Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([N:15]1[CH2:21][C:20]2[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:19]=2[S:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13]>ClCCl>[C:12]([N:15]1[CH2:21][C:20]2[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:9])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCSc2cccc(Cl)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCS(=O)c2cccc(Cl)c2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (1.14 g) in dichloromethane (100 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.34 g, prepared as Example 9 above) in dichloromethane (50 ml). The reaction mixture was stirred for 15 minutes, washed with water, dried and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 1.15 g (m.p. 119°-121° C.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2nccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Yield: 55.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, quinoxalin-5-ylamine (Intermediate 482) (540 mg, 3.7 mmol), 2-nitro-benzenesulfonyl chloride (986 mg, 4.46 mmol), pyridine (0.9 ml, 7.44 mmol) and DCM (10 ml) gave the title compound (679 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21][CH:22]([O:33][CH3:34])[CH2:23][CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26](OC)=[N:25]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.[Cl-:35].[NH4+:36].Cl>CO>[ClH:35].[ClH:35].[NH2:14][CH:15]([CH2:21][CH:22]([O:33][CH3:34])[CH2:23][CH:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26](=[NH:36])[NH:25]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: CCOC(=O)C(CC(CC1CCCCC(OC)=N1)OC)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(N)CC(CC1C=CC=CC(=N)N1)OC

Procedure:
The product of EXAMPLE 243 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27. This material is then lyophilized from aqueous HCl to generate the title material.
Reaction SMILES: [I:1]I.I(O)(=O)(=O)=O.S(=O)(=O)(O)O.[CH2:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O.C(O)(=O)C>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][C:24]([I:1])=[CH:25][C:20]=1[O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: II
Reactant: CCCCCCOc1ccccc1OCCCCCC
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCOc1ccc(I)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 213.7 %

Procedure:
To 750 mL of glacial acetic acid, 69.3 g (253 mmol) of iodine, 32.8 g (144 mmol) of periodic acid, 150 mL of distilled water, and 22.5 mL of concentrated sulfuric acid were added. The resulting mixture was stirred at ambient temperature for five minutes, and 80.00 g (287 mmol) of 1,2-dihexyloxybenzene was added. Then, the mixture was stirred at 40° C. for 24 hours. The obtained reaction mixture was cooled to ambient temperature, washed with a KOH aqueous solution (1 M, 1.5 L) and 3 L of distilled water, and extracted with 800 mL of chloroform. The organic phase was dried over MgSO4 and the solvent was evaporated. The residue was purified by column chromatography and was then distilled. As a result, 218.6 g of a light brown liquid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.C[C:26]([N:28](C)C)=O>O.ClCCl.[Zn].[C-]#N.[C-]#N.[Zn+2]>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:26]#[N:28])=[C:6]3[N:7]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: CC(=O)N(C)C
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 160 °C

Procedure:
400 mg 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above), 7.0 mg zinc powder, 75.0 mg Zn(CN)2 and 39.0 mg dichloride[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct were suspended in 10 mL dimethylacetamide and the mixture was heated for 45 min under microwave irradiation to 160° C. The workup was performed by diluting the mixture with water and dichloromethane, extracting the aqueous layer twice and drying the combined organic layers over Na2SO4. The compound was isolated by evaporation of the solvent and chromatography on silica gel (dichloromethane/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:17][NH:18][O:19][CH3:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:17][N:18]([O:19][CH3:20])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CONCc1ccc(F)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 91 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-chloro-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as a white solid (91% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.75 (2H, s), 6.38 (1H, s), 7.09 (1H, t, J=8.8 Hz), 7.23 (1H, m), 7.41 (1H, dd, J=2.4 Hz and J=6.8 Hz). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C, 52.25; H, 4.36; N, 3.87.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13].[H][H].[CH3:17]O>[Pd]>[CH3:17][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:14])=[C:5]([OH:13])[C:6]=1[NH2:10]
Reactant: CO
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: Cc1ccc(C(=O)O)c(O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
10 g (51 mmol) of 2-hydroxy-3-nitrobenzoic acid methyl ester was dissolved in 100 mL of methanol, 1.0 g of 5% Pd/C was added thereto, hydrogen gas was filled and stirred at room temperature for 24 hr. The reaction mixture was filtered through diatomite to remove the catalyst, followed by concentration under reduced pressure to obtain the title compound (8.4 g, yield: 99%).
Reaction SMILES: ClCCl.[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCCCC(O)=[O:24]>>[CH:13]1([NH:12][C:11]([NH:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of a 2.5g (7.68 mmol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25° C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2×40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2×10 ml of 50% ethanol and dried at 80° C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100° C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145°-147° C.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=2)[S:10][C:11]=1Br.IC>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=2)[S:10][C:11]=1[CH3:2]
Reactant: Cc1cc(-c2cc(Br)c(Br)s2)sc1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(-c2cc(Br)c(C)s2)sc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
n-BuLi (2.5M in hexane) (10 mL, 25 mmol) was added dropwise to a solution of 4,5-dibromo-4′,5′-dimethyl-2,2′-bithiophene (3.37 g, 9.57 mmol) in 100 mL of THF at −78° C. After 90 minutes upon addition, excess iodomethane (3.6 g, 25 mmol) was added dropwise by syringe, and the mixture was stirred for 30 min, then warmed to RT and stirred for another 3 hours. Solvents were evaporated and the residue was poured into water. The mixture was extracted with hexanes, dried over MgSO4, and the solvent was evaporated to give off-yellow solid (2.71 g, 9.43 mmol, 99% yield) of 4-bromo-4′,5,5′-trimethyl-2,2′-bithiophene. 1H NMR (600 MHz, CDCl3) δ 6.85 (s, 1H), 6.82-6.76 (m, 1H), 2.37 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H)
Reaction SMILES: [O:1]1CCOCC1.[CH2:7]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Se](=O)=O.O>C(Cl)(Cl)Cl>[C:7]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])(=[O:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCO1
Reactant: O=C(O)C1CCc2c(Cc3ccccc3)cccc21
Agent: O=[Se]=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O

Procedure:
To 60 ml. of dioxane are added 6.3 g. of 4-benzylindan-1-carboxylic acid and 2.8 g. of selenium dioxide and the mixture is refluxed for 12 hours. After cooling, water and chloroform are added and the insolubles are filtered off. The filtrate is extracted with chloroform and the chloroform layer is extracted with 5 % aqueous potassium carbonate. The extract is decolorized with activated carbon and rendered acidic with hydrochloride acid. The precipitate is extracted with chloroform and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from a 20:7 solvent mixture of cyclohexane and benzene. The described procedure gives 4-benzoylindan-1-carboxylic acid as crystals melting at 100°-102° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (0.51 g, 2.7 mmol) and DIEA (0.39 ml, 2.2 mmol) in THF (10 ml) was added the 5-isopropoxy-1H-pyrazol-3-amine (0.25 g, 1.8 mmol) solution at 0° C. After addition, the reaction mixture was stirred at 25° C. for 3 days and 60° C. for 24 hours. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.33 g, 63%). 1H NMR (400 MHz) δ 12.25 & 11.66 (s, 1H), 10.46 & 10.13 (s, 1H), 8.58 & 8.55 (d, J=8.8 Hz, 1H), 7.11 & 7.02 (d, J=8.8 Hz, 1H), 6.08 & 5.97 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 & 1.27 (d, J=6.0 Hz, 6H). MS: Calcd.: 297. Found: [M+H]+ 298.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>ClC1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)[N:11]=[C:10]2[NH2:12]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1CSCCN1
Solvent: Clc1ccccc1
Product: COc1cc2nc(N3CCSCC3)nc(N)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of 8.00 g of 2-chloro-6,7-dimethoxy-4-quinazolinamine and 6.90 g. of thiomorpholine in 80 ml of chlorobenzene was refluxed for 18 hrs. The reaction mixture was cooled to room temperature, and the precipitate was collected. There was deposited 8.00 g (70.2%) of white powder, mp 267°-269°, dec. The product was recrystallized from methanol to give an analytical sample, mp 270°-271°, dec.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2cccnc2)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 1-(1,1-dimethylethyl)-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (68 mg, 0.201 mmol) was suspended in ethanol (2 mL) followed by addition of sodium hydroxide (0.335 mL, 1.005 mmol). The mixture was stirred at room temperature for 2.5 h. The mixture was concentrated and the residue was diluted with water (1 mL) and acidified to pH 3 using 1N HCl. The precipitate was collected by filtration and further dried under high vacuum to give the product as an HCl salt, 60 mg (86%). LCMS E-S (M+H)=311.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82 (s, 9H), 2.60 (s, 3H), 7.60 (dd, J=7.96, 4.67 Hz, 1H), 8.08 (s, 1H), 8.57 (dt, J=8.34, 1.89 Hz, 1H), 8.70 (dd, J=4.80, 1.52 Hz, 1H), 9.39 (d, J=1.52 Hz, 1H), 14.03 (br. s., 1H).
Reaction SMILES: CO.C(Cl)(=O)C.[CH3:7][C:8]([O:11][C:12]([C@@H:14]1[CH2:30][S:29][S:28][CH2:27][C@H:26]([NH:31]C(OC(C)(C)C)=O)[C:25](=[O:39])[NH:24][CH2:23][CH2:22][C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16](=[O:40])[NH:15]1)=[O:13])([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH3:10][C:8]([O:11][C:12]([C@@H:14]1[CH2:30][S:29][S:28][CH2:27][C@H:26]([NH2:31])[C:25](=[O:39])[NH:24][CH2:23][CH2:22][C:17]2([CH2:18][CH2:19][CH2:20][CH2:21]2)[C:16](=[O:40])[NH:15]1)=[O:13])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSSC[C@@H](C(=O)OC(C)(C)C)NC(=O)C2(CCCC2)CCNC1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CSSC[C@H](N)C(=O)NCCC2(CCCC2)C(=O)N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
To a mixture of methanol (0.15 mL, 3.8 mmol) in 5 mL of ethyl acetate was added at 0° C., under an atmosphere of argon, acetyl chloride (0.27 mL, 3.8 mmol). The solution was stirred at 0° C. for 10 min, and at room temperature for 30 min. To the solution was added (8R,13R)-13-[[(1,1-dimethylethoxy)carbonyl]amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester (130 mg, 0.25 mmol). The mixture was stirred for 7 hours. The precipitate was collected on a glass frit and washed with ethyl ether. After drying under high vacuum, 92 mg of (8R,13R)-13-amino-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylic acid 1,1-dimethylethyl ester was obtained (96% yield based on recovered starting material after evaporation of the filtrate and washes).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:15][C@H:16]2[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]2)=[N:9]3)=[O:31])=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=398.1 (M+H+), was prepared in accordance with the general method of example 45 from 5-nitro-2-chloroquinoline, (R)-1-aminoindane and 4-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[OH-].[K+].[CH2:25](N)[CH2:26]N.C#C>C(O)(C)(C)C.C1COCC1>[C:25]([C@@:12]1([OH:22])[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)#[CH:26]
Reactant: NCCN
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: C#C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C#C[C@@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In an inert pressurizable vessel is placed 3-methoxyandrosta-3,5-dien-17-one (I Aa, 15 g) THF (60 ml), milled potassium hydroxide (15 g), t-butanol (1.5 ml), and ethylenediamine (10 ml). The stirred mixture is heated to 53° and a 15-pound partial pressure of acetylene is applied. These conditions are maintained for 3 hr at which time TLC indicates a mixture of ethisterone methyl enol ether and epiethisterone methyl enol ether. The reaction mixture is quenched with phosphate buffer (pH=7) and methylene chloride is used to isolate the product as an oil. The resulting oil is crystallized from toluene to give epi-ethisterone enol ether of approximately 90% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11](C(Cl)=O)[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC([C@H]2[C@@H](C3C=CC(Cl)=CC=3)N([C:54]([N:56]3[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][S:64]([CH3:67])(=[O:66])=[O:65])[CH2:58][CH2:57]3)=[O:55])C(C3C=CC=CC=3OCC)=N2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:54]([N:56]3[CH2:57][CH2:58][N:59]([CH2:62][CH2:63][S:64]([CH3:67])(=[O:65])=[O:66])[CH2:60][CH2:61]3)=[O:55])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and 1-(2-methanesulfonylethyl)-piperazine (example 11) in an analogous manner as described in example 8. LR-MS: 673.3 [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:14]1[CH2:16][CH2:15]1)#[N:11]>O.C(O)C>[NH2:11]/[C:10](=[N:8]\[OH:9])/[C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)CC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)/C(N)=N/O
Reaction time: 72 h
Yield: 92.7 %

Procedure:
Potassium carbonate (2.18 g, 16 mmol) was dissolved in water (8 mL) and hydroxylamine hydrochloride (1.1 g, 16 mmol) was added. A solution of (S)-tert-butyl 1-cyano-2-cyclopropylethylcarbamate (3.31 g, 16 mmol) in ethanol (24 mL) was added thereto and the resulting reaction mixture was stirred for 72 h. After evaporation of solvents, the residue was dissolved with ethyl acetate (20 mL) and then filtered. The filtrate was concentrated to yield crude product as yellow solid (3.61 g, 94%); MS (EI): m/e 244.2 [M+H]+.
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19]C=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: NC1CCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCCC1
Yield: 47 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (70 mg, 0.28 mmol), triethyl orthoformate (2 ml), cycloheptylamine (0.066 ml, 0.52 mmol), and acetic acid (0.1 ml) were used to give 45 mg (0.13 mmol, 47% yield) of the title compound.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)N)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.CC(O)=O>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:31]2[C:28]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:35][CH:36]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 39 g methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (Ketone 2) in a mixture of toluene (300 mL) and HOAc (150 mL) was added NaOAc (15 g) and 1-(4-methoxyphenyl)-1-(4-chlorobenzyl)-hydrazine hydrochloride (50 g). The reaction was stirred at r.t. for 3 days under argon in the dark. The mixture was poured onto H2O (1 L) and extracted with 3× EtOAc (500 mL). The EtOAc was washed with 3× H2O (500 mL) then once with NaHCO3 solution. The organic phase was dried (MgSO4), evaporated to dryness, and the residue crystallised from Et2O/hexane 2:1 to afford the title compound; m.p. 102°-103° C.
Reaction SMILES: Cl.[CH3:2][NH:3][N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18][C:17]=3[CH:28]=2)=[O:11])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[CH3:2][NH:3][N:4]=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[CH2:19][CH2:18][C:17]=3[CH:28]=2)=[O:11])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC)cc3)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 207 mg (0.48 mmol) of the ester from Example 57 were given 4 ml ethanol, 0.5 ml 2 N aqueous sodium hydroxide, and three drops of water, and the mixture was stirred overnight at room temperature. A precipitate was formed. It was brought to pH 5 with 2 N acetic acid, and the title compound was filtered with suction, washed with water and with ethanol, successively, and dried in vacuo. Yield: 0.12 g (68%) of a pale yellow powder, m.p. 275-276° C. (dec.).