Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][N:27]([CH3:28])[C:22]([C:17]1[NH:18][C:19]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11])=[CH:21][CH:20]=2)=[O:23]
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
110 mg 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylic acid are dissolved in 4 ml of tetrahydrofuran, combined with 51 mg carbonyldiimidazole and stirred for 3 hours at ambient temperature and for 1 hour at 40° C. After cooling to ambient temperature 600 μl of a 2 M solution of dimethylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. The solvent is eliminated in vacuo, the residue is divided between ethyl acetate and 0.5 N hydrochloric acid and the organic phase is washed with water and saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].BrCCC>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH2:37][CH2:36][CH3:38])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCCBr
Product: CCCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Yield: 31.4 %

Procedure:
The same procedure as E54 from 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (146.6 mg, 0.325 mmol), Hunig's base (0.171 mL, 0.976 mmol) and 1-bromopropane (80 mg, 0.651 mmol) in DCE (5 mL), except that the time was prolonged to 3 days, to afford the title compound (50 mg, 0.102 mmol, 31.2% yield). LCMS: rt=3.41 min, [M+H+]=493
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]4[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=4[S:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(-c3ccc(O)cc3)csc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)csc2c1
Temperature: 0 °C

Procedure:
To 80 ml. of N,N-dimethylformamide (DMF) were added 10.0 grams (0.039 mole) of 3-(4-hydroxyphenyl)-6-methoxybenzothiophene. The mixture was cooled to 0° C., and 6.6 grams (0.039 mole) of N-(2-chloroethyl)pyrrolidine hydrochloride were added followed by 2.81 grams (0.117 mole) of sodium hydride added in small portions. Effervescence developed, and, when the effervescence had ceased, the mixture was heated at 95° C. for 14 hours. To the mixture then were added 10 ml. of ethanol, and the solvents of the resulting mixture then were evaporated. The resulting residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated from the aqueous layer and was washed with 25 ml. of sodium chloride solution. The ethyl acetate solution then was extracted twice with 40 ml. of 1N hydrochloric acid. The acid layer was separated and rendered alkaline by addition of 50 ml. of 2N sodium hydroxide. The alkaline mixture then was extracted with 250 ml. of ethyl acetate. The ethyl acetate layer was separated, dried over magnesium sulfate, and evaporated to give 3-[4-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzothiophene as an oil. The oil was dissolved in methanol and treated with excess methanolic hydrochloric acid. The mixture was evaporated, and the solid residue was recrystallized from methanol to give 11.6 grams (76 percent) of the hydrochloride salt of 3-[4-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzothiophene, m.p. 200°-202° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36]([Cl:38])=[O:37]>CN(C=O)C>[ClH:38].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:36]([C:32]4[O:31][CH:35]=[CH:34][CH:33]=4)=[O:37])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzothiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 15.7 mg (0.12 mmol) of furan-2-carbonyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 12 mg (34.7% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:26]2
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54 mmol), (prepared as described for the starting material in Example 44), in DMF (1.5 ml) containing potassium carbonate (94 mg, 0.67 mmol) was heated at 100° C. for 1 hour. After cooling, the precipitate was collected by filtration, washed with ether, and dried under vacuum to give 6-methoxy-7-(3-methylsulphonylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline (195 mg, 87%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([NH:8][C:9](=[O:10])[N:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:14]=1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(NC)ccc2C)cc1
Reactant: CCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
660 μL (4.0 mmol, 1.5 eq) of heptyl isocyanate are added to a solution of 805 mg (2.72 mmol, 1 eq) of ethyl (E)-3-(2′-methyl-5′-methylaminobiphenyl-4-yl)acrylate in 8 mL of a 7/1 dichloromethane/triethylamine mixture. The reaction medium is stirred at 50° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 920 mg of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate are obtained in oil form. Yield=77%
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH3:13])[N:7]=1)[C:3](=O)[CH3:4].[NH2:14][C:15]([NH2:17])=[S:16]>>[CH3:13][C:8]1[N:7]=[C:6]([C:2]2[S:16][C:15]([NH2:17])=[N:14][C:3]=2[CH3:4])[CH:11]=[C:10]([CH3:12])[N:9]=1
Reactant: CC(=O)C(Br)c1cc(C)nc(C)n1
Reactant: NC(N)=S
Product: Cc1cc(-c2sc(N)nc2C)nc(C)n1

Procedure:
This material is prepared by reaction of 1-bromo-1-(2,6-dimethyl-pyrimidin-4-yl)-propan-2-one with thiourea following the procedure described for intermediate AC4.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:7][CH:21]=[N:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1ccc(-c2cnco2)cc1
Yield: 95.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (5.00 g), p-toluenesulfonylmethyl isocyanide (5.43 g) and potassium carbonate (5.60 g) in methanol (50 ml) was heated under reflux for 2 hours. After evaporation of solvent, ethyl acetate and saturated ammonium chloride solution were added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1) to give 5-(4-bromophenyl)oxazole as a pale yellow powder (5.77 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:7])=[O:6].FC1C=CC(C=O)=CC=1>>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([Cl:7])=[O:6])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: O=Cc1ccc(F)cc1
Product: O=C(Cl)c1ccc(F)cc1

Procedure:
The present invention relates to a process for the preparation of 3-chloro-4-fluorobenzoyl chloride which comprises reacting 4-fluorobenzaldehyde with a chlorinating agent in the presence of a free-radical initiator in the presence or absence of a solvent at from −20 to 200° C. to give 4-fluorobenzoyl chloride, and reacting the 4-fluorobenzoyl chloride with a chlorinating agent in the presence of a chlorination catalyst in the presence or absence of a solvent at from −20 to 200° C. to give 3-chloro-4-fluorobenzoyl chloride.
Reaction SMILES: [C:1]1(C)[C:2]([C:7](O)=[O:8])=C[CH:4]=[CH:5][CH:6]=1.[Li].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20]CCBr>C(O)C>[OH:8][CH2:7][CH2:2][CH2:1][CH2:6][C:5]1[CH:4]=[CH:17][CH:16]=[CH:15][C:14]=1[C:13]([O:18][CH2:19][CH3:20])=[O:12]
Reactant: BrCCCCOC1CCCCO1
Reactant: Cc1ccccc1C(=O)O
Agent: [Li]
Solvent: CCO
Product: CCOC(=O)c1ccccc1CCCCO

Procedure:
Compound XIV is prepared by the following series of reactions. (1) o-Toluic acid is converted to its dianion with lithium diisoprpylamide; (2) the dianion is treated with 4-(tetrahydropyranyloxy)butyl bromide and the crude alkylate is heated with ethanol and a catalytic amount of mineral acid to yield ethyl 2-(4-hydroxybutyl)-benzoate; (3) the hydroxy ester in ether is treated with phosphorus tribromide to yield reagent XIV.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.Br[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2.C(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[CH:25]1[C:24]2[CH:23]([N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:3][CH2:2]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
8.0 g (27.7 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 5.6 g (55.3 mmol) TEA are placed in 100 ml acetonitrile and cooled to ca. 0° C. under moisture exclusion. 6.8 g (27.7 mmol) 9-bromofluorene are added in solid form and the mixture is stirred two days at ca. 65° C. and two days at RT. Subsequently, the solvent is drawn off under vacuum to a large extent, and the residue is dispersed between CHCl3 and 10% NaOH. The organic phase is washed twice with water and dried over sodium sulfate. After the removal of the solvent, the residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2 to 94/6) and crystallized from 30 ml acetonitrile after drawing off the solvent. Colorless crystals with an MP of 131-132° C.; yield 2.5 g (20%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]([N-]C(C)C)(C)[CH3:45].[Li+].ICC>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:44][CH3:45])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (764 mg, 1.211 mmol; Example 185, Step C) in THF (6 mL) under argon was added 1.0M lithium diisopropyl amide solution in THF (1.211 mL, 1.211 mmol). The mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and iodoethane (0.117 mL, 1.454 mmol) was added. The resulting solution stirred at 0° C. for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 5 to 25% ethyl acetate/hexanes) to afford the title compound as a mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[NH:13][C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:6])=[O:5].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[N:13]([CH3:29])[C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:5])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 139 mg, 3.5 mmol) in DMF is added 7-methanesulfonyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (1.15 g, 3.2 mmol), prepared as in Reference 1, at 0° C. When H2 evolution has ceased, iodomethane (0.99 ml, 15.8 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (SiO2, EtOAc/hexane=1/1) to give 7-methanesulfonyl-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.85 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4]1[NH:5][N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]I.CN(C=O)C>O>[Cl:25][CH2:26][CH2:27][CH2:28][N:5]1[C:4]([CH2:3][CH:2]([CH3:18])[CH3:1])=[C:16]2[C:7]([C:8]([NH2:17])=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1
Reactant: ClCCCI
Reactant: CC(C)Cc1[nH]nc2c(N)nc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1c2c(nn1CCCCl)c(N)nc1ccccc12
Temperature: 40 °C

Procedure:
1-(2-Methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (2.4 g, 9.99 mmol, prepared as described in Example 9), potassium carbonate (5.5 g, 39.9 mmol), 3-chloroiodopropane (1.2 mL, 11.0 mmol), and DMF (110 mL) were combined and heated at 40° C. overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined extracts were washed with water and concentrated under reduced pressure. The residue was purified twice by chromatography on a HORIZON HPFC system (silica gel eluting with ethyl acetate) to provide 2-(3-chloropropyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:16]([CH2:15][CH:14]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:37])[CH3:36]
Reactant: COCOc1ccc(CC(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A portion of 144 mg of 60% sodium hydride were suspended in 15 ml of dimethylformamide and cooled to 0° C., followed by dropwise addition of 1.34 g of N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide, and then followed by addition of 391 mg of ethyl chlorocarbonate. After stirring at room temperature for four hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.49 g of N-ethoxycarbonyl-N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].C[N+](C)(C)[CH2:31][C:32]1[C:33]2[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:31][C:32]2[C:33]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:34]=3[S:35][CH:36]=2)[C:12]1=[O:20])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](C(=O)OC(C)(C)C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 80 °C
Yield: 71.8 %

Procedure:
To a solution of (S)-2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid tert-butyl ester (0.1 g, 0.34 mmol) in DMF (2 mL) were added K2CO3 (0.1 g, 0.69 mmol) and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium iodide (0.24 g, 0.69 mmol). The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 0.11 g (71%) of the desired product as an oily residue. LCMS (ESMS): m/z 451.33 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@H:65]([C:70]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](=[O:26])[N:27]([CH3:28])[CH3:29])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN(C)C(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)N(C)C)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.9 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N,N-dimethylbenzamide (23, 100 mg, 0.24 mmol), DCC (56 mg, 0.28 mmol) and DMAP (3 mg, 0.024 mmol) in ethyl acetate (5 mL), was added Fmoc leucine (84 mg, 0.24 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (140 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 45 mg (36%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([NH:5][CH3:6])([NH:3][CH3:4])=[O:2].[CH:7]([CH:9]=[O:10])=[O:8].[OH-].[Na+]>>[OH:8][CH:7]1[CH:9]([OH:10])[N:5]([CH3:6])[C:1](=[O:2])[N:3]1[CH3:4]
Reactant: CNC(=O)NC
Reactant: O=CC=O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)N(C)C(O)C1O
Temperature: 25 °C

Procedure:
Dimethylurea (2 moles, 176 parts) and glyoxal (2 moles, 290 parts of 40% aqueous solution) are mixed and the pH adjusted to 7 with sodium hydroxide. The reaction mixture is stirred at room temperature for several hours and the resulting white solid is filtered, washed with methanol and dried. White crystals, m.p. 140° C., are obtained in fine yield.