Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6](=O)[C:5](=O)[C:4]([CH3:10])([CH3:9])[O:3]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][NH2:21])=[NH:19])([O-:14])=[O:13]>C(O)C>[CH3:1][C:2]1([CH3:11])[C:6]2[N:19]=[C:18]([C:17]3[CH:22]=[CH:23][CH:24]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=3)[N:20]=[N:21][C:5]=2[C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: N=C(NN)c1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OC(C)(C)C(=O)C1=O
Solvent: CCO
Product: CC1(C)OC(C)(C)c2nc(-c3cccc([N+](=O)[O-])c3)nnc21

Procedure:
A mixture of 1.56 g. (0.01 mole) of 2,2,5,5-tetramethyl-3,4(2H,5H) furandione and 1.80 g. (0.01 mole) 3-nitro benzimidic acid hydrazide in 100 ml. absolute ethanol is refluxed under nitrogen for 18 hours at a bath temperature of 100°C. The excess water is removed from the condensate by using a Dean Stark trap filled with 3A molecular sieves. The resulting mixture is evaporated to dryness in vacuo at 40°C., and the resulting residue is recrystallized from hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-(m-nitrophenyl)furo[3,4-e]-as-triazine.
Reaction SMILES: C[C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[CH3:24][O-:25].[Na+].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1.CO>[CH3:24][O:25][C:2]([CH:4]1[CH2:5][CH2:6][C@H:7]2[C@H:12]3[C@H:11]([CH2:10][CH2:9][C@:8]12[CH3:23])[C@:16]1([CH3:22])[C:15](=[CH:20][C:19](=[O:21])[CH2:18][CH2:17]1)[CH2:14][CH2:13]3)=[O:3]
Reactant: C[O-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O=C1CCCCC1
Product: COC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A preferred process for preparing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, an especially preferred compound of the present invention, comprises the following steps: (a) pregnenolone (V), an available starting material, is treated by the haloform King reaction with iodine and pyridine to form the 20-pyridinum iodide derivative of the pregnenolone (VI); (b) the pyridinium iodide derivative (VI) is hydrolyzed to the methyl ester of 17-carboxy pregnenolone (VII) with sodium methoxide and methanol, the ester form being preferred for carrying out the following Oppenhauer reaction; (c) the methyl ester of 17-carboxy pregnenolone (VII) is treated with aluminum isopropoxide and cyclohexanone in an appropriate solvent such as toluene to yield methyl-4-androstene-3-one-17-carboxylate (VIII) (d) the methyl-4-androstene-3-one-17-carboxylate (VIII) thus formed is hydrolyzed to the 17-acid (IX) under acid conditions in a methanol: water solvent of approximately 4:1 proportions; (e) the 17 acid (IX) is then treated with an oxalyl chloride: pyridine complex of approximately 1:1 proportions in toluene or other suitable solvent, e.g. xylene, to form the 17-acid chloride (X); (f) the 17-acid chloride (X) is then treated in situ with an excess of diethylamine to form the 17β-N,N-diethylcarbamoyl-4-androstene-3-one (XI); (g) the 4-androstene-3-one (XI) thus formed is oxidized by treatment with sodium periodate and potassium permanganate, using tert-butanol and water as a solvent system, to the corresponding 5-oxo-3,5-secoandrostan-3-oic acid (XII); (h) the secoandrostanoic acid (XII) is then converted to the corresponding 4-aza compound (XIII) by treating it with methylamine in ethylene glycol for a period of about 1 hour over which time the reaction mixture temperature is raised to from 140°-180° C. where it is maintained from 0.5 to 5 minutes; (i) the resulting 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androsten-3-one (XIII) is then hydrogenated by treating it with hydrogen at room temperature to 60° C. or higher, using platinum oxide as the catalyst, to form the 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (XIV) final product, which is then separated and purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:25]=[N:26][C:27]([CH2:30][O:31][CH3:32])=[CH:28][CH:29]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:25]=[N:26][C:27]([CH2:30][O:31][CH3:32])=[CH:28][CH:29]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
Ethyl [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (1.36 g) was dissolved in a mixture of tetrahydrofuran (15 mL) and ethanol (15 mL). To the mixture was added 1M aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was neutralized with 1M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.30 g, 100%) as a yellow amorphous solid. MS 428 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:16])[CH:6]=1)=[O:4].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CC2CCCC(O)C2C=C1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1=CC2CCCC(=O)C2C=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3,5-Dihydroxy-4a,5,6,7,8,8a-hexahydro-naphthalene-2-carboxylic acid methyl ester (3 g, 13.5 mmol) in DCM (100 mL) is added PDC (5.33 g, 14.2 mmol). The suspension is stirred at room temperature overnight. Upon completion of the reaction, the mixture is filtered through a short silica gel pad rinsing with DCM. After evaporation of the solvent, the crude product is obtained as light yellow solid. Recrystallization with DCM and hexanes affords 2.4 g of 3-hydroxy-5-oxo-4a,5,6,7,8,8a-hexahydro-naphthalene-2-carboxylic acid methyl ester as white crystalline solid; LC/MS calculated for [M+H]+ C12H12O4: 221.1, found: 221.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:14]=[CH:13][N:12]=[N:11][C:10]=1[Cl:15].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:15][C:10]1[N:11]=[N:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])=[CH:14][CH:9]=1
Reactant: Clc1ccnnc1Cl
Reactant: NCCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCCCCCNc1ccc(Cl)nn1

Procedure:
A mixture of 5-amino-1-pentanol (433 mg, 4.2 mmol), dichloropyridazine (1.25 g, 8.39 mmol) and sodium carbonate (890 mg, 8.39 mmol) was stirred in 1,4-dioxane (40 ml) and heated at 70-80° for 3 days under an atmosphere of argon. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (300 ml) and water (38 ml). The organic layer was separated, dried and concentrated to give an orange solid which was chromatographed on silica, using hexane/ethyl acetate (1:1). The product, 5-(6chloro-3-pyridazinyl)amino-1-pentanol was isolated as a pale yellow solid (202 mg, 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:14]=1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A7) (60 mg, 0.11 mmol) in anhydrous DMF (10 mL) was added a slurry of 10% Pd/C (30 mg) in DMF (2 mL). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 72 hours then diluted with EtOAc (30 mL) and filtered through a plug of Celite, washing with EtOAc (50 mL). The filtrate was evaporated to dryness to give the title compound A8 as a brown oily residue (44 mg, 73%); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.52 (dt, J=8.0, 2.5 Hz, 2H), 7.25-7.17 (m, 4H), 6.92 (dd, J=7.2, 5.1 Hz, 2H), 6.88 (s, 1H), 3.72 (s, 2H), 3.68 (d, J=3.0 Hz, 3H), 3.61-3.56 (m, 4H), 3.07 (dd, J=9.3, 5.1 Hz, 6H), 2.06 (s, 3H), 1.48 (s, 9H). LC-MS-A: rt 6.260 min; m/z 546.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:18][C:11]3[NH:12][C:13](=[S:17])[NH:14][C:15](=[O:16])[C:10]=3[CH2:9][C:8]=2[CH:19]=1)([OH:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:18][C:11]3[NH:12][C:13](=[S:17])[NH:14][C:15](=[O:16])[C:10]=3[CH2:9][C:8]=2[CH:19]=1)=[O:3])[CH3:21]
Reactant: O=C(O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Suspend 7-carboxy-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (5 g.) in ethanol and pass in HCl gas until saturated. Reflux the mixture for 24 hours then cool, filter and wash with ethanol and ether to yield 7-ethoxycarbonyl(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O-])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([N+:23]([O-])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1.[Fe]>[CH2:26]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[C:13]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:23][C:12]2=[CH:11][N:10]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)/C([O-])=C/c1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a solution of potassium (1Z)-1-[2-(dibenzylamino)-5-nitropyridin-4-yl]-3-ethoxy-3-oxoprop-1-en-2-olate (5.0 g, 10.6 mmol) in acetic acid (151.4 mL) was added iron powder (2.43 g, 43.5 mmol) under a nitrogen atmosphere. The mixture was warmed to 60° C. and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to ca. 100 mL in volume. The concentrate was poured into rapidly stirring water (ca. 200 mL). The precipitate was observed. Ethyl acetate (150 mL) was added and the mixture was stirred until the solid was dissolved. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined extracts were washed with dilute NaHCO3 and saturated NaCl, and dried over Na2SO4. The solution was dark red. Consequently, activated charcoal (Darco G-60, 1.20 g) was added to the solution. After filtration through diatomaceous earth, the filtrate was concentrated to dryness to afford a dark brown solid. The solid was sonicated in toluene (ca. 75 mL) for 30 min. After standing at room temperature overnight, the solid was collected by filtration and rinsed with toluene to give ethyl 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.80 g, 19%) as a yellow solid. Further manipulation of the mother liquors provided additional material (0.19 g, 5%): mp 169-174° C.; 1H NMR (300 MHz, CD3OD) δ1.38 (3H, t, J=7.0 Hz), 4.37 (2H, q, T=7.0 Hz), 4.75 (4H, s), 6.64 (1H, d, J=0.9 Hz), 6.85 (1H, d, J=0.9 Hz), 7.21-7.27 (10H, m), 8.48 (1H, s); ESI MS m/z 386 [C24H23N3O2+H]+; HPLC (Method A) >99% (AUC), tR=20.1 min.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[nH]c(=O)c(Br)c1
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-5-methyl-2(1H)-pyridinone (25 g, 0.13 mol) and phosphorus oxychloride (500 mL) was boiled with stirring for 20 h. Phosphorus oxychloride was removed by distillation and the residue was poured onto ice/water (800 mL). The mixture was adjusted to pH 8.5 with 2 N sodium hydroxide solution and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue, 23.4 g of the title compound as a greyish solid was introduced into the next step without purification, MS (EI) 204.9, 206.9 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:28][SH:29])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:30])=[O:2])[CH2:28][SH:29])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CS)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: N
Product: O=C(N[C@@H](CS)C(=O)O)c1ccc(COc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared by saponification of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]cysteine methyl ester, prepared as in Example 242E, using the procedure of Example 165. 1H NMR (300 MHz, DMSO-d6) d 8.77 (d, 1H), 0.58 (d, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.63 (dd, 1H), 7.52 (m, 5H), 7.36 (m, 3H), 5.38 (s, 2H), 4.44 (m, 1H), 3.90 (dd, 1H), 3.72 (dd, 1H), 2.05 (s 3H). MS (DCI-NH3) m/e 423 (M+H)+, 440 (M+NH4)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:3])=[CH:17][CH:18]=1
Reactant: CS(N)(=O)=O
Reactant: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 91.2 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methoxy-acetamide (0.300 g, 0.89 mmol) with methanesulfonamide (0.127 g, 1.33 mmol) as described in the preparation oc compound 22 gave 0.304 g (91% yield) of the title amide as a white foam after chromatography. 1H NMR (400 MHz, CDCl3) 8: mixture keto-enol forms and of rotamers equilibrating to a major enol form after a few hours in chloroform: 1.95 (2H, m, CH2), 2.6 (2H, m, CH2), 3.34, 3.35 and 3.38 (3H, 3s, SO2CH3), 3.70, 3.71 and 3.74 (3H, 3s, OCH3), 6.57 (1H, s, CH), 7.0 (2H, m, aromatics), 7.15 (2H, m, aromatics), 9.05 (1H, broad s, NH); major form after equilibration: 1.97 (2H, m, CH2), 2.64 (2H, t, CH2), 3.38 (3H, s, SO2CH3), 3.74 (3H, s, OCH3), 6.57 (1H, s, CH), 7.0 (2H, m, aromatics), 7.15 (2H, m, aromatics), 9.05 (1H, broad s, NH). MS (ESI/pos) calculated for C15H20FN2O6S, [M+H]+: 374; found: 374.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[NH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([NH:13][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10])=[O:15])[CH3:18]
Reactant: CCOC(N)=O
Reactant: COC(=O)C1CCCCCC1=O
Product: CCOC(=O)NC1=C(C(=O)OC)CCCCC1

Procedure:
Using the method of Example 1 Part A, methyl 2-oxocycloheptanecarboxylate (50.5 g, 0.30 mole) was reacted with urethane to provide 59 g of methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]([C:33]1[CH:34]=[C:35]2[C:60](=[CH:61][CH:62]=1)[C:39]1[NH:40][C:41]([C@@H:43]4[CH2:47][C@H:46](C)[CH2:45][N:44]4[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[N:42][C:38]=1C=C2)=[CH:27][CH:26]=3)=[O:11])=[O:7])(C)(C)C.[F:69][CH:70]([F:127])[O:71]C1C=C(C2NC([C@@H]3CCCN3C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=2)C=CC=1C1C=C2C(=CC=1)C1NC([C@@H]3C[C@H](COC)CN3C(OC(C)(C)C)=O)=NC=1C=C2.C(OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O)(C)(C)C.COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:5][C:6]([NH:8][C@H:9]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]([C:33]1[CH:62]=[CH:61][C:60]([C:39]2[NH:40][C:41]([C@@H:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:49](=[O:59])[C@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:52])[CH3:53])=[N:42][CH:38]=2)=[CH:35][C:34]=1[O:71][CH:70]([F:127])[F:69])=[CH:27][CH:26]=3)=[O:11])=[O:7]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C1
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5OC(F)F)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)C(C)C)[nH]6)cc5OC(F)F)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1

Procedure:
Methyl (R)-1-((S)-2-(5-(4-(2-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was prepared according to the method employed in the synthesis of methyl (S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (2S,4S)-tert-butyl 2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate with (2S,4S)-tert-butyl 2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate and (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid. MS (ESI) m/z 907 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: BrCc1cccc(Br)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cccc(Br)c1
Reaction time: 6 h
Yield: 29.9 %

Procedure:
To a solution of 2.30 g (20 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 20 ml acetonitrile was added 2.90 g (21 mmol) of potassium carbonate. A solution of 5.00 g (20 mmol) of 3-bromobenzylbromide in 20 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (5.2 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane and the solid was washed, ice-cooled, collected by filtration and concentrated. Further, to the resultant solid residue was added tert-butyl methyl ether and the solid was washed, cooled, collected by filtration and dried to obtain 1.70 g (5.98 mmol) of 4-(3-bromobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: NS(=O)(=O)c1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(S(N)(=O)=O)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 3-bromoacetylbenzensulfonamide (T. Fujikura, K. Nigata, S. Hashimoto, K. Imai, and T. Takenaka, Chem. Pharm. Bull., 1982, 30, 4092-4101).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[NH:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: c1ccc(Cn2ccc3c(-c4cc5ncccc5c(N5CCOCC5)n4)cccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: c1cc(-c2cc3ncccc3c(N3CCOCC3)n2)c2cc[nH]c2c1
Temperature: 110 °C

Procedure:
To a solution of 7-(1-benzyl-1H-indol-4-yl)-5-morpholin-4-yl-1,6-naphthyridine, 4 (64 mg, 0.13 mmol, 1 eq) in dry anisole (1.5 mL) was added a suspension of AlCl3 in dry anisole (1.5 mL). The mixture was then heated at 110° C. for 0.5 h. Once cooled down, it was partitioned with H2O (15 mL) and extracted with EtOAc (3×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were then dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with CH2Cl2/MeOH (1:0-49:1) to yield the product, G, as a pale yellow solid (7.8 mg, 15%).