Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:31][CH:32]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(OCCN4CCOCC4)cc3)nn12

Procedure:
Into a Microwave vial, [A] 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.116 g, 0.000404 mol), [B] 4-(2-Morpholin-4-yl-ethoxy)-phenylamine (0.197 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 12% methanol). The collected fractions afforded [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine a yellow solid (22 mg, 12%). MP 125-126° C. LCMS (E/I+) 446.8 (M+H). NMR 1H (DSMO-d6)-9.20 (s, 1H), 8.91 (s, 1H), 7.79 (dd, 1H, JJ=1.60, 6.04 Hz), 7.61 (d, 2H, J=9.00 Hz), 7.45 (dt, 1H, JJ=1.40, 7.12 Hz), 7.21 (d, 1H, J=8.36 Hz), 7.12 (t, 1H, J=7.53 Hz), 6.92 (d, 1H, J=4.56 Hz), 6.89 n (d, 1H, J=4.64 Hz), 6.80 (d, 2H, J=9.00 Hz), 4.02 (t, 2H, J=5.80 Hz), 3.79 (s, 3H), 3.3.58 (t, 4H, J=4.68 Hz), 2.65 (t, 2H, J=5.68 Hz), 2.46 (t, 4H, J=4.48 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH2:3]([C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6])[CH3:2].[CH3:22][CH2:21][O:20][C:18](=[O:1])[OH:19]
Reactant: O=C1C=C(CCO)C(=O)N1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1=CC(=O)NC1=O
Product: CCOC(=O)O
Temperature: 25 °C

Procedure:
Hydroxy ethylmaleimide (29.87 g, 0.212 moles) and pyridine (16.7 g, 0.212 moles) were dissolved in THF (170 mL) and the solution was stirred at room temperature. Ethyl chloroformate (22.97 g, 0.212 moles) was added dropwise and stirred for 90 minutes. The pyridine salt was filtered off and the solution was combined with 200 mL of a 1N HCl solution. The product was extracted with methylene chloride and washed with a 1N HCl solution followed by water and then dried over magnesium sulfate. The red solution was concentrated and the red crystals purified by sublimation yielding white crystals, m.p. 52° C. (34.76 g, 77.04% ). 1H-NMR (CDCl3), δ, ppm): 1.26-1.34 (3H, —CH3, t), 3.81-3.87 (2H —NCH2—, t), 4.14-4.25 (2H, δ-CH2OC═O, q), 4.25-4.30 (2H, β-CH2O—, t), 6.74 (2H, —CH═CH—, s). 13C—NMR (CDCl3, δ, ppm): 14.2 (1C, —CH3), 36.8 (1C, —NCH2—), 64.3 (1C, δ—CH2O), 64.5 (1C, δ—CH2—), 134.4 (2C, —CH═CH—), 154.9 (1C, O(C═O)O), 170.4 (2C, —C═O).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][C:23](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCSc1nnc(N)s1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCSc1nn2c(=O)cc(-c3ccccc3)nc2s1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Three point seven (3.7) grams of 2-amino-5-hexylthio-1,3,4-thiadiazole, 3.4 g of ethyl benzoylacetate and 5 g of polyphosphoric acid were mixed and stirred at 130°-140° C. for 30 minutes. After cooling, chloroform and water were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 5.5 g of 2-hexylthio-7-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 99%. This substance was recrystallized from ethanol and the purified compound showed a m.p. of 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][CH2:4][N:5](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:7][C:8]=1[C:9]#[N:10].[H][H]>C(O)C.Cl.[Pd]>[ClH:1].[Cl:1][C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]=1[C:9]#[N:10]
Reactant: N#CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CC1=C(Cl)CCNCC1

Procedure:
1.45 gm (0.005 mol) of benzyl 4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-1-azepine-carboxylate were dissolved in 20 ml of ethyl alcohol by addition of 0.9 ml of semiconcentrated hydrochloric acid, and after the addition of 0.2 gm of palladium-on-charcoal, the mixture was hydrogenated in an autoclave at room temperature and under a hydrogen pressure of 5 bars. After half an hour, the uptake of hydrogen had ended. The catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was recrystallized from isopropyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 13.0 g (23.9 mmol) 5′-O-(4,4′-dimethoxytrityl)thymidine 16 in 50 ml DMF was added 3.0 g (44 mmol) imidazole and 3.6 g (23.9 mmol) tert-butyl-dimethylsilyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 300 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After concentration of the solution and recrystallization from ethyl acetate/hexane, the solid product 5′-O-(4,4′-dimethoxy)-3′-(tert-butyldimethylsilyl)thymidine 17 was used directely for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][O:7]2.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:21][CH:5]1[CH2:6][O:7]2
Reactant: Fc1ccc(F)c2c1C=CCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(F)c2c1OCC1OC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
5,8-Difluoro-2H-chromene (35 g, 0.21 mole) was dissolved in 500 ml DCM and MCPBA (77%, 93 g, 0.42 mole) was added. The reaction was stirred at room temperature for 30 minutes. 50 g Na2S2O3 in 500 ml water was added to quench the reaction. The organic layer washed with 2N NaOH solution (2×500 ml), brine (200 ml), dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane solution to give rise to 21.6 g pure product. The residue from mother liquor was purified by column chromatography (EtOAc/hexane from 0/100 to 25/75 in 55 minute, additional 1.4 g obtained). Total Yield: 23 g, 60%. 1H NMR (CDCl3 400 MHz δ 7.00 (m, 1H), 6.63 (m, 1H), 4.67 (d, J=12.4 Hz, 1H), 4.27 (m, 2H), 3.84 (d, J=4.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:17][O:16][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1COC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol) and oxetan-3-one (56 mg, 0.78 mmol) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (264 mg, 1.24 mmol). The resulting mixture was stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting oil was purified by column chromatography (Si—PCC, MeOH/DCM, 0-20%) affording 4-(Methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester as an oil (40 mg, 16%). 1H NMR (CDCl3, 300 MHz): δ 4.66 (t, J=6.6 Hz, 2 H); 4.61 (t, J=6.6 Hz, 2H); 4.16 (s, 2 H); 3.95 (p, J=6.6 Hz, 1 H); 2.63 (t, J=12.5 Hz, 2 H); 2.39 (tt, J=11.7, 3.7 Hz, 1 H); 2.20 (s, 3 H); 1.60 (d, J=12.5 Hz, 2 H); 1.46 (s, 9 H); 1.44-1.28 (m, 2 H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7](O)[C:8]3[C:13]([O:14][C:4]2=[CH:3][CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:16][NH:17][C:18]([NH:20][CH3:21])=[O:19].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:16][N:17]([CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:4]2[C:5]1=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)NC
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
A mixture of xanthydrol (2 g.), N,N'-dimethylurea (1 g.), toluene (15 ml.) and acetic acid (0.6 ml.) was refluxed for 20 minutes, evaporated to dryness, the residue was washed with water and dried. It was recrystallised from benzene and the crystals dried at 90°C./2mm. to give N,N'-dimethyl-N-9-xanthenylurea, m.p. 169°-170°C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[CH:16][C:15]2[O:11][C:12](=[O:20])[NH:13][C:14]=2[CH:19]=1)=[O:8]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of aluminum chloride (40 g) and 2-bromopropionyl bromide (32.4 g) in carbon disulfide (100 ml) was refluxed with stirring for 30 minutes. To the resultant mixture was added 2-benzoxazolinone (13.5 g) and the mixture was refluxed under stirring for 7 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diethyl ether to give 5-(2-bromopropionyl)-2-benzoxazolinone (13.5 g). mp. 191°-193° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CCCCCC.C(OCC)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC=CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.6 g, 15 mmol) was charged and washed with hexane twice. Into this flask, 1,3-dimethyl-2-imidazolydinone (20 ml) was added and a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (2.1 g, 15 mmol) and 3-methoxyacrylonitrile (1.2 g, 15 mmol) in 1,3-dimethyl-2-imidazolydinone (5 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (200 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The obtained organic layers were washed with saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1 to 2/1) to obtain 2.60 g (yield 92.0%) of a mixture of title compounds (IIa) and (IIb).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC1[N:45]=[CH:44][C:43]([CH2:46][CH3:47])=[CH:42][N:41]=1>C(Cl)Cl>[CH2:46]([C:43]1[CH:42]=[N:41][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:45][CH:44]=1)[CH3:47]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, Step 2, 0.15 g, 0.34 mmol) was dissolved in CH2Cl2 (10 mL). TFA (0.35 mL) was added and the mixture was stirred at ambient temperature for 5 h. An excess of TFA and CH2Cl2 was removed under reduced pressure and the residue was taken up in DMSO (6 mL). Potassium carbonate (1 g) was added, followed by addition of 2-chloro-5-ethylpyrimidine (63 μL, 0.50 mmol). The reaction mixture was degassed, purged with N2 and heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown solid. The crude product was triturated with hot hexane containing 1% of MeOH to give 0.14 g (92%) of the title compound as a cream-white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.19 (bs, 2H), 8.13 (d, 2H, J=8.6 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.5 Hz), 7.35-7.25 (m, 1H), 4.90-4.75 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.08 (s, 3H), 3.00-2.90 (m, 2H), 2.55-2.40 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.50-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (APCI), m/z 453 (M+H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C>O.[Ru](Cl)(Cl)Cl>[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]([OH:2])=[O:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(CO)CNC(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to a solution of 4.6 g of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol obtained in Reference Example (2a) (19.4 mmol) in a mixed solvent of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), and the mixture was stirred at room temperature for 16 hours. 11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for three days. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 3.16 g of crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid. 3.0 g of 1,1′-carbonylbis-1H-imidazole (18.5 mmol) was added to a solution of 3.1 g of the crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid obtained above (12.3 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for one hour. 20 ml of a 28% ammonia aqueous solution (914 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1 M hydrochloric acid aqueous solution and brine and dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate/n-hexane=2/1-3/1) to obtain 2.54 g of the title compound (yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[CH3:31])=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1CN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2C)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methylbenzylamine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].ClCCC(C)(C)C(O)=O.Cl[CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Brc1cnc2[nH]nc(I)c2c1
Agent: CC(C)(CCCl)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (4 g, 12.4 mmol) in DMF (50 ml) under nitrogen was stirred at 40° C. for 10 minutes. Sodium hydride (0.9 g, 37 mmol) was added to the DMF solution and the resulting mixture was allowed to stir at 40° C. for 1 hour. Then 2,2-dimethyl-propionic acid chloromethyl ester (chloromethyl pivalate) was added dropwise to the mixture. The reaction was stirred for another 2 hours. The reaction was quenched with saturated NH4Cl (20 ml) and worked up with ethyl acetate, brine, dried with Na2SO4, concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (5 g, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.07 (s, 9H), 6.37 (s, 2H), 8.30 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1Cl)([OH:3])=O.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.O.[CH3:38]N(C)C=O>>[CH3:38][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)=[CH:5][C:4]=1[C:1]([NH:36][CH2:35][C:25]12[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Reaction time: 14 h

Procedure:
A solution of 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (Example 5b, 0.10 g) and N,N′-carbonyldiimidazole (0.045 g) in dimethylformamide (3 ml) was stirred at room temperature for 2 h. 1-Adamantanemethylamine (0.050 ml) was then added and stirring continued for 14 h. The reaction mixture was poured into water and extracted with ethyl acetate three times. The ethyl acetate layers were combined and washed with 2M hydrochloric acid, 10% aqueous sodium hydroxide and brine, then dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel, eluting with 20-30% ethyl acetate in iso-hexane, gave the subtitle product as a gum which crystallised on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br>CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH2:11][Br:17])([O-:3])=[O:2]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
o-Nitroacetophenone (8.3 g, 50 mmol) in ether (100 ml) was treated with aluminium chloride (catalytic amount) followed by bromine (2.55 ml, 50 mmol) over 10 mins and the reaction stirred for 30 mins. The reaction was quenched with aqueous sodium bicarbonate, the ether layer separated, dried (MgSO4) and evaporated under reduced pressure. The residue was taken up in ethyl acetate, the solution was dried (MgSO4), and evaporated under reduced pressure to yield o-nitro phenacyl bromide as a yellow oil (9.45 g, 77%); δH (CDCl3) 7.2-8.35 (4H, m, aryl), 4.30 (2H, S, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([NH2:14])[CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.C(#N)C.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>CN(C=O)C>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:13][N:12]=1)=[O:33]
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Yield: 70 %

Procedure:
A solution of 5-(4-methoxyphenyl)-1H-pyrazol-3-amine and diisopropylethylamine in 10 volumes of a 9:1 mixture of acetonitrile:DMF was cooled to −10° C. 5-Bromovaleryl chloride was added dropwise over a minimum of 3 hr at −10° C. The resulting solution was held at −10° C. until reaction completion, generally 2 hr. The reaction mixture was quenched with water. The product was isolated by filtration, washed with water, TBME and suction dried. The product-wet cake was purified by re-slurrying in TBME at 35° C. for a minimum of 2 hr. The yield was 70-80%.