Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[CH:14]2.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[CH:14]2)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ccnc1SCc1cccc2cc(-c3nccs3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1ccnc1S(=O)Cc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 7-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-2-(1,3-thiazol-2-yl)-1H-indole (0.087 g) in ethyl acetate was added m-chloroperbenzoic acid (0.070 g) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.028 g, yield 31%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[N:43]=[CH:42][N:41]=[C:40]2[C:36]=1[N:37]=[CH:38][N:39]2[CH2:44][C:45](O)=[O:46])=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:39]2[CH:38]=[N:37][C:36]3[C:40]2=[N:41][CH:42]=[N:43][C:35]=3[NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(2-methylthioethoxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.80 (brs, 1H), 8.61 (d, 1H), 8.42 (s, 0.6H), 8.39 (s, 0.4H), 8.35 (m, 1H), 8.27 (m, 1H), 7.73 (m, 2H), 5.42 (s, 1.2H), 5.30 (s, 0.8H), 4.57 (s, 0.8H), 4.34-4.25 (m, 4.4H), 4.09 (m, 2.0H), 3.88 (t, 0.8H), 2.79 (t, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:17][C:18]1[C:19]([NH:31][CH3:32])=[N:20][C:21]2[CH:22]=[C:23]3[O:30]C[O:28][C:24]3=[CH:25][C:26]=2[CH:27]=1.B(Cl)(Cl)[Cl:34].[Cl-:37]>C(Cl)Cl>[ClH:34].[ClH:37].[OH:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([C:6]=1[CH2:17][C:18]1[C:19]([NH:31][CH3:32])=[N:20][C:21]3[C:26]([CH:27]=1)=[CH:25][C:24]([OH:28])=[C:23]([OH:30])[CH:22]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: CNc1nc2cc3c(cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12)OCO3
Reactant: ClB(Cl)Cl
Reactant: [Cl-]
Solvent: ClCCl
Product: CNc1nc2cc(O)c(O)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Product: Cl
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol 60 free base (28 mg, 65 μmol) in dry CH2Cl2 (5 mL) at 0° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer under N2 was added dropwise BCl3 (1.0 N solution in CH2Cl2, 0.30 mL, 0.30 mmol). After complete addition, the bath was immediately removed and stirring was continued overnight at RT. The reaction mixture was then carefully quenched with MeOH (3 mL) and the mixture was concentrated to dryness at 40° C. under vacuum before purification by prep. HPLC (eluent H2O:CH3CN:TFA=100:0:0.05 to 60:40:0.05 in 10 min) and lyophilisation. The residue was then dissolved in a 0.19 N HCl solution in MeOH (5 mL) before concentration at 40° C. under vacuum. Ion exchange on Amberlite IRA-400 (chloride form, 50 eq.) finally afforded 3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-2-(methylamino)quinoline-6,7-diol dihydrochloride 59 as a brown solid (10 mg, 31% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[N:35][OH:36])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:38](=O)[CH3:39].[OH-].[NH4+:42]>C(O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5[N:42]=[C:38]([CH3:39])[N:35]([OH:36])[C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC=O
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)C(=NO)CC4)cc2)CCC1
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(n1O)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(hydroxyimino)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (300 mg, 0.603 mmol) in ethanol (3.0 mL) was added acetaldehyde (68.1 μl, 1.206 mmol) followed by ammonium hydroxide (329 μl, 2.53 mmol). The reaction mixture was heated at 80° C. under a nitrogen atmosphere for 2 hours, then allowed to cool to room temperature and concentrated to dryness under reduced pressure and dried to give the crude product as a brown solid (306 mg, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][N:14]([CH3:24])[C:15]1[CH:23]=[CH:22][C:18](C(O)=O)=[CH:17][CH:16]=1.[C:25](OC(=O)C)(=[O:27])C>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]2[C:22](=[CH:23][C:15]([N:14]([CH3:13])[CH3:24])=[CH:16][CH:17]=2)[C:25](=[O:27])[O:5]1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)c(Cl)c1

Procedure:
Following a procedure similar to that described above in Example 1, part A, 36.6 g of 2-chloro-4-dimethylaminobenzaldehyde and 33.0 g of 4-dimethylaminobenzoic acid were interacted in acetic anhydride to obtain 52.1 g of 3-(2-chloro-4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=Z=H; Y=2-Cl-4-(CH3)2NC6H3) as a red crystalline solid which melted at 159°-160° C.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].CS(C)=O>O>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]2[S:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccccc3s2)cc1
Yield: 45.6 %

Procedure:
A solution of 4-dodecyloxybenzaldehyde (37.12 g, 0.128 mol), 2-aminobenzenethiol (16 g, 0.128 mol) and dimethylsulfoxide acid (200 cm3) was heated under reflux for 24 hours. The cooled solution was added to water and extracted into dichloromethane (3×50 cm3). The combined organic layers were dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethanol to give 23.1 g (45.7%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([Cl:11])=[C:5]2[NH:4][N:3]=1.[N:13]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.S(=O)(=O)(O)O>[Cl:11][C:10]1[CH:9]=[C:8]([CH3:12])[N:7]=[C:6]2[C:2](=[N+:1]=[N-:13])[N:3]=[N:4][C:5]=12
Reactant: Cc1cc(Cl)c2[nH]nc(N)c2n1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)c2c(n1)C(=[N+]=[N-])N=N2
Yield: 67.5 %

Procedure:
A solution of 3-amino-7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D7) (0.5 g) in water (13.5 ml) and concentrated sulphuric acid (2 ml) was treated at 0° with a solution of sodium nitrite (0.406 g) in water (2 ml) added dropwise with stirring. On completion of the addition the mixture was stirred at 0° for 20 min before bringing to pH 8 with saturated sodium carbonate. The resulting solid was collected and dried (0.18 g). The filtrate was extracted with chloroform (3×50 ml), the combined extracts dried with magnesium sulphate, filtered and evaporated to dryness to give a yellow solid which was combined with the solid originally collected, m.p. 119°-124° (combined yield 0.5 g). This crude material was recrystallised from cyclohexane to give the title compound as yellow needles (0.358 g, 68%), m.p. 123.5°-125° (decomposition). (Found: C, 43.51; H, 1.88; N, 35.79; Cl, 18.68. C7H4ClN5 requires C, 43.43; H, 2.08; N, 36.17; Cl, 18.31%). Found M+ 193.0154, C7H4ClN5 requires 193.0155.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O-:14])([O-])=O.[Cs+].[Cs+].[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[O:20][C:21]([CH2:11][OH:14])=[CH:22][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCc1ccc(-c2ccc(Cl)cc2)o1
Temperature: 80 °C
Yield: 35 %

Procedure:
The product from Example 11A (1.012 g, 5.72 mmol) in 10 mL of DMF was treated sequentially with PdCl2 (PPh3)2 (401 mg, 0.57 mmol), 4-chlorophenylboronic acid (1.78 g, 11.4 mmol), and Cs2CO3 (3.71 g, 11.4 mmol). The reaction was heated at 80° C. under N2 for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried (Na2SO4), filtered, and evaporated to a brown oil that was purified by flash chromatography (50% ethyl acetate/hexanes) to provide 345 mg (35%) the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](N1CC2(CCCC2)NCC1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([C:22]([NH2:27])([CH2:25][CH3:26])[CH2:23][NH2:24])[CH3:21].[CH3:28][C:29]([CH3:33])(O)[C:30]#N>>[C:1]([O:5][C:6]([N:27]1[CH2:28][C:29]([CH3:33])([CH3:30])[NH:24][CH2:23][C:22]1([CH2:25][CH3:26])[CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Reactant: CCC(N)(CC)CN
Reactant: CC(C)(O)C#N
Product: CCC1(CC)CNC(C)(C)CN1C(=O)OC(C)(C)C

Procedure:
2,2-Diethyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 2-ethyl-butane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[NH:30][CH2:29][CH:26]([N:27]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:15])[CH2:28]1)[CH2:25][CH2:24][CH2:23]2
Reactant: C1CC2CNC(C1)CN2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 0.81 g (3.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.66 g (3.3 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.35 ml (9.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 3 hr. After cooling to room temperature the solid was collected by filtration to give 0.52 g of the title compound, mp 245°-250°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([NH:32]C(=O)C(F)(F)F)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(N)=O>CO.C(NCC)C.CN(C)C=O>[NH2:32][C:30]1[N:31]=[C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=3)=[O:10])=[CH:12]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Agent: NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 127 mg (0.46 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 22 mg (0.55 mmol) of 60% sodium hydride, 155 mg (0.55 mmol) of N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide and 1 mL of N,N-dimethylformamide. The 130 mg of trifluoroacetamide product were heated to 60° C. in a mixture of 1 mL of methanol and 4 mL of diethylamine for 3 h, then overnight at 45° C. The product was filtered off and washed with a small amount of DCM. Yield: 36 mg of a white solid: LC-MSD, m/z for C23H20N4O2 [M+H]+=385.2; HPLC retention time: 0.8 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH:9][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
A mixture of 2-(p-chlorophenyl)glycine (37.1 g, 0.2 mol) in methanol is treated with triethylamine (20.2 g, 0.2 mol), stirred for 10 minutes, treated dropwise with ethyl trifluoroacetate (35.5 g, 0.25 mol), stirred for 4 days, diluted with methanol and treated with Dowex 50×8-100 ion exchange resin. The reaction mixture is stirred for 10 minutes and filtered. The filter cake is washed with methanol. The filtrates are combined and concentrated in vacuo to afford a yellow solid which is recrystallized from 1,2-dichloroethane to give the title compound as white crystals, 26.4 g (46.8% yield), mp 170°-172° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[CH2:19])[CH:17]=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:26])[CH2:23][N+:24]#[C-:25]>C1(C)C=CC=CC=1.[Cu-]=O>[CH3:20][O:21][C:22]([CH:23]1[CH:17]([C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH2:19])[O:18][CH:25]=[N:24]1)=[O:26]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C=C(C=O)CCCCNC(=O)OCc1ccccc1
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: C=C(CCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40° to a suspension of 0.12 g of 96.4% copper(I) oxide in 50 ml of toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced into a column filled with 60 g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate. 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:17]([Si:14]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(CC(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of 5-methyl-hex-1-yn-3-ol (5.0 g, 0.045 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 2.5 h and then treated with saturated NH4Cl (25 mL) and EtOAc (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.84 g, 97.5%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.90-0.88 (m, 15H), 1.53-1.46 (m, 1H), 1.65-1.58 (m, 1H), 1.87-1.77 (septet, J=6.6 Hz, 1H), 2.36-2.35 (t, J=1.84 Hz, 1H), 4.39-4.37 (m, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([F:30])[CH:29]=1)[NH2:26]>>[F:22][C:23]1[CH:24]=[C:25]([NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH:27]=[C:28]([F:30])[CH:29]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: Nc1cc(F)cc(F)c1
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3cc(F)cc(F)c3)cc2c2cc[nH]c12
Yield: 2.9 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 55 μL (0.55 mmol) of 3,5-difluoro-aniline. After purification by chromatography on silica gel (dichloromethane/methanol 95/5) then trituration in diethyl ether, 3 mg (2%) of 8-(3,5-difluorophenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[NH:23])OC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>CCO.CO>[ClH:1].[NH2:25][C:20](=[NH:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=N)Cc1ccc(CCc2csc(NC(C)=O)n2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Methyl 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoate hydrochloride (600 mg) was dissolved in EtOH (12 ml). Then ammonium chloride (136 mg) and ammonia in methanol (2 ml) were added to the solution. The reaction mixture was refluxed for 4 hours under N2 atmosphere. After cooled to r.t., the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with EtOH/diethyl ether to give N-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (338.6 mg) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:39](Br)[CH3:40]>CN(C=O)C.CCOC(C)=O.O>[CH2:39]([N:14]([CH:15]1[CH2:16][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:18]1)[C@H:11]1[CH2:12][CH2:13][N:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:10]1)[CH3:40]
Reactant: CCBr
Reactant: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C1CN(C(=O)c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
To a solution of Compound 16 (50 mg, 0.101 mmol) in dry DMF (1 mL) was added NaH (6 mg, 0.152 mmol) and the resulting mixture was stirred at room temperature for 20 min. EtBr (0.012 mL, 0.12 mmol) was added and the reaction mixture was heated to 130° C. overnight. The resultant mixture was diluted with EtOAc and water. The organic layer was washed with water and aq. NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5 TEA %) gave compound 53 (9 mg). MS m/z (M+H+) 522.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Ba+2].[OH-].COCCOC>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(I)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
A mixture of 2-chloro-4-iodotoluene(2.94 g, 11.63 mmol), phenyl boronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.44 mmol), DME (3 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenyl-phosphine)palladium(O) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80° C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 10% EtOAc in hexanes) to afford the title compound. 1H NMR (CDCl3 400 MHz) δ 7.62-7.54 (3H, m), 7.48-7.25(5H, m) and 2.43(3H, s) ppm.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)[C:6]1=[O:15]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)c2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred and heated for 2 hours at 70° C. The reaction mixture is cooled and poured onto water, whereupon an oily precipitate is formed. The supernatant aqueous phase is decanted and the residual oil is dissoved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1 part of 8-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 164.4° C.