Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][OH:17])[C:13]([NH2:15])=[O:14])(=O)C.[CH3:18]N.CO>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][OH:17])[C:13]([NH:15][CH3:18])=[O:14]
Reactant: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Reactant: CN
Solvent: CO
Product: CNC(=O)C(=NO)c1ccccc1CO
Yield: 67.4 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (1.00 g, E/Z≠65/35), a 40% methylamine/methanol solution (2.1 ml) and methanol (6.3 ml) was stirred at 40° C. for 6 hours. After the mixture was cooled by allowing it to stand, the solvent was evaporated under reduced pressure to obtain the crude product (E/Z≠98/2). This crude product was purified by column chromatography on silica gel (ethyl acetate) and crystallized from ethyl acetate-hexane to obtain the title compound as crystals (594 mg, E/Z≠93/7, yield: 67.4%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH:15]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH2:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: COCCC(NC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: COCCC(N)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [3-methoxy-1-(3-nitrophenyl)propyl]carbamate (1.5 g; 4.83 mmol; 1.00 eq.) in MeOH (2 mL) was added hydrogen chloride (12.08 ml; 4.00 M; 48.33 mmol; 10.00 eq.). The mixture was stirred for 2 h. After removal of the solvent, the residue was diluted with EtOAc, washed with K2CO3 solution, dried and concentrated. The crude product (1.0 g) was used as such for the next reaction without purification. LCMS [211 (M+1)].
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@@H:9]([OH:28])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([C@H:8]([NH:29][C:30](=[O:40])[O:31][C@@H:32]1[C@H:39]2[C@H:35]([O:36][CH2:37][CH2:38]2)[O:34][CH2:33]1)[C@@H:9]([OH:28])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:42]([CH3:44])[CH3:43])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(NS(=O)(=O)c1ccc(O)cc1)OC1CCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: CC(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-hydroxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.13 mmol, 75 mg) was combined with 2-bromopropane (0.26 mmol, 0.025 mL), potassium carbonate (0.65 mmol, 90 mg), tetrabutylammonium iodide (5 mg) and anhydrous DMF (1 mL). The reaction stirred under a nitrogen atmosphere at room temperature for 15 hours, then was heated to 50° C. for 3 hours. The reaction mixture was concentrated under vacuum to a residue and diluted with ethyl acetate (2 mL). The reaction was washed in distilled water and brine, and was dried over magnesium sulfate. The dried solution was then concentrated to an oil and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) to yield 61 mg (76%) of a white solid. Rf=0.50 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ7.69 (2H,d), 7.33-7.13 (6H,m), 6.96 (2H,d), 5.65 (1H,s), 5.02 (1H,m), 4.86 (1H,m), 4.80 (1H,m), 4.65 (1H,m), 3.99-3.80 (5H,m), 3.69 (2H,m), 3.11 (1H,br.s), 3.09-2.98 (3H,m), 2.91 (1H,m), 2.83 (1H,m), 1.89-1.72 (4H,m), 1.7-1.46 (4H,m), 1.38 (6H,d). MS (ESI): M+H=619.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CO>[CH2:22]([N:29]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=2)[C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Reactant: NCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A mixture of 6-fluoro-4-phenylisocoumarin-3-carboxylic acid (300 mg), benzylamine (230 mg), triethylamine (0.3 ml) and methanol (3 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (3 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with (diisopropyl ether) to give the title compound, 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ncccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate (5 mg) in methylene chloride (2 mL) and trifluoroacetic acid (0.50 mL) was stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 4 mg of 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN1CCCC1=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 36.5 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (156 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (85 mg, yield 36%) was obtained.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:12](=[O:40])[NH:13][CH:14]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[N:23]=[N:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=1)=[O:16])[CH2:10][CH3:11])C)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH2:27]([N:25]1[N:24]=[N:23][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:15](=[O:16])[CH:14]([NH:13][C:12](=[O:40])[C@@H:9]([NH:7][CH3:6])[CH2:10][CH3:11])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:26]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC[C@@H](C(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](NC)C(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound G in DCM (2 mL) is added TFA (2 mL) at 0° C. The solution is stirred at room temperature for 1 hr and dried under vacuum. The crude oil is purified by HPLC to provide the title compound. M+H+=467.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:5][N:4]=[N:3]1>C(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cn1nnnc1-c1cccc(N)c1
Yield: 73.6 %

Procedure:
1-Methyl-5-(3-nitrophenyl)tetrazole (Example 13, 350 mg) was hydrogenated at 20 psi in ethanol (30 ml) using 10% palladium on carbon (35 mg) for 15 minutes. The mixture was filtered then evaporated to dryness in vacuo to give the title compound as a grey solid (220 mg), mp 156°-157° C. Rf 0.23 in dichloromethane/methanol (5:1) on silica plates. 1H NMR (360 MHz, CDCl3) δ3.92 (2H, broad resonance), 4.16 (3H, s), 6.86 (1H, ddd, J1 =J2 =2 Hz, J3 =8 Hz), 7.01 (1H, broad d, J=8 Hz), 7.06 (1H, dd, J1 =J2 =2 Hz), 7.32 (1H, dd, J1 =J2 =8 Hz).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[S:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(OCC)C.C(O)(C)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[S:18])[N:22]([CH2:21][CH2:19][OH:20])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCOCC
Product: OCCN1C(=S)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Using the general procedure already described above, a solution containing 10.92 grams (40 moles) of 2-benzoyl-4-chlorophenylisothiocyanate in about 100 ml of ethyl ether was added dropwise to a stirred solution of 2.83 grams (44 moles) of ethanolamine in 200 ml of isopropanol. The reaction mixture was stirred overnight. The 6-chloro-3,4-dihydro-4-hydroxy-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinethione precipitated as a white solid. The product was washed with a mixture of ethyl ether and isopropanol to give the final product which had a melting point of 238°-240° C. Final yield was 93%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:25]1([C:23]2[C:22]3[CH:21]([N:28]([CH:30]4[CH2:31][CH2:32]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:34])[C:17]=3[CH:16]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:35])=[O:3])=[CH:12][CH:11]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C=CC(=O)O)cc3)cc(C3CC3)c21
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 3-{4-[4-cyclopropyl-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylic acid ethyl ester (Intermediate 164, 0.08 g, 0.17 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with 2M sodium hydroxide solution (2 mL, 4 mmol) and the resulting reaction mixture was refluxed overnight. The reaction mixture was cooled to ambient temperature, the volatiles were evaporated in vacuo, the residue was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a solid (0.04 g, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[CH:30]=1>>[F:24][C:25]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:31](=[O:35])[CH:30]=1
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 59.2 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (97 mg, 0.41 mmol) was reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 59%) as a green oil: ESI MS m/z 536 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[S:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2cccs2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)s2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc-hexanes) gave the product as a yellow foam (0.031 g, 11% yield). MS: m/z 529.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=2[O:35][CH3:36])[CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30](/[CH:31]=[CH:1]/[C:2]3[N:3]=[C:4]4[S:21][CH:20]=[CH:19][N:5]4[C:6](=[O:18])[C:7]=3[C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=3)=[CH:29][C:28]=2[O:35][CH3:36])[CH2:23][CH2:24]1
Reactant: COc1cc(C=O)ccc1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)ccc1OCC1CC1
Yield: 46.2 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 4-cyclopropylmethoxy-3-methoxybenzaldehyde (345 mg, 1.602 mmol) in presence of sodium ethoxide (163 mg, 2.418 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 297 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.35 (d, J=4.2 Hz, 2H), 0.64 (d, J=7.8 Hz, 2H), 1.30-1.38 (m, 1H), 3.83 (s, 3H), 3.84 (d, J=8.7 Hz, 2H), 6.70 (d, J=15.6 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.85-6.92 (m, 1H), 6.94-7.00 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.71 (d, J=7.8 Hz, 2H), 7.84 (d, J=15.0 Hz, 1H), 7.95 (d, J=5.1 Hz, 1H); ESI-MS (m/z) 499.32 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29](=[O:30])[NH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CS(C)=O.CS(O[CH2:40][CH2:41][O:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])(=O)=O>C1COCC1.CCOC(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[C:29](=[O:30])[N:28]([CH2:40][CH2:41][O:42][C:43]3[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=3[F:51])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3n(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
t-BuOK (1.0 g, 8.9 mmol) was added to a mixture of 4-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 9 mmol; from Step 2), THF (20 g) and DMSO (5 g) at room temperature. This mixture is added to a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (2.45 g, 9.00 mmol; from Example 54, Step 4) in THF (20 g). After being stirred at room temperature overnight, water (100 g) and EtOAc (200 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo. The residue was purified by chromatography on an MPLC-columnn using a continuous gradient (0-100% EtOAc in heptane) as eluent. Evaporation of solvent gave 0.5 g of the title compound as greasy crystals (not pure). 1H NMR analysis supports the stated structure. This material was used directly in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(N(CC)CC)C.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:42](=[O:43])[CH2:41][NH:40][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CNC(=O)OC(C)(C)C)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.25 h

Procedure:
A mixture of 5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 1.9 ml of triethylamine and 2.5 g of N—BOC-glycine in 25 ml of DCM is stirred until complete dissolution (about 15 min). 3.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added and the resulting mixture is stirred at RT for 3 h. After washing with 1 M sodium carbonate, the organic layer is dried over magnesium sulphate and evaporated. The residue is purified by column chromatography [silica, ethyl acetate]. The title compound is crystallized from diethyl ether.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Reactant: [N-]=C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2Cl2 (20 mL) was added oxalylchloride (130 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of Na2N3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm-1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ 0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J=8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1 =J2 =8.1 Hz, J3 =6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 0.4, 112.6 (d, JCF =26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF =241 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][C:33]2[CH2:34][CH:35]3[CH2:49][NH:48][CH2:47][CH2:46][N:36]3[CH:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:38]=2[CH:39]=1>O1CCCC1.C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][C:33]2[CH2:34][CH:35]3[CH:49]([C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:48][CH2:47][CH2:46][N:36]3[CH:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:38]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNC(C(=O)CNC(=O)OC(C)(C)C)C1C2
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
2-[(tert-Butoxy)carbonylamino]acetic acid (1 g) is dissolved in tetrahydrofuran (4 ml), and thereto are added dropwise triethylamine (0.8 ml) and isobutyl chloroformate (0.8 ml) at −20° C., and the mixture is stirred at −10° C. for 5 minutes. To the mixture is added dropwise a suspension of 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) in methylene chloride (15 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and extracted with methylene chloride. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=4:1) to give 8,9-dimethoxy-2-(tert-butoxycarbonyl)aminoacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (872 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 91 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-chlorobenzofuran, mp. 99°-100° C.