Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl>[C:52]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:28]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(N)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 80 mg (0.13 mmol) N-[4-amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide and 26 mg (0.20 mmol) N,N-diisopropylethylamine in 3 ml dichloromethane were added 12 mg (0.15 mmol) acetyl chloride at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with 10 ml dichloromethane and washed with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 82 mg (95%) of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=1>[NH4+].[Cl-].C(O)C.[Fe]>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CCNc1cc(Br)ccc1N
Temperature: 60 °C
Yield: 86 %

Procedure:
Iron powder (7 g, 0.12 mol) was added to a mixture of methyl 3-(5-bromo-2-nitrophenylamino)propanoate (12 g, 0.04 mol) in aq. NH4Cl solution (50 mL) and ethanol (100 mL). After heating at 60° C. for 2 h, the mixture solution was filtered. The filtrate was evaporated, diluted with water (100 mL), extracted with ethyl acetate (150 mL), dried and concentrated to give the crude product, which was purified by CombiFlash to afford methyl 3-((2-amino-5-bromophenyl)amino)propanoate (9.4 g, yield 84%). LRMS (M+H)+: 272 m/z. 1H NMR (300 MHz, CDCl3) δ 2.67-2.72 (d, 2H, J=6.3 Hz), 3.40-3.44 (d, 2H, J=6.3 Hz), 3.72 (s, 3H), 4.58 (br, 3H), 6.67-6.70 (d, 2H, J=8.1 Hz), 6.80-6.82 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])=[CH:26][CH:25]=1.CN(C=O)C>CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:36]=2)=[O:34])[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ccncc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12)c1ccncc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (0.48 g, 1.13 mmol), copper(I) iodide (16 mg, 0.084 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide (400 mg, 0.84 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed for 10 min then tetrakis(triphenylphosphine)palladium (0) (45 mg, 0.039 mmol) was added. The reaction mixture was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 390 mg (87%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a yellow solid. MS: (M+H)+=532.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[NH:28][C:27](=[O:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O=P(Cl)(Cl)Cl>[CH:30]1([O:29][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:19]([CH2:18][N:15]3[CH2:14][CH2:13][N:12]([S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:10])=[O:11])[CH2:17][CH2:16]3)[N:28]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Reactant: OC1CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc(OC4CCCCC4)c4ccccc4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-ylmethyl]-3H-quinazolin-4-one (83 mg, 0.2 mmol) in POCl3 (1 mL) was heated to 90° C. for 2 hours. Then the excess POCl3 was removed in vacuo. The residue was dissolved in toluene (5 mL) and then the solvent was removed in vacuo. This step was repeated twice more. The residue was then dissolved in THF (1 mL) and cyclohexanol (211 μL, 2 mmol) was added. The reaction was stirred at room temperature for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by HPLC (in the absence of TFA). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.72 (dt, J=9.5, 2.4 Hz, 2H), 7.52 (t, J=7.4 Hz, 1H), 7.01 (dt, J=9.5, 2.4 Hz, 2H), 5.39 (quintet, J=4.2 Hz, 1H), 3.90 (m, 5H), 3.16 (m, 4H), 2.90 (m, 4H), 1.66 (m, 10H); HPLC ret. time 2.93 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 497.3 (M+1)+.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].Br[CH:16]1[C:21](=O)[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17]1>CC(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[S:8][C:16]3[CH2:17][N:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=3[N:9]=2)=[CH:3][CH:4]=1
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CCOC(=O)N1CCc2nc(-c3ccncc3)sc2C1
Temperature: 25 °C
Yield: 20 %

Procedure:
Thioisonicotinamide (18 mmol) and calcium carbonate (200 mmol) were added to a solution of ethyl 3-bromo-4-oxopiperidine-1-carboxylate (5 g; 20 mmol) in 2-propanol (60 ml). The reaction mixture obtained was heated under reflux for 48 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 25° C. and filtered over Celite and the filter cake was washed several times with ethyl acetate. The organic phase was concentrated under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed successively with water and saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate, the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (30% ethyl acetate in hexane). The desired product was obtained in a yield of 20%.
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])=[CH:7][CH:6]=1)=O.[CH3:26][OH:27]>C(OCC)(=O)C>[CH3:26][O:27][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]([S:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CO
Reactant: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(Sc1ccccc1C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1 g (30.2 mmol) of 2-(4-methoxycarbonylphenylthio)-2-tert. butoxycarbonylcyclohexanone is dissolved, together with 0.37 g (3.3 mmol) of potassium tert. butylate, in 100 ml of methanol of reagent purity and the solutions is left to stand for 2 hours at room temperature. It is then diluted with 500 ml of ethyl acetate and the organic phase is washed with water and a saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation. After drying in a high vacuum 11.3 g of an oily product are obtained, which is sufficiently pure to be used for further reactions.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:53][C:54]1[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:55]=1[CH2:56]Br.[I-].[Na+]>O1CCCC1.CO>[F:53][C:54]1[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:55]=1[CH2:56][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=2)([C:24]2[CH:25]=[C:26]([CH3:39])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=2)[C:15]1=[O:23]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(Cc3ccc(F)cc3F)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
Combine a solution of 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.15 g, 0.250 mmol) in anhydrous tetrahydrofuran (6 ml), with 0.750 mL of 1N lithium bis(trimethlysilyl)amide in tetrahydrofuran. Stir the resulting mixture at room temperature for 0.25 h. In a separate flask, prepare a solution of 2,4-difluorobenzyl bromide (0.155 g, 0.750 mmol) and sodium iodide (0.011 g, 0.075 mmol) in anhydrous tetrahydrofuran. Stir at room temperature for 0.25 h then add this solution to the 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one. Stir and heat the resulting mixture at 60° C. for 18 h. Cool to ambient temperature and dilute with 6 ml of methanol. Absorb the crude intermediate on 1 g of silica gel and evaporate the solvent under reduced pressure. Chromatograph this residue on a silica gel column eluting with 1:9 ethyl acetate/hexane. Combine the isolated intermediate, 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2,4-difluoro-benzyl)-1,3-dihydro-indol-2-one, with 4 ml of 1N CsF in methanol. Stir and heat at 60 C for 1 h then remove solvent in vacuuo. Dissolve the residue in 10 ml of water and extract with ethyl acetate (4×7 ml). Pass the ethyl acetate solution over anhydrous sodium sulfate and concentrate under vacuum. Triturate the residue with diethyl ether to obtain 0.097 g (78%) of the titled compound as granular crystals: LCMS (system 2) tR=4.13 min (100%), ESMS (M+1) m/z=499.56
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([N:17]2[C:26]3[C:21](=[C:22]([CH3:30])[C:23]([F:29])=[C:24]([F:28])[C:25]=3[CH3:27])[C:20](=[O:31])[C:19]([C:32]([O:34]CC)=[O:33])=[CH:18]2)[C:12]([F:16])=[CH:13][C:14]=1[F:15])=O)(C)(C)C>Cl>[NH2:8][C:9]1[CH:10]=[C:11]([N:17]2[C:26]3[C:21](=[C:22]([CH3:30])[C:23]([F:29])=[C:24]([F:28])[C:25]=3[CH3:27])[C:20](=[O:31])[C:19]([C:32]([OH:34])=[O:33])=[CH:18]2)[C:12]([F:16])=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)c(C)c2c1=O
Agent: Cl
Product: Cc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Yield: 89.1 %

Procedure:
To 1.8 g of the ethyl 1-(3-tert-butoxycarbonylamino-4,6-difluorophenyl)-6,7-difluoro-5,8-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate obtained in the Reference Example 15 was added 10 ml of 12N hydrochloric acid, and the mixture was stirred under heating and reflux condition for 4 hours. After allowing to cool, the solid precipitate was collected by filtration, washed with water and ethanol successively, and dried to obtain 1.2 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=1)([O-])=O.O>C(O)(=O)C.[Zn]>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccccc2)cn1
Temperature: 105 °C
Yield: 90 %

Procedure:
8.2 2-Nitro-5-phenoxy-pyridine (11.3 mmol) is dissolved in acetic acid (30 ml) at 35° C. After addition of water (30 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 105° C. for 2.5 h. The reaction suspension is cooled to RT and filtrated. The filtrate is poured into 3.5% NaOH (700 ml) and extracted with dichloromethane. The combined organic phases are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Phenoxy-pyridin-2-ylamine is obtained as a pink powder in a yield of 90%; HPLC (method C): 1.32 min, LC-MS (method A): 0.531 min, 187.15 (M+H+).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=O.C(OCC)(=O)CC(C)=O.[CH3:20][N:21]([CH3:31])[N:22]=C(C)CC(OCC)=O>>[CH3:20][N:21]([CH3:31])[N:22]=[C:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CCOC(=O)CC(C)=NN(C)C
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)CCC(C)=NN(C)C

Procedure:
In the same manner but replacing ethyl levulinate with an equivalent amount of ethyl acetoacetate, ethyl acetoacetate dimethyl hydrazone, b.p. 88°-92° C/ 19-20 mm, νmaxCHCl3 3245, 3180 and 1728 cm -1, is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[NH:15][C:16](=[O:22])[CH2:17][O:18]C(=O)C)(=[O:3])[CH3:2].Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[NH:15][C:16](=[O:22])[CH2:17][OH:18])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c(NC(=O)COC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(C(=O)O)cc1NC(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.9 %

Procedure:
Compound 17 (0.200 g, 0.652 mmol) was dissolved in 0.1N NaOH (7.93 mL) and stirred at room temperature for 2 hours. The alkaline aqueous layer was acidified to pH 2 with cone HCl, extracted with ethyl acetate (2×15 mL), and the extracts were dried (Na2SO4) and concentrated on a rotary evaporator to give only 8 mg of 109. The aqueous layer was concentrated on a rotary evaporator to 25% of the original volume, cooled, and the solid which separated was filtered. This was dried under vacuum to give 109 (60 mg, 58% yield) as a white solid: mp 214°-215° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:11][CH2:12][CH2:13][CH2:14][O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: BrCCCOc1ccc2cn[nH]c2c1
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of 1H-indazol-6-ol (600 mg, 4.5 mmol), 1,3-dibromopropane (1.4 mL, 13.4 mmol) and anhydrous K2CO3 (618 mg, 4.5 mmol) in EtOH (20 mL) was heated to reflux and stirred overnight. Filtration gave a yellow solid which was purified by column chromatography (elution with PE/EtOAc=3:1) to afford 6-(3-bromopropoxy)-1H-indazole (intermediate 44) (84 mg, 7%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]#[N:25])=[CH:19][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
[2-hydroxy-2-(4-hydroxyphenyl)cyclohexyl][(methylethyl)sulfonyl]amine (3.40 g, 10.9 mmol), bromoacetonitrile (1.44 g, 1.1 eq) and potassium carbonate (1.80 g, 1.2 eq) were combined in acetone (20 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The solution was then filtered and the filtrate was concentrated under reduced vacuum to yield 3.71 g as a brown oil. This material was purified via silica gel chromatography employing the Water's Prep. 200 while eluting with a solvent of hexane/ethyl acetate 3:2 to yield the intermediate title compound (2.52 g, 67%) as a tan solid. Ion spray M.S. 351.2 (M*−1). Calculated for C17H24N2O4S: Theory: C 57.93, H 6.86, N 7.95. Found: C 57.61, H 6.84, N 8.12.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]2)[C:12]([CH3:26])([CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([OH:44])[C:38]([CH3:46])([CH3:45])[CH2:37]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OOC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1Cl>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH:22]([O:44][N:39]3[C:40]([CH3:43])([CH3:42])[CH2:41][CH:36]([O:35][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:37][C:38]3([CH3:46])[CH3:45])[CH:21]=[CH:20]2)[C:12]([CH3:26])([CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CCCC1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CC(C)(C)OOC(C)(C)C
Solvent: Clc1ccccc1Cl
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CC(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1
Temperature: 135 °C
Yield: 5.2 %

Procedure:
A mixture of 43.6 grams (122 mmol) of the compound prepared in Example 1A, 40.5 grams (147 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 17.8 grams (122 mmol) of di-tert-butyl peroxide and 50 ml of 1,2-dichlorobenzene is heated at 135° C. for 5.5 hours in a Fisher-Porter pressure bottle. Fresh di-tert-butyl peroxide (8.0 grams, 55 mmol) is added and the reaction mixture is heated at 135° C. for an additional three hours. The crude reaction mixture is purified by flash chromatography on silica gel (hexane; then 100:3 heptane:ethyl acetate) to afford 4.0 grams of the title compound as a while solid melting at 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[C:12]1([C@@H:18]2[CH2:22][O:21][C:20](=[O:23])[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:19]1[C@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:11]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(O)Cc1ccccc1F
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 107.7 g of o-fluorophenylacetic acid, 100 g of (R)-4-phenyl-2-oxazolidinone, 186 g of triethylamine, and 1.0 L of toluene is heated to an internal temperature of 80° C. (heating mantle temperature 90° C.) to afford a solution; 88.5 g of pivaloyl chloride is added over period of 30 minutes with efficient stirring while maintaining an internal temperature 80-85° C. and stirred at this temperature for 2 hours. An additional 44.1 g of pivaloyl chloride is added over a period of 15 minutes while maintaining an internal temperature 80-85° C., and the mixture is stirred at the same temperature for additional 3 hours. The mixture is cooled to an internal temperature of 40° C. over a period of 10 minutes and 300 mL of water (prewarmed to 40° C.) is added over a period of 2 minutes while maintaining an internal temperature below 40-45° C. (slightly exothermic reaction). The organic layer is separated and washed with 358 mL of 2.17 N HCl solution (prewarmed to 40° C.) and 100 mL of water (prewarmed to 40° C.) sequentially while maintaining an internal temperature 40-45° C. and concentrated to dryness under reduced pressure (58-61 mbar; bath temperature, 51-53° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4-(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 400 mL of tert-butyl methyl ether and the mixture is heated to reflux (internal temperature of 58-61° C.) to obtain a yellow solution. The solution is cooled to 20-25° C. over a period of 20 minutes and stirred at this temperture for 4 hours. The mixture is then further cooled to 5 to 9° C. and stirred at this temperature for additional 2 hours. The solids are collected by filtration and washed with a total of 27 mL of tert-butyl methyl ether (precooled to 5-9° C.) in three equal portions of 9 mL each. The product is dried at 45-50° C. (86-99 mbar) for 12 hours to obtain optically pure of 3-[2-(2-fluorophenyl)-1-oxoethyl]-4-(R)-phenyl-2-oxazolidinone as a white solid; m.p. 110-111° C.; [α]D: −110.4 (c=1, MeOH)
Reaction SMILES: [CH3:1][C:2]([NH:11][N:12]=C(C)C)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21]CC)=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:10][C:2]([N:11]1[C:19](=[O:21])[CH2:18][C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:12]1)([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=NNC(C)(C)Cc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)N1N=C(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
500 mg (2.45 mmol) of 1-(2-methyl-1-phenylpropan-2-yl)-2-(propan-2-ylidene)hydrazine was dissolved in 3.0 mL of glacial acetic acid, mixed with 429 mg (2.23 mmol) of ethyl 3-oxo-3-phenylpropanoate and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:1 to 9:1) as the eluent to give 330 mg of the desired product as a pale orange solid.