Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:21](O)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C1COCC1>[CH3:24][C:22]([C:21]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([N:13]=[N:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:15][CH:16]=1)=[O:25])=[CH2:23]
Reactant: Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C=C(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
0.6 g of sodium hydride was added carefully to a 3 neck flask equipped with a condenser, addition funnel, and magnetic bar. 75 ml of anhydrous THF was added and the mixture stirred for 10 minutes. A solution of 4.0 g 4-(4-nitrophenylazo)aniline in 75 ml THF was added drop-wise and the flask stirred at 50° C. The temperature was raised to 95° C., and the mixture was refluxed for 6 hrs. The mixture was allowed to cool to room temperature and then 6.0 g of methacrylic acid in 20 ml THF was added drop-wise. The mixture was again refluxed for 8 hrs. The solution was cooled to room temperature. THF was evaporated to reveal a dark orange solid. The solid was washed thoroughly with dilute HCl and water. The product was recrystallized in 95% methanol. The yield was 56%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc(F)cc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2ccc(F)cc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-4-fluorobenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides colorless crystals, mp 195°-197° C of 4-(2-carboxy-4-fluorobenzyloxy)phenylacetic acid.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C:4]1([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCCC1(C2CCN(C)CC2)c2ccccc2CCc2ccccc21
Yield: 7.8 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (0.33 g, 1.0 mmol) in 50 mL of absolute ethanol, and added 0.15 g of 10% palladium on carbon catalyst. Hydrogenated on a Paar shaker at 60 psi of hydrogen pressure for 24 hours. Filtered catalyst, and evaporated filtrate. Crystallized product from dichloromethane-ether to give 26 mg (8% yield) of 4-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methylpiperidine as a tan solid.
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+].C(O)(=O)C>CO>[OH:25][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH:2]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[OH:1])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Ethyl 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylbenzeneacetate (0.5 g) was dissolved in MeOH (10 mL), and sodium hydroxide solution (0.35 g, water 3 mL) was added. The reaction mixture was heated at reflux for 5 h, and cooled to 22° C., followed by the addition of acetic acid to reach a pH 4-5. MeOH (5 mL) was added to the solution and stirred for 1 h. The precipitate was collected by filtration to give 0.42 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid. 1H NMR (DMSO-d6) d 1.45-1.49(m, 2H), 1.67 (s, 6H), 1.67-1.78 (m, 6H), 2.12-2.20 (m, 2H), 2.45-2.50 (m, 2H), 2.68-2.78 (m 3H), 3.10 (broad s, 2H), 4.71 (m, 1H), 5.50 (broad s, 1H), 7.35 -7.40 (m, 2H), 7.45-7.55 (m, 8H), 7.76-7.78 (m, 4H). MH+ 502.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.NC(C(C)C)[C:23](OC)=[O:24]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]([CH2:17][O:24][CH3:23])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Product: COC[C@@H](C(=O)OC)N1Cc2ccc(Br)cc2C1=O
Yield: 65 %

Procedure:
The compound of example 353 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 2-amino-3-methylbutanoate hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:7]=[C:5]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:8]
Reactant: CC(C)CCC(=O)O
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(C)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 82 h

Procedure:
A mixture of 25 g (.215 mol) of 4-methyl valeric acid and 9.35 g (0.247 mol) of thionyl chloride was heated at reflux for 1.5 hour. The excess thionyl chloride was removed under reduced pressure using a cryogenic trap. The residue was taken up with 120 g (0.764 mol) of bromobenzene (Compound 27) and the mixture was cooled in an ice-bath and then treated with 23 g (0.172 mol) of anhydrous aluminum chloride through a powder addition funnel The mixture was stirred at room temperature for 82 h and then quenched by the addition of 50 ml of an ice/water mixture, followed by 30 ml of conc. HCl. The organic layer was separated and the aqueous layer extracted with 2×50 ml of ether. The organic extracts were combined and washed successively with water and saturated NaCl solution and then dried (MGSO4) The solvent was then removed in-vacuo and the residue purified by distillation (~80 degrees C./0.01 mm) to give the title compound as a colorless solid. PMR (CDCl3): & 0.94 (6 H, d, J~6.0 Hz), 1.53-1.68 (3H, m), 2.85-2.97 (2H, m)., 7.60 (2H, d, J~8.4 Hz), 7.83 (2H, d, J~8.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][CH2:18][CH2:19][O:20]C3CCCCO3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>Cl.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:17][CH2:18][CH2:19][OH:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(CCCOC3CCCCO3)OCc3ccccc32)cc1
Agent: Cl
Solvent: CCO
Product: OCCCC1(c2ccc(F)cc2)OCc2ccccc21

Procedure:
39.6 Parts of 1-(4-fluorophenyl)-1,3-dihydro-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]isobenzofuran were dissolved in 9.8 parts of a hydrochloric acid solution 0.1 M and 788 parts of ethanol and the whole was stirred and refluxed for 1 hour. The solvent was evaporated and the residue was taken up in methylbenzene and water. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24.2 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-propanol as a residue (intermediate 94).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23]O)[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][CH2:22][CH2:21][CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: OCCCCc1cccnc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCCCc2cccnc2)cc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.14 g), 3-pyridinebutanol (1.04 g), triphenylphosphine (2.07 g), and tetrahydrofuran (25 mL) was stirred at 0° C. while adding dropwise a solution of diethyl azodicarboxylate (1.37 g) in tetrahydrofuran (10 mL). The mixture was stirred for 2 hours at 0° C. and evaporated to dryness. The material was purified by HPLC (hexane-acetone; 2:1) to provide 1.4 g of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid methyl ester (4:1) molar hydrate as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.Cl.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])(=O)C.[Na+]>CN(C=O)C>[CH3:9][S:8][C:5]1[N:6]=[CH:7][C:2]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]=3[NH:15][C:10](=[O:12])[C:3]=2[N:4]=1
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nc(SC)ncc12
Temperature: 120 °C
Yield: 79.6 %

Procedure:
In a microwave vessel, methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1.0 eq, 274 mg, 1.18 mmol), 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (1.2 eq, 329 mg, 1.42 mmol), and sodium acetate (3.0 eq, 291 mg, 3.55 mmol) were mixed in anhydrous DMF (2 ml). The mixture was degassed by bubbling nitrogen gas in the solution for 10 min and the reaction heated under microwaves at 120° C. for 30 min. After cooling down the expected material crashed out of NMP. The solid was filtered, suspended in water filtered and dried. The material was triturated in AcOEt and filtered give a yellow solid. The same procedure was repeated 9 times using the same amounts of materials to provide methyl 3-(methylthio)-5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (283 mg, 10% yield). LCMS (ES): >95% pure, m/z 302 [M+l]+, 1H NMR (DMSO-d6, 400 MHz) δ 2.71 (s, 3H), 3.89 (s, 3H), 7.80 (dd, J=1.6, J=8.4, 1H), 7.97 (d, J=1.6, 1H), 8.59 (d, J=8.8, 1H), 9.98 (s, 1H), 12.34 (s, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][NH:10][CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13].Cl[CH2:15][CH2:16][S:17][CH3:18].[Br-].[Li+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][N:10]([CH2:15][CH2:16][S:17][CH3:18])[CH2:11][CH2:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: CSCCCl
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCN1CCc2[nH]c(=O)n(C)c(=O)c2C1
Yield: 45 %

Procedure:
36.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]-pyrimidine-2,4-dione, 23 g of 1-chloro-2-methylsulfanylethane (97% pure), 17.4 g of lithium bromide and 27 g of ethyldiisopropylamine in 700 ml of dimethylformamide were stirred for 14 h at 50° C. After the reaction mixture had been concentrated under reduced pressure, the residue was taken up with 400 ml of water and 400 ml, of dichloromethane, the pH was adjusted to 8 with sodium bicarbonate, with stirring, and the mixture was worked up by extraction with dichloromethane and water. 23 g of 3-methyl-6-(2-methylsulfanylethyl)-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were obtained from the combined dichloromethane phases after drying, concentration and recrystallization of the residue from isopropanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([C:18]#[N:19])[S:16][CH:17]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([C:18]#[N:19])[S:16][CH:17]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3csc(C#N)c3)cc21
Yield: 35.4 %

Procedure:
A mixture of 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile (0.23 g, 0.8 mmol) and Lawesson's reagent (0.38 g, 0.96 mmol) in anhydrous o-xylene was heated to reflux under nitrogen for 3 hours. The solvent was removed in vacuo and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/3:1) to afford the title compound as a yellow solid (85 mg, 35%): mp 242-243° C.; 1H-NMR (DMSO-d6) δ 12.22 (s, 1H, D2O exchangeable), 8.50 (d, 1H, J=1.2 Hz), 8.37 (d, 1H, J=1.0 Hz), 7.71 (m, 2H), 7.09 (d, 1H, J=8.0 Hz), 1.69 (s, 6H); MS (APCI) m/z 301 ([M+H]+, 100%); Anal. Calcd. For C15H12N2OS2: C, 59.97; H, 4.03; N, 9.33. Found: C, 59.67; H, 3.85; N, 9.14.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])=[CH:26][CH:25]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([C:27]5[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=5)[CH:31]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 3-(4-trifluoromethylphenyl)benzoic acid (151 mg, 0.57 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-(4-trifluoromethylphenyl)benzamide (67 mg, 67%). NMR; δH CDCl3 8.11,(1H, t), 7.87-7.85,(2H, m), 7.83,(2H, d), 7.77,(1H, m), 7.72,(4H, s), 7.63-7.57,(2H, m), 7.50,(1H, d), 7.41,(2H, d), 7.30,(1H, d), 6.25,(1H, t), 3.34,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.57,(2H, m), 0.29,(2H, m). LCMS: retention time 4.01 min, MH+529.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:18][CH2:17][C:10]2[N:11]=[N:12][C:13]([NH:15][NH2:16])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH3:19][C:20]([CH3:22])=O>>[CH2:1]([O:4][C:5]([N:7]1[CH2:18][CH2:17][C:10]2[N:11]=[N:12][C:13]([NH:15][N:16]=[C:20]([CH3:22])[CH3:19])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)=O
Reactant: C=CCOC(=O)N1CCc2nnc(NN)cc2C1
Product: C=CCOC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A solution of 4 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid allyl ester in 40 cc of acetone is heated at reflux on a water bath for 30 minutes. The title compound has a M.P. 134°-136° (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-])=O>ClCCl.[Pd]>[NH:1]1[C:4]2=[CH:5][N:6]=[CH:7][CH:8]=[C:9]2[CH:10]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccncc2[nH]1

Procedure:
To a solution of ethyl 3-(3-nitropyridin-4-yl)-2-oxopropanoate (1.0 eq) in dichloromethane was added 10% Pd/C (1.5 eq.) under nitrogen atmosphere at 110 psi in an autoclave for 48 hrs. Reaction mixture was filtered through celite and concentrated to get brown solid, which, on purification by column chromatography afforded the desired ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][CH2:7][C@@H:8]([CH3:16])[CH2:9][CH2:10][CH:11]1[C:13]([CH3:15])([CH3:14])[O:12]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:16])[CH2:9][CH2:10][CH:11]1[C:13]([CH3:15])([CH3:14])[O:12]1)[CH3:2]
Reactant: CCOC(=O)C=CC[C@@H](C)CCC1OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC[C@@H](C)CCC1OC1(C)C
Yield: 82.5 %

Procedure:
9.59 g of (5S)-7-((RS)-3,3-dimethyl-oxiranyl)-5-methyl-hept-2-enoic acid ethyl ester was hydrogenated at RT in 57 ml of AcOEt over 960 mg of Pd/C (5%) for 6 h. At that time, GC analysis indicated the complete disappearance of starting material. Filtration and flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 7.98 g of (5R)-7-((RS)-3,3-dimethyl-oxiranyl)-5-methyl-heptanoic acid ethyl ester (roughly 1/1 epimeric mixture) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[Cl:31][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCN1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 2.32 g (6.11 mmol) of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 35 mL of phosphorus oxychloride is heated under reflux for 1 hour, then cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid is collected by filtration, washed with cold water and dried to yield 1.989 g of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:21](=[O:39])(=[O:38])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[CH:27]4[CH2:37][CH:28]4[CH2:29][O:30][C:31]=3[C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[C:6]([CH2:8][CH2:9][CH:10]2[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]2)[CH:7]=1.[CH2:40](Cl)Cl>FC(F)(F)C(O)=O>[CH2:14]([N:12]1[CH2:13][CH:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:21]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:39])=[O:38])[CH2:11]1)[CH3:40]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CCC2CN(C(=O)OC(C)(C)C)C2)ccc2c1OCC1CC21
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC(CCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (1aRS,7bSR)-3-{2-[5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenyl]ethyl}azetidine-1-carboxylate (Intermediate 184, 0.397 g) in DCM (5 mL) and trifluoroacetic acid (5 mL) was left at room temperature for 30 minutes then evaporated in vacuo and the residue was dissolved in toluene and re-evaporated. The residue was dissolved in DCM (15 mL) and acetaldehyde (0.063 g) was added followed by sodium triacetoxyborohydride (0.301 g). The mixture was stirred at room temperature for 2 hours then diluted with ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-25% to give methyl (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.312 g) as a white foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([F:41])[CH2:37]1)=[O:35])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:33])[C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:8][C@H:9]([C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([F:41])[CH2:37]1)=[O:35])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:33])[C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12]
Reactant: COc1ccc(C(=O)N(C)c2ccc([C@H](C(=O)N(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3CC[C@H](F)C3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N(C)c2ccc([C@H](C(=O)N(C)C)[C@H](N)C(=O)N3CC[C@H](F)C3)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 17.6 mg (0.0346 mmol) of N-(4-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]-1-[(dimethylamino)carbonyl]-3-[(3S)-3-fluoropyrrolidin-1-yl]-3-oxopropyl}phenyl)-N-methyl-4-methoxybenzamide from Step H in 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid. After 1 h at ambient temperature, the solution was concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% to 80% acetonitrile in water) afforded the title compound as a foaming white solid. LC/MS 471.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CI.[CH3:15][N:16]([CH:18]=[O:19])C>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:16]1[CH2:15][CH2:5][CH2:4][CH2:3][CH2:2][C:18]1=[O:19]
Reactant: CN(C)C=O
Reactant: BrCc1ccc2ccccc2c1
Solvent: CI
Solvent: C1CCOC1
Product: O=C1CCCCCN1Cc1ccc2ccccc2c1
Yield: 97 %

Procedure:
Following the procedure described in Example 122, step 1, but substituting respectively 2-bromomethylnaphthalene for methyl iodide, and DMF for THF, the title compound 217 was obtained in 97% yield. MS (ESI)=254 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[N+:15]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
First, 300 g of 9,10-dihydrophenanthrene were dissolved in 2 L of acetic acid, and then 450 mL of fuming nitric acid (d=1.50) were dropped to the mixture. The reaction solution was stirred at room temperature for 7 hours. The reaction solution was poured into 5 L of water, and then the precipitated crystal was separated by filtration and recovered. The resultant crystal was washed with water and methanol, and was then dried under reduced pressure. Thus, 280 g of an orange crystal were obtained (in 74% yield).