Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:34]([O:35][CH3:36])=[CH:33][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:32])[CH2:14][CH2:15][NH:16][CH2:17][CH:18]3[CH2:25][C:24]4[C:19]3=[CH:20][CH:21]=[C:22]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:23]=4)[CH2:11][CH2:12][C:6]=2[CH:5]=1.C=O.[C:39]([BH3-])#N.[Na+]>C(#N)C>[ClH:1].[CH3:36][O:35][C:34]1[C:4]([O:3][CH3:2])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13](=[O:32])[CH2:14][CH2:15][N:16]([CH2:17][CH:18]3[CH2:25][C:24]4[C:19]3=[CH:20][CH:21]=[C:22]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:23]=4)[CH3:39])[CH2:9][CH2:8][C:7]=2[CH:33]=1
Reactant: [BH3-]C#N
Reactant: CNC(=O)COc1ccc2c(c1)CC2CNCCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)COc1ccc2c(c1)CC2CN(C)CCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At ambient temperature, to 0.83 g (1.72 mmol) of the compound obtained in Step C of Example 84, dissolved in 32 mL of acetonitrile, there are added, all at once, 1.4 mL (17.2 mmol) of 37% aqueous formaldehyde solution and then 0.22 g (3.44 mmol) of sodium cyanoborohydride. After stirring for 45 minutes at ambient temperature, concentration is carried out and the residue is taken up in 30 mL of water; the aqueous phase is extracted twice with 30 mL of dichloromethane; the organic phases are combined, washed with 30 mL of water and dried over magnesium sulphate. After concentration, the residue is chromatographed over silica (eluant: dichloromethane/ethanol/ammonia 95/5/0.5) to yield the desired compound in the form of the base.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]#[N:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)[N:17](Br)[C:15](=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C-]#N.[K+]>C(Cl)(Cl)(Cl)Cl.C(O)C.[W]>[C:15]([CH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]#[N:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1)#[N:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(C=CC#N)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C=CC#N)cc(CC#N)c1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 3-(3,5-Dimethyl-phenyl)-acrylonitrile (93) (15.7 g, 0.1M), NBS (18.58 g, 0.11M) and benzoyl peroxide (2.42 g, 10 mmol) in carbon tetrachloride (120 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered and the filterate was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a light yellow solid (94). A mixture of the crude product (94) and potassium cyanide (9.75 g, 0.15M) in ethanol (60 ml) and distilled water (30 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was partitioned between EA-ether (1:1) and water. The organic layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:1 to 2:1)) to afford 6.68 g (36%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.74 (2H, s), 5.91 (1H, d, J=16.5 Hz), 7.21 (3H, s), 7.34 (1H, d, J=16.5 Hz).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](O)=O>>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=[C:18]1[CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NCc1ccccc1
Reactant: O=C(O)CCl
Product: ClCc1nc2ccccc2n1Cc1ccccc1
Yield: 61.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-benzylbenzene-1,2-diamine (2.93 g, 14.78 mmol) and 2-chloroacetic acid (2.10 g, 22 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.34 g of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (Yield: 61%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH:15]([F:17])[F:16])[N:3]=1.[F-:18].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH:15]([F:17])[F:16])[N:3]=[C:2]2[F:18]
Reactant: FC(F)COc1cc2c(Cl)cccc2c(Cl)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1nc(OCC(F)F)cc2c(Cl)cccc12
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-(2,2-difluoroethoxy)isoquinoline (581 mg, 2.089 mmol) in DMSO (5 mL) was added CsF (349 mg, 2.298 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-3-(2,2-difluoroethoxy)-1-fluoroisoquinoline (450 mg, 82% yield) as a yellow solid. MS: MS m/z 262.1(M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](OC2C=CC=CC=2)=[N:19][C:20]#[N:21])=[CH:13][CH:12]=1>COCCOC>[C:20]([N:19]=[C:18]([O:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[NH:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)c1ncccc1N
Solvent: COCCOC
Product: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1

Procedure:
A stirred mixture of the product from Step 2 (0.738 g, 0.00538 mol), diphenylcyanocarbonimidate (1.28 g, 0.00538 mol) and ethylene glycol dimethyl ether (40 ml) was kept, under nitrogen, at ambient temperature (25° C.) for 7 hours. The mixture was concentrated and the residue was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([NH:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][NH:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COCCNc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a solution of 5-3 (325 mg, 1.0 mmol) in DMF (15 mL) were added cesium carbonate (650 mg, 2.0 mmol, 2.0 equiv) and Cu (19.5 mg, 0.30 mmol, 0.3 equiv). The solution was stirred at 100-110° C. for 60 min and added with 5-bromo-N-(2-methoxyethyl)pyridin-2-amine (29-2, 347 mg). The reaction mixture was stirred at 140° C. for 48 h. The reaction was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 29 (96 mg) in 16% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 1 H), 7.72 (d, 1 H), 7.71 (d, 1H), 7.24 (m, 1 H), 6.81 (s, 1 H), 6.72 (d, 1 H), 6.49 (s, 1 H), 3.59 (t, 1 H), 3.51 (t, 1 H), 3.35 (s, 3 H), 2.01 (s, 6 H), ESI-MS=m/z 447.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:14][C:15](N2CCCCC2)=[O:16])[N+:3]=1[O-:23].Cl.[OH-].[Na+].O1CC(=O)N=N1>>[NH2:1][C:2]1[N:3]2[O:23][C:15](=[O:16])[N:14]=[C:4]2[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: Nc1cc(N2CCCCC2)cc(NC(=O)N2CCCCC2)[n+]1[O-]
Agent: Cl
Agent: O=C1CON=N1
Agent: [Na+]
Product: Nc1cc(N2CCCCC2)cc2nc(=O)on12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
2-Amino-4-(1-piperidinyl)-6-[(1-piperidinylcarbonyl)amino]pyridine 1-oxide (5.37 g., 0.017 mole) is dissolved in 100 ml. of 3N hydrochloric acid. After stirring the acid mixture for 0.5 hr. at room temperature, the mixture is cooled and neutralized with 50% sodium hydroxide affording a solid. The solid is collected, washed with water and air dried to provide 3.7 g. of crude oxadiazolone product, m.p. 283° C. (dec.). Further purification is carried out by dissolving the crude product in 300 ml. of methanol and treating the solution with activated charcoal. Concentration of the methanol solution to a volume of approximately 125 ml. and cooling affords 2.9 g. (73% yield) of 5-amino-7-(1-piperidinyl)-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-2-one, m.p. 246.5° C. (dec.) (corr.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncccc1C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 10% palladium on carbon (2.5 g) and methyl 3-[2-(4-fluorophenyl)ethenyl]pyridin-2-carboxylate (12.4 g) in ethyl acetate (200 ml) was stirred vigorously under an hydrogen atmosphere at ambient temperature for four hours. The suspension was filtered through Celite and the filtrate concentrated under reduced pressure to give methyl 3-(4-fluoropbenethyl)pyridin-2-carboxylate as a mobile, pale yellow oil (11.72 g).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:26])=[C:11]([C@:13]3([CH3:25])[C:19]([F:21])([F:20])[C:18]([CH3:23])([CH3:22])[O:17][CH2:16][C:15](=[O:24])[NH:14]3)[CH:12]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[F:21][C:19]1([F:20])[C:18]([CH3:22])([CH3:23])[O:17][CH2:16][C:15](=[O:24])[NH:14][C@@:13]1([C:11]1[CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=[CH:9][C:10]=1[F:26])[CH3:25]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C3CCOCC3)ccc2F)C1(F)F
Yield: 95 %

Procedure:
A solution of (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one [Example 5a)] (256 mg, 693 μmol) in ethyl acetate (20 ml) was hydrogenated at room temperature for 16 hours using palladium on carbon (10%: 74 mg, 69.3 μmol) as the catalyst. The reaction mixture was filtered and evaporated to give the crude (R)-6,6-difluoro-5-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (244 mg, 95% yield) as a colorless oil. MS (ISP): m/z=372.2 [M+H]+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][N:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][N:44]=3)=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4n[nH]c5ccccc45)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1n[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.1 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(1H-indazol-3-yl)methanone (0.093 g, 0.176 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.059 g, 0.111 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][C:9]=1[F:10])([O-])=O.Cl.C(=O)(O)[O-].[Na+].C(OCC)C>CO.[Fe]>[F:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]([F:12])([F:13])[F:14])=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOCC
Product: Nc1cc(C(F)(F)F)ccc1F
Yield: 81.7 %

Procedure:
Twenty grams of 3-nitro-4-fluorobenzotrifluoride was dissolved in 50 ml of methanol. An iron powder (16 g) was added and concentrated hydrochloric acid was added dropwise with stirring. The reaction mixture was stirred overnight, followed by addition of sodium bicarbonate for neutralization. Then diethyl ether was added, and the insolubles were filtered off with cerite. The ether phase was separated, dried and concentrated under reduced pressure, giving 14 g of the contemplated product (yield 82%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:18]([O:22][C:23]([NH:24][NH:25][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-oxopiperidine-1-carboxylate (4.08 g, 17.5 mmol) in 50 mL of methanol was added tert-butylcarbazate (2.31 g, 17.5 mmol). The mixture was stirred at room temperature for 3 h and then was concentrated in vacuo to afford a white foam. This residue was taken up in 50 mL of 50% glacial acetic acid. To the resulting suspension was added sodium cyanoborohydride (1.1 g, 17.5 mmol) portionwise with vigorous stirring at room temperature. After the addition was complete the mixture was stirred for 3 h at room temperature. The mixture was neutralized with 1N NaOH/solid NaOH and then extracted twice with methylene chloride. The combined organics were washed with sat'd aq sodium bicarbonate and brine, dried (Na2SO4), filtered through a pad of silica gel and concentrated in vacuo to afford Example 12A, benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate, as a solid (6.0 g) which was pure enough to be used without purification. LRMS (ESI): 350.1 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.CS(C1N=C(C2C=NN(C)C=2)C=CN=1)=O.[NH2:32][C:33]1[C:34]([F:41])=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:41][C:34]1[CH:35]=[C:36]([CH3:40])[C:37]([O:39][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[CH:7][N:6]=2)=[CH:38][C:33]=1[NH2:32]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: Cn1cc(-c2ccnc(S(C)(=O)=O)n2)cn1
Agent: Cn1cc(-c2ccnc(S(C)=O)n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1Oc1nccc(-c2cnn(C)c2)n1

Procedure:
A mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine from Example A16 (1 g, 4.2 mmol), 5-amino-4-fluoro-2-methylphenol (1.2 g, 8.5 mmol) and K2CO3 (1.2 g, 8.6 mmol) were combined in DMF (10 mL) using a procedure analogous to Example A10 to provide 2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine (420 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 5.02 (br s, 2H), 3.88 (s, 3H), 1.88 (s, 3H); MS (ESI) m/z: 300.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:16][C:17]([C:19]1[C:23]2[CH2:24][CH2:25][CH2:26][C:27]3[C:28](=[N:29][C:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[O:50][CH3:51])=[N:31][CH:32]=3)[C:22]=2[N:21]([CH3:52])[N:20]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:54]>CO.C1COCC1.O1CCOCC1>[ClH:54].[ClH:54].[NH2:7][CH2:8][C@@H:9]([NH:16][C:17]([C:19]1[C:23]2[CH2:24][CH2:25][CH2:26][C:27]3[C:28](=[N:29][C:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[O:50][CH3:51])=[N:31][CH:32]=3)[C:22]=2[N:21]([CH3:52])[N:20]=1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1c(c(C(=O)N[C@H](CNC(=O)OC(C)(C)C)c3ccccc3)nn1C)CCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1c(c(C(=O)N[C@H](CN)c3ccccc3)nn1C)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl[(2S)-2-({[9-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-3-yl]carbonyl}amino)-2-phenylethyl]carbamate (0.010 g, 0.014 mmol) in MeOH (0.2 mL) and THF (0.5 mL), 4M HCl in dioxane (0.2 mL) was added. The mixture was stirred at room temperature for 4 h. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].[C:9](=O)([O-])[O-].[K+].[K+].IC.[H-].[Na+]>O.CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([O:8][CH3:9])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](O)CCCCCl
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H](C)CCCCCl
Temperature: 40 °C
Yield: 43 %

Procedure:
A mixture of (R)-1-chloro-5-hydroxyhexane, dimethylformamide (100 ml), powdered potassium carbonate (1 g), iodomethane (15.9 g, 112 mmol) and sodium hydride (2.0 g, 84 mmol) were combined was heated at 40° C. for 30 minutes. After cooling to room temperature, water (100 ml) was added cautiously and the mixture was extracted with hexanes (2×100 ml). The combined extracts were concentrated under vacuum and the residue was purified by column chromatography on silica gel eluting with hexanes followed by 10% ethyl acetate-hexanes to afford (R)-1-chloro-5-methoxyhexane (3.1 g, 43% yield for 2 steps) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.15 (d, 3H), 1.36-1.56 (m, 4H), 1.70-1.84 (m, 2H), 3.28 (s, 3H), 3.29 (m, 1H), 3.52 (t, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCCC)(=O)C>[Br:1][CH2:2][C@@H:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)CBr
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCCCOC(C)=O
Product: COC(=O)C[C@H](O)CBr
Temperature: 30 °C
Reaction time: 7 h

Procedure:
Methyl 4-bromo-3-oxobutyrate (300 mg), the above-mentioned wet bacterial cells (0.4 g), NADP+ (9 mg), glucose (750 mg), glucose dehydrogenase (manufactured by Amano Pharmaceuticals, Co., Ltd.) (1.2 mg), 100 mM phosphate buffer (pH 6.5) (15 ml) and butyl acetate (15 ml) are mixed. The mixture is stirred at 30° C. for 7 hr. During the stirring, 2M aqueous sodium carbonate solution is gradually added to adjust the pH of the reaction solution to 6.5±0.2. After the stirring has been finished, the reaction solution is centrifuged (1000×g, 5 min) to collect the organic layer. The organic layer is subjected to an analysis for content using gas chromatography under the following condition. The optical purity of methyl 4-bromo-3-hydroxybutyrate in the above-mentioned organic layer was also determined under the following condition. The organic layer was concentrated to give crude methyl (S)-4-bromo-3-hydroxybutyrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[CH:5]=[C:6]([O:38][CH3:39])[C:7](=[O:37])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[CH:28][C:27](=[O:34])[C:26]=1[O:35][CH3:36].ClC1C=C(C=CC=1)C(O)=[O:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:40])[CH:5]=[C:6]([O:38][CH3:39])[C:7](=[O:37])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:46][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:30](=[O:31])[C:29]([O:32][CH3:33])=[CH:28][C:27](=[O:34])[C:26]=1[O:35][CH3:36]
Reactant: COC1=CC(=O)C(OC)=C(CCCCCCC/C=C\CCCCCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC1=CC(=O)C(OC)=C(CCCCCCCC2OC2CCCCCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 Milligrams of 1,16-bis(2,5-dimethoxy-1,4-benzoquinon-3-yl)-cis-8-hexadecene was dissolved in 1 ml of methylene chloride, then to this solution was added 8 mg of m-chlorobenzoic acid and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the solvent was removed by evaporation under reduced pressure, and the residue obtained was purified by means of a preparative thin layer chromatography [adsrobent: "Silica gel 60 F254 " manufactured by E. Merck A. G., developing solvent: benzene-ethyl acetate (5:1 mixture by volume/volume)] to obtain 3 mg of 1,16-bis(2,5-dimethoxy-1,4-benzoquinon-3-yl)-8,9-epoxyhexadecane. Yellow oily substance.