Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:39])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[N:26]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29].C1CCCCC=1>[Pd].O1CCOCC1>[F:43][C:41]1[CH:40]=[C:4]([CH:3]=[C:2]([F:1])[CH:42]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:39])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:26]([CH:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[C:27](=[O:32])[C:28]([F:31])([F:29])[F:30]
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: Nc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
A mixture of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-nitro-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide (3.86 g, 6.4 mmol), cyclohexene (10 mL), dioxane (70 mL) and 10% Pd/C (0.42 g) was stirred at 100° C. for 4 hours. The reaction mixture was filtered over a celite pad washing thoroughly with THF and MeOH. After evaporation of the organic phase, purification of the crude by chromatography over silica gel (DCM/EtOH 9/1) gave 2.75 g of title compound (82% yield).
Reaction SMILES: O=[C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:10]=2[N:11]=1)=O.FC(F)(F)C([O-])=O.[NH4+:37]>O>[CH3:23][O:22][C:12]1[C:10]2[N:11]=[C:7]([C:5]3[NH:4][CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:37]=3)[S:8][C:9]=2[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccccc3)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4ccccc4)c[nH]3)nc12
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 0.18 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide and 0.57 g ammonium triflouroacetate was melted at 165° C. for 40 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:2 gave 0.07 g (41%) 4-methoxy-7-morpholin-4-yl-2-(4-phenyl-1H-imidazol-2-yl)-benzothiazole as yellow solid; M.p.: 226–233° C.; MS (ISP): m/e=393 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17](Cl)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([NH:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:21]=[CH:22][CH:23]=[CH:24]2)=[O:12])(=[O:7])[CH3:17]
Reactant: CC(=O)Cl
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc2ncccc2c1
Product: C=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(C)=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, acetyl chloride, and 6-quinolinamine the title compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=296.0.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:30]([OH:42])[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[C:30](=[O:42])[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-11-(trimethylsilyloxy)spirostan-12-ol was oxidized with chromium trioxide and pyridine in methylene chloride according to the procedure described in Org. Syn., 1976, 55, 84 to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]1[CH3:12].Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])(=O)C.[K+].C>CN(C)C(=O)C.[Pd].ClCCl>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:12])=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1Br
Reactant: CCOC(=O)c1ccn(C)c1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(-c2cc(Cl)ccc2C=O)n(C)c1C
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of 2-bromo-4-chlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdC12(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130° C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (2 g per g of product) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([OH:21])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.[F:36][C:37]([F:43])([F:42])[S:38](Cl)(=[O:40])=[O:39]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([O:21][S:38]([C:37]([F:43])([F:42])[F:36])(=[O:40])=[O:39])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)C(F)(F)F)nc1C(C)C
Temperature: 0 °C
Yield: 66.3 %

Procedure:
In a 300 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 2.9 g (10.0 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 1.7 g (16.8 mmol.) of triethylamine, and 50 mL of toluene. The mixture in the flask was chilled to 0° C. in an ice bath. To the chilled mixture was slowly added 2.4 g (14.1 mmol.) of trifluoromethanesulfonyl chloride, and the resulting mixture was subjected to reaction for 3 hours at the same temperature. After the reaction was complete, to the reaction mixture was added 30 mL of water. From the aqueous reaction mixture, an organic liquid portion was separated. The organic liquid portion was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained 2.8 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine having the below-mentioned characteristics as a colorless oil. The yield was 66% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8]O)[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13].S(Cl)([Cl:17])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>O>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][Cl:17])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)COc1c[nH]c(CO)cc1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1c[nH]c(CCl)cc1=O
Reaction time: 0.5 h

Procedure:
To crystals (10 g) of 2-(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid was added thionyl chloride (25 ml), and the mixture was stirred for 30 minutes. After cooling, dimethylformamide (125 ml) was added to the reaction mixture, and the resultant mixture was stirred for an hour. The resultant mixture was poured into cold water (750 ml) and the aqueous solution was adjusted to pH 3 with an aqueous sodium bicarbonate solution and then cooled with ice for 2 hours. Precipitated crystals were collected by filtration and washed with water to give crystals (8.7 g) of 2-(4-oxo-6-chloromethyl-1,4-dihydropyridin-3-yloxy)acetic acid. (This product was converted to its hydrochloride monohydrate, m.p. 150° to 155° C. by recrystallizing from a mixture of 10% hydrochloric acid (5 ml) and water (5 ml).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.[Pd]>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=[C:5]1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1nccc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc2sc(-c3nccc4ccccc34)cc2c1
Yield: 79 %

Procedure:
Benzo[b]thiophene-2-ylboronic acid (997 mg, 5.6 mmol) and 1-chloroisoquinoline (946 mg, 5.8 mmol) were dissolved in toluene (20 ml) and ethanol (10 ml), and palladium catalyst (220 mg, 0.19 mmol) and 2M sodium carbonate solution (20 ml) were added thereto, followed by refluxing under a N2 atmosphere for 5 hours. The reaction solution was added to H2O, and the mixture was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 1.16 g, yield: 79%).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][NH:17][CH3:18]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][N:17]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:18]
Reactant: COC(=O)c1oc2ccccc2c1CBr
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1oc2ccccc2c1CN(C)C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a solution of methyl 3-bromomethylbenzofuran-2-carboxylate (269 mg, 1.0 mmol) in DMF was added dimethylamine (2M solution in THF, 1.5 ml, 3 mmol). The reaction mixture was stirred for 1-2 h, diluted with ethyl acetate (50 ml), washed twice with saturated aqueous sodium bicarbonate solution (50 ml) and finally with brine (50 ml). The organic extract was dried over sodium sulfate and then concentrated in vacuo. Purification by flash chromatography on silica gel (5% methanol in dichloromethane) gave methyl 3-dimethylaminomethylbenzofuran-2-carboxylate (131 mg, 0.57 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-].[K+].Cl>C(O)C.CS(C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(CNc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(NCc3ccc(C(=O)O)cc3)ccc21
Yield: 57.3 %

Procedure:
2 g of this ester and 2.5 g of potassium hydroxide in 45 ml of 5:1:3 ethanol/dimethyl sulfoxide/water were refluxed for 1 hour. At room temperature, 20 ml of 2N hydrochloric acid were added to the solution. The precipitate was filtered off, recrystallized from methanol and yielded 1.1 g of the title compound of melting point 225°-231° C.
Reaction SMILES: [OH:1][C:2]1([CH2:20][OH:21])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:19][CH2:18][CH2:17][S:16]2)[CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C:2]1([OH:1])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:16][CH2:17][CH2:18][S:19]2)[CH2:3]1)(=[O:24])[CH3:23]
Reactant: COc1ccc(OC)c2c1CC(O)(CO)CC21SCCS1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC21SCCS1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.6 g of rac-1',2',3',4'-tetrahydro-3'-hydroxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] were dissolved in 30 ml of dry pyridine and 1.5 g. of acetic anhydride were added to the solution. The mixture was left to stand at room temperature for 20 hours and then poured into ice-cold 5-M sulphuric acid. The resulting mixture was extracted with ethyl acetate, the extracts were washed with water and sodium hydrogen carbonate solution, dried and evaporated to give 1.8 g of rac-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless oil which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[C:26]([C:27]([F:30])([F:29])[F:28])=[N:25][N:24]=[N:23]3)[CH:19]=[CH:18][C:17]=2[O:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:9]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)(C)(C)C.[ClH:49].C(O)C>O1CCOCC1>[ClH:49].[ClH:49].[CH2:32]([O:31][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[C:26]([C:27]([F:29])([F:30])[F:28])=[N:25][N:24]=[N:23]2)=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
From 3-{tert-butoxycarbonyl-[2-(1-butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (345 mg, 0.51 mmol) using 4M-hydrogen chloride in dioxan (5 ml) at 40° C. to give the title compound as a white crystals from ethanol (218 mg). Found C, 51.78; H, 5.62; N, 15.13; C24H29F3N6O.2HCl.0.5H2O (556.46), requires C,51.80; H, 5.80; N, 15.10%. Mass spectrum (thermospray +ve) m/e 475 (MH+).
Reaction SMILES: CC1(C)OC(=S)NC2C=CC(C3N(C)C(C#N)=CC=3)=CC1=2.[H-].[Na+].[C:24](=[O:26])=[O:25].CC([O:30][C@@H:31]1[C@@H:36]([O:37]C(C)=O)[C@@H](Br)[O:34][C@H:33]([C:42](OC)=[O:43])[C@H:32]1[O:46]C(C)=O)=O>CN(C)C=O>[O:37]=[CH:36][C@@H:31]([C@H:32]([C@@H:33]([C@@H:42]([C:24]([OH:26])=[O:25])[OH:43])[OH:34])[OH:46])[OH:30]
Reactant: O=C=O
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of tanaproget (0.292 g, 1.0 mmol) in anhydrous dimethyl formamide (DMF) (10 mL) was added dropwise under a nitrogen atmosphere to a solution of sodium hydride (NaH) (0.052 g, 2.2 mmol) in DMF (50 mL) that was cooled to approximately −70° C. (dry ice). After stirring for 10 min, a solution of acetobromo-α-D-Glucuronic acid methyl ester (0.396 g, 1 mmol) in DMF (10 mL) was added dropwise. The reaction solution was then warmed to room temperature, and stirred for a total of 24 hours. After 24 hours, the reaction solution was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic layers were washed with saturated sodium chloride (NaCl) solution (100 mL), dried (magnesium sulfate, MgSO4), and the solvent removed in vacuo. Aliquots of the crude material were chromatographed under low-pressure reversed-phase C18 (RediSep/ISCO, 125×25 mm ID, 40 μm particle size) conditions with a gradient of 50-95% acetonitrile/water. Fractions eluting with 75-80% acetonitrile/water contained the S-protected (D)-Glucuronic acid derivative (2) of tanaproget. A total of approximately 200 mg of (2) was obtained at 95% purity based on NMR spectroscopic analysis (32% isolated yield). All chemicals were purchased from Aldrich (Milwaukee, Wis.) and used without further purification or drying.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]([NH2:18])=O)[CH:11]=[CH:12][CH:13]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH2:18])[CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14.3 %

Procedure:
A 1.0 M solution of LiAlH4 in THF (6.0 mL, 6.0 mmol) was added dropwise to a suspension of 3-(3-chloro-phenyl)-acrylamide (1.0 g, 5.51 mmol) in 30 mL THF at 0° C. The reaction was warmed to room temperature and was stirred for 5 h. An additional 4 mL of 1 M LiAlH4 was added and the reaction was stirred for 18 h. An addition 2 mL of 1 M LiAlH4 was added and the reaction was stirred for 24 h. The reaction mixture was quenched by dropwise addition of water. The mixture was concentrated in vacuo to remove THF and was diluted with water. The aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in CHCl3 and the organic solution was washed with 1M HCl. The aqueous solution was basified to pH 11 with 1M NaOH and the product was extracted into CHCl3. The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a yellow oil (0.134 g). 1H NMR (400 MHz, CDCl3) δ 7.20-7.22 (m, 3H),7.16 (m, 1H), 2.74 (t, 2H), 2.61 (t, 2H), 1.74 (m, 2H); MS 170 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCn1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCn1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 100 %

Procedure:
Benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 1.3 mmol) was stirred in methanol (9.5 mL) with Pd/C (70 mg, 0.070 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (350 mg, 99%). ESI-MS m/z calc. 269.2. found 270.5 (M+1)+; Retention time: 0.80 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29]C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]>CN(C=O)C.N1CCCCC1>[NH2:29][C:13]1([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:2]([NH2:1])=[O:3])[C:12]=3[N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCN(C(=O)OCc4ccccc4)CC3)nc12
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(C3(N)CCN(C(=O)OCc4ccccc4)CC3)nc12
Yield: 35.6 %

Procedure:
A mixture of Example 49A (0.035 g, 0.1 mmol) in DMF (2 ml) and piperidine (0.5 ml), was stirred at room temperature for 2 h. The mixture was concentrated under vacuum then crystallized from MeOH to provide 0.014 g (64%) of the desired product. MS (ESI) m/e 416 (M+Na)+. 1H NMR (DMSO-D6) δ ppm 8.14 (s, 1H), 7.84 (d, J=7.02 Hz 1H), 7.73 (s, 2H) 7.37-7.40 (m, 4H), 7.31-7.37 (m, 2H), 5.11 (s, 2H), 3.51-3.68 (m, 6H), 2.32 (s, 2H), 1.88 (d, J=13.43 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C1CCCCC1)CC(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[CH:20]1([CH:21]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:22][OH:23])[CH2:24][CH2:22][CH2:21][CH2:20][CH2:24]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1
Agent: B
Product: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of N-(t-butyloxycarbonyl)cyclohexylglycine (2.0 g, 7.77 mmol) in anhydrous THF (10 mL) was cooled to 0° C. Borane solution (1 M in THF, 15.5 mL, 15.5 mmol) was added slowly and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with MeOH (5 mL), volatiles were evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated NaHCO3/water, brine, dried (sodium sulfate), and evaporated to give tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 11a (1.26 g, 66.7%), MS (CI) m/z 144.2 (MH+−Boc).
Reaction SMILES: C(O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CC1N[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C(=O)C=1.C([NH2:26])=O>C([O-])=O.[Cr+3].C([O-])=O.C([O-])=O.[Cr]>[CH:21]1[CH:22]=[CH:23][C:18]([N:14]=[N:4][C:3]2[CH:2]=[CH:8][C:7]([NH2:26])=[CH:6][CH:5]=2)=[CH:19][CH:20]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: NC=O
Agent: [Cr+3]
Agent: [Cr]
Agent: O=C[O-]
Product: Nc1ccc(N=Nc2ccccc2)cc1

Procedure:
A chromium complex of ##STR1## Anthranilic acid→3-Methyl-1-phenyl-5-pyrazolone; then heat with chromium formate in formamide solution for 6 hr. at 113°-115° C. to form the chromium complex which contains 1 atom of chromium per 2 mol. dye.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>CCO>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12](=[N:30][OH:31])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=NO)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of the ketone 483 (2.47 g, 6.6 mmol) in EtOH (35 mL) is added hydroxylamine hydrochloride (1.83 g, 26.4 mmol) followed by pyridine (2.13 mL, 26.4 mmol). The mixture is stirred at 80° C. for 8 h. The reaction mixture is cooled, the solvent is evaporated, and the residue dissolved in EtOAc, washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (7:3) gives 1.95 g of the product 484. 1H NMR (CDCl3) δ 7.55 (d, 2 H), 7.50-7.10 (m, 10 H), 7.00-6.70 (m, 2 H), 6.50-6.35 (m, 1 H), 5.30-5.00 (m, 2 H), 3.80 (d, 3 H); MS: m/z 391 (M++1).