Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4](=[O:14])[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([CH3:41])C(O)=O.C(N(CC)CC)C.[C:49](=O)(O)[O-:50].[Na+]>CN(C)C=O>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4](=[O:14])[CH2:3][CH:2]1[NH:1][C:49](=[O:50])[CH2:41][CH2:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[Cl:29]
Reactant: NC1CC(=O)c2ccccc2NC1=O
Reactant: CC(C(=O)O)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(Cl)cc1Cl)NC1CC(=O)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask was charged with 3-amino-3,4-dihydro-1H-benzo[b]azepin-2,5-dione (4 g, 17.6 mmole), EDC (3.38 g, 17.6 mmole), HOBT (2.38 g, 17.6 mmole), 2,4-dichlorophenyl propionic acid (3.86 g, 17.6 mmole), Dimethylformamide (100 mL), and triethylamine (1.78 g, 17.6 mmole). The reaction mixture was stirred at room temperature for 1 hr. and then poured into saturated sodium bicarbonate (500 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting solid was swished with a minimum of hot chloroform and filtered to give the product, 5.8 g (84%) mp 234°-236° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH3:39][O:40][C:41]1[CH:60]=[CH:59][C:44]([CH2:45][C@H:46]([CH2:50][C:51]([N:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:52])[C:47]([OH:49])=O)=[CH:43][CH:42]=1>>[CH2:26]([NH:25][C:23](=[O:24])[C@H:22]([CH3:30])[CH2:21][C@H:20]([OH:31])[C@@H:19]([NH:18][C:16](=[O:17])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:47](=[O:49])[C@H:46]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:60][CH:59]=1)[CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C[C@H](CC(=O)N2CCCCC2)C(=O)O)cc1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCCCC1)Cc1ccc(OC)cc1
Yield: 23.5 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 150 mg (0.27 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 6(a)] and 86 mg (0.28 mmole) of 2(R)-(4-methoxybenzyl)-3-(piperidinocarbonyl)propionic acid, to afford 47 mg of the title compound as a white powder, melting at 120°-122° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1cccnc1
Product: CCOC(=O)c1nc(-c2cccnc2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.0 g) and 3-aminomethylpyridine (5.3 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(3-pyridyl)imidazole-4-carboxylate (4.0 g). 0.5 g therefrom was dissolved in ethyl alcohol (10 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(3-pyridyl)-imidazole-4-carboxylic acid (0.39 g), melting point 140-142° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>C(Cl)Cl.C(OCC)(=O)C>[CH2:41]([S:43]([NH:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:45])=[O:44])[CH3:42]
Reactant: CCS(=O)(=O)Cl
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl) benzamide (100 mg, 0.28 mmol) and i-Pr2NEt (0.2 mL, 1.1 mmol) in CH2Cl2 (5 mL) was added ethanesulfonyl chloride (0.05 mL, 0.53 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by High Throughput Purification System (HiTOPs) to provide N-((1-((1-(ethylsulfonamido)cyclopentyl)methyl) piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Reaction SMILES: [CH:1]([O:4][N:5]=[C:6]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](O)[CH:8]=1)([CH3:3])[CH3:2].[CH:19]1(O)[CH2:24][CH2:23][CH2:22]CC1.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]([O:4][N:5]=[C:6]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:22][CH2:23][CH:24]([CH3:19])[CH3:26])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)ON=C(c1cccc(O)c1)n1cncn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)CCc1cccc(C(=NOC(C)C)n2cncn2)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
2.0 g of 1-(O-isopropyl-3-hydroxybenzohydroximoyl)-1H-1,2,4-triazole, 1.6 g of cyclohexanol, and 4.3 g of triphenylphosphine were dissolved in 100 ml of THF. The mixture was maintained at about 5° C. To the solution was added 10 ml of a THF solution dissolving 2.8 g of diethyl azodicarboxylate drop by drop for 30 minutes. The mixture was stirred for 8 hours at room temperature. The solvent in the resultant mixture was removed under reduced pressure. The residue was purified by column chromatography (eluate: hexane/ethyl acetate=4/1), thus obtaining 2.1 g (yield: 78%) of the desired product (transparent viscous liquid) having a refractive index of [nD20 ] 1.5490 at 20° C.
Reaction SMILES: Cl.[C:2](=[NH:12])([O:9]CC)[C:3]1C=CC=CC=1.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([O:22][C:24]1([CH:29]=[CH:28][CH:27]=[CH:26][CH2:25]1)[CH:30]=[N:12][C:2](=[O:9])[CH3:3])[CH3:21]
Reactant: Cc1ccccc1
Reactant: CCOC(=N)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC1(C=NC(C)=O)C=CC=CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
First, 10 g of ethyl benzimidate hydrochloride, 150 mL of toluene, and 11 g of triethylamine (Et3N) were put into a 500-mL three-neck flask and the mixture was stirred at room temperature for 10 minutes. After a predetermined time elapsed, with a 50-mL dropping funnel, a mixed solution of 3.8 g of acetyl chloride and 30 mL of toluene was added dropwise to this mixture, and the mixture was stirred at room temperature for 24 hours. The obtained mixture was suction-filtered, and the obtained filtrate was concentrated to give N-(1-ethoxybenzylidene)acetamide (a yellow oily substance, 100% yield). The synthesis scheme of Step 1 is shown in (B-1) below.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.C(N(CC)CC)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
A mixture of t-Boc-Val-OSu (3.14 g, 10 mmol) and H-Lys(CBZ)-OCH3.HCl (3.31 g, 10 mmol) in THF (300 ml) was treated at room temperature with triethylamine (1.38 ml) and left stirring for 17 hr. The resulting solution was evaporated in vacuo and the residue was dissolved in EtOAc (500 ml). The organic solution was washed successively with water (2×200 ml), 5% citric acid (2×200 ml), water (2×200 ml) and dried over Na2SO4. The dried solution was filtered and evaporated in vacuo to give (VI) (4.9 g; 99%) as a foam. T.l.c. RfE4 =0.64.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[I:14]([O-])(=O)=O.[K+].II.Cl>C(O)C.O>[OH:1][C:2]1[C:7]([I:14])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: [O-][I+2]([O-])[O-]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)c1ccc(O)c(I)c1O
Temperature: 25 °C
Yield: 558.3 %

Procedure:
Mechanically stir suspensions of 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (818 g, 4.54 mol) in ethanol (3 L) and water (6 L) in two separate 22-L Morton flasks. Treat each suspension with potassium iodate (170 g, 794 mmol) and iodine (410 g, 1.62 mol) and allow to stir over night at room temperature. Dilute the mixtures with water (2 L), adjust pH to 4 by adding 5N hydrochloric acid, then extract twice with 4 L of ethyl acetate. Wash organic layers once with dilute aqueous sodium bisulfite, brine, dry with magnesium sulfate, filter, combine both filtrates, and evaporate to 2.6 Kg of a black solid. Chromatograph 500 g portions of the solid on 3.5 Kg of silica gel, eluting with 80% dichloromethane in heptane to provide the title compound (1357 g, 49% yield) in approximately 97% purity (HPLC shows 97% purity, with 3% 3,5-diiodo analog; LCMS confirms both. HPLC Rt=4.75 min; 1H NMR (CDCl3) δ 14.07 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.02 (s, 1H), 3.53 (hept, J=8.0 Hz, 1H), 1.24 (d, J=8.0 Hz, 6H); MS (m/z): 307.0 (M+1).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH2:31].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH:31][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 96.1 %

Procedure:
To a suspension of 0.89 g of 2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid and 0.79 g of L-histidine methyl ester dihydrochloride in 23 ml of N,N-dimethylformamide were added 0.70 ml of diphenylphosphoryl azide and 1.50 ml of triethylamine with stirring under ice-cooling, and then the mixture was additionaly stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To the residue was added diethyl ether, and the precipitate was collected by filtration to obtain 1.25 g of N-[2-(1-naphthylmethyl)-3 -(morpholinocarbonyl)propionyl]-L-histidine methyl ester as a white powder. To a soluiton of 0.98 g of the ester compound in 10 ml of methanol was added 0.52 g of hydrazide monohydrate, and then the mixture was stirred for 4 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 0.23 g of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidine hydrazide having an Rf1 value of 0.49 as a white powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]1[C:19](=[O:20])[N:18]2[C@H:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:23][CH2:24][N:17]2[C:16](=[O:32])[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+].O1CCOCC1>CCOC(C)=O.O>[CH2:5]([O:4][C:2]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]2[C@H:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22][CH2:23][CH2:24][N:17]2[C:16](=[O:32])[CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
Benzyl chloroformate (1.07 g) was added dropwise to a stirred ice cold mixture of the (1S, 9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-l-carboxylate (GB 2,128,984; 1.55 g, 5.21 mmol), NaHCO3 (0.66 g, 7.82 mmol), dioxan (32 ml) and water (8 ml). The mixture was kept at 5° C. for 15 min then for 2 h at room temperature. The mixture was diluted with EtOAc (50 ml), washed twice with sat. NaHCO3 solution, dried (MgSO4) and concentrated. The oily residue was purified by flash chromatography to afford 211d (1.98 g, 88%) of a colourless oil: [α]D24 -56.4 (c 1.0, CH2Cl2); IR(thin film) 3325, 2979, 2946, 1728, 1677, 1528, 1456, 1422, 1370, 1340, 1272, 1245, 1156, 1122, 1056, 916, 734, 699; 1H NMR (CDCl3) δ7.29 (5H, m), 5.81-5.72 (1H, m), 5.26-5.20 (1H, m), 5.05 (2H, s), 4.69-4.51 (2H, m), 3.48-3.36 (1H, m), 2.81-2.51 (2H, m), 2.34-2.19 (2H, m), 1.90-1.54 (4H, m), 1.41 (9H, s); Anal. Calcd for C22H29N3O6 ·H2O: C, 58.79; H, 6.92; N, 9.35. Found: C, 59.10; H, 6.57; N, 9.25; MS (ES +) 454 (M+ +Na, 87%), 432 (M+ +1, 100).
Reaction SMILES: CS(O[C@@H:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[C@@H:7]1OS(C)(=O)=O)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+].C(O)(=O)C>CO>[N:32]([C:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:33]=[N-:34]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Conversion of 6α,7α-dihydroxy-4-androstene-3,17-dione to the corresponding 6α,7α-dimethanesulfonate ester by treatment with methanesulfonyl chloride in pyridine in a manner similar to that described in Example 22B followed by treatment of the resulting 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in dimethylformamide in a manner similar to that described in above Example 22C does not yield an identifiable amount of 6-azido-4,6-androstadiene-3,17-dione. Similarly, treatment of 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in aqueous methanol in the presence of acetic acid in a manner similar to that described in Example 6, does not yield an identifiable quantity of 6-azido-4,6-androstadiene-3,17-dione.
Reaction SMILES: [C:1]1(=[O:6])O[CH:2]1[CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:4][CH:3]=[C:2]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:1]2=[O:6]
Reactant: CCC1OC1=O
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCCc2c(Cl)cccc21

Procedure:
Reaction of alpha-butyrolactone with chlorobenzene in the presence of aluminum chloride, as described in U.S. Pat. No. 3,657,400, produced 5-chloro-3,4-dihydro-1(2H)-naphthalenone. The latter was formylated with a combination of phosphorous oxychloride and dimethylformamide, yielding 1,5-dichloro-3,4-dihydronaphthalen-2-carboxaldehyde; mp 83.5°-84°, which was then reacted with ethyl thioglycolate and triethylamine in pyridine, as described in J.C.S. Perkin I, 2956 (1973), to produce ethyl 6-chloro-4,5-dihydronaphtho[1,2-b]thiophen-1-carboxylate; mp 81°-82°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li:21])CCC>C1C=CC=CC=1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Li:21])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: CCCCCCCCOc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: [Li]c1ccc(OCCCCCCCC)cc1

Procedure:
31.38 g (110.0 mmol) of 1-bromo-4-octyloxybenzene in 80 ml of benzene and 81 ml (130.0 mmol) of a 1.6-molar n-butyllithium solution in hexane are stirred at room temperature under argon for 4 hours. The 4-octyloxyphenyllithium formed as a white precipitate is filtered off under argon, washed twice with 20 ml of n-hexane, dried in vacuo and slowly added dropwise as a solution in 60 ml of tetrahydrofuran at 0° C. under argon to a solution of 11.51 g (100.0 mmol) of 2,6-difluoropyridine in 80 ml of tetrahydrofuran. After a reaction time of 1 hour at 0° C., sodium chloride solution is added, the mixture is taken up in ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered, the solvent is removed from the filtrate, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate), giving 4.00 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine. ##STR17##
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10](=[O:44])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[N:19]([C:34]3[C:35]4[C@H:42]([CH3:43])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:20][C:21]3([CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:14]=12)([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[C:5]([O:9][C:10](=[O:44])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[N:19]([C:34]3[C:35]4[C@H:42]([CH3:43])[CH2:41][CH2:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:20][C:21]3([CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[C:14]=12)([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Temperature: 25 °C
Yield: 96.2 %

Procedure:
10% Pd/C (110 mg, 0.92 mmol) and ammonium formate (585 mg, 9.25 mmol) were added to (R)-tert-butyl(1′benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.00 g, 1.85 mmol) in MeOH (20 mL) The reaction was heated to reflux for 6 hours, at which point the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give (R)-tert-butyl(1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (800 mg, 96%), which was used without further purification. Boc2O (462 mg, 2.12 mmol) was added to a solution of (R)-tert-butyl(1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (800 mg, 1.77 mmol) in DCM (25 mL). The reaction mixture was stirred overnight. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The crude residue was purified by column chromatography (4:1 hexane:EtOAc) to give (R)-tert-butyl 4-((tert-butoxycarbonylamine)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (856 mg, 88%) as a foam. LCMS (APCI+) m/z 550 [M+H]+; Rt=4.36 min.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CC(C)([O-])C.[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridin-4-amine (Description 49) (1 g, 2.51 mmol) in THF (10 mL) and DMF (5 mL) was added sodium tert-butoxide (0.603 g, 6.28 mmol) and benzenesulfonyl chloride (0.648 mL, 5.02 mmol). The reaction mixture stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 30 mL) and extracted with DCM (25 mL×4). The combined organics were dried and concentrated. The residue was purified via normal phase chromatography eluted with a gradient of 0-50% ethyl acetate in DCM, to afford the title compound (1.12 g). LCMS (A) m/z: 539 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[CH:8]OCC)[C:6]#[N:7])[CH3:2].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([NH2:7])=[N:20][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=1)=[O:12])[CH3:2]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccccc2)nc1N
Yield: 80.5 %

Procedure:
2-(Ethoxymethylene)-2-cyanoacetic acid ethyl ester (78.2 g) and phenylhydrazine (50.0 g) were dissolved in ethanol (500 mL), and the mixture was refluxed for 3 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Hexane (500 mL) was added, to the residue, and the residue was washed by suspending and filtered. The obtained solid was vacuum dried to give the title compound (86.0 g) as a white solid.