Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][N:15]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=2)O1.Br[C:27]1[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([O:20][C:18]([N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[CH:17]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CC3)n1
Temperature: 90 °C
Yield: 61.4 %

Procedure:
A mixture of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate (288) (69 mg, 0.2 mmol), ethyl 2-bromothiazole-4-carboxylate (43 mg, 0.2 mmol), K2CO3 (69 mg, 0.5 mmol), tetrabutylammonium bromide (6.0 mg, 0.02 mmol) and dichlorobis(triphenylphosphine)palladium(II) (6.0 mg, 0.003 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was heated to 90° C. for 24 hours. After cooling the mixture was extracted into DCM, washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc (9:1), to provide 46 mg (61%) of the desired product ethyl 2-(1-(tert-butoxycarbonyl)indolin-6-yl)thiazole-4-carboxylate (28C): 1H NMR (300 MHz, CDCl3) δ 8.13 (1H, s), 7.18 (1H, dd), 6.95 (1H, dd), 6.43 (1H, dd), 4.44 (2H, m), 3.99 (2H, m), 3.11 (1H, t), 2.97 (1H, t), 1.54 (9H, s), 1.45 (3H, t). LC/MS (APCI): m/z 375.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][NH:8]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][N:8]1[S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: O=c1c(-c2ccccc2)c[nH]n1-c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)n1cc(-c2ccccc2)c(=O)n1-c1ccccn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
23.7 g (0.1 mole) of 1-pyrid-2-yl-4-phenyl-pyrazolin-5-one are dissolved in 200 ml of dioxane. After addition of 10.1 g (0.1 mole) of triethylamine, 11.5 g (0.1 mole) of methanesulphonyl chloride are added dropwise at room temperature, while cooling gently. The mixture is subsequently stirred at room temperature for a further 2 hours and at 70° C. for 5 hours, cooled and stirred into 1 l of water. The crystals are filtered off with suction, dried in air and recrystallized from ethanol. 22.5 g (71% of theory) of 1-pyrid-2-yl-2-methylsulphonyl-4-phenyl-pyrazolin-5-one of melting point 112°-114° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([S:12]C(=O)N(C)C)[CH:5]=1.CO[Na].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([SH:12])[CH:5]=1
Reactant: COC(=O)c1cc(OC)cc(SC(=O)N(C)C)c1
Agent: CO[Na]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(S)cc(OC)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 3-dimethylcarbamylthio-5-methoxybenzoic acid methyl ester (500 mg, 1.86 mmol) in THF (10 mL) at room temperature was added MeONa (0.5 M in MeOH, 10.0 mL, 5.0 mmol, 2.69 eq.). The reaction was refluxed for 2 h, then cooled to room temperature and added to 1.0 N HCl aqueous solution (150 mL). The resulting mixture was extracted with EtOAc/hexanes (1:1, 150 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 3-mercapto-5-methoxybenzoic acid methyl ester (0.365 g). The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccc(Cl)nc3)n2)CCN1

Procedure:
75 mg (0.14 mmol, 84% purity) of the compound of Example 40A is reacted analogously to the synthesis of the compound of Example 4 with 15 mg (0.15 mmol) of 2-oxopiperazine. 56 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1([C:8]([NH2:10])=[O:9])[CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:29]([I:30])=[C:25]2[N:24]=[C:23]([CH3:38])[N:22]=1>CN(C=O)C.C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[C:29]([I:30])=[C:25]2[N:24]=[C:23]([CH3:38])[N:22]=[C:21]([N:6]3[CH2:7][C:4]([NH:3][CH2:1][CH3:2])([C:8]([NH2:10])=[O:9])[CH2:5]3)[N:26]2[N:27]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Reactant: CCNC1(C(N)=O)CNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)C1
Reaction time: 2 h

Procedure:
To a solution of 3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1g; 0.55 g, 2.5 mmol) and diisopropylethylamine (1.3 ml, 7.6 mmol) in DMF (10 ml) was added a solution of 4-chloro-7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-1A-1e; 0.93 g, 2.3 mmol) in methylene chloride (10 ml). After stirring 2 hours, the methylene chloride was removed, in vacuo, and the mixture was extracted from water, adjusted to pH 8 with saturated aqueous NaHCO3, with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), and then concentrated, in vacuo, to afford a yellow solid. The material was then triturated from methylene chloride/methanol to afford I-6A-1a (0.73 g, 62%) as a colorless solid: +APcI MS (M+1) 512.0; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=7.9 Hz, 1H), 7.43-7.34 (m, 3H), 6.99 (d, J=4.7 Hz, 1H), 5.42 (d, J=4.7 Hz, 1H), 5.24 (br d, J=9.5 Hz, 1H), 4.81 (br d, J=9.5 Hz, 1H), 4.69 (br d, J=9.5 Hz, 1H), 4.13 (br d, J=9.5 Hz, 1H), 2.68-2.58 (m, 2H), 2.54 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH:20]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[CH:30][CH:29]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 48.2 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and 4-isopropoxyaniline (0.151 g, 1.00 mmol) in MeCN (2 mL) was heated at 120° C. for 35 mins in a microwave reactor. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 5:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.100 g, 48%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.20-7.14 (m, 1H), 7.12-7.08 (m, 4H), 7.04 (s, 1H), 6.62 (d, 1H), 6.48 (d, 2H), 4.34 (sep, 1H), 1.77 (s, 9H), 1.22 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 160.1, 155.5, 131.4, 129.7, 129.3, 128.9, 128.1, 125.2, 124.1, 116.1, 109.9, 70.5, 61.9, 27.9, 22.0; Mass Spectrum: M−H+ 414.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:14])=[CH:8]2
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (17.20 g), 1H-1,2,3-benzotriazol-1-ol (8.29 g) and N,N-dimethylformamide (150 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (11.8 g) at room temperature, and the mixture was stirred at 50° C. for 20 min. The mixture was allowed to cool to room temperature, and 28% aqueous ammonia (3.4 ml) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, washed with cooled ethyl acetate, and dried to give the title compound (11.47 g, yield 67%) as colorless crystals. melting point 244-245° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].I[CH3:20]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:20][N:12]1[CH2:11][CH:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cc2ccncc2)cc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC=C(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
4-(4-Nitrobenzyl)pyridine (64 g) and TBAI (6 g) were dissolved in CH2Cl2 (500 mL) and the solution was suspended with NaOH (aq. 5N, 450 mL) in a 3 L 3-necked round bottom flask. With vigorous stirring, iodomethane (213 g) was added and stirred vigorously at RT for 60 h (or until blue color disappears). The reaction was quenched with dimethylamine (100 mL) and MeOH (300 mL) and stirred for 2 h. NaBH4 (19 g) was added to the mixture in small portions. The reaction mixture was stirred for 30 min at RT, then partitioned between CH2Cl2/H2O (500 mL/500 mL). The organic layer was collected and the aqueous layer was washed with CH2Cl2 (300 mL×3). The combined organic layers was washed with brine then concentrated in vacuo. The residue was purified on a silica wash-column (7% TEA in EtOAc). The desired fractions were combined and concentrated under vacuum to give the desired compound as a dark gray solid. (MS: M+1=261).
Reaction SMILES: O[C:2]1([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6][N:5](C)[CH2:4][CH2:3]1.[ClH:19]>>[ClH:19].[NH:5]1[CH2:4][CH:3]=[C:2]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]1
Reactant: CN1CCC(O)(c2cnc3ccccc3c2)CC1
Agent: Cl
Product: C1=C(c2cnc3ccccc3c2)CCNC1

Procedure:
This product was prepared from the compound of Example 7 and using the procedure described in Stages A and B of Example 6. The compound obtained was converted to a salt using an alcoholic solution of hydrogen chloride.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[N:16]([CH2:20][C:21]#[C:22][CH3:23])[C:15]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]4)=[N:14][C:13]=3[N:12]([CH3:38])[C:10]2=[O:11])=[CH:5][CH:4]=1)=O.[NH2:39]OS(O)(=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[N:16]([CH2:20][C:21]#[C:22][CH3:23])[C:15]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:25]4)=[N:14][C:13]=3[N:12]([CH3:38])[C:10]2=[O:11])=[CH:5][CH:4]=1)#[N:39]
Reactant: NOS(=O)(=O)O
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1ccc(C=O)o1)c(=O)n2C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1ccc(C#N)o1)c(=O)n2C

Procedure:
Prepared by reacting 1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with hydroxylamine-O-sulfonic acid and pyridine in toluene at reflux temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH:9]([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C(F)F

Procedure:
The title compound was prepared from 1-(4-bromo-phenyl)-2,2-difluoro-ethanone (1.6 g) (for synthesis, e.g.: G. K. Prakash et al; Journal of Fluorine Chemistry; 112; 2001; p 357) by standard reduction with NaBH4 (0.515 g) in THF (20 ml) at RT and 2 h reaction time as colorless oil (1.23 g). MS (m/e)=236 [MH+].
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[C:15]([Cl:14])=[N:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2-chloronicotinoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91 (t, 3 H) 1.31-1.39 (m, 2 H) 1.58-1.67 (m, 2 H) 2.19 (s, 3 H) 2.21 (s, 3 H) 3.93-3.98 (m, 2 H) 6.15 (s, 1 H) 7.47 (dd, 1 H) 7.94 (dd, 1 H) 8.41 (dd, 1 H); MS (ESI) m/z 323 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2cc(Cl)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cc(Cl)ccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 5.6 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,5-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 218 mg (1.04 mmol) of 4-(2-(diethylamino)ethoxy)aniline was heated at 180° C. for 30 minutes and then cooled. The residue was subjected to column chromatography on silica gel eluted with dichloromethane/methanol/acetic acid/water in a ratio of 240:24:3:2. Product containing fractions were combined, evaporated and the residue re-evaporated with toluene. The residue was dissolved in dichloromethane (40 ml), washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated to give 15 mg (6%) of 3-(2,5-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 138° C. [Mass spectrum (ESI) MH+ =514].
Reaction SMILES: C(=S)([O-])N.[NH2:5][C:6]1[S:7][C:8]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[S:18]>N1C=CC=CC=1>[O:15]=[C:14]1[C:8]2[S:7][C:6]([NH:5][C:17](=[S:18])[O:19][CH2:20][CH3:21])=[N:10][C:9]=2[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: CCOC(=S)Cl
Agent: NC([O-])=S
Solvent: c1ccncc1
Product: CCOC(=S)Nc1nc2c(s1)C(=O)CCC2

Procedure:
The desired thiocarbamate is obtained in analogy with the preparation of Z-13 b, starting from 101 g of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (602 mmol) in 3.4 l of pyridine and 75 g of ethyl chlorothioformate (602 mmol). Yield: 84 g
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:27])[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][CH2:24][CH3:25].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[CH3:1][O:2][N:3]([CH3:27])[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-:36])=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N(C)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)N(C)OC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate N-methoxy-N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (4.01 g, 10.9 mmol) by reaction with m-CPBA (6.13 g) to provide N-methoxy-N-methyl-6-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide followed by reaction with p-toluenesulfonyl chloride (2.53 g, 13.3 mmol) and ammonium hydroxide solution (40 mL) to provide 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methylhexanamide) as an off-white solid after recrystallization from a mixture of ethyl acetate and hexane, mp 134-135° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:16]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2].[BH4-].[Na+].O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].Cl.C(=O)([O-])O.[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:17][CH:16]=2)[CH2:6][CH:5]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=Nc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)CC1C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC(=O)N1c2ccccc2C(Nc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)CC1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
[Step 2] 715 mg of 1-acetyl-2-methyl-4-[(4-tert-butyldiphenylsilyloxymethylphenyl)imino]-1,2,3,4-tetrahydroquinoline, 74 mg of sodium borohydride, and 488 mg of cerium trichloride heptahydrate were dissolved in 8 mL of methanol, and the solution was stirred for 2 hours at 50° C. After completion of the reaction, 1 N hydrochloric acid was added to the reaction liquid, and the mixture was stirred for 30 minutes. The reaction liquid was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then was extracted with chloroform. The organic layer was washed with a saturated solution of sodium hydrogen carbonate and saturated brine, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate 1:1), and thus 615 mg (85%) of 1-acetyl-4-[(4-tert-butyldiphenylsilyloxymethylphenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a yellow oily substance (cis:trans=3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(=O)c3ccccc3)cc(CCNC(C)=O)c2c1

Procedure:
To a solution of 11 g (45.2 mmol) of N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide and 7.7 g (57.7 mmol) of AlCl3 in 60 cm3 of nitrobenzene, add dropwise 57.9 mmol of benzoyl chloride, at 12° C. and under nitrogen. Allow to react for 2 hours at 12° C. and pour the reaction mixture onto ice. Extract with dichloromethane, dry over magnesium sulfate, concentrate and then chromatograph the crude material on silica (eluent CH2Cl2 /CH3OH: 99/1).
Reaction SMILES: [Mg].[CH3:2][OH:3].C[O-].[Mg+2].C[O-].[CH2:9]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:9]([C:18]1[CH:19]=[C:20]([CH:2]=[O:3])[C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CO
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (24 g, 0.98 mol), methanol (570 ml), toluene (240 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (224 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off to an internal temperature of 70° C. at a pressure of 350 mm Hg. The mixture was cooled to 25° C. and toluene (300 ml) was added. Anhydrous hydrochloric acid (38 g) was added to the reaction mixture over a period of 1.5 hours. Methanol (200 ml) was then added to the mixture and the pot was rigged for an atmospheric pressure fractional distillation. An azeotrope of methanol/toluene was distilled off to a pot temperature of 100° C. The pot was then cooled to 90° C. and paraformaldehyde (94.8 g, a commercial sample containing 5-7% by weight water) slurried in toluene (200 ml) was added over a 1 hour period. During the addition of paraformaldehyde, volatile reaction by-products were continually removed. The reaction mixture was maintained at a temperature of 90° C. for an additional hour after the paraformaldehyde addition was complete. The reaction temperature was then cooled to 70° C. and sulphuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 30 minutes. After phase separation, the organic phase was washed twice with 200 ml portion of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 62% yield was obtained.