Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20].C([O:24]CC)C>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])=[O:24]
Reactant: CCOCC
Reactant: CC(=O)Nc1ccccc1CSc1nc2ccccc2[nH]1
Product: CC(=O)Nc1ccccc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The title compound was prepared by the method of Example 3 using 1.80 g of the title product of Example 5 instead of the title product of Example 2. Trituration with diethylether gave 1.52 g of the title compound: m.p. 201-202.5° C. Anal. Calc'd. for C16H15N3O2S: C, 61.32; H, 4.82; N,13.41; S, 10.23. Found: C, 61.00; H, 4.90; N, 13.28; S, 10.50.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[S:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[CH3:10][N:11]1[C:19]2[C:18](=[O:20])[N:17]=[C:16]([C:21]3[CH:22]=[C:23]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:25][C:26]=3[O:27][CH2:28][CH3:29])[NH:15][C:14]=2[C:13]([CH2:34][CH2:35][CH3:36])=[N:12]1>CC(C)=O>[CH3:36][CH2:35][CH2:34][C:13]1[C:14]2[N:15]=[C:16]([C:21]3[CH:22]=[C:23]([S:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:31])=[O:32])[CH:24]=[CH:25][C:26]=3[O:27][CH2:28][CH3:29])[NH:17][C:18](=[O:20])[C:19]=2[N:11]([CH3:10])[N:12]=1
Reactant: CCCc1nn(C)c2c(=O)nc(-c3cc(S(=O)(=O)Cl)ccc3OCC)[nH]c12
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 22 °C
Reaction time: 2 h

Procedure:
In a 0.25 L reactor equipped with mechanical stirrer and thermometer, 100 ml of acetone was added. The reactor was maintained at room temperature (22° C.). 5.35 g of N-methyl piperazine (1.1 equivalents) followed by 4.16 g of NaOH solution (47%, 1 equivalent) were added. 20 g of 1-[[3-(4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl chloride was added portion-wise (5 g each). The reaction mixture was kept at room temperature with mixing for 1 hour. The reaction mixture was kept at 5° C. for 2 hours. During that period, sildenafil base precipitated. After filtration, the cake was washed with water (50 ml). 29.24 g wet sildenafil base was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (245 mg, 1.35 mmol) in THF (2.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (83 mg, 2.02 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-chloro-3-nitrobenzaldehyde (46) (250 mg, 1.35 mmol) in THF was added dropwise. After 2 hours, water was added and the solvent concentrated in vacuo. The solid was filtered and dried to provide the crude title compound. Yield: 190 mg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2I)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C=O)C.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[CH:20]=[CH2:21])=[CH:4][CH:3]=1
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc(Cl)cc1
Yield: 89.2 %

Procedure:
A solution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl2(PPh3)2 (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90° C. under argon overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with 5% LiCl solution (2×), brine and dried (MgSO4). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.40-7.13 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 6.50 (dd, J=18, 11.7 Hz, 1H), 5.27 (d, J=11.7 Hz, 1H), 5.03 (d, J=18 Hz, 1H), 2.50 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[Cl:25]>C(O)C>[Cl:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1cnccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol) was dissolved in absolute ethanol (10 mL), then triethylamine (350 μL, 2.5 mmol) and 4-(bromomethyl)-3-chloropyridine (350 mg, 1.7 mmol) in absolute ethanol (5 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in diethyl ether, filtered, washed with water plus diethyl ether, and then dried in vacuo to afford to 2-{[(3-chloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (158 mg, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.46 (s, 2H), 6.03 (bs, 1H), 7.63 (d, J=5.0 Hz, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.63 (s, 1H); LRMS (ES+) m/z 268 (100%, M+1), 270 (65%, M+3).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C(OCC)C.Cl.[NH4+].O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([OH:12])([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(CBr)cc1
Agent: Cl
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CCC(O)(Cc2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of 1-ethoxycarbonyl-4-piperidone (39 ml, 0.26 mol) in diethylether (150 ml) was added dropwise at room temperature to a solution prepared from 4-methyl-benzylbromide (237 g, 1.28 mol) and Mg (31.2 g, 1.28 mol) in diethylether (300 ml). Room temperature was maintained for 45 min with stirring and the mixture was then refluxed for 5 h. It was cooled to 0° C., diluted with diethylether (700 ml) and hydrolyzed with saturated ammoniumhydrochloride solution (200 ml) and water (350 ml). Insoluble material was removed by filtration over Celite", the residue washed twice with diethylether (2×500 ml) and the organic phase was separated. The water layer was extracted with diethylether, the organic phases were pooled and dried with MgSO4 and the solvent evaporated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 2:1) to give 4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-carboxylic acid ethylester (70.5 g, 99%) as a yellowish oil, MS: m/e=278 (M+H+).
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(C)c4)cc3)c2cc1OC
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 3-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 41 mg of the title compound (yield: 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1.C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:19]1([OH:22])[CH2:20][CH2:21][S:17][CH2:18]1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CCSC1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at −78° C. under N2 is treated with see-butyllthium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at −78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at −78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf=0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf=0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:3]2[C:2]([S:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:9][CH:10]=1)#[N:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(-c2nccnc2Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1nccnc1-c1ccc(C#N)c2ccccc12
Temperature: 130 °C
Yield: 63.1 %

Procedure:
A mixture of 4-(3-chloropyrazin-2-yl)-1-naphthonitrile (0.16 g, 0.6 mmol), methyl thioglycolate (0.127 g, 1.2 mmol) and sodium carbonate (0.082 g, 0.78 mmol) in DMF (1 mL) was heated under microwave irradiation to 130° C. for 1 hour. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to yield methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate (0.127 g, 63%).
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]=[O:7].[NH4+].[Cl-]>CCOCC>[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:2]
Reactant: COc1cc(Br)c(C=O)cc1OC(C)C
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(Br)c(C(C)O)cc1OC(C)C
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A mixture of Mg turnings (231 mg, 9.51 g·atom) in dry Et2O (3.0 mL) was stirred at 0° C. under a nitrogen atmosphere then treated, dropwise, with a solution of iodomethane (680 μL, 10.9 mmol) in dry Et2O (2.0 mL). After 0.5 h a solution of aldehyde 36 (1.00 g, 3.66 mmol) in dry Et2O (10 mL) was added, dropwise, to the reaction mixture that was then allowed to warm to 18° C. at which temperature it was stirred for a further 1 h. After this time NH4Cl (15 mL of a 20% w/v aqueous solution) then Et2O (20 mL) were added to the reaction mixture. The separated organic phase was washed with H2O (1×20 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 37 (1.05 g, 99%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](Cl)[CH:5]=O.[NH2:9][C:10]([NH2:12])=[S:11].C>O>[CH3:1][O:2][C:3]([C:4]1[S:11][C:10]([NH2:12])=[N:9][CH:5]=1)=[O:8]
Reactant: COC(=O)C(Cl)C=O
Reactant: NC(N)=S
Agent: C
Solvent: O
Product: COC(=O)c1cnc(N)s1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 2.4 g of 2-chloro-3-oxo-propionic acid methyl ester (7-2), water 20 ml and 1.75 g of thiourea was refluxed for 2 hours. The mixture was cooled to room temperature and 0.25 g of norit was added and filtered. A solution of 2.5N sodium hydroxide was added to the filtrate until neutral pH. The filtration yielded 1.23 g (44%) of 2-aminothiazole-5-carboxylic acid methyl ester (7-3).
Reaction SMILES: N1C(F)=NC(F)=NC=1[F:3].[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1C=CC=CC=1>C(#N)C>[C:10]([F:3])(=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)F
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 85 %

Procedure:
To a solution of cyanuric fluoride (16 g, 0.12 mole in acetonitrile (125 ml) was added within 10 mins. a solution of oleic acid (80 g., 0.30 mole) and pyridine (24 g., 0.3 mole) in 125 ml. acetonitrile. The reaction mixture was stirred for 50 min and poured into ice-water, extracted with ether, and the organics dried over sodium sulfate. Removal of solvent and distillation in vacuo afforded oleoyl fluoride (85%, bp 184-186/12 torr).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:34])=[O:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-dimethoxybenzenesulfonyl chloride: ESMS m/e: 504.2 (M+H)+.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:49]=[C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:47]=[CH:46][C:45]=1[NH2:56].CCN(C(C)C)C(C)C.N12CCN(CC1)CC2>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:45]2[CH:46]=[CH:47][C:48]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[CH:49][C:44]=2[F:43])=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)cc1F
Agent: C1CN2CCN1CC2
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(N2CCOCC2)ccc1Nc1ncc(Br)n2ncnc12

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.105 g, 0.89 mmol), 2-fluoro-4-morpholin-4-yl-phenylamine (93 mg, 0.474 mmol), DIPEA (0.123 mL, 0.706 mmol) and 1,4-diazabicyclo[2.2.2]octane (53 mg, 0.472 mmol) in 2-propanol (2 mL). The reaction mixture is partitioned between DCM and 10% citric acid (aq) solution, the organic layer is separated and washed with 10% citric acid solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The title compound is isolated as a pale red solid (77 mg, 42%) and used in the next step without further purification. LCMS: Rt 3.48 min (89%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:13])[CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(CCl)n1
Product: Nc1nc(Cl)cc(CCl)n1
Reaction time: 0.17 h

Procedure:
47.9 Parts of 2-amino-4-chloromethyl-6-hydroxypyrimidine was added portionwise to 410 parts of phosphorus oxychloride with stirring. The mixture was placed in an oil bath at 130° C. and stirred until all the solid had dissolved and then for a further 10 minutes. The solution was cooled and the excess of phosphorus oxychloride was removed in vacuo. The residual viscous oil was poured onto 300 parts of ice with stirring and the pH of the resulting mixture was adjusted to pH 8 by the portionwise addition of solid sodium bicarbonate. The mixture was extracted four times with diethyl ether. The ether extracts were combined, dried over anhydrous magnesium sulphate and evaporated to give a pale-yellow solid. Recrystallisation from carbon tetrachloride gave pure 2-amino-4-chloro-6-chloromethylpyrimidine m.p. 126°-128° C.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:20](O)(=[O:29])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1(/[CH:22]=[CH:21]/[C:20]([N:15]2[CH2:16][CH2:17][C:18](=[O:19])[N:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Product: O=C(/C=C/c1ccccc1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in example 11A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-cinnamic acid gave the title compound as off-white solid. MS: 370.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:16][N:17]=[CH:18][C:3]=12.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C([O-])(O)=O.[Na+]>[C:20]1([CH2:19][O:1][C:2]2[C:7]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:9])=[CH:6][N:5]=[C:4]3[NH:16][N:17]=[CH:18][C:3]=23)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)c1cnc2[nH]ncc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)c1cnc2[nH]ncc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
To a solution of [4-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone (50 mg, 0.21 mmol) in methanol (1 mL) and saturated aqueous NaHCO3 solution (10 mL) was added benzyl bromide (0.027 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 h and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (SiO2, 230-400 mesh, eluted with 1:19 MEOH/CH2Cl2) to afford the title compound (13 mg, 20%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]2=[O:30])[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Yield: 79 %

Procedure:
The mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (compound 35, 10.0 g, 37.4 mmol), N-(3-bromopropyl)phthalimide (compound 34, 9.09 g, 33.9 mmol) and potassium carbonate (11.7 g, 84.8 mmol) in DMF was stirred at room temperature. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The obtained product was washed with EtOH to provide the title compound (11.2 g, 80%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](C(OC)=O)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (4.00 g, 13.0 mmol) was taken up in THF (30 mL) and MeOH (10 mL) under N2. NaOH (2 M, 19.5 mL, 39.0 mmol) was added, and the reaction was stirred at room temperature for 45 min. The solution was quenched with 1 M citric acid and extracted with EtOAc (2×). The combined organic extracts were washed with water and brine, dried (MgSO4), and evaporated. The resulting yellow oil was dissolved in 1:1 EtOAc:water (100 mL) and stirred at 85° C. for 2 h. The mixture was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated to give [4-(tert-Butoxycarbonyl)phenyl]acetic acid as a tan solid. 1H NMR (DMSO-d6, 600 MHz) δ 12.42 (bs, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 3.64 (s, 2H), 1.51 (s, 9H). MS: cal'd 259 (MNa+), exp 259 (MNa+).