Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[OH-].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[CH2:19]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCOCCOCCOCCOCCO
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To Compound 1 (5.2 g, 21.8 mmol), potassium hydroxide (1.2 g, 21.4 mmol) was added; this was followed by stirring on an oil bath at 130° C. for 15 minutes, after which the oil bath was removed and benzyl chloride (2.7 g, 21.3 mmol) was gradually added. This was again heated to 130° C. and stirred for 2 hours. After the solution was allowed to cool to room temperature, water was poured to stop the reaction, and extraction from methylene chloride was conducted. The combined organic phases were dried with sodium sulfate, filtered, and concentrated under reduced pressure, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate—5% methanol-ethyl acetate solution) to yield Compound 19 (light-yellow oil 2.3 g, 32%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-])=O>[Pd].CCO.CO>[NH2:1][C:4]1[C:5]([CH:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[OH:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])c1c(C(O)c2ccccc2)ccc2cccnc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1c(C(O)c2ccccc2)ccc2cccnc12
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
Palladium on Carbon (10%, 38 mg) was added to a solution of (8-nitro-quinolin-7-yl)-phenyl-methanol (Intermediate 214) (500 mg, 1.78 mmol) in EtOH (20 ml) and the mixture was stirred under an atmosphere of hydrogen for 1.5 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (443 mg, 99%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([F:13])=[CH:5][CH:4]=1)#[N:2].[ClH:14]>C(O)C.[Pd]>[ClH:14].[F:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)c2ccccc12
Yield: 44 %

Procedure:
A solution of 1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite®, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.
Reaction SMILES: B.[Na].C[O:4][C:5](=O)[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:29])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:28])[CH2:18][CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl>O1CCCC1.CO>[CH:19]1([CH2:18][C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@H:6]2[CH2:5][OH:4])=[O:29])=[O:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc21
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([C@@H]1CCCN1C(=O)CC1CCc2ccccc21)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
0.57 g of sodium boron hydride was added with stirring to 9 ml of a 80% methanol solution under ice-cooling. To the mixture was added dropwise 1.15 g of 1-[1-(2-indanylacetyl)-L-prolyl]-L-proline methyl ester dissolved in a mixed solution of 5 ml of tetrahydrofuran and 5 ml of methanol. After addition, the mixture was stirred for 15 hours at room temperature. The reaction mixture was acidified by adding diluted hydrochloric acid and extracted with ether. The organic layer obtained was washed with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 0.73 g of 1-[1-(2-indanylacetyl)-L-prolyl]-L-prolinol as an oily substance. (yield: 68%)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:15]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:14]2[N:19]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:17]=[C:16]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=1[C:43]([F:46])([F:44])[F:45])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-fluoro-2-(trifluoromethyl)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 27 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-fluoro-2-(trifluoromethyl)benzenesulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:37]([Cl:43])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[ClH:43].[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]2[C:20]([C:21]=1[O:22][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OC(=O)C(C)(C)C)c2ccccc2n1-c1ccccc1
Reaction time: 3 h

Procedure:
12.6 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.03 mole) are mixed with 150 ml of methylene chloride, 4.2 ml of triethylamine (0.03 mole) and 3.9 ml of pivaloyl chloride (0.03 mole) and the reaction mixture allowed to stand for 3 h at room temperature. The mixture is subsequently washed with a saturated sodium chloride solution, dried over sodium sulfate and filtered. The solution is then evaporated, the residue dissolved in methylene chloride and purified by means of low pressure chromatography over silica gel acid. As the elution agent, first methylene chloride and subsequently methylene chloride containing 10% methanol are used. The 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-pivaloyloxy-1-phenylindole hydrochloride obtained as the residue after the evaporation of the eluate is then recrystallized from isopropanol. Melting point: 157°-159°.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]([C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)[NH2:9]>C(Cl)Cl>[C:5]([NH:9][NH:8][C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1)(=[O:7])[CH3:6]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
Acetic anhydride (1.6 g) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3 g) in methylene chloride (30 ml) under ice cooling and then the stirring was continued for 15 minutes. The solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of methylene chloride and diisopropyl ether to give 3-(2-acetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.37 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[CH:6]=1.[Br-].[CH3:9][C:10]1[N:15]=[C:14]([Zn+])[CH:13]=[CH:12][CH:11]=1.C1COCC1>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1csc(Br)c1
Reactant: Cc1cccc([Zn+])n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(Cl)cs2)n1
Temperature: 40 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén Chemica Scripta, 1971, 1, 33) (1.50 g, 7.60 mmol) and 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (23.00 mL, 11.39 mmol) is added Pd(PPh3)4 (0.18 g, 0.15 mmol). The solution is heated at 40° C. overnight, diluted with Et2O (50 mL), washed with sat. NH4Cl (40 mL), dried over MgSO4, filtered on concentrated. The residue is purified by ISCO column chromatography (5%-20% EtOAc/hexane gradient) furnish the title compound (0.45 g, 2.15 mmol, 28%). 1H NMR (CDCl3), δ 2.56 (s, 3H), 7.02 (d, 7.7 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.9, 7.7, 1H).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16](O)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(hydroxy-pyridin-2-yl-methyl)-4′-methyl-biphenyl-3-carboxylic acid (25 mg, 0.078 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (35 mg, 0.17 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2N11]) to afford a light color solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>C(Cl)Cl>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)[N:7]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])[C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (2 g, 4 mmol, Example 7) in CH2Cl2 (20 mL) reacted with 2-(trimethylsilyl)ethoxymethyl chloride (660 mg, 4 mmol, Aldrich) under the conditions of Example 127a to give the title compound as a light-brown oil. MS (ESI, pos. ion) m/z: 564.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>CCOCC>[CH:12]1([C:15]([O:11][CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CC1
Reactant: OCCSc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCSc1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.88 g. 2-(4-chlorophenylthio)ethanol and 1.35 g. cyclopropylcarboxylic acid chloride in 50 ml. ether is added 2 equivalents pyridine. The reaction mixture is stirred overnight at room temperature and worked up as in Example 5 to yield 2-(4-chlorophenylthio)ethyl cyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To 2,6-dichloropurine (25.0 g) (available from, for example, Aldrich, UK) was added ethyl acetate (260 ml), followed by p-toluenesulfonic acid (0.253 g). The mixture was heated to 50° C. and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50° C. for 4 hours. The reaction mixture was evaporated in vacuo to give the title compound as a yellow solid (36.9 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][CH:17]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:1][CH2:2]1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C2OCC(C)(CO)CO2)cc1

Procedure:
1,1,1-tris(Hydroxymethyl)ethane (12.0 g), p-tolualdehyde (12.0 g), benzene (100 ml) and toluene-p-sulphonic acid (100 mg) were heated under reflux in a Dean and Stark water trap until no more water separated. The benzene was removed and the crude product was crystallised from light petroleum (b.p. 60°-80°) ethyl acetate as white needles, m.p. 104.5°-105.5°. (cis:trans isomer ratio 82:18). The following compounds were prepared in a similar manner from 1,1,1-tris(hydroxymethyl)ethane and the corresponding aldehyde R1CHO.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:10]([Br:25])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnn2c1Br
Temperature: 60 °C
Yield: 83 %

Procedure:
Ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.0 g, 6.11 mmol) was suspended in ACN and treated with N-bromosuccinimide (1.20 g, 6.72 mmol). The dark suspension was heated to 60° C. for 1 h. The suspension was cooled and filtered. The brown solid was washed with ACN and MeOH. The product was collected by filtration to give 2.06 g of a yellow brown solid (83%). 1H-NMR (DMSO-d6) δ 8.26 (d, J=8.8, 2H), 8.07 (s, 1H), 7.64 (d, J=8.8, 2H), 4.02 (q, J=7.0, 2H), 0.95 (t, J=7.0, 3H); MS [M+H]+=406.1, 408.0; LCMS RT=2.93.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:4]=2[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(OCC)(=O)C.C(O)C>[O:1]=[C:2]1[CH2:7][S:6](=[O:20])[C:5]2[S:8][C:9]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:10][C:4]=2[NH:3]1
Reactant: NS(=O)(=O)c1cc2c(s1)SCC(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c(s1)S(=O)CC(=O)N2
Reaction time: 8 h

Procedure:
To a mixture of 2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (0.25 g, 1 mmol) in ethyl acetate (8 ml) and ethanol (8 ml) was added 3-chloroperoxybenzoic acid (0.43 g, 80-85% pure, 2 mmol). The reaction mixture was stirred overnight and the resulting solid collected, triturated with hot ethyl acetate and dried to give 0.25 g, 2,3-dihydro-2,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 222°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:23][C:24]3[CH:25]=[C:26]([Cl:30])[CH:27]=[N:28][CH:29]=3)=[C:16]([CH:22]=2)[C:17]([O:19]CC)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:23][C:24]3[CH:25]=[C:26]([Cl:30])[CH:27]=[N:28][CH:29]=3)=[C:16]([CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Example 8 (81 mg, 0.170 mmol) in MeOH (3 mL) and water (1.0 mL) was added LiOH (89.6 mg, 3.74 mmol). The solution was stirred overnight and the solvent was evaporated to yield a white solid which was recrystallized from chloroform/ethanol. Isolated yield of the title compound: 46.5 mg, 61%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 3 mmol) was added to a solution of N-benzyl-1-(4-methoxyphenyl)methanamine (example 5-46b, 750 mg, 3.3 mmol) and triethylamine (500 mg, 3.6 mmol) in dichloromethane (15 mL). The reaction was stirred at ambient temperature for 4 hours then concentrated on the rotovap. The crude was purified on silica gel to afford N-benzyl-4-cyano-N-(4-methoxybenzyl)benzene-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 3H), 4.26 (s, 2H), 4.31 (s, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 7.07 (m, 2H), 7.21 (m, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:18]([N:6]1[CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Reaction time: 8 h

Procedure:
1-Benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid methyl ester and LiOH are dissolved in THF/H2O, and then stirred overnight. After removal of solvent, the residue is neutralized to PH=6-7, and then extracted by EA. The organic layer is washed with water and brine, dried, and concentrated to afford 1-benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[CH:25][CH:26]=1
Reactant: Ic1cnccn1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cnccn4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and iodo-pyrazine.