Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14].Cl>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A solution of 6-bromo-1H-indole (2.34 g, 11.9 mmol) in dry THF (25 mL) was cooled in an ice bath. Sodium hydride (1.12 g of 60% dispersion in oil, 28.0 mmol) was added. The mixture was stirred for 30 minutes under nitrogen at room temperature, then cooled in an ice bath. Iodomethane (1.6 mL, 26 mmol) was added: The reaction mixture was stirred for 2 hours at room temperature, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane as an eluant to yield 6-bromo-1-methyl-1H-indole 2.04 g (81.6% 9.71 mmol) as a yellow oil. 1HNMR (200 MHz, DMSO-d6): δ7.7 (s, 1H), 7.5 (d, 1H, J=8.6 Hz), 7.35 (d, 1H, J=2.1 Hz), 7.15 (d, 1H, 7.3 Hz), 6.4 (d, 1H, J=1.3 Hz), and 3.75 ppm (s, 3H).
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+:11].[C:12](=[S:14])=[S:13]>>[CH2:1]([S:9][C:12]([S-:14])=[S:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K+:11]
Reactant: CCCCCCCCS
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCSC(=S)[S-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
438.9 g (520.6 ml, 3 moles) of 1-octanethiol were refluxed (with stirring) for about 1 hour with 66 g. (1 mole 85% purity) potassium hydroxide flakes. 72.5 ml (91.33 g., 1.2 moles) of CS2 were then added (dropwise) with stirring to the mixture which had been cooled to 0° C. in an ice-water bath. The mixture was stirred for about 1 hour after addition was complete, and then allowed to warm to room temperature. The resulting white solid precipitate was filtered, thoroughly washed with anhydrous ethyl ether, and dried overnight in a vacuum oven at 35° C. 250.1 g. of potassium octylthioxanthate were obtained (96% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][CH:41]([NH2:43])[CH3:42])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:43][CH:41]([CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[CH3:42])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)Nc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (907 mg, 3.01 mmol) in acetonitrile (150 mL) was added diisopropylethylamine (1.05 g, 6.03 mmol) followed by 5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-amine (920 mg, 3.01 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h while monitoring by LC-MS. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica) using 2-3% of methanol in chloroform to give 2-chloro-7-(2,4-difluorophenyl)-N-(5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine as a yellow solid (650 mg, 1.140 mmol, 37.8% yield). LC-MS (M+H)+=570.0. 1H NMR: (400 MHz, CDCl3) δ ppm 8.85 (1H, s), 8.07 (1H, d, J=8.4 Hz), 8.00-7.96 (2H, m), 7.00-6.97 (1H, m), 6.81-6.78 (2H, m), 4.47-4.31 (5H, m), 2.72-2.64 (3H, m), 2.50 (3H, s), 2.04-1.98 (3H, m), 1.78-1.74 (2H, m), 1.32-1.25 (3H, m).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[O:25][C:26]([CH3:29])=[N:27][N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[OH:31][CH2:30][CH2:32][NH:33][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[O:25][C:26]([CH3:29])=[N:27][N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Solvent: CS(C)=O
Product: Cc1nnc(-c2cccc(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)o1
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.05 g, 0.12 mmol) (from Example 9 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The reaction mixture was purified by reverse-phase chromatography (C18 column) eluting with acetonitrile-water to give 4-amino-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 15.0 mg, 29%).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[S:5].[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH:2][NH:3][C:4]([NH2:6])=[S:5])=[O:11]
Reactant: NNC(N)=S
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Thiosemicarbazide hydrochloride (2.55 g, 20.0 mmol) was mixed to pyridine (20 ml), and 2,4-dichlorobenzoyl chloride (2.81 ml) was added thereto. The mixture was stirred at a room temperature for 14 hours. The solvent was distilled off. Water was added to the resulting residue, and the mixture was stirred. The precipitate was separated by filtration. 2,4-Dichlorobenzoylthiosemicarbazide (2.11 g, 8.00 mmol) obtained from the precipitate by through circulation drying was mixed to toluene (25 ml), and methanesulfonic acid (0.78 ml) was added to the mixture. The resulting mixture was heated and stirred for 6 hours. The mixture was allowed to cool to a room temperature. Then, the precipitate was separated by filtration, neutralized with water and 25% ammonia water, and stirred for 30 minutes. The precipitate was separated by filtration, washed with water, and subjected to through circulation drying to give the title compound (1.14 g, 58%) as a white substance.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])(C)C)=[O:9])C.ClC1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>C1COCC1.CCOC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To a suspension of NaH (60% dispersion, 0.900 g, 22.5 mmol) in 40 mL of THF was added malonic acid tert-butyl ester ethyl ester (4.00 mL, 21.1 mmol) and the mixture stirred for 15 min at RT. To this mixture was then added 2-chloro-5-nitro-pyridine (2.56 g, 16.0 mmol) and the reaction stirred for 10 h at RT. The mixture was diluted with 100 mL of EtOAc and washed with NH4Cl (2×100 mL) and brine (100 mL) and dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DCM (20 mL), TFA (10 mL) was added and the mixture stirred for 2 h at RT. The mixture was concentrated, the residue dissolved in 100 mL of EtOAc and washed with NaHCO3 (2×100 mL) and brine (100 mL) and again dried over Na2SO4 and concentrated in vacuo. The title compound was purified by flash chromatography eluting with 30% EtOAc/hexanes to give 2.35 g (70%) of a light yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 9.38 (d, J=2.6 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.99 (s, 2H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([Br:51])=[CH:47][N:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[Br:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:46][CH:47]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(C(=O)Nc2ccc(Br)cn2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
A solution of triphenylphosphine (243 mg, 0.92 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (165 mg, 0.92 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200 mg, 0.84 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-5-bromopyridine (363 mg, 2.10 mmol) and was stirred at 25° C. for 10 d. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium bicarbonate solution (25 mL). The organic layer was separated and was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-pyridin-2-yl)-amide (100 mg, 30%) as an off-white foam: mp 57-64° C.; EI-HRMS m/e calcd for C17H15BrClN3O (M+) 391.0087, found 391.0092.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:6][C:7](=[O:25])[C:8]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[C:10]([C:11]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[O:12])[CH:9]=1)[CH2:4][OH:5]>O.[Ni]>[NH2:22][C:20]1[CH:21]=[C:8]([C:7]([NH:6][CH:3]([CH2:4][OH:5])[CH2:2][OH:1])=[O:25])[CH:9]=[C:10]([CH:19]=1)[C:11]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[O:12]
Reactant: O=C(NC(CO)CO)c1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: O
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 90 °C

Procedure:
N,N′-Bis-(2-hydroxy-1-hydroxymethyl-ethyl)-5-nitro-isophthalamide (40 g) is dissolved in water (600 mL), and then heated to 90° C. to dissolve. Raney Ni (5 g) is added, and allowed to react for 10 h under a H2 pressure of 1.5 MPa. Raney Ni is removed by filtration and the filter cake washed with 20-30 mL of water. The filtrate and washings are combined to obtain the aqueous solution of 5-Amino-N,N′-bis-(2-hydroxy-1-hydroxymethyl-ethyl)-isophthalamide, which can be utilized directly in the iodination reaction or concentrated and then re-crystallized using methanol to obtain solid product.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.ClC(OC)=O.[NH3:27].[OH-].[Na+]>C(N(CC)CC)C.O1CCCC1>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH2:27])=[O:19])=[CH:20][CH:21]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: N
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (1.05 g) and dry tetrahydrofuran (30 ml) was stirred at ambient temperature whilst triethylamine (1.1 ml) was added. The mixture was stirred at ambient temperature for 0.5 h then cooled to 3° C. and methyl chloroformate (1.2 ml) was added dropwise over 5 to 10 minutes at 3-9° C. The mixture was stirred for 1 hour at 3-9° C. and then added to concentrated aqueous ammonia solution (70 ml, SG 0.880) with rapid stirring. The mixture was stirred for 2 hours at 5° C. and allowed to warm up to ambient temperature. The mixture was concentrated under reduced pressure and then treated with 1M sodium hydroxide solution (200 ml). The mixture was stirred for 0.5 hour and then filtered. The solid obtained was stirred with 2M sodium hydroxide solution (50 ml) for 6 hours and then allowed to stand at ambient temperature for 18 hours. The mixture was filtered to give a solid which was washed with water and dried. This solid was purified by flash column chromatography on silica using dichloromethane/industrial methylated spirit/triethylamine (25:2.5:1.5) as the mobile phase. The appropriate fractions were combined and concentrated to give a residue which was washed with water and dried under vacuum at 40° C. to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 290-293° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][NH2:26]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][NH2:26])=[O:2])=[CH:5][N:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Temperature: 90 °C
Yield: 76.4 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (1.0 g, 3 mmol), hydrazine (3.09 g, 62 mmol) and ethanol (1 mL) was heated at 90° C. for 5 h. The mixture was cooled and concentrated to give a white residue that was triturated with chloroform and filtered. The filtrate was concentrated to afford the title compound (743 mg, 49%) as a white solid. MS: m/e=325.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14]>C(O)(=O)C>[CH3:13][C:14]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1S
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2s1

Procedure:
A suspension of 3-aminoquinoline-4-thiol (about 12 g) in a mixture of acetic anhydride (150 mL) and acetic acid (300 mL) was heated at reflux overnight. The reaction mixture was filtered to remove a fine solid. The filtrate was evaporated under vacuum. The residue was diluted with ethanol then refluxed for 30 minutes. The solution was concentrated under vacuum and the residue diluted with water. The aqueous residue was made basic with sodium hydroxide and then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to provide 12.8 g of crude product. A sample (800 mg) was recrystallized from hexane to provide 2-methylthiazolo[4,5-c]quinoline as yellow needles, m.p. 95.5-97.5° C. Analysis: Calculated for C11H8N2S: % C,65.97; % H, 4.03; % N, 13.99; Found: % C, 65.96; % H, 4.16; % N 14.08.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.OO.Cl.[CH:15](=[O:17])C>[Cl-].[Na+].[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:15][O:17][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC=O
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: O=[W](=O)([O-])[O-]
Agent: Cl
Agent: OO
Product: CON1C(C)(C)CC(=O)CC1(C)C
Reaction time: 2 h
Yield: 64 %

Procedure:
The intermediate, 1-oxy-2,2,6,6-tetramethyl-piperidin-4-one, can be produced by reacting 2,2,6,6-tetramethyl-piperidin-4-one with 1.75 equivalents of hydrogen peroxide in 2M sodium chloride solution, with 1 mol % sodium tungstate added, for 12 h at 50°. When the reaction is complete, the solution is slightly acidified with 2 N hydrochloric acid to pH 5, then 3 equivalents of acetaldehyde and two equivalents of 30% hydrogen peroxide are added slowly at 50°. The mixture is stirred at 90° for 2 h, and then cooled. The work-up, as above in example E, gives 64% of liquid product, crystallizes slowly.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl.CO>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:44][CH2:43]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)nc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4ccccn4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 96.8 %

Procedure:
The title compound was prepared from 42 mg (0.096 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 36 mg (0.18 mmol) of 4-(2-pyridylpropyl)piperidine.2 TFA (from EXAMPLE 72, Step B) using a procedure analogous to that described in EXAMPLE 71, Step A. Flash chromatography using 25:1 v/v CH2Cl2/MeOH provided 58 mg (97%) of the title compound: 1H NMR (500 MHz) δ 0.94-3.28(35H), 3.82 (s, 3H), 5.11 (ABq, J=11.9, 2H), 6.88-7.35 (11H), 7.58-7.61 (m, 1H), 8.52 (d, J=4.1, 1H); ESI-MS 624 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([C:26](O)=[O:27])=[CH:22][N:21]=3)[C@H:16]([CH3:29])[CH2:15]2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[CH3:48][NH:49][O:50][CH3:51]>C(Cl)Cl.CN(C=O)C>[CH3:51][O:50][N:49]([CH3:48])[C:26]([C:23]1[N:24]=[CH:25][C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[N:13][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:9]([CH3:31])[C:10]=3[CH3:30])[CH2:15][C@H:16]2[CH3:29])=[N:21][CH:22]=1)=[O:27]
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)O)cn3)[C@H](C)C2)c1C
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 0 °C
Yield: 75.8 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid (50 mg, 0.120 mmol) is dissolved in CH2Cl2 (300 μL). The mixture is cooled to 0° C. and oxalyl chloride (32 μL. 0.358 mmol) is added followed by DMF (3 drops). While stirring, the reaction is warmed to room temperature over 3 h. Diisopropylethylamine (209 μL, 1.2 mmol) is added dropwise followed by addition of N,O-dimethylhydroxylamine hydrochloride (14 mg, 0.144 mmol). Allow the reaction to stir for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (42 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:20][C:19]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[N:25]=5)=[N:18][N:17]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)OC3(CCNCC3)C=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:10]3([CH2:15][CH2:14][N:13]([C:16]4[S:20][C:19]([C:21]5[N:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[N:25]=5)=[N:18][N:17]=4)[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nnc(-c2nnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Agent: Fc1ccc(C2=CC3(CCNCC3)Oc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(O)Cn1nnc(-c2nnc(N3CCC4(C=C(c5ccc(F)cc5)c5ccccc5O4)CC3)s2)n1
Temperature: 81 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-(5-(5-(4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine]-1′-yl)-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl)acetate A mixture of 4-(4-fluorophenyl)spiro[chromene-2,4′-piperidine] (171 mg, 0.58 mmol) (Example 6, Step 2), Intermediate 2 (203 mg, 0.64 mmol) and K2CO3 (144 mg, 1.04 mmol) was suspended in dry DME (3 mL). The reaction mixture was stirred under N2 at an external temperature of 81° C. for 1.5 h. Then the reaction mixture was cooled down to room temperature, diluted with DCM (5 mL), washed with 5% KHSO4 (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oily residue was purified by Combiflash™ chromatography (SiO2 (12 g), eluting with 10-60% EtOAc/hexanes) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:33])[N:20]([CH:24]5[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:33])[N:20]([CH:24]5[CH2:25][CH2:26][CH:27]([C:30]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:32])[CH2:28][CH2:29]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:36]([F:37])([F:39])[F:38])[CH:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCC(C(=O)O)CC5)C4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCC(C(=O)NS(C)(=O)=O)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
4-[(5Z)-5-({1-[4-Methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)cyclohexanecarboxamide was prepared from 4-[(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid (Example 22) following General Procedure L using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[OH:29])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound II-bq was prepared in 50% yield from 3,3:17,17-bis(ethylendioxy)-7(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.37 (s, 1H), 2.99 (m, 1H), 2.58-0.67 (m, 19H), 1.12 (s, 3H), 0.82 (s, 3H).