Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20](F)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloroaniline (13.91 ml, 137.00 mmol) and 5-benzyloxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF (120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.5 mmol) dropwisely under nitrogen atmosphere. The mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 23.80 g, 89.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.80 (s, 1H), 8.66 (s, 1H), 7.64 (m, 1H), 7.34 (m, 7H), 6.92 (m, 1H), 6.78 (m, 1H), 5.26 (s, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([Cl:15])=[CH:9][C:10]([F:14])=[C:11]([CH3:13])[CH:12]=1.[C:16](=[O:18])=[O:17].O>C(OCC)C>[Cl:15][C:8]1[CH:9]=[C:10]([F:14])[C:11]([CH3:13])=[CH:12][C:7]=1[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: Cc1cc(Br)c(Cl)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(=O)O)c(Cl)cc1F
Reaction time: 1 h

Procedure:
n-Butyllithium (1.69 M hexane solution; 14 ml) was added dropwise to a solution of 5-bromo-4-chloro-2-fluorotoluene (5.6 g) in absolute diethyl ether (100 ml) at -70° C. in a nitrogen gas stream, and the mixture was stirred at the same temperature for 1 hour. Carbon dioxide was blown into the mixture at -70° C. for 30 minutes. The temperature of the reaction mixture was given back to room temperature to conduct stirring for 2 days. Diethyl ether and water were added to the reaction mixture to conduct liquid separation. A water layer was collected, to which concentrated hydrochloric acid was added to acidify the water layer. The water layer was then Extracted with diethyl ether. An organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (3.3 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:13][C:7]1([CH3:12])[C:6]2[CH:14]=[C:2]([O:1][S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=3[Cl:22])(=[O:32])=[O:31])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[O:8]1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-hydroxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.00 g, 5.17 mmol), prepared according to the procedure in example 69, in methylene chloride (25 mL) at 0° C. was added triethylamine (0.9 mL, 6.45 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (1.27 g, 5.17 mmol) was added. The solution was stirred for one hour, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Trituration with ether gave (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (1.55 g, 75%). 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 8.13 (dd, J=8.2, 1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.5 Hz, 1H), 7.60 (t, J=8.05 Hz, 1H), 7.02 (dd, J=8.7, 2.6 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 1.48 (s, 6H). MS (ESI) m/z 400/402/404 ([M−H]−); Anal. calcd for C16H13Cl2NO5S: C, 47.78; H, 3.26 N, 3.48. Found: C, 47.14; H, 3.46; N, 3.49.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@H:17]([O:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:37])=[C:26]2[CH3:38])=[CH:22][CH:21]=1)[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:39]=[CH:40][C:20]([O:19][C@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])=[CH:21][CH:22]=2)[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:24].O>CC(C)=O>[Br:12][C:4]1[C:3]2[O:13][CH2:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)([OH:24])[NH:1][C:2]=2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: Nc1c(O)c(Br)cc(F)c1[N+](=O)[O-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1c(F)cc(Br)c2c1NC(O)(c1cccnc1)CO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 1.9 mmol) and potassium carbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 5 minutes and 2-bromo-1-pyridin-3-ylethanone hydrobromide (530 mg, 1.9 mmol) was added as a solid over 5 minutes. The mixture was stirred at rt for 5 minutes and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes gave the desired compound, 0.69 g, 99%. LCMS calculated for C13H10BrFN3O4 (M+H)+: m/z=370.1, 372.1. found: 370.0, 372.0.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1NCCc2ccccc21
Reactant: BrCCCCBr
Product: O=C1c2ccccc2CCN1CCCCBr

Procedure:
from 3,4-dihydroisoquinolin-1(2H)-one and 1,4-dibromobutane
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2)c1
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2CCC(C)C)c1
Temperature: 78 °C

Procedure:
To a solution of 4-Methyl-2-(5-piperidin-2-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 10b (30.0 mg, 0.067 mmol) in CH3CN (0.5 mL) was added 1-iodo-3methylbutane (16.0 mg, 0.08 mmol) and cesium carbonate (44.0 mg, 0.134 mmol). The reaction was heated to 78° C. overnight. The reaction was cooled to room temperature, concentrated in vacuo, diluted with EtOAc, washed with NaHCO3, and brine. The solution was filtered, and concentrated, then purified via Gilson HPLC to give the compound as a light yellow oil. (31.8 mg, 92%) Calculated for C31H42F3NO2 (M+H) 517.67, Found 518.4.
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[C:11](Cl)[CH:12]=[C:13](CN3CCN(C)CC3)[C:8]=2[O:7][CH:6]=1)(=O)C.O.Cl>CO>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5](=[O:4])[CH2:6]1
Reactant: CC(=O)Oc1coc2c(CN3CCN(C)CC3)cc(Cl)cc12
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1COc2ccccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 141 %

Procedure:
A solution of 5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3-yl acetate (0.12 g, 0.37 mmol) in methanol (8.0 mL) was added with water (2.0 mL) and concentrated hydrochloric acid (0.20 mL), and the mixture was stirred at 80° C. for 4 hours. The solvent was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate, and the solution was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain 5-chloro-7-[(4-methylpiperazin-1-yl)methyl)]benzofuran-3(2H)-one (0.070 g, 67%).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][S:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Cl:22][C:17]1[CH:16]=[C:15]([S:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: NCCN
Reactant: CCOC(=O)CSc1cc(Cl)cc(Cl)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(SCC2=NCCN2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (2.70 ml, 5.39 mmol, 2 M solution). A solution of ethylenediamine (0.36 ml, 5.39 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 1 h at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (3,5-dichloro-phenylsulfanyl)-acetic acid ethyl ester (0.72 g, 2.70 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.21 g, 30%) which was collected by filtration; MS (ISP): 265.0, 263.1, 261.1 ([M+H]+.).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)[CH3:4].C[O:15][CH:16](OC)[C:17](=O)[CH:18]=[CH:19]N(C)C>C(O)C>[CH3:4][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17]([CH:16]=[O:15])=[CH:18][CH:19]=[N:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC(C)Oc1ccc(NN)cc1
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A solution of [4-(propan-2-yloxy)phenyl]hydrazine hydrochloride (1 g, 4.93 mmol, 1.00 equiv) and (4,4-dimethoxy-3-oxobut-1-en-1-yl)dimethylamine (1.4 g, 8.08 mmol, 1.64 equiv) in ethanol (20 mL) was refluxed for 3 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Acetone (10 mL) and 6N hydrochloric acid (10 mL) was added to dissolve the residue and the resulting solution was stirred at room temperature overnight. The reaction was diluted with 100 mL of dichloromethane and then washed with 3×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 3.0-7.0% of methanol in dichloromethane to yield 200 mg (18%) of 1-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-5-carbaldehyde as a yellow oil. LCMS (method A, ESI): RT=1.48 min, m/z=230.9 [M+H]+.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Si:15]([O:22][C@@H:23]1[C@@:40]2([CH3:41])[C:27](=[CH:28][CH:29]=[C:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]3[CH2:32][CH:33]=[C:34]2[CH2:42][O:43][CH2:44][CH:45]2[O:49][C:46]2([CH3:48])[CH3:47])[CH2:26][C@@H:25]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[Si:15]([O:22][C@@H:23]1[C@@:40]2([CH3:41])[C:27](=[CH:28][CH:29]=[C:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]3[CH2:32][CH:33]=[C:34]2[CH2:42][O:43][CH2:44][CH2:45][C:46]([OH:49])([CH3:47])[CH3:48])[CH2:26][C@@H:25]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH2:24]1)([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:17])[CH3:16]
Reactant: CC1(C)OC1COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
At room temperature, a solution of 1.0M L-SELECTRIDE in tetrahydrofuran (0.25 ml, 0.25 mmol) was added to a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(2,3-epoxy-3-methylbutoxymethyl)androsta-5,7,16-triene (48.3 mg, 0.0768 mmol) in tetrahydrofuran (2 ml) and stirred at the same temperature for 1 hour. To the solution, was further added a solution of 1.0M L-SELECTRIDE in tetrahydrofuran (0.2 ml, 0.2 mmol), followed by stirring at the same temperature for 1 hour. After cooling the reaction solution with ice, a 3N aqueous sodium hydroxide solution and then hydrogen peroxide solution were added. Immediately after the addition, the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=10:1, developed twice) to give the titled compound (42.0 mg, 87%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12].[CH3:20]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:20]=[C:16]([O:17][CH3:18])[C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccccc1F)C(=O)OC
Product: COC(=O)c1nn(-c2ccccc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of methyl 2-[(2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (5.02 g, 18.7 mmol) in N,N-dimethylformamide dimethyl acetal (35 mL) was refluxed for 1 h. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane/AcOEt (2/1) to give the title compound (4.70 g, 90% yield) as off-white crystals: mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.29-7.36 (2H, m), 7.44-7.51 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13H11FN2O4: C, 56.12; H, 3.98; N, 10.07. Found: C, 56.17; H, 3.97; N, 10.25.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]12[O:31]CCCO1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:33][C:34]4([CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:39][N:40]=[C:21]3[C:20](=[O:31])[C:19]=2[CH:18]=1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Reactant: N#CC1(CCl)CCCC1
Product: O=C1C2=NCC3(CCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 478 [M−H]. m.p.: 142.9.8-144.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C(=O)C>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH3:18])[C:13]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(C)=O)cc1-c1c(Br)cnn1C
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl]-acetamide (25.0 kg) in N,N-dimethylacetamide (DMA, 140.5 kg) in a 400 L glass lined jacketed reactor with overhead stirring under nitrogen at 45 to 55° C. internal temperature N-bromosuccinimide (NBS, 19.0 kg) was charged in portions at such a rate as to maintain internal temperature to less than 55° C. The reaction mixture remained a solution at this dilution of DMA and internal temperature of 50.9° C. An “in process check” of the reaction mixture to determine reaction completion after at least 1 hr of stirring at 50° C. showed that the reaction mixture was substantially free of the starting material. Upon cooling of the reaction mixture to an internal temperature of 34° C. water (150 kg) was added in a controlled manner into the reactor to maintain an internal temperature between 40-55° C. A slight exotherm was observed during the reaction quench. The product slurry was then cooled to −5 to 5° C. and filtered through a corrosion resistant filter/dryer. The wetcake was re-slurried, washed with water (2×25 kg), and dried under full house vacuum (˜30 in Hg) with a jacket temperature of 65° C. producing N-[3-(4 bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy phenyl]-acetamide (31.6 kg, 100% purity by HPLC, 96.1% yield).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.[OH-].[Na+]>O>[C:1]12([C:11]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N1CC2CCC(C1)O2)C12CC3CC(CC(C3)C1)C2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-Adamantanecarbonyl chloride (19.87 grams, 0.1 mole, pulverized) (Aldrich Chemical Co., Inc., Milwaukee, Wisc.) was added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water. The reaction mixture was heated at 30° C. for 3 hours and then left overnight at room temperature. The product (22 grams) was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v). The product had a melting point of 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[CH3:23][O:24]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[CH:23]=[O:24]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Temperature: 0 °C

Procedure:
4-(4-methoxyphenoxy)-5-methyl-7-nitroindane (5.0 g) and dichloromethyl methyl ether (3.02 mL) were dissolved in dichloromethane (50 mL). To the solution was added dropwise titanium tetrachloride (3.67 mL) under ice-cooling with stirring. The reaction mixture was stirred at room temperature under an argon atmosphere for 20 hours. After adding ice water (300 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with hexane (50 mL) and diethyl ether (5 mL), and the insoluble material was collected by filtration and washed with hexane to give the title compound (4.37 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)=[O:5].[CH2:17]1COCC1.C[Mg]Br.Cl>>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:4](=[O:5])[CH3:17])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
A 250 mL RB flask was charged with N-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 27.5 mmol) and THF (100 ml, 1220 mmol), then cooled to 0 C. Methylmagnesium bromide (18.3 ml, 55.0 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was not quite complete, so additional MeMgBr (3 mL) was added and the mixture was stirred overnight. The mixture was then neutralized using 2N HCl and the aqueous layer was extracted with DCM (200 mL×2) and EtOAc (200 mL×2). The organic layer was dried with MgSO4, filtered, and concentrated to give a yellow oil. The aqueous layer contained some product, so the layer was concentrated and then filtered thru a reverse phase C18 column, first eluting with water than with MeOH. The MeOH layer was concentrated to give a yellow oil which was combined with the yellow oil from the organic layer. The combined portions were purified by MPLC eluting with a gradient of 2-6% MeOH/DCM. 1-(quinolin-6-yl)ethanone (4.074 g, 86.6% yield) was isolated as a yellow oil which solidified upon standing.