Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:25][CH2:24]1.C(O)C.O>Cl.C(OCC)(=O)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:39][C:36]4[CH:35]=[CH:34][C:33]([S:30]([NH:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)(=[O:32])=[O:31])=[CH:38][CH:37]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(NS(=O)(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Yield: 42.2 %

Procedure:
A mixture of 0.0203 g (0.000066 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.0207 g (0.000077 mole) of N-(1-methyl-piperidin-4-yl)-4-nitro-benzenesulfonamide, 0.6 mL of ethanol, 2.4 mL of water and 2 drops of hydrochloric acid was heated at reflux for 17 hrs. The mixture was taken up in 50 mL of ethyl acetate and washed successively twice with 7 mL of 1M sodium hydroxide, twice with 7 mL of water and 7 mL of brine. The organic layer was concentrated under reduced pressure and the residue purified by silica gel chromatography, elution with dichloromethane-methanol 95:5-80:20) gave 0.0151 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide (I-64) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]4[C:25]=3[C:26](=[O:36])[N:27]([CH3:35])[CH2:28]4)[C:20]([C:37]([F:40])([F:39])[F:38])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)([O-])[O-])=CC=3OC)N=2)=C2C=1CN(C)[C:47]2=[O:52]>>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]4[C:25]=3[C:26](=[O:36])[N:27]([CH3:35])[CH2:28]4)[C:20]([C:37]([F:39])([F:38])[F:40])=[CH:19][N:18]=2)=[C:14]([O:52][CH3:47])[CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: COc1cc(CP(=O)([O-])[O-])ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc(Br)c3c2C(=O)N(C)C3)n1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Diethyl[4-({4-[(7-cyano-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 161) using [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1 H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate. MS (ES+): m/z 605.19 (100) [MH+] HPLC: tR=1.09 min (UPLC, purity).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2cc(CN3CCN(CCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.5 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]phthalimide (45.0 mg, 0.111 mmol) was dissolved in acetonitrile (2 mL), and the solution was added with 1-(2-hydroxyethyl)piperazine (57 mg, 0.440 mmol), acetic acid (0.508 mL, 8.87 mmol) and sodium triacetoxyborohydride (118 mg, 0.557 mmol), followed by stirring at room temperature for 2.5 hours. The reaction mixture was added with water and sodium carbonate, 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 flash column chromatography (hexane/ethyl acetate=4/1, 1/1) to obtain 3-amino-6-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}phthalimide (22.2 mg, yield 38%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOCC.O>[O:20]=[C:19]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCN
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCNC(=O)COc1ccccc1
Yield: 53 %

Procedure:
To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml of Et2O and 50 ml of water was added one portion of NaHCO3 (4.2 g). After 2 hr the layers were separated and the organic phase was washed (1N HCl, brine), dried (MgSO4), and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil.
Reaction SMILES: [N:1]1([S:6]([C:9]2[NH:10][C:11](=[O:15])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:10]=2)(=[O:8])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cccc(S(=O)(=O)n2cccc2)[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(S(=O)(=O)n2cccc2)n1

Procedure:
To a stirred solution of 2-(pyrrole-1-sulphonyl)pyrid-6-one (0.22 g) in dichloromethane (20 cm3) under nitrogen at 0° C. was added in solution of mesyl chloride (0.124 g) in dichloromethane (5 cm3) and triethylamine (0.109 g).
Reaction SMILES: [CH2:1]([C:4](=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[O:6])[CH2:2][CH3:3]>[Pd]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[O:6])[CH2:2][CH3:3]
Reactant: CCCCC=C(C=O)CCC
Agent: [Pd]
Product: CCCCCC(C=O)CCC

Procedure:
The output from the aldolization comprising crude 2-propylheptenal was hydrogenated selectively in the liquid phase over the palladium catalyst H 14535 (0.5% of Pd on aluminium oxide), procured from Degussa, at 160° C. and 2.5 MPa in a circulation apparatus to form 2-propylheptanal. For this purpose, 200 ml/h of starting material were passed continuously over 400 ml of catalyst, corresponding to a space velocity over the catalyst of 0.5 h−1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:15]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC(N(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-fluoro-2-methyl-1-nitrobenzene (13.6 g), dimethylpyrrolidin-3-ylamine (10.0 g), potassium carbonate (12 g) and DMF (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 249.32 (C13H19N3O2) was obtained in this way; MS (ESI): 250 (M+H+).
Reaction SMILES: [C:1]([CH:3]([CH:8]([CH3:18])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=O)[C:4]([O:6][CH3:7])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:25].O>C(OCC)(=O)C>[Cl:25][C:1]1[NH:2][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[C:8]([CH3:18])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C#N)C(C)C(=O)c1ccccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)[nH]c(-c2ccccc2F)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a solution of methyl 2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate (31.0 g) in ethyl acetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water (twice) and saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as white crystals (yield 19.3 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]1([N:14]=[C:15]=S)[CH2:13][CH2:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:11]1([NH:14][C:15]2[NH:9][C:5]3[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]=3[N:10]=2)[CH2:13][CH2:12]1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: S=C=NC1CC1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2nc(NC3CC3)[nH]c2cc1Cl
Yield: 70.5 %

Procedure:
4,5Dichloro-1,2-phenylenediamine (6.04 g, 34.1 mmol), cyclopropyl isothiocyanate (3.69 g, 37.2 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (20.1 g, 47.4 mmol) and pyridine (135 mL) were used according to general procedure I. The product was recrystallized from acetonitrile to afford 5.82 g (70%) of a yellow solid; m.p. 223-225° C. Anal. Calcd for C10H9Cl2N3: C, 49.61; H, 3.75; N, 17.36. Found: C, 49.53; H, 3.78; N. 17.12.
Reaction SMILES: Cl[C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][C:15]1[CH:14]=[CH:13][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:11][O:12][C:2]=2[C:16]=1[Cl:17])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccccc1)c1ccc(O)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc2c(-c3ccccc3)noc2c1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 2,3-dichloro-4-hydroxybenzophenone oxime and 2.6 g of sodium hydride in 50 ml of dimethylformamide and 50 ml of toluene is heated to 118° C. and maintained at this temperature for 50 minutes. Thereafter, the reaction is permitted to cool prior to the dropwise addition of 7.9 g of ethyl bromoacetate in 50 ml of dimethylformamide. After the addition is complete the reaction mixture is stirred at ambient temperature for 40 minutes. To the well stirred mixture water is added dropwise to decompose any excess sodium hydride. The toluene is evaporated under vacuum and the resulting precipitate is collected by filtration and then rinsed with ether to yield the product ethyl[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate having a melting point of 130° to 132° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18]Cl)=[CH:13][CH:12]=1.CO.O.C(O)(C)C.[K+].[Br-]>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Fc1ccc(SCCl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: O=c1ncc(Cl)cn1CSc1ccc(F)cc1

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 4-fluoro-1-(chloromethylthio)benzene (10 mmol) in a manner similar to that described in Example 2. The reaction time was 21/2 h. Yield: 1.60 g (59%) of the N- and O-isomers in the ratio 2:1. The N-isomer was isolated by its lower solubility in methanol; m.p. 179° C. (MeOH/H2O/ isoPrOH). 1H NMR (DMSO/d6): δ 5.25 (CH2), 6.9-7.7 (Ph), 8.07 and 8.53 (H-4 and H-6, J 4 Hz). IR (KBr): 1660 cm-1 (CO). (Found: C49.80; H2.54. Calc. for C11H8ClFN2OS: C48.81; H2.98). MS [70 eV, m/z (% rel. int.]): 270/272 (4/2,M), 143/145 (100/32).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1.00 g, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at room temperature was added 2M trimethylsilyldiazomethane (8.75 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotory evaporator to yield the title compound (1.06 g, 4.38 mmol, 100% yield) as a white solid. MS m/z 243 (MH+). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3H) 3.89 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]([CH2:18][C:19](OCC)=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:19](=[O:20])[CH2:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cccc(NC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of m-anisidine (10 g), ethyl benzoylacetate (19 g) and pyridine (2 drops) in xylene (20 mL) was heated to reflux for 5 hr. The mixture was cooled to r.t. and concentrated. The residual material was subjected to chromatography (silica gel; hexane/EtOAc (4:1)), affording the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].[CH3:17]C1C=CC(S(C)(=O)=O)=CC=1.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[N:7]([CH3:17])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A mixture of 0.96 g (5.0 mmol) of 7-chloro-2-methyl-4(3H)-quinazolinone and 0.20 g (4.8 mmol) of lithium hydroxide monohydrate in 25 ml of tetrahydrofuran is heated at reflux with stirring for 0.5 h. After cooling to room temperature, 0.89 g (4.8 mmol) of methyl p-toluene sulfonate is added and the reaction mixture heated at reflux for 4 hours. The reaction mixture is neutralized with con. HCl and the solvent removed in vacuo to give a residue. The residue is slurried with 50 ml of water, filtered, washed with 50 ml of 0.5M sodium hydroxide, followed by (3×50 ml) of water. The solid is dried to give 0.73 g (73%) of the desired product, m.p. 162°-165° C. None of the isomeric O-alkylated product is detected by HPLC.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10](=[O:13])(=[O:12])[NH2:11].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[S:10](=[O:13])(=[O:12])[NH2:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(C#N)cc2S(N)(=O)=O)CC1

Procedure:
43.5 Grams of 4-Chloro-3-sulfamoylbenzonitrile (0.2 mole) were stirred with 45 g of N-methylpiperazine and 50 ml of dimethylformamide for 1 hour at a temperature of from 115° to 120° C., and the reaction solution was subsequently introduced into 0.5 l of water. The crystalline precipitate was suction-filtered, and the moist crude product which had been washed with water, was recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](/[CH:26]=[CH:27]/[C:28](=O)[CH3:29])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH3:29])[CH:27]=[CH:26]4)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1

Procedure:
To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200 mL of acetic acid/ethanol (3:2) was added 2.25 g (40.2 mmole) of iron powder and the mixture was heated at reflux under nitrogen for 8 hours. After the reaction was complete, 150 mL of water was added and the mixture filtered through a pad of celite. The filtrate was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using a gradient elution commencing with 20% ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of the title compound as a yellow oil 1H-NMR (CDCl3): doublet 8.1 δ (1H); doublet 7.6 δ (2H); doublet 7.45 δ (1H); multiplet 7.2 δ (4H); multiplet 4.6 δ (1H), multiplet 4.3 δ (3H); multiplet 4.1 δ (1H); singlet 2.5 δ (3H); singlet 2.4 δ (3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].[K+]>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: OCCCCCCCCCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
25.9 g (170 mmol) of 4-hydroxy-3-methoxybenzaldehyde and 38.9 g (155 mmol) of 11-bromoundecan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 23.57 g (170 mmol) of potassium carbonate and 2.47 g (15 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 12 h, the reaction mixture is cooled to room temperature and poured to icy water. The precipitate is filtered off, digested in 500 mL of water and the mixture was neutralized with hydrochloric acid 37%. The precipitate is filtered off, washed with water and dried overnight at 40° C. 48.5 g of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde are obtained as a slightly pink solid (97% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C([O:3][C:4](OCC)([CH3:28])[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([C:13]2[N:14]=[C:15]3[C:7]([C:5](=[O:6])[C:4](=[O:3])[CH3:28])=[CH:8][NH:9][C:10]3=[N:11][CH:12]=2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25]
Reactant: CCOC(C)(OCC)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)=O)c3n2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
2,2-Diethoxy-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.027 mg, 0.06 mM) was dissolved in 3 ml dichloromethane and 0.3 gm silica gel was added followed by 0.03 ml 10% aqueous citric acid solution. After stirring overnight 0.03 ml trifluoroacetic acid was added and stirred again overnight. To the orange mixture was added aqueous sodium bicarbonate, the mixture filtered and the silica gel rinsed with a methanol/dichloromethane mixture (20/80). The rinses were concentrate and the oil purified on a preparative thin layer chromatography plate eluting with methanol/dichloromethane (4/96). The product was dissolved in acetonitrile to induce crystallization, stripped and dried overnight at 2 torr in a vacuum oven at 60° C. to give 1-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propane-1,2-dione. (M+H)+=356.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([NH2:35])=[N:27][C:28]([NH2:34])=[N:29]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44]>O1CCCC1>[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([NH2:35])=[N:27][C:28]([NH2:34])=[N:29]3)[CH2:16][CH2:17]1)(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1nc(N)c2c(OCCN3CCNCC3)cccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2c(OCCN3CCN(S(=O)(=O)c4ccccc4F)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 310 %

Procedure:
In an 8 mL vial triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-(2-piperazin-1-yl-ethoxy)-quinazoline-2,4-diamine trifluoroacetate (50 mg; 0.1 mmol) in 1.5 mL of tetrahydrofuran. 2-Fluorobenzene-sulfonyl chloride was added and reaction stirred at room temperature for 16 hours. Reaction was purified by reprecipitation with ethanol and (0.5:1) 1N NaOH. Solids were filtered to obtain 14 mg of title compound. (310% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (m, 3H), 7.48 (m, 2H), 7.32 (t, J=8.4 Hz, 1H), 7.18 (br s, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.87 (br s, 2H), 4.16 (t, J=5.2 Hz, 2H), 3.17 (br s, 4H), 2.77 (t, J=5.2 Hz, 2H), 2.52 (m, 4H).
Reaction SMILES: C(OC([NH:11][C:12]([CH3:35])([CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:21]=2)=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:11][C:12]([CH3:34])([CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(CC(C)(C)NC(=O)OCc3ccccc3)cc2)cc1CC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CC(C)(C)N)cc2)cc1CC(C)C
Yield: 91 %

Procedure:
The mixture of methyl 4′-[2-[[(benzyloxy)carbonyl]-amino]-2-methylpropyl]-3-isobutyl-4-biphenylcarboxylate (570 mg), ammonium formate (351 mg) and palladium on carbon powder (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 3 hours. The catalyst was filtered off, and the filtrate was diluted with chloroform-methanol (19:1). The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated to give methyl 4′-(2-amino-2-methylpropyl)-3-isobutyl-4-biphenylcarboxylate (372 mg).