Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([O:36]CC)=[O:35])=[N:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([OH:36])=[O:35])=[N:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1nccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)nccc3c2)cc1
Temperature: 90 °C
Yield: 47.7 %

Procedure:
A 1 N solution of sodium hydroxide (156.4 μL, 156.4 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-isoquinolinecarboxylate (43.9 mg, 78.2 μmol) in tetrahydrofuran and methanol (1:1, 1.6 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (156.4 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 19.9 mg (48%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-isoquinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.64 (br s, 1H), 8.63 (d, J=9 Hz, 1H), 8.55 (d, J=6 Hz, 1H), 8.29 (s, 1H), 8.06 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.65-7.61 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 533 (M+H)+.
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[C@@H:3]1[C@@H:7]2[O:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:6]2[CH2:5][C@H:4]1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.C(B(CC)CC)C.CCCCCC>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[O:8][C@H:7]3[CH2:3][C@H:4]([N:20]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:30])[CH2:5][C@H:6]3[CH2:11][O:10]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Agent: CCB(CC)CC
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)C[C@@H]3O2)cc1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a solution of O-[(4aS,6R,7S,7aR)-6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl] O-phenyl thiocarbonate (56.9 mg, 0.107 mmol) in toluene (4.00 mL) was added tris(trimethylsilyl)silane (0.0700 mL, 0.227 mmol). Air (2.00 mL) was bubbled through the solution and a 1.00 M solution of triethylborane in hexane (0.0320 mL, 0.0320 mmol) was added and the reaction was stirred for 2 h. More tris(trimethylsilyl)silane (0.0700 mL, 0.227 mmol) and 1.00 M triethylborane in hexane (0.0300 mL, 0.0300 mmol) were added, and the mixture was stirred another 6 h. The mixture was then concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in DCM to afford the title compound (16.9 mg, 42%). LC/MS: Rt=2.03 min, ES+ 380. (AA standard).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][N:45]1[CH:49]=[C:48]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]5[N:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][O:30][CH2:31][CH2:32]6)=[CH:22][N:23]=5)[CH:13]=4)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:47]=[N:46]1
Reactant: Brc1cnc2nnn(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(OCCN6CCOCC6)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
Under an argon atmosphere, 225 mg (0.24 mmol) of 6-bromo-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]pyrazine are dissolved in 5 ml of ethylene glycol dimethyl ether, and 102 mg (0.48 mmol) of tripotassium phosphate trihydrate and 55 mg (0.26 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole are added. The reaction mixture is evacuated and flushed with argon twice. 14 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. 10 ml of water are added to the reaction mixture, during which an oil precipitates out. This is extracted with dichloromethane and with dichloromethane comprising about 10% of MeOH, the aqueous phase is adjusted to pH 14 using 32% NaOH and again extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and purified by means of preparative HPLC, giving 42 mg of 6-(1-methyl-1H-pyrazol-4-yl)-1-{3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzyl}-1H-1,2,3-triazolo[4,5-b]-pyrazine (“A2”); the product is in the form of the TFA salt; Rt.=2.26 (method A), LCMS: 499 (M+H);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[N:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH:3]=1.[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25][N:13]1[C:12]2[N:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:20])(=[O:21])[N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:14]1=[O:15]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: Cc1cc(C)nc(N2C(=O)Nc3ncccc3S2(=O)=O)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cc(C)cc(C)n3)S(=O)(=O)c3cccnc32)c(F)c1
Yield: 50 %

Procedure:
The title compound (85 mg, 0.18 mmol) was prepared from 2-(4,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF2) (110 mg, 0.36 mmol), 2,6-difluoro-4-methoxybenzyl bromide (103 mg, 0.43 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMF (3 mL) using the methods of (115).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:11][S:12]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1

Procedure:
To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethytamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent:hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product.
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)/C(/N)=N/[N+]([O-])=O.[O:18]=[C:19]([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(Cl)Cl>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:18])[CH3:27]
Reactant: CCOCC
Reactant: CC(=O)CCCCC(=O)O
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CCCCC(C)=O
Reaction time: 0.17 h

Procedure:
To a rapidly stirred mixture of diethyl ether (175 ml) and 40% KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. The ethereal layer was transferred to a solution of 6-oxo-heptanoic acid 1-1 (5.0 g, 34.68 mmol) and CH2Cl2 at 0° C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30% to 50% EtOAc/hexanes) gave ester 1-2 as a clear oil.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])[C:10](C)=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[C:9](=[O:13])[CH:10]=[CH2:11]
Reactant: Cc1ccc(C)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1cc(C)ccc1C

Procedure:
Paraxylene (0.5 mL), methacryloyl chloride (110 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (89 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C=O)C>[F:10][C:11]1[CH:23]=[C:22]([N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]2=[O:9])[CH:21]=[CH:20][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: Cc1c[nH]c(=O)c(C)c1
Reactant: Fc1cc(I)ccc1CN1CCOCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(=O)n(-c2ccc(CN3CCOCC3)c(F)c2)c1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 3,5-dimethylpyridin-2(1H)-one (0.22 g, 1.80 mmol), 4-(2-fluoro-4-iodobenzyl)morpholine (0.58 g, 1.80 mmol), K2CO3 (2.48 g, 18 mmol), CuI (0.02 g, 0.1 mmol) and DMF (3 mL) was refluxed under N2. The reaction process was monitored by TLC. The reaction mixture was cooled to rt and filtered. To the filtrate was added H2O (10 mL) and CH2Cl2 (20 mL). The CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.28 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:24]1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1>CC(N(C)C)=O>[NH2:10][CH2:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][N:15]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:14][CH2:13]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CCOC(=O)C1(CN)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(CN)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
N-Ethyldiisopropylamine (3.70 ml, 21.26 mmol) was added to ethyl 4-(aminomethyl)piperidine-4-carboxylate (Intermediate 9) (3.3 g, 17.7 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.72 g, 17.72 mmol) in DMA (35 ml). The resulting solution was stirred at 60° C. for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford ethyl 4-(aminomethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (5.08 g, 95%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 180 °C
Yield: 30 %

Procedure:
To a mixture of 2-methylindole (3.28 g, 25 mmol), 4-benzyloxy iodobenzene (7.76 g, 25 mmol), potassium carbonate (2.65 g, 25 mmol), and N-methylpyrrolidinone (250 mL) was added copper (I) bromide (0.5 g, 3.5 mmol). The stirred solution was heated to 180° C. and maintained for 18 hr. The reaction mixture was cooled, poured onto ice and extracted with ethyl acetate. After washing the organic layer with water and brine, and drying over anhydrous MgSO4 the solvent was removed to yield a dark liquid. Purification by silica gel chromatography (2% ethyl acetate-hexanes) provided the title compound as a white solid (30%): mp 95-96° C.; 1H NMR (DMSO-d6): δ 2.24 (3H, s), 5.19 (2H, s), 6.38 (1H, s), 6.93-7.04 (3H, m), 7.20 (2H, d, J=11.9 Hz), 7.23 (2H, d, J=3.1Hz), 7.32-7.53 (8H, m); MS m/z (M+H)+ 314: Anal. for C22H19NO 0.1H2O: Calc'd: C, 83.83; H, 6.14; N, 4.44. Found: C, 83.84; H, 6.18; N, 4.29.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.O>[N+]([O-])(O)=O>[CH:2]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1)=[O:1]
Reactant: O=c1c(CO)coc2ccccc12
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=Cc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity of 35.2 g. (0.2 mole) of 3-(hydroxymethyl)chromone is dissolved in 250 ml of concentrated nitric acid with stirring at 25° C. There is no initial heat of reaction. The temperature gradually rises to 30° C over the next several minutes and is kept there for about five minutes with ice-acetone bath cooling. Water, 600 ml, is added to the reaction solution. The separated, pale yellow solid is filtered, washed well with water and dried to give 25 g. of crude aldehyde melting at 145°-148°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([Cl:24])=[O:21])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Temperature: 80 °C

Procedure:
To a stirred suspension of 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (0.75 g) in benzene (5 mL) was added thionyl chloride (2.8 mL) in benzene (5 mL) followed by heated at 80° C. for 45 min to give a clear orange solution. Evaporation to dryness gave 0.80 g of the title compound as an orange solid, which was used without further purification.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][NH:9]1)=[O:7].[CH2:16](O)[CH2:17][CH2:18]C>>[CH2:4]([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][NH:9]1)=[O:7])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCO
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C)CN1
Agent: Cl
Product: CCCCOC(=O)[C@@H]1C[C@H](N(C)C)CN1
Temperature: 115 °C

Procedure:
Concentrated hydrochloric acid (0.3 ml) is added to a mixture of (2S,4S)-4-dimethylamino-pyrrolidine-2-carboxylic acid methyl ester dihydrochloride (400 mg) and 1-butanol (4 ml) and heated for 18 hours at 115° C. After cooling the reaction mixture is evaporated then partitioned between dicloromethane and aqueous sodium bicarbonate solution and the dichloromethane layers dried and evaporated to give the title compound as a brown oil which is used without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl.C(OC1C=CC([NH:27]N)=CC=1)(=O)C1C=CC=CC=1>>[ClH:1].[F:2][C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:27]
Reactant: NNc1ccc(OC(=O)c2ccccc2)cc1
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Product: NNc1ccc(F)cc1F

Procedure:
The 2,4-difluorophenylhydrazine hydrochloride (m.p. 244°-246° C.) was prepared from 2,4-difluoroaniline hydrochloride using a procedure similar to that described in Example 5 for the preparation of 4-benzoyloxyphenylhydrazine hydrochloride.
Reaction SMILES: Cl[C:2]1(Cl)[CH:8]2[CH:4]([CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7]2)[C:3]1=[O:16].O1C[CH2:19]1>[Zn].C(O)(=O)C>[CH2:9]([CH:5]1[CH:4]2[CH:8]([CH2:2][C:3](=[O:16])[CH2:19]2)[CH2:7][CH2:6]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CO1
Reactant: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCC1CCC2CC(=O)CC12

Procedure:
The product is dehalogenated as in Example 1C using zinc and acetic acid and the 4-heptylbicyclo[3.2.0]heptan-6-one is converted to the oxirane (Formula I, X=--(CH2)6 --CH3) by the process of Example 2 using dimethylsulfonium methylide at room temperature. By the process of Example 3 there is formed 4-heptylbicyclo[3.3.0]octan-7-one.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:14]1[C:21]([Cl:22])=[N:20][C:18](Cl)=[N:17][C:15]=1[Cl:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.O>[Cl:16][C:15]1[N:14]=[C:21]([Cl:22])[N:20]=[C:18]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:17]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCNCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCN(CCCCCC)c1nc(Cl)nc(Cl)n1

Procedure:
Dihexylamine (6.3 mL, 27 mmol) was added to a mixture of cyanuric chloride (5 0 g, 27 mmol) and sodium carbonate (2.9 g, 27 mmol) in acetonitrile (50 mL). The reaction mixture was heated to reflux for 16 h and then allowed to col to ambient temperature. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography through silica get (elution with 3:1 hexanes:chloroform) to afford 2,4-dichloro-6-dihexylamino-1,3,5-triazine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(CO)on1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.4 %

Procedure:
14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate was dissolved in 80 ml of N,N-dimethylformamide, and 6.13 g of imidazole and 13.57 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 23.82 g of ethyl 5-(t-butyldimethylsilanyloxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[C:20]=2[N+:26]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].NC1C(N)=C(OC2C=CC(NC(=O)OC(C)(C)C)=C(F)C=2)C=CN=1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[C:20]=2[NH2:26])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c2ccccc12
Agent: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1F
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12

Procedure:
The title compound was prepared from tert-butyl-4-(2-amino-3-nitropyridin-4-yl-oxy)naphthalen-1-yl-carbamate (3b) (0.50 g, 1.26 mmol) by the same method as described for compound (4a) as a brown solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[O:10][N:9]=[C:8]([C:11]([NH:13][CH2:14][C@@H:15]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[N:18]2)[CH3:16])=[O:12])[CH:7]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([C@@H:15]([CH3:16])[CH2:14][NH:13][C:11]([C:8]3[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[O:10][N:9]=3)=[O:12])[N:18]=2)[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Sodium borohydride (6.41 mg, 0.169 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-5-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide (33.7 mg, 0.085 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to about 3 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 96%. 1H-NMR (400 MHz; CDCl3): δ 1.57-1.65 (m, 3H) 3.75-3.84 (m, 1H), 3.87-3.95 (m, 1H), 4.57-4.67 (m, 1H), 5.03 (q, 1H), 6.61 (d, 1H), 6.62 (s, 1H), 7.50 (d, 1H), 7.56-7.63 (m, 1H), 7.65-7.69 (2× s, 1H), 7.81 (dd, 1H), 8.01 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19](=[O:21])[CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.36 mmol) and triethylamine (715 mg, 7.08 mmol) in dichloromethane (10 mL) was added acetyl chloride (221 mg, 2.83 mmol) at 0° C., then the mixture was stirred for 2 h at 0° C. Water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (3×10 mL) and dried with Na2SO4. The residue was concentrated then purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (500 mg, 83%) as yellow oil. LC-MS: [M+H]+, 254, tR=1.533 min.