Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>CCCCO.CO>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([NH:37][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:38][CH:39]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: FC(F)(F)c1cccnc1N1CCc2nc(N3CCOCC3)nc(Cl)c2CC1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCCCO
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nc(N3CCOCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 180 °C
Yield: 92.6 %

Procedure:
To a solution of 4-chloro-2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (30 mg, 0.08 mmol) in n-BuOH (2 mL) was added 4-tert-butylaniline (23 μL, 0.15 mmol). The mixture was heated in the microwave at 180° C. for 90 min, then was cooled to rt, diluted with MeOH, and filtered through quaternary amine resin, carbonate form (500 mg). The filtrate was concentrated and the residue was purified (FCC) to give the title compound (39 mg, 99%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.2 [M+H]+. 1H NMR (CDCl3): 8.40-8.37 (m, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.31 (m, 2H), 6.96-6.89 (m, 1H), 6.35 (s, 1H), 3.80-3.70 (m, 8H), 3.64-3.54 (m, 4H), 3.11-3.04 (m, 2H), 2.88-2.82 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1B(O)O)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:37]=1)[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][C:5]=2[C:9]#[N:10])=[CH:40][CH:41]=1)[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: N#Cc1cccc(C#N)c1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C#N)cccc2C#N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 12.1 %

Procedure:
To a mixture of 2,6-dicyanobenzene boronic acid (0.516 g) and anhydrous K2CO3 (0.2 g) in toluene (10 mL) under N2 was added N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (0.5 g). Pd(PPh3)4 (0.1 g) was added and the mixture was heated at 90° C. for 8 h. The mixture was cooled, diluted with EtOAc and washed successively with water and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1/1) to yield 58 mg of N-(2,6-dichlorobenzoyl)-4-(2,6-dicyanophenyl)-L-phenylalanine methyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C>[C:15]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
A mixture of 20.0 grams (0.0785 mole) of α-bromo-p-pivaloyl toluene, 30.0 grams (0.157 mole) of potassium acetate and 60 milliliters of glacial acetic acid is refluxed for 20 hours. The acetic acid is removed in vacuo, and the residue is treated with ice water and then extracted with methylene chloride. The methylene chloride extract is washed with 2N sodium hydroxide solution, dried with magnesium suflate, and then filtered and evaporated to give α-acetoxy-p-pivaloyl toluene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.C(Cl)Cl.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:25])=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol;) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[CH3:27][NH2:28].Cl>O.O1CCOCC1>[CH3:27][NH:28][C:13]([C:6]1[NH:7][C:8]2[C:3]([C:4](=[N:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:5]=1)=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[O:15]
Reactant: COC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: CN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 18 h

Procedure:
Combine 5,7-dichloro-4-[benzenesulfonylimino]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester (1.0 g, 2.4 mmol) and 40% methylamine in water (25 mL) and dioxane (50 mL). Stopper and stir for 18 hours. Evaporate in vacuo to give a yellow oil. Dissolve the oil in water (15 mL) and add 1M hydrochloric acid solution (15 mL). Stir for 15 minutes and then filter to obtain a solid. Rinse the solid with 1M hydrochloric acid solution and water. Recrystallize from acetonitrile/water to give the title compound as a solid: mp; 196°-197° C. Elem. Anal. calculated for C17H13Cl2N3O3S.H2O: C, 47.68; H, 3.53; N, 9.81. Found: C, 47.55; H, 3.42; N, 9.78.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([N:24]1[CH2:25][CH2:26][N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:23]1=[O:22])=[O:35]
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3)ccn2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A mixture of 2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.528 mmol) and TEA (3.2 mL, 22.93 mmol) in DCM (5 mL) was cooled to 0° C., treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, sonicated and the resulting solid collected via filtration to afford N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (167 mg, 66%). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (d, J=2.5 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.19 (t, J=9.1 Hz, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.28 (dd, J=11.7, 2.7 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 7.03 (dd, J=9.1, 2.5 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.77 (m, 8 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (dd, J=12.5, 10.6 Hz, 2 H), 1.71 (qd, J=12.2, 4.5 Hz, 2 H), 1.60-1.57 (m, 2H); MS (ESI) m/z: 481.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([OH:14])=O)=[O:7].[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:10]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2C)cc1OC
Reactant: NC1CCC1
Product: COc1ccc(C(=O)Nc2cc(C(=O)NC3CCC3)ccc2C)cc1OC

Procedure:
Using an analogous procedure to that described in Example 8, 3-(3,4-dimethoxybenzamido)-4-methylbenzoic acid was reacted with cyclobutylamine to give the title compound; Mass Spectrum: M+H+ 369.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reaction time: 8 h

Procedure:
3-Methyl-1,3-butanediol (1.5 mL, 14.1 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.1 mmol). The mixture is stirred overnight then washed with 1 M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (METHOD 2): tR=5.67 min; Mass spectrum (ES+): m/z=258 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-ethoxycarbonylhexahydropyridine (5 g, 32 mmol) and triethylamine (3.2 g, 32 mmol) in 15 ml of benzene is added dropwise to phosgene, with ice-bath cooling. After the addition is complete, the mixture is allowed to warm to RT and is stirred for 2 hours. The reaction is diluted with benzene to about 150 ml, washed with water (3X), dried over sodium sulfate and stripped to give N-chlorocarbonyl-2-ethoxycarbonylhexahydropyridine.
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[C:15]([CH3:23])[N+:14]=2[O-])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=[C:15]([CH2:23][Cl:5])[N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCl)nc1-c1ccc(F)cc1

Procedure:
Methane sulfonyl chloride (7.11 ml) was added to a stirred solution of 2-(4-fluorophenyl)-3-(methoxycarbonyl)-6-methylpyridine-1-oxide (12.0 g) in toluene (300 ml) and the mixture heated at reflux under an inert atmosphere for 16 hours. The solution was partially concentrated under reduced pressure and then applied directly to a silica flash column and eluted with ethyl acetate/iso-hexane (1:5) to give methyl 2-(4-fluorophenyl)-6-chloromethylpyridin-3-carboxylate as a white crystalline solid (13.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Cl)(=[O:15])[CH3:14].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])(=[O:15])[CH3:14]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(=O)OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
A mixture of 50 g (300 mmol) of 5-hydroxy-2-nitrobenzaldehyde, 59 g (330 mmol) 6-chlorohexanol acetate, 5 g of potassium iodide, and 50 g of potassium carbonate in 500 ml of dry DMF was heated to 100° C. under dry nitrogen for 3 h. The reaction was cooled, filtered and evaporated to a dark oil. The crude product was dissolved in 500 ml of ethyl acetate, and the organic layer was washed twice with 300 ml of saturated sodium carbonate, and twice with 300 ml of brine, dried filtered and evaporated. Distillation (180° C., 0.2 mm) gave a yellow oil which solidified on cooling, to yield 81.5 g (263 mmol, 88%) of 5-(6-acetoxyhexyl)oxy-2-nitrobenzaldehyde, m.p. 42°-43° C.
Reaction SMILES: [P:1]12([S:13]P3(SP(SP(S3)([S:9]1)=S)(=S)[S:3]2)=S)=[S:2].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].[S-2].[Na+].[Na+]>>[CH2:21]([O:20][Si:19]([CH2:18][CH2:17][CH2:16][S:3][P:1](=[S:2])([S:13][CH2:16][CH2:17][CH2:18][Si:19]([O:20][CH2:21][CH3:22])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[S:9][CH2:16][CH2:17][CH2:18][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:26][CH2:27][CH3:28])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:22]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [Na+]
Agent: [S-2]
Product: CCO[Si](CCCSP(=S)(SCCC[Si](OCC)(OCC)OCC)SCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 314.1 %

Procedure:
A mixture of 30.8 g (69.2 mmol) P4S10, 200.0 g (830.3 mmol) chloropropyltriethoxysilane and 32.4 g (415.3 mmol) sodium sulfide (Na2S) is initially introduced into a 500 ml three-necked flask in an argon atmosphere and is heated to 200° C. After stirring at 200° C. for 2.5 h, insoluble constituents are filtered off. All the volatile constituents are removed in vacuo. 168.5 g (79% yield) of tetrathiophosphoric acid S,S,S-tris (triethoxysilylpropyl) ester are obtained as a pale yellow clear liquid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](=[O:18])[CH2:16]Br)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[CH2:19]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]([CH2:16][C:15]([C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:18])[CH2:27][CH2:28][NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cc1ccccc1)NCCNCc1ccccc1
Reactant: CC(=O)Oc1ccc(C(=O)CBr)cc1OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(C)=O

Procedure:
3',4'-Bis(acetoxy)-2-bromoacetophenone was reacted with N-[2-(benzylamino)ethyl]-2-phenylacetamide using a similar procedure to that described in Example 1 for the analogous pivaloyloxy derivative to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(acetoxy)acetophenone, which was isolated as its free base and converted to its hydrochloride salt with ethereal hydrogen chloride to give a solid, m.p. 140°-145° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[N:4]([CH2:22][CH2:23][CH3:24])[N:3]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[Cl:25][S:26]([C:16]1[CH:15]=[CH:14][C:13]([O:18][CH2:19][CH2:20][CH3:21])=[C:12]([C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[N:3][N:4]([CH2:22][CH2:23][CH3:24])[C:5]=3[N:6]=2)[CH:17]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 3-methyl-6-(2-n-propoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 21; 0.5 g, 0.0017 mol) and chlorosulphonic acid (3 ml), by the same procedure as Preparation 3, and was obtained as a white powder (0.587 g, 90%), m.p. 148-150° C. Found: C, 50.88; H, 4.67; N, 13.30. C18H21ClN4O4S requires C, 50.88; H, 4.98; N, 13.19%.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(C(C)=O)C>[O:1]([CH2:8][CH2:9][CH2:10][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCOc1ccccc1
Reactant: C1CNCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: c1ccc(OCCCN2CCNCC2)cc1

Procedure:
A mixture of 3-phenoxy-1-chloro-propane (1 mole), sodium iodide (1 mole) and anhydrous piperazine (4 moles) is added to methyl ethyl ketone (1000 ml). The mixture is refluxed during 24 hours, with stirring. The solvent is removed in vacuo over a water-bath and the residue is poured over water. The aqueous phase is extracted with methylene chloride and then washed twice with water. The solvent is removed and the residual oil is distilled. B.p. = 115° C./0.05 mm Hg.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCBr
Reactant: OCCCSc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCSc1ccccc1

Procedure:
3-(Phenylthio)-1-propanol (3.00 g), 1,6-dibromohexane (5.5 ml), aqueous 12.5M sodium hydroxide (27 ml) and TAB (802 mg) were vigorously stirred at room temperature overnight. The mixture was diluted with water (60 ml), extracted with diethyl ether (3×90 ml), and the combined, dried organic extracts were evaporated. The residual oil was purified by FCC eluting with System B (1:99→1:24) to give the title compound (4.01 g) as a colourless oil. T.l.c. (System B 1:3) Rf 0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C1CCNCC1.CC=C(C)C.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[C:37]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:8])[CH2:25][CH2:24]1)(=[O:41])[CH2:38][CH2:39][CH3:40]
Reactant: CCCC(=O)Cl
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Agent: CC=C(C)C
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
A small sample of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (60 mg, 0.16 mmol) was weighed out in a 4 mL sealable vial, followed by (piperidinomethyl)polystyrene (0.12 g, 0.32 mmol). To this was added 10 mL of amylene-stabilized chloroform and butyryl chloride (18.0 μL, 0.17 mmol). The vial was capped and placed in a shaker, where it was kept at room temperature for 24 h, then at 50° C. for 36 h. The crude reaction mixture was then applied to a 2 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to a dry residue, which was purified by preparative thin layer chromatography. Elution with 9:1 dichloromethane-methanol provided the title compound (9 mg, 13%), isolated in 98% purity by HPLC analysis (Method C: gradient from 50% acetonitrile-50% water with 0.1% trifluoroacetic acid to 90% acetonitrile-10% water with 0.1% trifluoroacetic acid over 10 min; hold 2 min; back to 50% acetonitrile-10% water with 0.1% trifluoroacetic acid over 1 min; hold 2 min; 0.5 ml/min; Waters Symmetry Cl18, 3.5 μM column, 4.6 by 75 mm; 25° C.).
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:32])[N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:15]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][N:14]2[C:13](=[O:32])[CH:12]=[CH:11][C:10]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)=[N:15]2)=[N:35][CH:36]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)cn1
Temperature: 80 °C

Procedure:
5 ml of water and 5 ml of acetonitrile are added to 150 mg (0.35 mmol) of 6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-2H-pyridazin-3-one, 63 mg (0.35 mmol) of 5-bromopyrazin-2-ylamine and 167 mg (1.99 mmol) of sodium hydrogencarbonate, and the mixture is degassed a number of times. Under an argon atmosphere, mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is subsequently heated at 80° C. for 15 h with stirring. A further 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are subsequently added, and the mixture is stirred at 80° C. for a further 24 h. The hot suspension is filtered. The filtrate is concentrated to half. After cooling to room temperature, the resultant precipitate is filtered off with suction and washed with a little water. The residue is purified by means of preparative HPLC; yield: 21 mg of “A280”; HPLC: Rt=2.68 min (method C); LC-MS: 392 (M+H).