Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:36]
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (6.1 mg, 0.021 mmol) in 0.7 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0033 mL, 0.023 mmol) and the reaction stirred at rt. After 1 hour the reaction was quenched with MeOH, evaporated, triturated with hot EtOAc, hexane added, and the solid filtered to give the title compound as a white solid (8.8 mg, 85%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.77-8.82 (m, 1H), 8.63 (br. s, 1H), 8.33 (d, J=3.2 Hz, 1H), 8.09-8.13 (m, 1H), 7.54-7.59 (m, 2H), 7.29-7.48 (m, 5H), 7.06-7.12 (m, 2H), 4.34-4.42 (m, 1H), 3.79-3.87 (m, 1H), 3.54-3.69 (m, 2H), 3.00-3.11 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH:4]([C:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[CH:7][CH:6]=1>CO.[Pd]>[CH3:26][N:2]([CH3:1])[CH2:3][CH:4]([C:19]1([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: CN(C)CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Yield: 80.5 %

Procedure:
1-[2-(Dimethylamino)-1-(4-benzyloxyphenyl)ethyl]cyclohexanol (30 g) was dissolved in methanol (600 ml), charged with 10% palladium on carbon (3 g) and hydrogenated pressure for 6 h at room temperature. The catalyst was filtered, washed with methanol, and combined filtrate evaporated under reduced pressure to give 18 g (81.08%) of the 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]/[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2ccccc2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
E-(R)-1-(2-((2-(2-Methylphenyl)-2-phenylethenyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (1.1 g, 0.0028 mol, prepared similarly to the method described in Example 50) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.7 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid solution (ca. 1.0 ml) was added (with cooling) followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to provide the title compound (0.70 g, 62%).
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.I[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]>C1COCC1.C(OCC)(=O)C>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)CCI
Reactant: COC1=NC(C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirred solution of 2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (1 mL, 5.58 mmol) in THF (13.5 mL) under argon at −78° C. was added a solution of n-butyllithium (2.5 M, 2.3 mL, 5.75 mmol). The solution was stirred at −78° C. for 30 minutes. A solution of 1-Iodo-3,3,3-trifluoropropane (925 μL, 5.87 mmol) in THF (11.5 mL) was added slowly. The resulting solution was stirred at −78° C. for 5 hours, warmed to room temperature and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NH4Cl solution, water and brine. The organic layer was then dried (MgSO4), concentrated and purified by flash chromatography to yield 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine (915 mg, 59%). 1H-NMR: 400 MHz, (CDCl3) δ: 4.04-3.99 (m, 1H), 3.98-3.95 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.29-2.20 (m, 1H), 2.18-2.04 (m, 3H), 1.94-1.84 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[CH2:23][C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1.[N:33]([O-])=[O:34].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]2[N:4]([N:30]=[N:31][N:32]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20]([NH:21][C:22](=[O:28])[C:23](=[N:33][OH:34])[C:24](=[O:27])[CH2:25][Cl:26])[C:19](=[O:29])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)nn2nnnc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NO)C(=O)CCl)[C@H]3SC2)nn2nnnc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-7-(4-chloro-3-oxobutyramido)-3-cephem-4-carboxylic acid (6.72 g; 0.0171 mole) in acetic acid (60 ml), a solution of sodium nitrite (1.65 g; 0.0239 mole) in water (6 ml) was added at 5°-10° C. After stirring for 3.5 hours at room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (4×200 ml). The combined extracts were washed with water, dried over NaSO4 and evaporated to a foam. Trituration of this product with diethyl ether afforded the title compound as a beige powder, 6.3 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:38]1([CH2:44][CH2:45][CH2:46]O)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[N:13]1([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([O:1][CH2:46][CH2:45][CH2:44][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Reactant: OCCCN1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1cc2cc(OCCCN3CCCCC3)ccc2[nH]1)N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 246 mg (1 mmol) (5-hydroxy-1H-indol-2-yl)-morpholin-4-yl-methanone, 1 g (ca. 3 mmol) polymerbound triphenylphospine (Fluka), 179 mg (1.25 mmol) piperidinepropanol and 461 mg (2 mmol) di-tert.-butyl azadicarboxylate in 20 ml THF was stirred for a prolonged period of time at room temperature. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 98/2 to DCM/2N NH3 in methanol 9/1. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after drying at 40° C. under vacuum 47 mg (13%) of the title compound as white solid. MS (m/e): 372.4 (MH+, 100%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH:21]([C:23]#[N:24])[CH2:20][CH2:19][O:18]2)[C:12]([F:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:25][C:12]1[C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH:21]([C:23]#[N:24])[CH2:20][CH2:19][O:18]2)=[N:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: N#CC1CCOC(CNc2nc(OCc3ccccc3)ccc2F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: N#CC1CCOC(CNc2nc(O)ccc2F)C1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 95.8 %

Procedure:
A mixture of 4-(((6-(benzyloxy)-3-fluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.586 mmol), AMMONIUM FORMATE (111.3 mg, 1.758 mmol) and Pd—C (10%, wet, 25 mg) in methanol (4 ml) was stirred at 70° C. for 45 min and cooled. The mixture was then filtered to remove Pd—C and inorganics, the filterate was then concentrated and dried further via high vacuum to afford 141 mg (96% yield) of the crude product as a light pink solid. LCMS (m/z): 252.1 [M+H]+; retention time=0.540 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:25])[CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1
Reactant: CC(C)n1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reaction time: 5 h
Yield: 59.6 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) and 10% Pd—C (0.444 g) in EtOH (40 mL) was hydrogenated under balloon pressure at room temperature for 5 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (670 mg) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].C(OCC)(=O)C.O>CN(C)C=O>[F:8][C:9]([F:16])([F:15])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N=c1cccc[nH]1)C(F)(F)F
Temperature: 57.5 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
In 25 ml of N,N-dimethylformamide, 4.7 g (50 mmol) of 2-aminopyridine was dissolved, and 35.5 g (250 mmol) of ethyl trifluoroacetate was added thereto. After that, the mixture was stirred at 55 to 60° C. for 15 hours, and then 100 ml of ethyl acetate and 100 ml of water were added thereto. The resultant mixture was stirred, and then phase separation was conducted. The ethyl acetate layer was further washed with 100 ml of water and with 100 mL of aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, 9.05 g of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide was obtained (95.6%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][C:8]=1[O:9][CH3:10].[Br:20][C:21]1[CH:22]=[C:23]([C:34](O)=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28]=2[CH:29]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:34]([NH:1][CH2:2][C:3]2[C:4]([CH3:19])=[CH:5][C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[N:7][C:8]=2[O:9][CH3:10])=[O:35])[C:24]2[C:25]([CH3:33])=[CH:26][N:27]([CH:30]([CH3:31])[CH3:32])[C:28]=2[CH:29]=1
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.40 g, 1.496 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.44 g, 1.486 mmol), and HOAt (0.21 g, 1.543 mmol) in DMF (25 mL) was added EDC free base (0.25 g, 1.610 mmol). The reaction was stirred at RT overnight then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 30% EtOAc in hexanes) to give the product tert-butyl (5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.81 g, 1.485 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.42 (s, 1H), 8.41 (t, J=4.8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.99 (d, J=1.8 Hz, 1H), 4.40 (d, J=5.1 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 2.10 (d, J=1.0 Hz, 3H), 1.47 (s, 9H), 1.38 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 545.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[CH3:12])=[O:9])[CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: CC(NC(=O)c1cc(N)ncn1)c1ccc(OCC(F)(F)F)nc1
Reactant: O=C(Cl)C1CC1
Product: CC(NC(=O)c1cc(NC(=O)C2CC2)ncn1)c1ccc(OCC(F)(F)F)nc1

Procedure:
The title compound is prepared from 6-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (30 mg, 0.09 mmol, Step-1 of Example 117, single enantiomer) and cyclopropanecarbonyl chloride (14 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH:4]=[CH:5][Cl:6].[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].N1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:8]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][Cl:1])/[CH:4]=[CH:5]/[Cl:6]
Reactant: O=C(C=CCl)CCl
Reactant: COC(=O)CC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C(=O)OC)=C(/C=C/Cl)CCl

Procedure:
Titanium tetrachloride (0.1 dm3, 0.9 mole) in carbon tetrachloride (0.1 dm3) was added to stirred tetrahydrofuran (0.25 dm3) at 0° over 5 minutes. To the yellow solution a premix of 1,4-dichloro-3-buten-2-one (0.0556 kg, 0.4 mole) and dimethyl malonate (0.0528 kg, 0.4 mole) in tetrahydrofuran (0.2 dm3) was added dropwise over 10 minutes maintaining the temperature at 0°. A solution of pyridine (0.13 dm3, 1.6 moles) in tetrahydrofuran (0.1 dm3) was added to the above brown mixture dropwise over 30 minutes at 0° and the resultant mixture stirred at ambient temperature for three hours and then treated with water (1 dm3). The mixture was separated, the aqueous phase re-extracted with dichloromethane (2×0.25 dm3) and the combined organic extract washed with brine (2×0.1 dm3) and then dried over magnesium sulphate (0.10 kg). Filtration and evaporation of the filtrate under reduced pressure gave a red oil which crystallised on standing. Yield 0.064 kg (63.3%), m.p. 56°.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.O=[C:20]1[CH2:29][CH2:28][C:27]2[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=2[CH2:21]1>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=5[CH2:21]4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4nonc4c3)C(=O)C1)C2

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 402 [M+1]+.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[Br:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[C@@H:11]([OH:19])[C@@H:10]([OH:20])[C:9]([CH3:22])([CH3:21])[C:8]=2[CH:7]=1.C([Li])CCC.C(N1CCCCC1)=[O:29]>O1CCCC1>[CH2-:1][C:2]([CH3:4])=[O:3].[Br:5][C:6]1[C:15]([CH:16]=[O:29])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[C@H:11]([OH:19])[C@H:10]([OH:20])[C:9]([CH3:22])([CH3:21])[C:8]=2[CH:7]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)[C@H](O)[C@H](O)C2(C)C
Reactant: O=CN1CCCCC1
Agent: [CH2-]C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)c2cc(C=O)c(Br)cc2C(C)(C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a −78° C. solution of 9.04 g (25.6 mmol) 2-bromo-cis-6,7-dihydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene acetonide in 110 ml tetrahydrofuran was added 32.0 ml (51.1 mmol) of a 1.6M solution of n-butyllithium in hexanes. After 1 hour at −78° C., 5.79 g (51.1 mmol) of 1-formylpiperidine was added. After 20 minutes at −78° C., the resulting mixture was quenched with water. Upon warming to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography with elution with 5% ethyl acetate/hexane to yield 5.65 g (73%) of 3-bromo-cis-6,7-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde acetonide(MH+=303).
Reaction SMILES: I[Si](C)(C)C.[Cl:6][C:7]1[CH:58]=[CH:57][C:10]([CH2:11][CH:12]2[N:17]3[C:18](=[O:52])[CH:19]([NH:33][C:34]([CH:36]4[CH2:41][CH2:40][N:39](C(OCC5C=CC=CC=5)=O)[CH2:38][CH2:37]4)=[O:35])[CH2:20][N:21]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])(=[O:24])=[O:23])[CH:16]3[CH2:15][N:14]([CH:53]([CH3:55])[CH3:54])[C:13]2=[O:56])=[CH:9][CH:8]=1>C(#N)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[N:17]3[C:18](=[O:52])[CH:19]([NH:33][C:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[O:35])[CH2:20][N:21]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])(=[O:24])=[O:23])[CH:16]3[CH2:15][N:14]([CH:53]([CH3:55])[CH3:54])[C:13]2=[O:56])=[CH:57][CH:58]=1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCNCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2 h
Yield: 86.6 %

Procedure:
103 mg (0.517 mmol) of iodotrimethylsilane were added to a solution of 104 mg (0.129 mmol) of benzyl 4-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]piperidine-1-carboxylate in 2.5 ml of acetonitrile at room temperature with stirring. After 2 hours, the mixture was concentrated. The residue was purified on a Varian Bond-Elut SCX ion exchange cartridge (elution with methanol, then with 3N—NH3 in methanol). The purified amine was converted into the hydrochloride salt. 75 mg of the desired compound were obtained. LC/MS (expected monoisotopic MW=669.13; measured value (M+H)=670)
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:17])[CH:9]=[CH:10]C2C=CC=CC=2)[CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-]>O>[CH3:18][C:1]1[CH:2]=[C:3]2[C:4]([CH:10]=[CH:9][C:8](=[O:17])[NH:7]2)=[CH:5][CH:6]=1
Reactant: Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc2ccc(=O)[nH]c2c1
Yield: 903.9 %

Procedure:
N-m-tolylcinnamamide (2 g, 0.834 mmol) and AlCl3 (1.12 g, 0.834 mmol) were heated for 1 h at 100° C. Water was added and the solid was filtered to provide 1.2 g of crude product.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[Cl-].[Li+].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C([Cu])#N>O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:23]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N#Cc1ccc(Cl)cc1Br
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1C(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Bromo-4-chlorobenzonitrile (1.00 g, 4.62 mmol) was added to isopropylmagnesium chloride×lithium chloride complex (1.05 M in tetrahydrofuran, 4.62 mL, 1.05 mmol) at −15° C. under argon atmosphere. After stirring for 1.5 h 3-bromobenzoyl chloride and CuCN×2LiCl complex solution (1M in tetrahydrofuran, 0.092 mL, 0.0924 mmol) were added and the temperature was raised to 0° C. After 2 h stirring the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and diluted with water. The product was extracted with ethyl acetate and the organic phase was washed with water and concentrated. The residue was purified with flash chromatography using dichloromethane in heptane (0% to 100%) affording 1.03 g (70% yield) of the title compound. 1H NMR (DMSO-d6) δ 8.12 (d, J=8.28 Hz, 1 H), 8.00-7.92 (m, 3 H), 7.88 (d, J=2.01 Hz, 1 H), 7.77 (d, J=8.03 Hz, 1 H), 7.60-7.53 (m, 1 H); MS (ES) m/z 320, 322 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.C(N(CC)CC)C.CS(C)=O>O>[CH:8]1[C:9]2[C:4](=[C:3]([CH:2]=[O:1])[C:16]3[C:11]([C:10]=2[CH:17]=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c2ccccc2c(CO)c2ccccc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 0.83 h

Procedure:
To a solution of 1.20 g. of 10-hydroxymethyl-9-anthracenecarboxaldehyde in a mixture of 14 ml. of triethylamine and 20 ml. of dry dimethylsulfoxide is added a solution of 4.80 g. of sulfur trioxide pyridine complex in 25 ml. of dry dimethylsulfoxide. The mixture is stirred for 50 minutes and then poured into 200 ml. of water. The crystals are collected and washed with water, giving 1.18 g. of the desired product as orange crystals, mp. 224°-245° C.