Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([F:39])[CH:33]=2)=[C:29]([CH3:40])[CH:28]=[C:27]([CH3:41])[N:26]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[C:30]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([F:39])[CH:33]=3)=[C:29]([CH3:40])[CH:28]=[C:27]([CH3:41])[N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nc(C)cc(C)c2Cc2ccc(C)c(F)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(Cc2ccc(C)c(F)c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-3-(3-fluoro-4-methylbenzyl)-4,6-dimethyl-pyridine (0.17 g) in methanol (5 mL) was added sodium methoxide (28% methanol solution, 0.028 mL), and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was removed, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol=10/1) to give the title compound (0.081 g).
Reaction SMILES: CC([N:5]([C:9]1[S:10][C:11]([Cl:21])=[C:12]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C:13]=1[Cl:14])C(=O)[O-])(C)C.Cl>CO>[Cl:14][C:13]1[C:12]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[C:11]([Cl:21])[S:10][C:9]=1[NH2:5]
Reactant: Cn1nccc1-c1c(Cl)sc(N(C(=O)[O-])C(C)(C)C)c1Cl
Agent: Cl
Solvent: CO
Product: Cn1nccc1-c1c(Cl)sc(N)c1Cl
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of 1,1-dimethylethyl[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbamate (700 mg, 2.010 mmol) in methanol (10.05 ml) at 25° C. was added HCl (10.100 ml, 40.4 mmol)[4M in dioxane]. After 12 h, the reaction mixture was concentrated affording the HCl salt of [3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine (640 mg, 1.909 mmol, 95% yield) as a purple foam: LCMS (ES) m/e 284, 286 (M, M+2)+.
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:40]#[N:41])[CH2:39][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([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][N:41]=[C:21]3[C:20](=[O:31])[C:19]=2[CH:18]=1)(=[O:15])=[O:16])[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)CCCCC1
Product: O=C1C2=NCC3(CCCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclohexanecarbonitrile (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 492 [M−H]
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][CH2:40][N:41]([CH3:52])[C:42](=[O:51])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:39][CH2:40][N:41]([CH3:52])[C:42](=[O:51])[O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN(C)C(=O)OCc2ccccc2)c1=O
Temperature: 85 °C
Yield: 55.9 %

Procedure:
To N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 4.3 g) in acetonitrile (5 mL) was added potassium carbonate (2.84 g) followed by benzyl 2-chloroethyl(methyl)carbamate (2.69 g) and the reaction heated at 85° C. for 16 h under nitrogen. After cooling to room temperature, the mixture was evaporated to dryness and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was separated and further extracted into DCM (2×20 mL). The combined organics were evaporated to leave crude benzyl 2-(2-(2-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4-dihydropyrazin-2-ylamino)propan-2-yl)phenoxy)ethyl(methyl)carbamate (3.50 g) as a gum. Ethanol (150 mL) and P/C (0.611 g of 5%) were added and the reaction stirred under H2 atmosphere (2 bar) for 4 h. The mixture was filtered through Celite (washing pad with aliquots of ethanol) and the combined filtrates evaporated to leave the crude product (2.1 g). Recrystallisation from ethyl acetate gave the title product (1.15 g) as a white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:6][CH2:5]1.C1(C[Mg]Br)CC1.[CH3:13][C:14]1[C:18]([C:19]2[CH:20]=[C:21]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:32])[C:22]3[N:26]=[C:25]([O:27]CC)[NH:24][C:23]=3[CH:30]=2)=[C:17]([CH3:39])[O:16][N:15]=1>C1COCC1>[CH3:13][C:14]1[C:18]([C:19]2[CH:20]=[C:21]([C:31]([OH:32])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:6][CH2:5][CH:4]=[CH2:3])[C:22]3[NH:26][C:25](=[O:27])[NH:24][C:23]=3[CH:30]=2)=[C:17]([CH3:39])[O:16][N:15]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: BrCC1CC1
Agent: Br[Mg]CC1CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Magnesium metal (20 mg, 0.82 mmol) was taken up in THF (1.5 mL) and (bromomethyl)cyclopropane (100 mg, 0.71 mmol) was added dropwise and the reaction was heated to 65° C. for 1 hr. (Cyclopropylmethyl)magnesium bromide (0.5 M, 0.83 mL, 0.41 mmol) was then added dropwise to a solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) in dry THF (1.4 mL) which was cooled to 0° C. Reaction mixture was allowed to stir for 10 mins, quenched with water and extracted three times with EtOAc. Combined organic layers were washed once with water and concentrated. Residue was dissolved in a mixture of EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL) and heated for 2 hours at 65° C. Reaction was then concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: P([O-])([O-])([O-])=O.OC1[C@@H]([C@@H](O)CO)OC(=O)C=1O.[OH-].[Na+].[CH2:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:31])=[CH:27][C:28]=2[OH:30])[O:23][C@H:22]([C:32]2[CH:37]=[C:36](O)[C:35]([OH:39])=[C:34]([OH:40])[CH:33]=2)[C@@H:21]1[O:41]C(C1C=C(O)C(O)=C(O)C=1)=O>O.C(OCC)(=O)C.C(#N)C>[CH:37]1[C:32]([CH:22]2[O:23][C:24]3[CH:25]=[C:26]([OH:31])[CH:27]=[C:28]([OH:30])[C:29]=3[CH2:20][CH:21]2[OH:41])=[CH:33][C:34]([OH:40])=[C:35]([OH:39])[CH:36]=1
Reactant: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Oc1cc(O)c2c(c1)OC(c1ccc(O)c(O)c1)C(O)C2
Reaction time: 0.25 h

Procedure:
To 0.25 mL of the resulting plasma were added 0.25 mL of a phosphate buffer (obtained by dissolving 48 g of NaH2O4, 20 g of vitamin C and 1 g of EDTA-2Na thoroughly in 1 L of distilled water and then adjusting pH of the resulting mixture to 3.9 with 0.1 mol/L NaOH) and 0.5 mL of acetonitrile, followed by thorough mixing. After addition of 3 mL of ethyl acetate and mixing, the resulting mixture was centrifuged at 3000 r/min at 4° C. for 15 minutes to obtain an upper ethyl acetate layer. The above-described extracting operation was repeated three times. The ethyl acetate layers thus obtained were collected, dried on a rotary evaporator and then dissolved in 0.9 mL of a 1:8 water-methanol mixture. The resulting solution was provided for HPLC chromatodisk. After filtration with 4.0 mL of methanol, the filtrate was dried over the rotary evaporator again. The catechin extract thus obtained (dried portion) was dissolved in 0.3 mL of a 9:1 water-acetonitrile mixture. A 0.1 mL portion of the resulting solution was provided for Chemiluminescence Analyzer (ultraweak light detector; product of Tohoku Electric Industrial Co., Ltd.) and the amount of epigallocatechin gallate (EGCg), a typical ingredient of catechins, in the plasma was measured. The catechin concentration was expressed by the amount (ng/mL) of epigallocatechin gallate per mL of plasma.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>C(OCC)(=O)C>[Cl:20][C:19]([Cl:22])([Cl:21])[CH2:18][O:17][C:15](=[O:16])[NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (10° C.) solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (3.75 g, 24.5 mmol) and NaOH (1.5 g in 20 mL water) in ethyl acetate (45 mL) was added 2,2,2-trichloroethyl chloroformate (7.52 g, 35.5 mmol) over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate and the layers separated. The organic layer was washed with water, brine, dried over MgSO4, and concentrated under reduced pressure. The residue was diluted with ethyl acetate/dichloromethane and treated with aminomethyl silica (10 g) for 1 hour. The mixture was filtered and the filtrated concentrated under reduced pressure to provide the product.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=Cc1ccc(OCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Aqueous 1N Sodium hydroxide solution (6.0 mL, 12.0 mmol) was added to a solution of 4-hydroxycinnamic acid (536.0 mg, 3.2 mmol) in ethanol (10.0 mL). 2-Bromoethylbenzene (575.0 mg, 3.1 mmol) was then added to the reaction mixture and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to afford a white residue, which was taken up in water. The aqueous phase was then acidified with concentrated hydrochloric acid to produce a white precipitate which was isolated by filtration and washed with water, then dried to afford (544.0 mg, 66.8%) of the desired 4-phenethyloxycinnamic acid as a white powder. 1H NMR (300 MHz, DMSO) δ 3.82 (3H, s, OCH3), 4.78 (2H, s, CH2), 6.92 (2H, d, 2×ArH, J=7.5 Hz), 7.16 (2H, d, 2×ArH, J=7.5 Hz), 7.52-7.60 (1H, m, ArH), 7.62-7.72 (1H, m, ArH), 7.98 (1H, m, ArH).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH2:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[C:24]=2[CH:23]=[CH:22][N:21]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][N:2]([CH2:10][CH2:11][NH:12][S:30]([C:25]1[C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:31])=[O:32])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CN(CCN)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCNS(=O)(=O)c1cccc2cnccc12)Cc1ccccc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In 70 ml of methylene chloride were dissolved 3.24 g of 2-(N-methyl-N-benzylamino)ethylamine and 2.0 g of triethylamine, and to the solution was added dropwise 50 ml of a methylene chloride solution containing 3.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for one hour, and then the reaction solution was washed with water and extracted with a 10% aqueous hydrochloric acid solution. The aqueous layer was washed with chloroform, rendered alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and then the chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: chloroform) to give 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) in a yield of 84%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN(C)CCCl
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(OCCN(C)C)cc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
4-Methyl-3-nitrophenol (2.0 g, 13 mmol), 1-chloro-2-dimethylaminoethane hydrochloride (3.8 g, 26 mmol), and K2CO3 (5.4 g, 39 mmol) were added to 2-butanone (30 mL). The mixture was refluxed for 12 h after which TLC analysis revealed consumption of the starting phenol. The reaction was cooled, diluted with saturated NH4Cl, and extracted with EtOAc. The organic layers were dried (Mg2SO4), filtered, concentrated, and purified via flash silica gel chromatography to afford the title compound (2.6 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.34 (s, 6H), 2.53 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.5 Hz, 2H), 7.10 (dd, J=8.4, 2.7 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H).
Reaction SMILES: [N+](=[CH2:3])=[N-].C(OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][C@H:21]([CH2:23][C@H:24]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH2:25][CH3:26])[NH:20][CH2:19][C@@H:18]2[O:32][CH:33]([C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][CH2:50][N:49]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:48]=3[CH:58]=2)[S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Mg+2].[N+](=C)=[N-]>CO>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][C@H:21]([CH2:23][C@H:24]([C:27]3[N:28]([CH3:3])[N:29]=[N:30][N:31]=3)[CH2:25][CH3:26])[NH:20][CH2:19][C@@H:18]2[O:32][CH:33]([C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][CH2:50][N:49]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:48]=3[CH:58]=2)[S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])=[CH:13][CH:12]=1
Reactant: C=[N+]=[N-]
Reactant: CC[C@H](C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OC(c2ccc3c(c2)N(CCCOC)CCO3)S(=O)(=O)c2ccc(C)cc2)CN1)c1nnn[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: CC[C@H](C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OC(c2ccc3c(c2)N(CCCOC)CCO3)S(=O)(=O)c2ccc(C)cc2)CN1)c1nnnn1C
Reaction time: 2.5 h

Procedure:
A freshly prepared solution of diazomethane/diethylether (from Diazald®) is added dropwise to a solution of 0.201 g of 6-[(3R,4R,6S)-4-(4-methoxy-phenyl)-6-[(R)-2-(1H-tetrazol-5-yl)-butyl]-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine (from example 64a) in 8 ml of methanol at 0° C. After 2.5 hours, solid magnesium sulfate is added to decompose any excess diazomethane and then the reaction mixture is concentrated. The resulting residue is suspended in dichloromethane, filtered and re-concentrated. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound together with its N-methylated regioisomer.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH:11]1[CH3:12]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:10]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH:11]1[CH3:12]
Reactant: CC1COC2(CCNCC2)O1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1COC2(CCN(c3ccc(C#N)cc3)CC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-fluorobenzonitrile (1.22 g, 10.0 mmol) and 4-piperidone propylene ketal (2.02 g, 12.85 mmol) was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (34).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)#[N:2].[OH:15]O.[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:14]=[CH:13][C:6]2[O:7][C:8]3([C:11](=[O:12])[C:5]=2[CH:4]=1)[CH2:10][CH2:9]3)(=[O:15])[NH2:2]
Reactant: N#Cc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyanospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (185 mg.) in ethanol (10 ml.) were added dropwise 5.5 ml. of 7% aqueous solution of hydrogen peroxide and 3.7 ml. of ethanol, then, to the mixture, was added 2 N aqueous solution of sodium hydroxide to adjust pH 10 and the solution was stirred at 60° C. for 2 hours. After cooling, the reaction mixture was neutralized with diluted hydrochloric acid and diluted with ice-water. The preciptating crystals were collected by filtration, washed with water and recrystallized from ethanol to give colorless needles of 5-carbamoylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (106 mg.). m.p. 243°-244° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>O1CCCC1.CO>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]([OH:29])[CH3:28])=[N:25][CH:26]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: CC(=O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(C)O)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (46 mg, 1.2 mmol) was added to a solution of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethanone (45 mg, 0.12 mmol) in tetrahydrofuran (300 μl) and methanol (300 μl) and then the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (2 mL) and diluted with dichloromethane (3 mL). The mixture was stirred for 16 hours, filtered through a CELITE pad, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient) to afford 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethanol. MS ESI calc'd. for C19H18F3N4O [M+H]+ 375. found 375. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.54 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 5.39 (s, 1H), 4.80-4.72 (m, 1H), 2.35 (s, 3H), 1.38 (d, J=5.5 Hz, 3H).
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=3)=O)(C)C.C(N(CC)CC)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[C:24]1([O:23][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[N:8][C:7]([CH:5]=[O:4])=[C:19]([CH2:20][O:21][CH3:22])[C:18]3=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCc1c(C=O)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 153.5 %

Procedure:
330 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 10 ml of toluene with 0.62 ml of triethylamine and 0.2 chlorotrimethylsilane and heated for 45 minutes to a bath temperature of 50°-60° C. After concentration by evaporation to about 6 ml, it is cooled to -78° C. under argon and 1.25 ml of a 1.2 molar diisobutyl aluminum hydride is instilled in hexane. After 30 minutes at -78° C., it is mixed with 3 ml of ethanol and 0.75 ml of 1N NaOH. It is mixed with ethyl acetate and very little water. The organic phase is separated and concentrated by evaporation without drying. The residue is mixed with hexane and yields 440 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carbaldehyde. 254 mg of it is mixed in 2.5 ml of dimethylfuran with 67.5 mg of hydroxylamine hydrochloride and 69 mg of potassium hydroxide powder and allowed to stand for 16 hours at room temperature. The batch is poured on ice and the precipitate is suctioned off and rewashed with water. 133 mg of 6-(1-isoquinolyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime of melting point 215°-218° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(=O)(O)[O-].[Na+].[I:15]I>CO.O>[F:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:6])=[C:7]([I:15])[CH:8]=1
Reactant: II
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(N)c(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline).