Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12.[Br:25]Br>C(Cl)(Cl)Cl>[Br:25][C:23]1[S:22][C:7]2[C:8]3[N:3]([CH2:4][CH2:5][C:6]=2[CH:24]=1)[C:2](=[O:1])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:10][C:9]=3[C:18]([O:20][CH3:21])=[O:19]
Reactant: BrBr
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sc(Br)cc1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g of methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate are dissolved in 32 ml of chloroform, whereupon the solution was treated at 0° with 0.55 ml of bromine in 1 ml of chloroform and stirred at room temperature overnight. After washing with 2N sodium hydroxide solution and saturated sodium chloride solution, drying over magnesium sulfate and evaporation, the residue in toluene/ethyl acetate (4:1) was chromatographed on silica gel. There was obtained pure methyl 2-bromo-4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 170.5°-171° (from isopropanol).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[N+:9]([O-:12])(O)=[O:10].[CH:13]12[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:23]1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=1>C(Cl)Cl>[N+:9]([C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:23]3)[C:19]=2[CH:18]=1)([O-:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to −78° C. and treated with 1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.5 g, 13.7 mmol) in CH2Cl2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was stirred at −78° C. for 30 minutes then warmed to 0° C. for 1 hour. The reaction mixture was poured into a vigorously stirred ice (100 g). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×30 ml). The organic layer was combined and washed with H2O (3×30 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (20 mL) and H2O (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4.2 g). Chromatography yielded pure product as a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanes Rf 0.23). 1H NMR (400 MHz, CDCl3 8.12 (br d, J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43–3.35 (m, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS m/e 300 (M+).
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:19]([O:20][CH3:21])=[CH:18][C:8]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])=[O:10])=[C:7]([N+:22]([O-])=O)[C:6]=1[O:25][CH3:26].[H][H]>CO.[Ni]>[NH2:22][C:7]1[C:6]([O:25][CH3:26])=[C:5]([CH3:4])[C:19]([O:20][CH3:21])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Hydrazine hydrate (1.26 g, 39.37 mmol) was added dropwise to a solution of 190 (2.13 g, 6.56 mmol) in methanol (50 mL) gently refluxing over Raney nickel (1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product as a brown glass (191) (1.91 g, 6.50 mmol) which was protected directly as the troc-carbamate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnc2cc(F)ccc2c1O
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc(F)ccc2c1Cl

Procedure:
A mixture of 7-fluoro-4-hydroxyquinoline-3-carbonitrile (2.02 g, 10.7 mmol) and a few drops of N, N-dimethylformamide in 16.0 mL of thionyl chloride is heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo and toluene (20 mL) is added and the mixture is again concentrated in vacuo to provide 2.18 g of 4-chloro-7-fluoroquinoline-3-carbonitrile as a yellow solid, mp 163-165° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH2:10][OH:11])[CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+].CO>C(#N)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])([CH2:8][OH:9])[CH2:10][OH:11])[CH:17]=1
Reactant: NC(CO)(CO)c1cc(Br)ccc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=C(CCl)NC(CO)(CO)c1cc(Br)ccc1F
Reaction time: 2 h

Procedure:
A solution of chloro-acetyl chloride (6.39 ml, 80 mmol) in 10 ml ACN was added dropwise to a mixture of 2-amino-2-(5-bromo-2-fluoro-phenyl)-propane-1,3-diol (5.3 g, 20 mmol) and K2CO3 (11.1 g, 80 mmol) in 90 ml ACN while the temperature did not rise above 35° C. The mixture was stirred for 2 h. MeOH (40 ml, 99 mmol) were added and after 5 min stirring the mixture was filtered over celite and washed with MeOH. The filtrate was acidified with citric acid solution (10%, aqueous) (pH 4-5) and partly evaporated. The remaining aqueous layer was extracted with EtOAc. The organic layer was washed with NaHCO3 solution (10%, aqueous) and brine, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([O:31]C)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg (57%) of the acid. HR—MS: m/z Calculated for C22H22N2O6S 443.1271; Found 443.1270.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CO.[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[C:22]([CH2:25]OC)[C:23]#[N:24])=[C:15]([CH3:28])[CH:14]=1>C[O-].[Na+].CS(C)=O>[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][C:22]2[C:23]([NH2:24])=[N:7][C:6]([NH2:8])=[N:5][CH:25]=2)=[C:15]([CH3:28])[CH:14]=1
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)cc1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(C)c(Cc2cnc(N)nc2N)cc1OC
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
In step 2, 3-(4,5-dimethoxy-2-methyl-phenyl)-2-methoxymethyl-acrylonitrile and sodium methoxide were dissolved in dry DMSO and stirred for 3.5 hours at 85° C. under nitrogen. Guanidine carbonate was then added to the stirring solution, after which the temperature was raised to 125° C. for three hours, during which methanol removed via a Dean-Stark trap. The solution was cooled to room temperature, diluted with water, and the crude filtrate was recrystallized in DMF to yield 5-(4,5-dimethoxy-2-methyl-benzyl)-pyrimidine-2,4-diamine as a white solid. Mp: 232° C. Mass Spec (M+H): 275.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([OH:23])=[O:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]([OH:23])=[O:22])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=C(O)CBr
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2-benzoylphenol (1.95 g) in DMF (30 ml) was added sodium hydride (60% oil) (400 mg). The mixture was stirred for 30 minutes at room temperature, to which was then added methyl ester of bromoacetic acid (1.0 ml). The mixture was stirred for 2 hours under cooling with ice-water. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with water, which was then dried. The solvent was distilled off, and the residue was purified by means of a silica gel (40 g) column chromatography (hexane-ethyl acetate=3:1) to afford methyl ester of 4-chloro-2-benzoylphenoxyacetic acid as colorless crystals (2.21 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH2:20][CH2:21][CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
An ice-cold solution of diethyl malonate (5.81 ml, 40 mmol) in dimethylformamide (60 ml) was treated portionwise with sodium hydride (1.6 g, 40 mmol 60% dispersion in oil). After 0.25 h 3-phenylpropylbromide (6.71 ml, 44 mmol) was added and the reaction stirred overnight at room temperature. Work-up and chromatography as described in Example 37a) gave the title compound as a colourless oil (10.8 g, 97%);
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:12]2[O:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:19]O>>[CH3:5][O:6][C:7]1[C:12]2[O:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cccc(OC)c2o1

Procedure:
Thionyl chloride (10 ml) was added dropwise to methanol (100 ml) with stirring under ice-cooling. 7-Methoxybenzo(b)furan-2-carboxylic acid (10 g) was successively added, and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g). This was used in the next reaction without purification. Acetone oxime (4.8 g) was dissolved in tetrahydrofuran (100 ml), and butyllithium (1.6M hexane solution) (80 ml) was added dropwise to this solution at −5° C. with stirring. Thereafter, the mixture was stirred under ice-cooling for 1 hr, and a solution (50 ml) of methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g) in tetrahydrofuran was added. The mixture was stirred at room temperature for 20 hr. A solution of sulfuric acid (28 g) dissolved in tetrahydrofuran (120 ml)-water (30 ml) was prepared, into which the reaction mixture was poured. The mixture was refluxed under heating for 2 hr. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 10 h

Procedure:
To a stirred and a cooled solution of lauryl alcohol (186.0 g, 1.0 mole) and triethyl amine (121.0 g, 1.2 mole) in dichloromethane (600 ml), p-toluene sulphonyl chloride (228.0 g, 1.2 mole) in dichloromethane (400 ml) was slowly added and the reaction was continued at room temperature for 10 hours. The reaction mixture was then washed with 20% sodium chloride solution (500 ml). The washed organic layer was dried over anhydrous sodium sulphate. Removal of solvent under vacuo resulted in colorless oil that solidified on keeping to yield lauryl tosylate. (309.0 g, 91%), m. p. 29° C. (literature m. p. 29° C.).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: c1ccc(CSc2nc3ccccc3[nH]2)cc1
Yield: 77.6 %

Procedure:
15 g of 2-mercaptobenzimidazole and 16.5 g of benzylbromide were dissolved in 50 ml of ethanol and the mixture was refluxed with a water bath for 5 hours. After cooling, the formed crystals were collected and recrystallized from ethanol to obtain 18 g of compound (7).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[CH:24]=[N:23][C:13]2[NH:14][C:15](=[S:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:9][C:10]1[CH:24]=[N:23][C:13]2[N:14]=[C:15]([S:22][CH3:3])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(SC)nc2ncc(Br)cc2c1=O
Yield: 75.2 %

Procedure:
A mixture of iodomethane (1.33 g, 0.58 mL), 8.7 g potassium carbonate and 1.88 g of the title compound of Step B was stirred at room temperature in 50 mL of dimethylformamide for 3 h. A 1 mL portion of saturated aqueous NaHCO3 was added and the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was partitioned between 200 mL each of methylene chloride and water, and the organic layer was removed. Further washing of the organic phase with water and saturated aqueous NaCl followed by drying (Na2SO4) and concentration under reduced pressure delivered 1.8 g of the crude product. This material was then subjected to silica gel chromatography using 70:30 hexane:ethyl acetate as eluant to afford 1.48 g of the title compound of Step C, a compound of the invention, as a white solid melting at 124-127° C. 1H NMR (400 MHz, CDCl3): δ 1.03 (t,3H), 1.76-1.90 (m,2H), 2.7 (s,3H), 4.1 (t,2H), 8.63 (s,1H), 8.89 (s,1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH2:25])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH:25][C:43](=[O:44])[CH2:42][Cl:41])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(N)c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a suspension of N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonamide (2.14 g, 4.86 mmol), sodium acetate (472 mg, 5.75 mmol) and acetic acid (0.33 ml, 5.76 mmol) in tetrahydrofuran (20 ml) was added dropwise chloroacetyl chloride (0.45 ml, 5.64 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration and dried in vacuo. A suspension of the obtained solid in diethyl ether was stirred at room temperature for 1 hr. The solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-indole-6-sulfonamide (2.22 g, yield 89.9%). The obtained crude product was used for Step 10 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Br)cc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 4-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.55 (br s, 1H), 8.08 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.52-7.58 (m, 3H), 7.32 (d, 2H, J=8.3 Hz), 4.55 (s, 2H). [M+H] calc'd for C13H11BrN2O2, 307, 309; found 307, 309.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:7]2=[N:6][C:5]=1[CH3:17].[H][H]>CO.[Pd]>[OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([O:15][CH3:16])[C:7]2=[N:6][C:5]=1[CH3:17]
Reactant: [H][H]
Reactant: COc1cccn2c(=O)c(CCO)c(C)nc12
Agent: [Pd]
Solvent: CO
Product: COC1CCCn2c1nc(C)c(CCO)c2=O
Yield: 70.2 %

Procedure:
A mixture of intermediate 10 (14 g) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst was filtered off. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 10 g (71%) of (±)-6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (intermediate 11).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH:21][C:22]([C:24]2[C:32]3[CH:31]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=4)[S:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:35]2[N:34]=[C:33]([C:30]3[S:29][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22](=[O:23])[NH:21][CH:18]5[CH2:19][CH2:20]5)[C:32]=4[CH:31]=3)[C:38]([F:39])=[CH:37][N:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3F)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 72.8 %

Procedure:
(4-(3-Aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester (0.542 g, 2.23 mmol) is added to a stirred suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.388 g, 1.12 mmol) and diisopropylethylamine (0.585 mL, 3.36 mmol) in anhydrous 1,4-dioxane (10 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 24 hours. At room temperature, the mixture is concentrated and chromatographed on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 0-7%, to give 4-{3-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-ylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (452 mg). The product is dissolved in CH3OH (80 mL) and dichloromethane (20 mL) and a small stream of anhydrous HCl gas is bubbled through the stirred solution for 3 minutes. The warm solution is capped with a glass stopper and stirred at room temperature overnight. After concentration, the title compound is obtained as a yellow solid (441 mg). ES+(m/z) 455 [M(free base)+H].
Reaction SMILES: [Cl:1][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][NH:7][C:6]=2[N:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CC(N(C)C)=O>[CH2:17]([N:7]1[CH2:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[N:16][C:6]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1C(=O)C(C)(C)CNc2nc(Cl)ncc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(C)CN(Cc2ccccc2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
2-Chloro-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (50 mg, 0.21 mmol) and benzylbromide (30 μl, 0.25 mmol) in DMA (0.5 ml) was treated with sodium hydride 60% oil dispersion (9 mg, 0.23 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes, loaded on silica, ˜50 mL silica) to give the title compound as a white solid (63 mg, 91%). NMR DMSO D6 1.00 (6H, s), 3.22 (3H, s), 3.53 (2H, s), 4.91 (2H, s), 7.28-7.39 (5H, m), 8.12 (1H, s); MS (ES+) 331.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(F)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cccc(F)c1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield from 1-(3-fluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.93 (3H, s), 3.15 (3H, s), 5.65 (1H, d, J=12.4 Hz), 7.11-7.16 (1H, m), 7.34-7.39 (1H, m), 7.57-7.67 (2H, m), 7.81 (1H, d, J=12.4 Hz).
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[C:8]2[CH:9]=[CH:10]O[C:7]=2[CH2:6][CH2:5][CH2:4]1>C(O)C>[O:2]=[C:3]1[CH2:4][CH2:5][CH2:6][C:7]2[NH:1][CH:10]=[CH:9][C:8]1=2
Reactant: O=C1CCCc2occc21
Reactant: N
Solvent: CCO
Product: O=C1CCCc2[nH]ccc21
Yield: 96 %

Procedure:
To a mixture of 3 ml of ethanol and 7 ml of 29% aqueous ammonia was added 1.0 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran, and then the mixture was subjected to reaction in a sealed tube at 150° C. for 12 hours. After completing the reaction, the reaction mixture was concentrated. The resulting residue was applied to a column of silica gel and eluted with a mixed solvent of acetone and ethyl acetate to give 950 mg (yield: 96%) of 4-oxo-4,5,6,7-tetrahydroindole being a light yellowish crystal.