 g), 4-chloropyridine, hydrochloride salt (2.85 g) and triethylamine (4.90 ml) in xylene (75 ml) was heated at 145° C. for 27 hours. The solvent was evaporated and the residue partitioned between methylene chloride (150 ml) and water (100 ml), the pH being adjusted to ˜10 with 0.880 ammonia. The aqueous phase was extracted with a further methylene chloride (50 ml). The combined organic phases were washed with water, dried (Mg SO4) and evaporated. The residue was purified by column chromatography using a 19:1 mixture of methylene chloride and methanol as eluent to give 4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine (1.89 g);
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=O.[C:18]([O:25][CH2:26][CH3:27])(=[O:24])[C:19](OCC)=O.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH2:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C1COCC1.CCO>[CH2:26]([O:25][C:18]([C:19]1[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:38]([C:35]2[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:37][CH:36]=2)[N:39]=1)=[O:24])[CH3:27]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a solution of 1M NaHMDS in THF in 120 mL of THF was added dropwise pinacolin (3.1 mL, 25 mmol) at 78° C. After 1 hour, diethyl oxalate (3.7 mL, 27.5 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction was quenched by adding 1N HCl solution (50 mL). The reaction mixture was extracted with EtOAc and dried with MgSO4. The mixture was concentrated in vacuo. The product 2h was used without further purification. To a solution of 2h (1 g, 5 mmol) in EtOH (50 mL) was added 4-methylsulfonylphenylhydrazine 1a (1.22 g, 5.5 mmol) at room temperature. The reaction mixture was stirred overnight and refluxed for 3 hour. After cooling, the solvent was removed in vacuo. The resulting solid was purified by column chromatography with hexanes/EtOAc (1:1) to afford the titled compound (1 g, 57% yield) as a white solid. mp 174.9-177.6° C. 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=9 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 6.76 (s, 1H), 4.27 (q, J=7 Hz, 2H), 3.35 (s, 3H), 1.27 (t, J=7 Hz, 3H), 1.16 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].I[CH2:28][CH2:29][O:30]C1CCCCO1.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:29][OH:30])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ICCOC1CCCCO1
Reactant: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.23 g, 0.689 mmol) was dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere. Sodium hydride (0.025 g, 1.03 mmol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-(2-iodo-ethoxy)-tetrahydropyran (0.3 g, 1.17 mmol) was added and the mixture was refluxed for 2 hours. Additional portions of 2-(2-iodo-ethoxy)-tetrahydro-pyran (0.5 g, 2 mmol) were added to the mixture during seven hours. After cooling and adding water, THF was evaporated and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 2 N aqueous sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue (which is Compound (IV) where Pr is tetrahydropyranyl) was dissolved in ethanol and acidified with 2 N aqueous hydrogen chloride solution. The mixture was stirred at room temperature over night, evaporated and extracted with dichloromethane. After washing with water the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography with dichloromethane/methanol 9.5/0.5 as eluent. Yield 0.17 g, 59%.
Reaction SMILES: [NH2:1][CH:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([C:16]([CH:18]=[CH2:19])=O)C.[CH2:20](O)CCC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([C:18]1[CH:19]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:1][CH:20]=1)[CH3:14]
Reactant: C=CC(=O)CC
Reactant: CCOC(=O)CC(N)C(=O)OCC
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Yield: 84.6 %

Procedure:
Diethyl 1-amino-1,2-ethylenedicarboxylate (1.7 g) and α-ethylacrolein (0.84 g) are dissolved in n-butanol (10 ml), and thereto is added p-toluenesulfonic acid (35 mg). The mixture is refluxed for 15 hours (the degree of reaction of aminodiester is 97%). After distilling off the solvent, the residue is subjected to silica gel column chromatography, eluting with chloroform/methanol (1:0-1:0.01), to give diethyl 5-ethylpyridine-2,3-dicarboxylate (1.93 g., 84.6%). The product has a purity of 92.2% by liquid chromatographic analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:20](=[O:21])[CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1cccc(F)c1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(F)c2)c1C

Procedure:
4-[2-(3-Fluorophenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-Fluorophenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 93%. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.61 (s, 3H), 4.03 (s, 2H), 4.35 (q, 2H), 7.00 (m, 3H), 7.27 (m, 1H), 7.49 (d, 1H), 9.57 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): □□□ 11.76, 14.38, 46.93, 60.84, 113.64, 116.30, 125.13, 127.17, 129.94, 137.42, 161.64, 193.02 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.76, 14.38; CH2 carbons: 46.93, 60.84; CH carbons: 116.30, 125.13, 127.17, 129.94 ppm. LC/MS: 91.29%, m/z=289.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([NH:12][C:11](=S)[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1.[NH3:24].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:15]3([CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:8]3([N:12]=[C:11]([NH2:24])[C:10]([CH3:14])=[N:9]3)[C:6]=2[CH:7]=1
Reactant: N
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(=S)N1
Solvent: CO
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazole]-4″(3″H)-thione (Example 29 Step 3, 365 mg, 0.92 mmol) and 7M ammonia in MeOH (10 mL, 70.00 mmol) was prepared in a microwave vial. The vial was sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in 7M ammonia in MeOH (4 mL) and heated once more at 120° C. for 30 min using MW. Again, the mixture was concentrated, 7M ammonia in MeOH (10 mL, 70.00 mmol) was added and the mixture was heated at 120° C. The mixture was concentrated and the crude product was dissolved in 20% MeOH in DCM and filtered through a silica pad and eluted with 20% MeOH in DCM. After concentration of the organic layer, DCM was added to the residue. A solid was formed which was filtered off and washed with DCM, yielding 94 mg of the title compound (27% yield). The mother liquor was concentrated, Et2O was added and the solid was filtered off and dried, yielding a second crop of the title compound (85 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (d, 1 H), 1.43 (m, 3 H), 1.80 (d, 2 H), 1.95 (m, 2 H), 2.20 (s, 3 H), 3.07 (d, 1 H), 3.21 (s, 3 H), 6.68 (d, 1 H), 6.74 (br. s., 2 H), 6.87 (d, 1 H), 7.31 (dd, 1 H); MS (ES+) m/z 379 [M+H]|.
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5](Cl)=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.CCOCC>[Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: Clc1ccc2sc3c(Br)cnc(Cl)c3c2c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncc(Br)c3sc4ccc(Cl)cc4c23)cc1
Reaction time: 0.05 h

Procedure:
A mixture containing 4-bromo-1,8-dichloro[1]benzothieno[3,2-c]pyridine-4-methoxybenzylamine (5 equiv), K2CO3 (4.0 equiv) in DMF (0.2 M) was placed in a microwave reactor at 200° C. for 3.3 min. The reaction was diluted with EtOAc and ether and washed with H2O. The organic solvents were separated and evaporated. The desired product was purified by flash chromatography (10% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:36]2[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=2)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1ccc(F)c(F)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: Cc1ccccc1
Solvent: CCO
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(F)c(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 90 °C
Yield: 99.8 %

Procedure:
9-Benzyloxy-6-[(2-bromophenyl)methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (169) (150 mg, 0.311 mmol) and 3,4-difluorphenylboronic acid (56.5 mg, 0.358 mmol) were suspended in a mixture of toluene/ethanol (10 ml/1 ml), treated at room temperature under argon with tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.4 μmol) and 2M sodium carbonate solution (342 μl, 684 μmol) and the reaction mixture was then heated at 90° C. for 7 h. The reaction was quenched with water and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 25 g silica gel with methanol/dichloromethane (gradient: 0 to 10% methanol). All fractions containing product were combined and concentrated to afford 9-benzyloxy-6-[[2-(3,4-difluorophenyl)phenyl]methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (160 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10])(C)(C)C.O.[ClH:20]>CCOCC>[ClH:20].[NH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: N#C[C@@H]1CCCN1C(=O)CN
Reaction time: 1 h
Yield: 98 %

Procedure:
(S)-[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1c (13.7 g, 54.2 mmol) was dissolved in 140 mL of ether and 40 mL of water with stirring. Upon cooling by an ice-water bath, 37% hydrochloric acid (90 mL) was dropwise added and the reaction mixture was stirred for 1 hour at the same temperature. The mixture was concentrated under reduced pressure and the residue diluted with ether was filtered with a filtering centrifuge to obtain the title compound (S)-1-(2-amino-acetyl)-pyrrolidine-2-carbonitrile hydrochloride 1d (10 g, yield 98%) as a white powder.
Reaction SMILES: [N:1]1([CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N+:15]([O-])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N.[H][H].C[OH:28]>[Ni]>[NH2:15][C:9]1[CH:8]=[C:7]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:10]=1[C:11]([NH2:12])=[O:28]
Reactant: N#Cc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Reactant: CO
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NC(=O)c1ccc(C(c2ccccc2)n2ccnc2)cc1N
Yield: 82.9 %

Procedure:
A solution of 6 parts of intermediate 52, namely 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzonitrile, in 316 parts of methanol saturated with ammonia was hydrogenated at room temperature and normal pressure with 3 parts of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was co-evaporated with a mixture of methanol and methylbenzene, yielding 4.8 parts (82.9%) of 2-amino-4-[(1H-imidazol-1-yl)phenylmethyl]benzamide (interm. 53).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16]#[N:17]>O1CCOCC1>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCCCCl
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 23.6 grams of benzimidazole in 300 ml of dioxane was added 9.8 grams of a 50% dispersion of sodium hydride in mineral oil and the resulting mixture was stirred at room temperature for two hours. A solution of 20.7 grams of 4-chlorobutyronitrile in 100 ml of dioxane was added and the mixture was refluxed for 5 hours. Then, an additional 3 grams of sodium hydride suspension was added and the mixture was refluxed for 17 hours. The mixture was then filtered, concentrated, and washed with petroleum ether to remove the mineral oil. The residual brown oil was then chromatographed on silica gel packed with chloroform and eluted with chloroform and chloroform containing increasing quantities of methanol. The fractions eluted with 0.5% and 1% methanol were combined and the solvent was evaporated to leave residual crude 1H-benzimidazole-1-butanenitrile.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([O:35]CC)=[O:34])[CH:21]([C:28]([O:30]CC)=[O:29])[CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])[CH3:15].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([OH:35])=[O:34])[CH:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])=[O:18])[CH3:15]
Reactant: CCOC(=O)CC(C(=O)OCC)C(CC(=O)N(Cc1ccc2ccccc2c1)C(C)C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)CC(C(=O)O)C(CC(=O)O)C(=O)O
Reaction time: 8 h
Yield: 52 %

Procedure:
The N-acylated compound obtained in the above step (1) was treated in the same manner as in Example 27 to obtain triethyl 4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-1,2,3-butanetricarboxylate. The obtained ester was dissolved in 1 ml of tetrahydrofuran, and then 0.5 ml of a 3N sodium hydroxide aqueous solution was added thereto. The mixture was left to stand at room temperature overnight. The reaction solution was diluted with ethyl acetate and then acidified by an addition of 1N hydrochloric acid, and it was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Lobar column™, size A, RP-8, manufactured by Merck Co.; acetonitrile/0.1% trifluoroacetic acid aqueous solution=1/1) to obtain 14 mg (yield: 52%) of the above-identified compound as white powder.
Reaction SMILES: [Mg+2].[Br-].[Br-].CCOCC.C(N(C(C)C)CC)(C)C.[C:18]([C:21]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH:22]=1)([CH3:20])=[CH2:19].C[O:28][C:29](=O)[CH:30]=[CH2:31]>C(Cl)Cl>[CH3:19][C:18]1[CH2:20][CH2:31][C@@H:30]2[C@@H:22]3[C:21]=1[CH2:25][CH2:24][C@@H:23]3[O:26][C:29]2=[O:28]
Reactant: C=C(C)C1=C[C@@H](O)CC1
Reactant: C=CC(=O)OC
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C2CC[C@@H]3OC(=O)[C@H](CC1)[C@H]23
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
Anhydrous MgBr2.Et2O (759.2 mg, 2.940 mmol) was suspended in DCM (3.5 mL), treated with Diisopropylethylamin (1.0, 760 mg, 5.880 mmol) and stirred for 15 minutes until the suspension turns magenta. Then compound (7a) (182.4 mg, 1.469 mmol) dissolved in DCM (11.5) was added slowly within 15 minutes. After stirring for 1 hour Methylacrylate (0.27 mL, 257.9 mg, 2.995 mmol) was added dropwise. The resulting mixture was stirred for 5½ hours before it was quenched with saturated aqueous NH4Cl. For a better phase separation potassium sodium tartrate was added and the solution extracted with DCM (4×). The combined extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (hexane/EtOAc 6/1) furnished 194.3 mg of compound (8a) as white solid with 74% yield.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[C:8]([OH:17])(=[O:16])[C@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[OH:10].C(O)CO>O>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:13]([C@H:11]([C@@H:9]([C:8]([O-:17])=[O:16])[OH:10])[OH:12])([O-:15])=[O:14]
Reactant: O=C(O)C1CCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: OCCO
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]

Procedure:
The method described in Example 1 above was followed using DL-AzeOH (2.9 g; 29 mmol), D-tartaric acid (4.3 g; 29 mmol), ethylene glycol (5.5 g) and water (4.5 g) to yield 3.9 g (109%, as calculated from the theoretical yield) of L-AzeOH-D-tartrate with a d.e. of 60%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][C:8]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccccc2)c2ccc(O)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
(E)-1-(3-Hydroxyphenyl)-3-phenylprop-2-en-1-one (48.7 g, 217 mmol) obtained in Step 1 and CF3COOH (161 mL, 10 eq) were placed into a flask and stirred for 24 h at 80° C. After cooling to room temperature, toluene (200 mL) was added and the solution was concentrated to remove TFA under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated in vacuo to obtain the desired product (48.0 g, 99%).
Reaction SMILES: BrBr.Br[C:4]12[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]3[CH:18](Br)[C:8]1([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=13)[CH2:7][N:6]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]2=[O:31].C([SnH](CCCC)CCCC)CCC.C1C=CC=CC=1>C(Cl)Cl>[CH:25]1([CH2:24][N:6]2[CH2:7][C:8]34[CH2:18][CH:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:4]3[C:5]2=[O:31])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]4=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C1N(CC2CCCCC2)CC23c4ccccc4C(c4ccccc4C12Br)C3Br
Agent: BrBr
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C1C2c3ccccc3C3CC2(CN1CC1CCCCC1)c1ccccc13

Procedure:
The above product (2.94 g) is treated with 1.41 g of bromine in methylene chloride at room temperature. The resulting crude 12b,13-dibromo-2-cyclohexylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrol-1-one is heated under reflux with 9 g of tributyltin hydride and 25 ml of anhydrous benzene for 3 days. The benzene is removed and the residue is concentrated further using short-path distillation (1 micron, 125° bath temperature). Crystallization of the residue from isopropyl alcohol gives 2.39 g of 2-cyclohexylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrol-1-one; nmr spectrum: τ 2.2-3.3 (m, 8); 5.9-6.2 (m, 2); 6.6-7.0 (m, 4); 8.1 (m, 2) and 8.1-9.7 (m, 11).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:29][C:30]=1[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccccn4)s3)n2)CC(C)(C)N1
Yield: 13 %

Procedure:
The title compound was prepared as described for Example 25, using [4-(5-bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5) and 3-tributylstannylpyridine. Yield: 13%.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[C:12](=[CH2:13])[C:9]2([CH3:11])[CH3:10].C(OOC(C)(C)C)(C)(C)C.[OH-].[Na+]>>[CH3:10][C:9]1([CH3:11])[CH:8]2[CH2:17][CH:14]([CH2:15][CH2:16]2)[CH:12]1[CH2:13][CH2:6][C:5]([OH:4])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C2CCC(C2)C1(C)C
Agent: CC(C)(C)OOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C2CCC(C2)C1CCC(=O)O

Procedure:
To refluxing acetic anhydride (1050 g., 10 moles), there is added dropwise over six hours a solution of camphene (136 g., 1 mole) and di-tert-butyl peroxide (0.1 mole, 14.6 g.). After complete addition, the mixture is heated at reflux for five hours. The cooled reaction mixture is concentrated under reduced pressure to leave a yellow-orange residual oil, 750 ml. of 2.5N NaOH is added to the residue which is then heated on the steam bath for one hour. The cooled solution is extracted once with ether, made acidic with concentrated HCl, and extracted thoroughly with ether. The dried (Na2SO4) ether extracts are concentrated under reduced pressure and the residue distilled under vacuum.