Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[C:16]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCc1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCc1ccncc1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 4-hydroxymethylpyridine (10.02 g) and triethylamine (9.27 g) in tetrahydrofuran (100 ml) was dropped a solution of hexadecanoyl chloride (25.2 g) in tetrahydrofuran (80 ml) under cooling in an ice bath and stirring, which was continued for one hour at the same temperature. A resulting precipitate was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in diether ether, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (250 g) using methylene chloride-ethyl acetate as an eluent to give 4-hexadecanoyloxymethylpyridine (14.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:19])[CH2:10][C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[CH2:21]([N:28]1[C:13](=[O:15])[CH:12]=[C:11]([CH2:10][N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:19])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)CN(C)c1cc(Cl)cc(Cl)c1
Reactant: NNCc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(Cc1cc(=O)n(Cc2ccccc2)[nH]1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-((3,5-dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol) and benzyl hydrazine chloride (388 mg, 2.0 mmol) in EtOH (5 mL) was added anhydrous triethylamine (570 uL, 4.0 mmol). The resulting solution was stirred at room temperature overnight. After evaporating the volatiles, the residue was purified on a silica gel column, eluting with a mixture of MeOH and dichloromethane (1% to 2% MeOH) to afford the product as a pale yellow solid (320 mg, 88%). The solid was then recrystallized in dichloromethane/hexane to give the product as a white solid. 1H NMR (DMSO-d6, 500 MHz): δ=11.00 (br s, 1H), 7.28 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.0 Hz, 1H), 7.11 (d, J=7.0 Hz, 2H), 6.74 (d, J=1.5 Hz, 2H), 6.69 (s, 1H), 5.12 (s, 1H), 5.01 (s, 2H), 4.33 (s, 2H), 2.98 (s, 2H); 13C NMR (DMSO-d6, 125 MHz): δ=152.7, 151.0, 146.8, 138.0, 134.4X2, 128.4X2, 127.1, 127.0X2, 114.4, 110.6X2, 84.6, 50.3, 49.2, 38.9 ppm; MS (ESI): m/z 284.0 [M+H]+; CHN calculated for C18H17Cl2N3O: C, 59.68; H, 4.73; N, 11.60. found: C, 59.79; H, 4.68; N, 11.48.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#[N:20].B(O)(O)[C:28]1[CH:33]=CC=[C:30](F)[CH:29]=1>ClCCl.CO>[C:25]1([C:24]2[N:20]=[CH:19][C:21]([C:12]3[NH:8][C:9]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[N:10][CH:11]=3)=[CH:22][N:23]=2)[CH:26]=[CH:30][CH:29]=[CH:28][CH:33]=1.[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccnc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ncc(-c3cnc(-c4cccnc4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C. 3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the method described in Example 8, Steps A and B except the commercially available 3-cyanopyridine was used instead of 3-fluorobenzonitrile; Rf 0.25 with 95:5 v/v dichloromethane-methanol; melting point 308° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.32 (s, 2H), 9.20 (d, 1H), 8.58 (dd, 1H), 8.44-8.31 (m, 3H), 8.12 (m, 1H), 7.57-7.46 (m, 4H); MS (ESI+) m/z 300.1 (M+1); H-PGDS FPBA IC50: 0.079 μM; H-PGDS inhibitor EIA IC50: 0.021 μM.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5](N2C3C(=CC(F)=C(C4CCC(N)C4)N=3)C(=O)C(C(O)=O)=C2)=[CH:4][CH:3]=1.[CH:29]1([N:32]2[C:41]3[C:36](=[CH:37][C:38]([F:48])=[C:39]([CH:42]4[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]4)[N:40]=3)[C:35](=[O:49])[C:34]([C:50]([OH:52])=[O:51])=[CH:33]2)[CH2:31][CH2:30]1.C(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:29]1([N:32]2[C:41]3[C:36](=[CH:37][C:38]([F:48])=[C:39]([CH:42]4[CH2:46][CH2:45][C:44](=[N:47][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:43]4)[N:40]=3)[C:35](=[O:49])[C:34]([C:50]([OH:52])=[O:51])=[CH:33]2)[CH2:30][CH2:31]1
Reactant: NC1CCC(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Reactant: NC1CCC(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(C2CC2)c2nc(C3CCC(=Nc4ccccc4)C3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
In a round-bottomed flask equipped with a magnetic stirring bar are placed 2 grams of (I) the product of Example 2 (Z= ##STR31## A=N, R=cyclopropyl, R3 =H, R1 =OH), 20 ml of toluene, and 1.5 ml of benzaldehyde. The system is equipped with a Dean-Stark trap containing four angstrom molecular sieves. The reaction mixture is heated at reflux for one day and cooled to room temperature. The solid imine (I) Z= ##STR32## A=N, R=cyclopropyl, R3 =H, R1 =OH) is collected by suction filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].CNC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound. LCMS: 491.25 (M+1)+; HPLC: 99.58% (@254 nm) (Rt; 3.984; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.75 (s, 1H), 8.19 (t, 1H), 8.05 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.41 (s, 1H), 7.24 (s, 1H), 5.86 (s, 1H), 5.44 (t, 1H, J=5.6 Hz), 4.59 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=4 Hz), 3.85 (d, 2H, J=10.4 Hz), 3.32 (2H merged in solvent peak), 3.03 (s, 1H), 2.64 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36]>O1CCCC1.C(Cl)(Cl)Cl.C(O)(C)C>[CH2:16]([O:15][C:13](=[O:14])[C:11]1[CH:12]=[C:2]([O:1][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=2[N+:35]([O-:37])=[O:36])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[O:18][C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:33])([F:34])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:35]([O-:37])=[O:36])[CH3:17]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OCC)cc1Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of diethyl 2,5-dihydroxyterephthalate (127 mg, 0.5 mmol) and sodium hydride (60%, 20 mg) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 30 minutes followed by the addition of 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (75 mg, 0.26 mmol). After 45 mintues, more 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (63 mg, 0.22 mmol) was added. Tetrahydrofuran (1 mL) was added after each addition of 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene. After 18 hours at room temperature, more 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (75 mg) was added and the temperature was increased to 60° C. for 2 hours. The reaction was diluted with chloroform/isopropanol, washed with brine and purified on silica gel to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 8.82 (d, J=2.2 Hz, 2H), 8.27 (dd, 2H), 8.18 (s, 2H), 7.48 (d, J=9 Hz, 2H), 4.15 (q, J=6.8 Hz, 4H), 0.98 (t, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C1COCC1>[Cl:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)=[O:37]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 0.21 g (0.6 mmol)[6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine and 94 μl (0.67 mmol) triethylamine in 5 ml dry THF is treated dropwise with a solution of chloro-acetyl chloride (51 μl, 0.64 mmol) in 0.5 ml of dry THF at RT. After stirring for 30 min small amounts of insoluble material is removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography using ethyl acetate/methanol 100:2 to 100:4 as eluent. The title compound is obtained as light brown solid HPLC tR=9.36 min; MS-ES+: (M+H)+=420.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][O:24][CH2:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CCOCC>C1CCCCC1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH2:26])[CH2:23][O:24][CH2:25]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C4(NS(=O)C(C)(C)C)COC4)ccc3c2)CC1
Agent: Cl
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(N)COC4)ccc3c2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {3-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-yl}-amide (86 mg, 0.19 mmol) in methylene chloride (2 mL, 30 mmol) was added 2.0 M of hydrogen chloride in ether (0.188 mL, 0.376 mmol) and was stirred 10 min. A precipitate formed and cyclohexane was added to dilute the mixture. After removal of solvent, the residue was dissolved in methylene chloride, 1 M aq. NH4OH was added and the extracted organic layer was dried and chromatographed with MeOH/CH2Cl2 (20-40%) to give 3-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)oxetan-3-amine as a solid (44.8 mg, 67%). LCMS: Rf=1.55 min 337.20 ([M−16]). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.84 (d, J=1.4 Hz, 1H), 7.81-7.70 (m, 2H), 7.66 (d, J=1.9 Hz, 1H), 7.22-7.12 (m, 2H), 5.09 (d, J=6.7 Hz, 2H), 4.81 (d, J=6.7 Hz, 2H), 4.29 (tt, J=4.2, 10.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 2H), 1.91 (d, J=12.5 Hz, 2H), 1.56-1.39 (m, 2H), 1.29-1.02 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](=[C:13]([CH2:16][CH2:17]Cl)[CH2:14]Cl)([CH3:12])[CH3:11]>O>[C:10](=[C:13]1[CH2:16][CH2:17][C:6]2([CH:5]=[C:4]([CH3:8])[C:3](=[O:9])[C:2]([CH3:1])=[CH:7]2)[CH2:14]1)([CH3:12])[CH3:11]
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)=C(CCl)CCCl
Solvent: O
Product: CC1=CC2(C=C(C)C1=O)CCC(=C(C)C)C2
Temperature: 15 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
2,6-Dimethylphenol (2.4 g, 0.02 mol) was added to a solution of Ba(OH)2.8H2O (6.6 g, 0.021 mol) in distilled water (12 mL). The mixture was cooled to 15° C. and 2-isopropylidene-1,4-dichlorobutane (3.6 g, 0.022 mol) was added over 1 hour under nitrogen. Stirring at room temperature was continued for 5 hours and then the reaction mixture was extracted with ether. The ether extracts were washed with 10% sodium hydroxide, water, and dried (Na2SO4). Concentration gave 4.7 g of crude material which was mainly the alkylated phenol having the structure: ##STR33## A sample purified by preparative glc had the following spectral characteristics:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=O)[CH3:20])[C:3]=1[S:22]([CH3:24])=[O:23].Cl.[NH2:26][CH2:27][CH2:28][SH:29].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2([CH3:20])[NH:26][CH2:27][CH2:28][S:29]2)[C:3]=1[S:22]([CH3:24])=[O:23]
Reactant: NCCS
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)c1c(C2(C)NCCS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 1.7 %

Procedure:
A mixture of 1 g (2.5 mmol) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-acetyl-4-methylsulfinyl-1H-pyrazole, 0.284 g (2.5 mmol) of 2-aminoethanethiol hydrochloride, 348 microliters (2.50 mmol) of triethylamine, 50 mg of p-toluenesulfonic acid and 30 ml of benzene was heated to reflux with removal of water overnight. The mixture was successively cooled, filtered, evaporated, chromatographed so as to give 20 mg of the title compound as white solid; melting point 85° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([O:10][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[C:23]([F:22])([F:32])[F:33])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(NC(C)=O)nc1OCc1ccccc1C(F)(F)F
Yield: 61.2 %

Procedure:
Ethyl 2-(acetylamino)-4-hydroxy-1,3-thiazole-5-carboxylate (6.04 g, 26.2 mmol) was dissolved in 100 mL of N,N-dimethylformamide with stirring. Potassium carbonate (3.98 g, 28.8 mmol) was added in a single portion. 2-Trifluoromethylbenzyl bromide (6.58 g, 27.5 mmol) in 20 mL of N,N-dimethylformamide was added via syringe. The reaction was stirred for 16 hours and poured into water and ethyl acetate. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 6.23 g (61%) of ethyl 2-(acetylamino)-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.92 (m, 1H), 7.82-7.71 (m, 2H), 7.58 (m, 1H), 5.60 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[CH2:11][CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][N:8]3[C:7]=2[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2=NCCC2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Yield: 44.9 %

Procedure:
2-(4-Chlorobenzyl)-1-pyrroline (9 g, 50% strength, 25 mmol), dissolved in MeOH (75 ml) is treated with phenacyl bromide (4.97 g, 25 mmol) and then with NaHCO3 (2.5 g, 30 mmol) and stirred at RT for 16 h with exclusion of light. Precipitated crystallizate is filtered off with suction and washed with MeOH. 3.3 g (45%) of product are obtained after drying.
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([OH:24])[CH2:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:32]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34][CH2:33]1.C([O-])(=O)CCCCCCC>CCOCC.C(Cl)Cl>[C:32]([O:24][CH:12]([CH2:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:39])[CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC
Reactant: O=C1CCCC(=O)O1
Agent: CCCCCCCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)O

Procedure:
A solution of 2-hydroxy-3-octanoyloxypropyl octanoate (5.0 g.) in ether (30 ml.) was stirred with triethylamine (2.04 ml.) and glutaric anhydride (1.66 g.) for 3.5 hours. Further glutaric anhydride (0.8 g.) was then added together with triethylamine (1.0 ml.). This mixture was heated under reflux until no further starting octanoate could be detected by thin layer chromatography (silica: methylene chloride). The cooled reaction mixture was washed with 1M hydrochloric acid (2×20 ml.), then with water (2×20 ml.), dried (MgSO4) and evaporated to give 2-octanoyloxy-1-(octanoyloxymethyl)ethyl hydrogen glutarate as an oil (6.62 g.); NMR (CDCl3): 0.9 (6H, t, CH3), 1.1-2.1 (22H, m, CH2), 2.4 (8H, m, CH2CO), 4.0-4.4 (4H,m, CH2O), 5.1-5.4 (1H, br.t, CHO), 9.6 (1H, br.s, CO2H)ppm. Mass spectrum (major diagnostic peaks based on M=458, using chemical ionisation techniques): m/e 476 (M+NH4), 360 (M +NH4 --HO2C.(CH2)3.CO2H)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH2:1]([N:8]1[C:12]2[C:13]([Br:18])=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc2ncn(Cc3ccccc3)c2c1
Agent: N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc2ncn(Cc3ccccc3)c2c1Br
Yield: 29 %

Procedure:
To a solution of 3-benzyl-5-aminobenzimidazole (0.88 g, 3.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.35 g (1.2 mmol, 29%) of the product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (370 mg, 66%). MS (ISP) 555.2 [(M+H)+]; mp 206–208° C.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:12]2=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:47]I>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:47])=[C:13]2[C:9]=1[CH:10]([OH:27])[N:11]([C:18]([CH3:19])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:26])[C:12]2=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Oc3ccccc3)c2C1O
Yield: 74.8 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (700 mg, 1.95 mmol) was dissolved in THF (28 mL), and the solution was treated with TMEDA (0.94 mL, 6.2 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 6.20 mL, 6.24 mmol) and iodine (594 mg, 2.34 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0, 99/1) to obtain 4-phenoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (708 mg, yield 75%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1.[OH:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:18][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:11])[CH:17]=2)=[N:4][CH:5]=1
Reactant: Oc1ccnc(O)c1
Reactant: COc1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc[nH]c(=O)c2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromomethyl-5-methoxy-pyridine (preparation 11a, 2.00 g crude material), 2,4-dihydroxypyridine (1.06 g, 9.5 mmol) in acetonitrile (20 mL) and DMF (5 mL) is added K2CO3 and the mixture is stirred for 4 h at 50° C. and overnight at room temperature. The reaction mixture is diluted with water (60 mL) and extracted several times with ethyl acetate. The organic layer is dried over Na2SO4, concentrated under reduced pressure and purified via reverse phase HPLC chromatography (Waters XBridge 5 μm, gradient 25%→95% methanol in water+0.3% NH4OH).