Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([S:18][C:19]2[CH:20]=[N:21][C:22]([NH:32][C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:64][C:65](=[NH:67])[CH3:66]>CN(C=O)C.CCOC(C)=O>[CH3:66][C:65]1[N:67]=[C:15]([CH:14]([S:18][C:19]2[CH:20]=[N:21][C:22]([NH:32][C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)=[C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[O:16][N:64]=1
Reactant: CC(=N)NO
Reactant: Cc1csc(Nc2ncc(SC(C(=O)O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(Nc2ncc(SC(c3nc(C)no3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Placed 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)acetic acid (0.250 g, 0.449 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0638 g, 0.494 mmol) in DMF (10 mL) and added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate(V) (0.119 g, 0.449 mmol) and stirred for 30 minutes. Added N-hydroxyacetamidine (0.0366 g, 0.494 mmol) and heated to 110° C. for 4 days. The reaction was diluted with EtOAc and washed with water, dried, filtered and concentrated. The residue was purified by reverse phase chromatography to provide the title compound (0.122 g, 35.6%) Product was contaminated with ˜15% acid. Crude material was used in Step B.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]1(N)[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]1[N+:11]([O-:13])=[O:12].Cl[C:18]([O:20][CH2:21][CH2:22][Cl:23])=[O:19].CCCCCC>O1CCOCC1>[Cl:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:16])([F:15])[F:1])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: O=C(Cl)OCCCl
Reactant: NC1=CC([N+](=O)[O-])C(N)(CC(F)(F)F)C=C1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(Nc1ccc(CC(F)(F)F)c([N+](=O)[O-])c1)OCCCl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of N1 -(2,2,2,-trifluoroethyl)-2-nitro-p-phenylene-diamine (6) (0.705 g, 3 mmol), 2-chloroethyl chloroformate (0.515 g, 3.6 mmol) and CaCo3 (0.40 g, 4 mmol) in dioxane (10 ml) was stirred at 80° C. for 20 minutes, filtered and washed with ethyl acetate. The combined filtrate was washed with water and brine, dried (Na2SO4), and evaporated to give a brown oil. Trituration with hexane gave 2-chloroethyl-N-[4-(2,2,2-trifluoroethyl)-3-nitrophenyl]-carbamate (8) as an orange solid. The unpurified carbamate (8) was dissolved in aqueous ethanol (ETOH: H2O, 15/5 ml) and powdered KOH (1.35 g) was added. The mixture was stirred at 90° C. for 20 minutes and then poured onto crushed ice (20 g) . The resultant mixture was extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), and evaporated to give 0.544 g (65% yield) of N1 -(2,2,2-trifluoroethyl)-N4 -(2-hydroxyethyl)-2-nitro-p-phenylenediamine (9): mp 93°-95° C.; MS m/e 279(M+); 1HNMR (acetone-d6), δ3.25 (m, 2H), 3.76 (m, 2H), 3.91 (bs, 1H), 4.34 (m, 2H), 4.98 (bs, 1H), 7.19 (m, 2H), 7.35 (s,1H), 7.80 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:16](=[C:17]([C:22](OC)=[O:23])[CH:18]=[CH:19][C:20]=4[Cl:21])[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH2:22][OH:23])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 40 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
To a solution of methyl 1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (2.00 g, 4.39 mmol) in tetrahydrofuran (15.0 mL) was added lithium tetrahydroborate (382.8 mg, 17.58 mmol) at 0° C. The reaction mixture was stirred at 40° C. for 15 hrs. The starting material wasn't consumed completely. The reaction mixture was stirred at 50° C. for 4.5 hrs. After cooling, the reaction mixture was quenched with water at 0° C. The solvent was concentrated and the precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (1.70 g, 3.97 mmol, 90%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:21]([C:23]1[CH:28]=[C:27]([C:2]2[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COCOc1cc(CC(=O)OC)c(-c2cccc(C=O)c2)c(OCOC)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Methyl 2-bromo-3,5-bis(methoxymethoxy)phenylacetate (630 mg, 1.8 mmol)-obtained in the step 2 in Example 1 was dissolved in a mixed solvent of 1,2-dimethoxyethane (10 mL) and water (2 mL), and in an argon atmosphere, 3-formylphenylboronic acid (400 mg, 2.7 mmol), bis(tri-o-tolylphosphine)palladium(II) dichloride (140 mg, 0.17 mmol) and cesium carbonate (1.1 g, 7.2 mmol) were added thereto, and stirred under heat for 10 hours. The reaction mixture was cooled to room temperature, then filtered, and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/2) to obtain methyl 2-(3-formylphenyl)-3,5-bis(methoxymethoxy)phenylacetate (500 mg, 75%).
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:29]>C1COCC1>[ClH:29].[ClH:29].[NH2:8][CH:9]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: COc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.3 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetate (C44) (560 mg, 1.43 mmol) in THF (20 ml), was added 37% hydrogen chloride (1.0 ml, 12.2 mmol). The reaction was stirred at RT for 15 hours. Then a second portion of 37% hydrogen chloride (1.0 ml, 12.2 mmol) was added, and the reaction was stirred at RT for additional 48 hours. The solvent was evaporated to obtain (R)-quinuclidin-3-yl 2-amino-2-(4-methoxyphenyl)acetate dihydrochloride (521 mg; quantitative yield).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:33][CH:34]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
To a solution of docosyl bromide (25 g, 0.064 mol), potassium carbonate (9.0 g) and sodium iodide (9.6 g) in acetone (150 ml), ethyl p-hydroxybenzoate (10.2 g, 0.061 mol) was added, and then reacted for 12 h under reflux with stirring. After cooling, the reaction mixture was filtered to remove inorganic materials, taken up in H2O (500 ml), and extracted with CH2Cl2 (3×100 ml). The organic layer was separated, washed with H2O, dried over MgSO4, and evaporated to dryness. The resultant residue was recrystallized from ethyl acetate to give ethyl 4-docosyloxybenzoate (27 g) as a white crystals; mp 56.5°-59.5° C. Then ethyl 4-docosyloxybenzoate (27 g) was stirred in H2O (120 ml) and ethanol (150 ml) containing sodium hydroxide (4.6 g) for 6 h under reflux. After cooling, the reaction mixture was acidified with hydrochloric acid, the resultant precipitate was filteted, washed with H2O and recrystallized from acetic acid to give the title compound as a white needles; yield: 18.5 g (72.7%); mp 99.0°-101.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-])=O)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2>O1CCCC1.C(OCC)(=O)C.ClCCl.[Pd]>[NH2:17][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c([N+](=O)[O-])c2nc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reaction time: 22 h
Yield: 78.5 %

Procedure:
6,7-Dichloro-2,3-dimethoxy-5-nitroquinoxaline (20 g, 0.066 mol) and 5% w/w palladium-on-carbon (50% wet) (1.2 g) were suspended in a mixture of tetrahydrofuran (0.12 L) and ethyl acetate (0.12 L). The mixture was hydrogenated at 60° C. and 414 kPa (60 psi) for 22 hours, cooled, diluted with dichloromethane (0.48 L) and the catalyst removed by filtration through celite (trade mark) filter aid. The solution was concentrated under reduced pressure with the gradual addition of toluene. The mixture was then filtered and the solid was washed with toluene (20 ml) to give the title compound as a brown solid (14.2 g, 78%), m.p. 182-4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][S:32]1(=[O:38])=[O:37]>>[O:37]=[S:32]1(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][N:31]1[C:26]1[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCCCN1c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using conditions analogous to those described in Example 1 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(2-bromophenyl)-1,2-thiazinane 1,1-dioxide. MS (ESI): mass calcd. for C20H19FN4O2S, 398.12; m/z found, 399.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.38-8.33 (m, 1H), 8.08-8.02 (m, 1H), 7.62 (m, 1H), 7.45-7.39 (m, 4H), 7.34 (dd, J=12.5, 1.7, 1H), 3.76-3.65 (m, 2H), 3.24-3.10 (m, 2H), 3.00-2.89 (m, 2H), 2.35-2.23 (m, 2H), 2.22-2.10 (m, 2H).
Reaction SMILES: COC(C)(C)C.[C:7]([O:12][CH:13]([O:17][C:18]([CH3:20])=[S:19])[CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:8][CH2:9][CH3:10]>O>[C:7]([O:12][C@@H:13]([O:17][C:18]([CH3:20])=[S:19])[CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)OC(CCC)OC(C)=S
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC(=O)O[C@H](CCC)OC(C)=S
Reaction time: 120 h
Yield: 10 %

Procedure:
A mixture of 33 mL methyl-tert-butyl ether (MTBE) and 0.33 mL water was stirred until a clear solution was obtained (ca. 5 hrs). To this solution was added methylthiocarbonyloxybutyl butanoate (2e) (2.0 g) and PLE/MPEG (60 mg/1 g; 12.65 g). The resulting suspension was stirred at room temperature. The reaction was monitored by 1H-NMR using a chiral solvating agent. After ca. 5 days, the reaction was quenched by filtration through a pad of CELITE® 545. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). Evaporation of the solvent afforded 0.20 g (20% yield) of the title compound (16). The enantiomeric excess as determined by chiral HPLC was 90% e.e.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH:12]=O)=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3].[I-:28].[Na+].C[Si](C)(C)Cl.C[SiH2]O[Si](C)(C)C>C(#N)C>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH2:12][I:28])=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Reactant: [I-]
Agent: C[SiH2]O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CI
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a solution of 3;3 g of 2-chloro-5-[dimethyl-(1,1,2-trimethylpropyl)silanyloxy]-6-formyl-3-methoxy-benzoic acid allyl ester in 4 ml of acetonitrile were added 1.8 g of sodium iodide and 1.6 ml of trimethyl-chlorosilane. A white precipitate occurred. The mixture was stirred for 5 min at 20° C. The suspension was cooled to 0° C. and 1.48 ml of tetramethyldisiloxane were added. The mixture was stirred for 2 hours at 0° C. and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The aqueous phase was extracted twice with 20 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using diethyl ether/hexane (3:1, v/v) as eluent to afford 3.39 g of 2-chloro-5-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy]-6-iodomethyl-3-methoxy-benzoic acid allyl ester as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5]CN.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH:19]=[CH:20][C:21]#[C:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH3:27][N:28](C)C=O>>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]#[C:21]/[CH:20]=[CH:19]/[CH2:18][N:28]([CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:27]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN(C)C=O
Reactant: NCCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
N-(3-bromobenzyl)methylamine (2.00 g; 10.0 mmol) and sodium carbonate (1.51 g; 14.3 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 1-bromo-6,6-dimethyl-2-hepten-4-yne (1.92 g; 9.52 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. The mixture was stirred for 1 hour at room temperature, and the reaction was stopped by pouring the mixture into ice/water, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 1.64 g of the target compound as yellow oily matter (yield: 53.8%).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([C@@H:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 h. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-chloro-phenol to give [1-(4-chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [Cl:1][CH:2]([CH:8](OC)OC)[CH:3](OC)OC.[CH3:13][NH:14][C:15]([NH2:17])=[O:16]>Cl.C(O)C>[CH3:13][N:14]1[CH:3]=[C:2]([Cl:1])[CH:8]=[N:17][C:15]1=[O:16]
Reactant: COC(OC)C(Cl)C(OC)OC
Reactant: CNC(N)=O
Agent: Cl
Solvent: CCO
Product: Cn1cc(Cl)cnc1=O
Reaction time: 96 h
Yield: 20 %

Procedure:
A mixture of 2-chloro-1,1,3,3-tetramethoxypropane (0.05 mol), N-methylurea (0.04 mol) in 10 N HCl (10 ml) in ethanol (100 ml) was allowed to stand at room temperature for 4 days. The reaction mixture was then evaporated, the residue dissolved in water (100 ml) and the pH of the solution adjusted to 8 by means of Na2CO3. The mixture was then extracted with chloroform (4×30 ml) and the dried (Na2SO4) extracts evaporated. The residue was recrystallised from acetone; yield 20%. The physical data for the product was identical to those measured for the compound as prepared by the method of Example 2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][OH:16])[CH3:11])=[CH:6][N:5]=1)[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]2[CH:50]=[CH:49][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]3=[O:48])=[CH:20][CH:19]=2)[CH3:11])=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C(C)=NOCCO)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 410 mg of 2-[1-(2-ethoxy-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 19), 655 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 480 mg of triphenylphosphine and 319 mg of diethyl azodicarboxylate, 763 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1(=O)CCCCC1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[C:1]1([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCNC1
Solvent: c1ccccc1
Solvent: O=C1CCCCC1
Product: C1=C(N2CCCC2)CCCC1

Procedure:
1 g of para-toluenesulphonic acid is added to a mixture of 20 mmol of cyclohexanone and 22 mmol of pyrrolidine in 200 ml of dry benzene. The reaction mixture is stirred at reflux until, in the infra-red, the ketone has disappeared, with the enamine concomitantly appearing. The solvent is then evaporated off and the crude residue is purified by distillation in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)[CH:22]=2)(=[O:29])=[O:28])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Br)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
2-Amino-5-bromobenzenesulfonamide (0.60 g, 2.39 mmol) was dissolved in pyridine (6 ml) and 3-(3,4-dichlorophenyl)-phenylsulfonyl chloride (0.82 g, 2.51 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (0.70 g, 55% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[C:31]([C:37]([F:40])([F:39])[F:38])=[N:32][C:33]([NH2:36])=[N:34][CH:35]=4)=[N:18][C:17]=3[C:16]=2[CH3:41])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:41][C:16]1[C:17]2[N:18]=[C:19]([C:30]3[C:31]([C:37]([F:40])([F:39])[F:38])=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:20]=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:22]=2[S:23][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3C(F)(F)F)nc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3C(F)(F)F)nc12
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 30 mg of 4-[2-(2-Amino-4-trifluoromethyl-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester in 4.0 M of hydrogen chloride in 1,4-dioxane was stirred for 1 h. The mixture was evaporated. The product was purified by reverse phase HPLC to yield 6 mg of 323. MS (Q1) 495.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22]COC)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C2C(=CC(OC)=C([N+]([O-])=O)C=2)N=CN=1.ClC1C(F)=C(C=CC=1[F:50])N>>[Cl:1][C:2]1[C:3]([F:50])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccc(F)c(Cl)c1F
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3-chloro-2,4-difluoro-aniline; other starting materials were prepared as example 1.