Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:26]([CH3:40])=[CH:25][C:24]=1[SH:41])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[C:26]([CH3:40])=[CH:25][C:24]=1[S:41][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1OCCO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and an addition funnel were added tosyl bromide (6.07 g, 26.0 mmol), CCl4 (70 mL) and NEt3 (3.59 mL, 26.0 mmol), and this solution was cooled to 0° C. The 2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzenethiol material prepared in Example OOO (4.6 g, 13.0 mmol) was dissolved in CCl4 (70 mL) and added dropwise to the tosyl bromide solution. The addition was complete in 3.5 hours, at which time the ice bath was removed and the reaction stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with saturated NH4Cl and dried (MgSO4). The solvent was then evaporated and the residue was submitted to flash chromatography (1:1 CH2Cl2 :hexane) to yield the title compound. 1H NMR (CDCl3) δ 0.04 (s, 6 H), 0.85 (s, 9 H), 1.20 (s, 9 H), 2.01 (s, 3 H), 2.37 (s, 3 H), 3.93 (t, 2 H), 3.99 (t, 2 H), 6.82 (s, 1 H), 7.0 (s, 1 H), 7.19 (d, 2 H), 7.44 (d, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([CH3:1])=[N:3][C:4]=2[NH2:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.7 %

Procedure:
70 mg (0.47 mmol) of 2-methyladenine was dissolved in a mixed solvent composed of DMF (15 ml) and water (5 ml). To this solution, 0.26 g (1.88 mmol) of potassium carbonate and 0.5 ml (about 2 mmol) of benzyl bromide were added and stirred at room temperature for 16 hr. After the solvent was removed by vacuum distillation, the residue was extracted with chloroform, dried over anhydrous magnesium sulfate and then concentrated. The resultant residue was purified by column chromatography (eluent:dichloromethane:methanol=50:1-30:1) to thereby obtain 0.12 g of 9-benzyl-2-methyladenine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:40](=[O:41])[CH2:39][C:38]([NH:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[O:43])=[CH:23][C:22]=3[F:28])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(CN(C)C)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of the amine 150 (334 mg, 0.85 mmol), 3-(2-methoxyphenylamino)-3-oxopropanoic acid (27) (355 mg, 1.70 mmol), 1-hydroxybenzotriazole (275 mg, 2.04 mmol) in dimethylformamide (8.5 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) and the reaction mixture was stirred at room temperature until completion of the reaction. The dimethylformamide was evaporated and the residue was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated to afford title compound 146 as a white solid (180 mg, 36% yield). 1H NMR (DMSO-d6) 6 (Ppm): 10.59 (s, 1H), 9.64 (s, 1H), 8.52-8.50 (m, 1H), 8.08-8.06 (m, 2H), 7.88 (d, J=12.9 Hz, 1H), 7.78 (m, 2H), 7.51-7.38 (m, 4H), 7.07 (s, 2H), 6.92 (m, 1H), 6.65 (m, 1H), 3.86 (s, 3H), 3.65 (s, 2H), 3.48 (s, 2H), 2.18 (s, 6H). MS (m/z): 585.2 (M+H).
Reaction SMILES: Cl.C([O:6][C:7](=[O:69])[C@H:8]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64]C(C)(C)C)=[CH:60][CH:59]=1)[NH:9][C:10]([C:12]1([CH2:17][C@H:18]([C:50]([O:52]C(C)(C)C)=[O:51])[CH2:19][NH:20][C:21](=[O:49])[C@H:22]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(C)(C)C.C1(OC)C=CC=CC=1>ClCCl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][CH2:19][C@@H:18]([C:50]([OH:52])=[O:51])[CH2:17][C:12]1([C:10]([NH:9][C@H:8]([C:7]([OH:69])=[O:6])[CH2:57][C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
Hydrogen chloride gas was passed through a stirred, ice cold solution of N-{1-[3-(N2,N6 -dibenzyloxycarbonyl-(S)-lysylamino)-2-t- butryloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)- tyrosine-t-butyl ester (from Example 81, 0.445 g, 0.47 mmole), and anisole (0.765 g, 7.1 mmole) in dry dichloromethane (10 ml) until saturation was achieved. A precipitate formed. After stirring for 1.5 hours, the solvent was evaporated under reduced pressure, and the residue azeotroped with dry dichloromethane. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The phases were separated, and the organic phase washed with two further portions of aqueous sodium bicarbonate. The combined aqueous phases were re-extracted with diethyl ether, and then acidified with 1M hydrochloric acid to pH 2. The aqueous phase was extracted with ethyl acetate (2x) and the combined organic phases dried (MgSO4), filtered and the solvent evaporated to yield a foam, which was azeotroped with methylene chloride to yield the title compound as a solid foam (0.325 g, 89%). Found: C,62.81; H,6.68; N,6.92. C41H50N4O11 0.4 CH2Cl2 requires C.61.17; H,6.33; N,6.93%.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[O-]CC.[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[N:24]1[C:28]([NH2:29])=[C:27]([N:30]=O)[CH:26]=[N:25]1>CCO>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[C:18]=1[N:24]1[C:28]2=[N:29][C:3]([OH:5])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[N:30]=[C:27]2[CH:26]=[N:25]1
Reactant: Nc1c(N=O)cnn1-c1c(F)cccc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2cnn(-c3c(F)cccc3F)c2nc1O
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
To a solution of diethyl malonate (4.1 mL, 27 mmol) in 10.0 mL of EtOH at RT was added sodium ethoxide (10 mL of the 21% wt. in denatured ethyl alcohol, 28 mmol) followed by 5 min later, the addition of 1-(2,6-difluorophenyl)-4-nitroso-1H-pyrazol-5-amine (5.13 g, 23 mmol) as a solid. The resulting mixture was refluxed for 4 h. The volatiles were removed under reduced pressure and the remaining residue was partitioned between 50 mL of EtOAc and 30 mL of saturated NH4Cl solution. The precipitated rusty solid was filtered, rinsed with 2×5 mL of water followed by 2×10 mL of EtOAc. The rusty solid was dried in vacuum oven at 45° C. for 4 h to provide 4.3 g of ethyl 1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate. The filtrate was transferred to a separatory funnel. The EtOAc layer was separated and washed with brine, dried and concentrated. Purification of the dark brown residue on a silical gel column (25-65% EtOAc in Hexanes) afforded 1.1 g of ethyl 1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate as a brown solid. MS (ES+): 321.1 (M+H)+. MS (ES+): 343.0 (M+Na)+.
Reaction SMILES: COP([CH2:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])(=O)OC.[H-].[Na+].[C:18]([O:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][CH2:25][CH:26]2[CH:30]=O)(=[O:20])[CH3:19].C(O)(=O)C>O1CCCC1.C(OCC)C.O1CCOCCOCCOCCOCCOCC1>[C:18]([O:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][CH2:25][CH:26]2/[CH:30]=[CH:7]/[C:8]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:9])(=[O:20])[CH3:19]
Reactant: CC(=O)OC1CCC2C(C=O)CCC12
Reactant: COP(=O)(CC(=O)C1CCCCC1)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCC2C(/C=C/C(=O)C3CCCCC3)CCC12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Dimethyl(2-cyclohexyl-2-oxoethyl)phosphonate (3.3 g) was added to a stirred suspension of sodium hydride (0.34 g) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) in dry tetrahydrofuran (90 ml) in an atmosphere of argon and the mixture was stirred for 12 hours. The mixture was then cooled to 0° C. and treated dropwise with 6-acetoxy-2-formylbicyclo[3,3,0]octane (1.05 g; prepared as described in Reference Example 21 and predominantly in the 2β-configuration). The reaction mixture was allowed to warm to room temperature and then it was stirred for a further period of 24 hours. A solution of glacial acetic acid (400 mg) in diethyl ether (1 ml) was then added and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and the resulting solution was washed with water (10 ml) and then with saturated aqueous sodium chloride solution (10 ml), dried over magnesium sulphate, and concentrated in vacuo. The resulting oil was treated with acetic anhydride (1 ml) and pyridine (4 ml) at 20° C. and left to stand for 12 hours. Concentration at 0.01 mmHg gave an oil, which was subjected to chromatography on a silica gel column, eluting with mixtures of ethyl acetate and hexane (1:6 v/v and then 1:1 v/v), to give (E)- 6-acetoxy-2-(3-cyclohexyl-3-oxoprop-1-enyl)bicyclo[3,3,0]octane (0.84 g), predominantly in the 2β-configuration.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][N:11]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4])[C:13]([F:17])=[CH:12][N:11]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
To a mixture of (2S)-2-amino-3,3-dimethyl-butan-1-ol (5.0 g, 42.7 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.7 g, 42.7 mmol) in DMF (50 mL) was added triethylamine (7.1 mL, 51.2 mmol). After 90 minutes, the reaction was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient) to afford 6.7 g of the desired product, 1, as a sticky solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.48 minutes (M+H) 248.32.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=C)(=[O:5])[CH2:2][CH2:3][CH3:4].[O:27]=[O+][O-]>CO.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)CCC)cnc12
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccc(O)cc1C
Temperature: 25 °C
Yield: 42 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline (5.0 g, 14.4 mmol) was stirred at -60° C. in a mixture of methanol (100 ml) and dichloromethane (200 ml) and ozone bubbled through for 15 minutes. The ozone mixture was flushed out of the reaction with nitrogen. Dimethylsulphide (2.5 ml) was added and the mixture allowed to warm to room temperature. The solvent was evaporated and the residue was chromatographed (silica gel, methanol 1% in dichloromethane) to afford 3-butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.1 g, 42%) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 90.5 %

Procedure:
The title compound (92 mg) was prepared as in Example 177, Steps C and D, using 159 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 156 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C16H20FN3, 273.16. found, m/z 274.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.42-7.35 (m, 2H), 7.33-7.27 (m, 2H), 4.37 (m, 1H), 3.46-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.81-2.74 (m, 2H), 1.41 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1.N1C=CC=CC=1>[Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
A suspension of 12.8 g (35.4 mmol) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-1-carboxamide in a mixture of 50 ml of dioxan and 7 ml of pyridine was treated at 7 to 10° with 6.5 ml of trifluoroacetic anhydride. The suspension was stirred at room temperature for 2.5 hours and poured into 200 ml of water. After 1 hour the suspension was suction filtered. There were obtained 12.1 g (100%) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of m.p. 253°-254°.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([CH3:24])=[N:6][C:7]2[N:8]([N:11]=[C:12]([CH3:23])[C:13]=2[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]=1[OH:10].S(Cl)(Cl)=O>C1C=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]=[C:15]([CH3:22])[C:14]=1[C:13]1[C:12]([CH3:23])=[N:11][N:8]2[C:9]3[O:10][CH2:2][CH2:3][C:4]=3[C:5]([CH3:24])=[N:6][C:7]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(O)c(CCO)c(C)nc23)c(C)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCO4)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A solution of 6-(2-hydroxyethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (500 mg, 1.54 mmol) and thionyl chloride (0.26 mL) in benzene (30 mL) was heated under reflux for two hours. After cooling to room temperature, the resulting crystals were collected by filtration. A suspension of the resulting crystals in 2% sodium carbonate was stirred at room temperature for two hours. The crystals were collected by filtration and purified by silica gel column chromatography (50-70% ethyl acetate/hexane), to give the title compound (310 mg) as pale brown crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13](=[NH:16])SC)[CH2:7][CH2:6]2.[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH2:22])[CH3:18]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([NH:12][C:13]([NH:22][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[NH:16])[CH2:7][CH2:6]2
Reactant: CSC(=N)NN1CCc2cc(Cl)ccc21
Reactant: CCOC(CN)OCC
Agent: Cl
Product: CCOC(CNC(=N)NN1CCc2cc(Cl)ccc21)OCC

Procedure:
6 g of 1-(5-chlorindolin-1yl)-2-methylisothiourea hydrochloride and 10 ml of aminoacetaldehyde diethyl acetal were heated to a bath temperature of 120° for 1 hour. The excess aminoacetaldehyde diethyl acetal was removed by evaporation in a vacuum and the evaporation residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulphate and was evaporated to dryness. The 1-(5-chloroindolin-1-yl)-3-(2,2-diethoxyethyl)guanidine obtained as the evaporation residue was crystallized as the naphthalene-1,5-disulphonate having a M.Pt. of 163° -165° (from ethanol/ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:43][C:44]1[C:45]([OH:54])=[C:46]([CH:51]=[CH:52][CH:53]=1)[C:47]([O:49][CH3:50])=[O:48].Cl>CN(C=O)C.O>[OH:54][C:45]1[C:44]([NH:43][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:53][CH:52]=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cc3ccccc3[nH]2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 170.8 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid (965 mg, 1.2 mmol) in DMF (15 mL) was added HOBt (740 mg, 1.1 mmol), DIPEA (1.98 g, 3.0 mmol) and EDCI (1.05 g, 1.1 mmol). The mixture was stirred at room temperature for 30 min. Then methyl 3-amino-2-hydroxybenzoate (835 mg, 1 mmol) was added. The mixture was stirred at room temperature for 10 hr. To the resulting mixture, water (10 mL) and aqueous hydrochloric acid (1 N) were added to pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, dried by anhydrous sodium sulfate and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1) to obtain methyl 2-hydroxy-3-(1H-indole-2-carboxamido)benzoate as a solid (530 mg, yield 26%). LC-MS (ESI) m/z 296 [M+1]−.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
6-Amino-9-benzyl-2-(2,2-dimethyipropyl)aminopurine (69 mg, 0.22 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (75 mg, yield 87%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.FC(F)(F)S(O)(=O)=O>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 160 parts of benzene is added to a mixture of 170 parts of 85 per cent strength by weight phosphoric acid and 30 parts of trifluoromethanesulfonic acid at from 75° to 78° C, whilst stirring vigorously. After a further 6 hours, the organic phase is separated off and 79 parts (87.7% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][OH:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(CC2OCCC[O:43]2)C=CC=CC=1.O>CN(C=O)C>[C:22]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:43])=[O:34])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCCOCCc1ccccc1
Reactant: c1ccc(CC2OCCCO2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCOCCc1ccccc1

Procedure:
Pyridinium dichromate (100 g) was added to a solution of 3-[2-phenylethoxy]-propanol (13.6 g) (prepared from 2-phenylmethyl-1,3-dioxane following the method described in Can. J. Chem., 1974, 52, 888) in DMF (400 ml). The whole was rapidly stirred for 6 hours at which point water was added. This was then extracted with ether (×3). The combined ethereal layers were extracted with 10% aqueous sodium hydroxide solution (500 ml). The basic solution was made acidic pH 1-2 with concentrated hydrochloric acid and extracted with ether. These ethereal extracts were then combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield the subtitled compound (7.6 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH2:23][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1C#CCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 0.121 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)-methylene]-6-methoxy-7-[3-(piperazin-1-yl)prop-1-ynyl]benzofuran-3(2H)-one (0.0453 g, 90%).