Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[CH2:21][C:22](OCC)=O)[CH3:2].CC[O-].[Na+].C(O)C.C([O-])(=O)C.[NH4+:39]>C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9]([CH:8]2[CH2:21][C:22]=1[NH2:39])=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)=[O:27])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN1CCc2cc(OC)c(OC)cc2C1CC(=O)OCC
Agent: CC(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
A solution of 3-(1-ethoxycarbonylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 17.1 g, 45.0 mmol) in cyclohexane (340 mL) was treated with sodium ethylate (9.67 g, 135 mmol) and heated in an oil bath, and the ethanol formed during the reaction was removed by distillation over 30 min, while more cyclohexane was added in order to keep the reaction volume constant. After cooling the reaction mixture was neutralized with acetic acid and concentrated. The residue was dissolved in dichloromethane/water 1:1 and brought to pH 10 with concentrated ammonium hydroxide solution. The organic layer was separated, dried (MgSO4), and evaporated. The residue was dissolved in methanol (270 mL) and ammonium acetate (42.3 g, 548 mmol) was added. After stirring at r.t. for 90 min, the reaction mixture was evaporated and the residue partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was dried (MgSO4), evaporated, and chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 97.5:2.5:0.25) to afford the title compound (9.90 g, 66%). Light yellow solid, MS (ISP) 333.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Br)cc(O)c21

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one (fraction A) and 79 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one are obtained by reaction of 800 mg of the imine with 7.9 ml of boron tribromide solution (1H in dichloromethane).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH:9]=[CH:10][CH2:11]Cl)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:4]3[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1cccnc1C=CCCl
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1C=CCN1CCc2nc(N)sc2CC1
Yield: 45 %

Procedure:
Prepared from 3-(3-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 45% of theory, Melting point: 188°-190° C. (ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (3.7 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After stirring for 4 h, the solvents were removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. After standing at room temperature overnight, the mixture was filtered to give 6.4 g (79%) of a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([C:13]3[N:14]=[C:15]([NH2:18])[S:16][CH:17]=3)=[C:8]([CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH3:19])[C:9]([C:13]3[N:14]=[C:15]([NH:18][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:16][CH:17]=3)=[C:10]([CH3:12])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(OCC2CC2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCC2CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-amine (4-5, 0.410 g, 1.51 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.470 g, 2.62 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered, and recrystallized in toluene to give N-{4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (4, 0.41 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1 H), 8.80 (d, J=4.9 Hz, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J=7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J=6.5 Hz, 2 H), 0.32 (d, J=5.7 Hz, 2 H). ESI-MS: m/z 380.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[CH3:18]
Reactant: CCN(CC)CCNc1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCN(C(=O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 8.0 g (33 mmol) of N,N-diethyl-N'-naphthalenyl-1,2-ethanediamine in 100 mL of tetrahydrofuran is treated with a solution of 6.8 g 4-fluorobenzoyl chloride in 50 mL of tetrahydrofuran and stirred at room temperature. After one hour, the solvent is evaporated on the rotary evaporator. The residue is dissolved in 200 mL of methylene chloride and washed with 200 mL of water and 4N sodium hydroxide to pH=14. The organic layer is dried over sodium sulfate, filtered and the solvent evaporated to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C1(C)C=CC=CC=1>[O:11]([C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of cis-4-phenoxy-cyclohexanecarboxylic acid methyl ester (0.55 g, 2.3 mmol) and hydrazine hydrate (0.11 g, 2.3 mmol) was heated at 120° C. for 24 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.50 g, 92%) as light yellow foam, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([CH2:9][C:10]2[CH:15]=[C:14]([NH:16]C(=O)C(F)(F)F)[CH:13]=[CH:12][C:11]=2[S:23](Cl)(=[O:25])=[O:24])=[N:6][N:5]=1)[CH2:2][CH3:3].[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35][O:34][B:33]([OH:36])[C:32]=2[CH:37]=1.N1C=CC=CC=1>C(#N)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([S:23]([NH:27][C:28]2[CH:29]=[CH:30][C:31]3[CH2:35][O:34][B:33]([OH:36])[C:32]=3[CH:37]=2)(=[O:24])=[O:25])=[C:10]([CH2:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][N:6]=2)[CH:15]=1
Reactant: CCCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a stirred solution of 2-((5-propyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (430 mg, 1.05 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (234 mg, 1.57 mmol) in 5 mL of ACN was added pyridine (253 uL, 3.13 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (410 mg, yield 75%).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][CH2:20][CH:8]([C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=2[CH:6]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[OH:1][CH:2]([CH2:21][NH:25][CH:22]([CH3:24])[CH3:23])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][CH2:20][CH:8]([C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=2[CH:6]=1
Reactant: c1ccc2c(c1)C1CCC2c2cc(OCC3CO3)ccc21
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc2c(c1)C1CCC2c2ccccc21
Reaction time: 20 h

Procedure:
40.95 g of 2-[2,3-epoxy-propoxy]-9,10-dihydro-9,10-ethano-anthracene and 48 ml of isopropylamine are dissolved in 700 ml of absolute alcohol and the solution is boiled for 20 hours under reflux. The reaction mixture is then evaporated to dryness and the residue is recrystallised from 180 ml of toluene. 2-[2-Hydroxy-3-isopropylamino-propoxy]-9,10-dihydro-9,10-ethano-anthracene thus obtained, melts at 126°-127° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccnc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)pyridine (3.00 g), potassium carbonate (1.89 g), vanillin (2.08 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzaldehyde as colorless crystals (3.61 g, 81%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: CC[O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].N[CH:16]([C:19](O)=[O:20])CS>>[C:19]([N:10]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7][C:6]1([CH3:14])[C:4]([OH:3])=[O:5])(=[O:20])[CH3:16]
Reactant: NC(CS)C(=O)O
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Product: CC(=O)N1C(C(=O)O)CSC1(C)C(=O)O

Procedure:
By an operation similar to that in Synthetic Example 13 and using 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester synthesized from DL-cysteine by a method similar to that in Reference Example 2, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (trans form) was obtained as a white solid (yield 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:34][CH:35]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:29][C:30]2[CH:35]=[N:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1ccc(-c2ccccc2)nc1
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3ccccc3)nc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 265-1 and 5-(chloromethyl)-2-phenylpyridine (360 mg) synthesized in Reference Example 21 were dissolved in N,N-dimethylformamide (10 mL), potassium tert-butoxide (200 mg) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:2 to 2:1) to give the title compound (740 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3C2CCCCO2)[C:5]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][N:13](C4CCCCO4)[C:14]=3[CH:15]=[CH:16][CH:17]=2)=[N:6][CH:7]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[C:5]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cc(Cl)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cc(Cl)cnc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of N-(5-chloro-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (96.8 mg, 178 μmol) in DCM/MeOH (4.0 mL, 1:1) was treated with (+/−)-10-camphorsulfonic acid (91 mg, 391 μmol) and the stirred mixture placed in an oil bath at 40° C. The heater was turned off and the mixture stirred for 16 h. LCMS showed predominantly monodeprotection, so an additional 90 mg of CSA was added (4.4 equiv. total). The mixture was heated at 40° C. until LCMS indicated complete deprotection. The mixture was cooled and purified by ion exchange chromatography (washing with MeOH, eluting off with 2 N NH3/MeOH). The product was concentrated, taken up in MeOH (3 mL), sonicated and allowed to stand. N-(5-Chloro-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine (55 mg, 82% yield) crystallized out and was collected by filtration as an orange solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 11.29 (br. s., 1H); 10.17 (br. s., 1H); 10.04 (s, 1H); 9.27 (d, J=2.69 Hz, 1H); 8.93 (s, 1H); 8.40 (s, 1H); 8.30 (d, J=2.69 Hz, 1H); 7.89 (d, J=9.54 Hz, 1H); 7.52 (d, J=9.54 Hz, 1H); 2.15 (s, 3H). m/z (ESI, +ve) 377.0 (M+H)+.
Reaction SMILES: C(#N)C.Cl.[CH2:5]([O:7][C:8]1[C:27]([C@H:28]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]2)=[CH:26][C:11]([CH2:12][C:13]2[CH:22]=[C:21]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]3)[C:14]=2C(O)=O)=[CH:10][C:9]=1[O:39][CH3:40])[CH3:6]>C(OCC)(=O)C>[CH:14]1[C:15]2[C:21]([CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][C:13]=1[CH2:12][C:11]1[CH:10]=[C:9]([O:39][CH3:40])[C:8]([O:7][CH2:5][CH3:6])=[C:27]([C@@H:28]2[O:29][C@H:30]([CH2:37][OH:38])[C@@H:31]([OH:36])[C@H:32]([OH:35])[C@H:33]2[OH:34])[CH:26]=1
Reactant: CCOc1c(OC)cc(Cc2cc3cccccc-3c2C(=O)O)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1c(OC)cc(Cc2cc3cccccc-3c2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 92.1 %

Procedure:
Acetonitrile and a 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid (5 ml) were added to 2-[4-ethoxy-3-methoxy-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylic acid (50 mg) and the mixture was refluxed with heating for 10 minutes. A 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid was further added to the reaction mixture and the mixture was refluxed with heating for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxy-3-methoxyphenyl]-D-glucitol (42 mg).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29]>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Anhydrous DMF solution (10 ml) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2.72 g, 10 mol) was mixed with 60% sodium hydride (0.4 g, 10 mmol) and stirred at room temperature for 1 hour. The reaction solution was cooled to −60° C., mixed with 2-acetoxy-1-bromoethane (1.67 g, 10 mmol) and then returned to room temperature while stirring for 1 hour. The reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure, the thus obtained residue was mixed with diisopropyl ether (20 ml) and the thus precipitated crystals were collected by filtration to obtain 1.90 g of the title compound (5.3 mmol, 53% in yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=2)[C:30]([NH2:33])=[CH:31][CH:32]=1>C(Cl)Cl.CCO>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:34]([C:35]2[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:33]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1ccc(Nc2cc(F)ccc2N)n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a suspension of (S)-Boc-alaninamide (614 mg, 3.27 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (621 mg, 3.27 mmol) in one portion under a nitrogen atmosphere. The resulting mixture stirred at RT for 1 h. The volatiles were removed in vacuo and to the resulting residue was added 4-fluoro-N2-(1-methyl-1H-pyrazol-3-yl)-benzene-1,2-diamine (350 mg, 1.70 mmol) in absolute EtOH (5 mL) and the mixture stirred at 80° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and an aqueous solution of NaHCO3. The organic fraction was dried, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) to afford the title compound as a purple oil (187 mg, 31%). LCMS (Method B): RT 3.18 min [M+H]+ 360.05
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C@:14]([OH:17])([CH3:21])[C@H:15]2[CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Mg]Br
Reactant: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1F
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc(C#N)c1F

Procedure:
Using 2-fluoro-3-methyl-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (60 mg) and methylmagnesium bromide-THF solution (2.19 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as colorless crystals (yield: 40 mg, 63%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>CO>[O:5]1[CH:3]([CH2:1][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=3)[CH:14]=2)[CH2:4]1
Reactant: ClCC1CO1
Reactant: Oc1cccc(Cc2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(Cc2cccc(OCC3CO3)c2)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
19 g of epichlorohydrin is added to a mixture of 18.5 g of 3-(2-pyridylmethyl)phenol, 4.2 g of sodium hydroxide and 200 ml of methanol, and the resulting mixture is stirred at about 50°C for 3 hours. The methanol is then removed, water is added to the residue, and the aqueous solution is extracted with 200 ml of benzene. The benzene layer is washed with 5% sodium hydroxide and with water, and dried over anhydrous magnesium sulfate. The benzene is removed to give 15.0 g of 1,2-epoxy-3-[3-(2-pyridylmethyl)-phenoxy] propane as oil.