Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:21][O:22][CH2:23][N:9]1[C:8]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:7]=2[S:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: COCCl
Reactant: COC(=O)c1ccc2c(c1)Nc1nccnc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1c2cc(C(=O)OC)ccc2Sc2nccnc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
415 g of methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate was suspended in 2.5 l of N,N-dimethylformamide in a nitrogen atmosphere. Then 66 g of sodium hydride (oily: 60% or more) was added in portions thereto while maintaining the mixture at −10 to 0° C. Then the resulting mixture was stirred for 1 hour. Next, 110 g of chloromethyl methyl ether was dropped thereinto while maintaining the mixture at a temperature not exceeding 5° C. After the completion of the reaction, the reaction mixture was poured into ice, extracted with methylene chloride twice, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, diisopropyl ether was added to the residues and the crystals thus precipitated were taken up by filtration to thereby give 335 g of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(N)cc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-chloro-4-methoxyaniline to yield 2-[(3-chloro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[CH2:6][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:18]I>C(#N)C>[CH:1]1([NH:4][C:5](=[O:17])[CH2:6][N:7]([CH3:18])[C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=C(CN[C@@H]1C[C@H]1c1ccccc1)NC1CC1
Reactant: CI
Solvent: CC#N
Product: CN(CC(=O)NC1CC1)[C@@H]1C[C@H]1c1ccccc1
Yield: 81.9 %

Procedure:
To a solution of N-cyclopropyl-N-methyl-trans-2-(phenylcyclopropyl amino)acetamide (example 1, 240 mg, 1 mmol) in acetonitrile (10 mL), methyl iodide (140 mg, 1 mmol) was added and the solution was refluxed for 1 h. The mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (DCM:MeOH, 10:1) to afford the title compound as a white solid (200 mg, 57%). 1HNMR (CDCl3) δ (ppm): 0.44 (s, 2H), 0.73 (dd, 2H), 0.93 (m, 1H), 1.02 (m, 1H), 1.89 (m, 1H), 2.04 (m, 1H), 2.29 (s, 3H), 2.67 (m, 1H), 3.13 (m, 2H), 6.84 (br, 1H), 6.98 (d, 2H), 7.11 (q, 1H), 7.14 (m, 2H), 7.18 (d, 2H). MS (M+H): 244.7.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][S-:12].[Na+]>CO>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a mixture of 5-chloro-2-nitropyridine (3 g, 18 mmol) in MeOH (20 mL), sodium methanethiolate (1.4 g, 20 mmol) was added at 0° C. and the mixture stirred at 20° C. for 2 hours. The resulting suspension was filtered and washed with water, and dried in vacuum to afford crude 117a as a yellow solid (2 g, 66%) without purification for next step. MS: [M+H]+ 171.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]O.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: OCCCc1c[nH]c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(CCCBr)c2c1
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (2.15 g, 11.2 mmol), carbon tetrabromide (4.80 g, 14.5 mmol) and triphenylphosphine (4.40 g, 16.7 mmol) in methylene chloride is stirred for 1 h and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane 3/7) to afford the title product as an oil, 1.97 g (69% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(Cl)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(Cl)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-chlorobenzoxazole (100 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (69 mg, 0.36 mmol) the title compound was obtained (92 mg, 58%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.37(t, 1H), 8.09–8.05(m, 2H), 7.92(d, 1H), 7.79(d, 1H), 7.47(m, 2H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS m/z 474.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](OCC)=[O:17])=[N:5][CH:4]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](=[O:17])[N:5]2[CH:4]=1
Reactant: CCOC(=O)C(=CNc1ncc(OC)c2ccccc12)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c3ccccc3c(OC)cn2c1=O
Yield: 79 %

Procedure:
A mixture A mixture of diethyl 4-methoxyisoquinolylaminomethylenemalonate (460 mg., 1.33 mmoles) and diphenyl ether (4.6 ml.) was placed in an oil bath at 210°, the temperature of which, was increased to 260° during 5 minutes. Dilution of the solution with Skellysolve B caused the product (315 mgs., 79% yield), m.p. 190°-193°, to separate. Recrystallization from ethyl acetate raised the m.p. to 202°-204°.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([O:11][CH3:12])=[CH2:10]>>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:9]([O:11][CH3:12])[CH3:10])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=COC
Product: COC(C)Oc1ccc(Br)cc1
Yield: 90 %

Procedure:
Using p-bromophenol (17.3 g, 0.1 mole) and methyl vinyl ether (14.0 g, 0.2 mole), the reaction was carried out in the same manner as described in Synthesis Example 1, (1), and the crude oil (24 g) was purified by distillation under reduced pressure to afford 20.8 g of p-bromo-(1-methoxyethoxy)benzene as a pale yellow oil having a boiling point 89-90° C./2 mmHg.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].[OH-].[Na+].O>CS(C)=O.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:29][N:28]=2)([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)(CC2CCCC2)c2ccc(Br)cn2)cc2cccnc21
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 43.1 %

Procedure:
To a mixture of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(5-bromo-pyridin-2-yl)-2-cyclopentyl-ethanol (0.28 g, 0.53 mmol), sodium methanesulfinate (82 mg, 0.8 mmol), and copper (I) iodide (10 mg, 0.05 mmol) in dimethylsulfoxide (5 mL) was added sodium hydroxide (4 mg, 0.106 mmol). The resulting mixture was heated at 95° C. After stirring for 12 h, the mixture was poured into water (10 mL), extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(5-methanesulfonyl-pyridin-2-yl)-ethanol (0.12 g, 43%): LC/MS m/e calcd for C26H27N3O5S2 [M+H]+ 526.65, observed 526.3.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([CH3:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([S:35]([N:34]([CH3:39])[CH3:33])(=[O:37])=[O:36])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([CH3:22])=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(C)cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(N(S(C)(=O)=O)S(=O)(=O)N(C)C)c(C)cc1OC
Yield: 54.4 %

Procedure:
A mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide (500 mg), triethylamine (823 mg), dimethylaminosulfonyl chloride (1.17 g), and methylene chloride (20 ml) is refluxed for 39 hours. The reaction mixture is washed with aqueous sodium hydrogencarbonate. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0.5-1% methanol/methylene chloride. The eluate is evaporated to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-[N-(dimethylaminosulfonyl)methanesulfonamido]benzamide (351 mg) as an oil. This product is mixed with tetrahydrofuran (3 ml) and 10% sodium hydroxide (3 ml) and warmed at 80° C. for 1 hour. The reaction mixture is evaporated to remove the tetrahydrofuran, acidified with hydrochloric acid, made alkaline with sodium hydrogencarbonate, salted out with sodium chloride, and shaken with methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 3% methanol/methylene chloride. The eluate is evaporated to remove the solvent. The residue is washed with ether/isopropyl ether and filtered to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide (211 mg). The product is recrystallized from acetonitrile/isopropyl ether to give crystals melting at 129° to 129.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(Br)c3)C2)c1

Procedure:
The compound of Example 21 was prepared according to the general preparation protocol A from 3-bromobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:16])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:16])[N:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: O=c1c([N+](=O)[O-])cccn1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])cc(Br)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
10 ml of a dimethylformamide solution containing 1 g of 3-nitro-1-phenyl-1,2-dihydropyridin-2-one was incorporated with 988 mg of N-bromosuccinimide, followed by stirring at room temperature overnight. Further, it was stirred at 50° C. for 3 hours. The reaction mixture was poured into ice-water, and the resulting precipitates were collected by filtration, to give 1.27 g of the title compound.
Reaction SMILES: C(OC([O:8][NH:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[NH:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:18]2)=[CH:13][CH:12]=1)C)C(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:8][NH:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[NH:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:18]2)=[CH:13][CH:12]=1
Reactant: CC(C)COC(C)ONC(=O)c1ccc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NO)c1ccc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)cc1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
N-(1-Isobutoxyethoxy) 4-{6-[(naphthalen-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}-benzamide (117 mg, 0.25 mmol) was stirred in DCM (10 ml) at r.t. and 4M HCl in dioxane (0.5 ml) was added. The reaction was allowed to stir for 30 min and then the solvent was removed in vacuo. The residue was purified by Gilson HPLC to give the title compound as a pink solid (13 mg, 14%). LCMS purity 98%, m/z 374 [M+H]+. 1H NMR (300 MHz, CD3OD) δ: 2.25 (2H, br s), 2.71 (1H, s), 3.32 (2H, m), 3.71 (2H, d, J=9.3 Hz), 4.54 (2H, s), 6.61 (2H, d, J=8.1 Hz), 7.62 (5H, m), 7.95 (4H, m), no peaks for NH/NHOH due to CD3OD.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)CCCC2
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCCC2
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
118 g (0.73 mole) of 5,6,7,8-tetrahydro-2-naphthol methyl ether are dissolved in 320 ml of methylene chloride, and 177 ml of chlorosulfonic acid in 160 ml of methylene chloride are added. The mixture is stirred for 10 minutes at 5° C. and is poured into ice water. The organic phase is separated off and dried with MgSO4. The solvent is removed by evaporation and the residue is recrystallized from acetone/petroleum ether.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7](=[O:9])[CH3:8])(=O)[CH3:4].OC1C=[CH:15][C:14]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1COCC1>[C:7]([O:6][C:3]1[CH:12]=[CH:13][C:14]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:15][CH:4]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)s1
Temperature: 25 °C

Procedure:
Sodium hydride and acetic anhydride were added to a THF solution of methyl 5-(4-hydroxyphenyl)thiophene-2-carboxylate and the whole was stirred at room temperature to obtain methyl 5-[4-(acetyloxy)phenyl]thiophene-2-carboxylate. ES: 277.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(OCC)(=O)C>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)CCl
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: COC(=O)CN1CCN(C)CC1
Reaction time: 17 h
Yield: 94.6 %

Procedure:
Methyl chloroacetate (8.8 ml., 0.10 mole) was added to a solution of N-methylpiperazine (24.4. ml., 0.22 mole) in ethyl acetate (140 ml.) and the mixture was stirred for 17 hours. The reaction mixture was filtered and the solvent was removed under vacuum. The resulting oil was dissolved in methylene chloride-methanol (9:1) and purified by flash chromatography (silica) to give 2-(4-methyl-1-piperazinyl)acetic acid, methyl ester as an oil (16.3 g, 95%).
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>C(O)C>[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:13][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Oc1ccc2c(c1)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Temperature: -5 °C
Yield: 47.9 %

Procedure:
To a solution of potassium hydroxide (0.67 g, 9.80 mmol) in ethanol (30 ml) is added 5,6,7,8-tetrahydro-2-naphthol (1.45 g, 9.80 mmol) and 4-(2-bromoethoxy)benzaldehyde (2.25 g, 9.80 mmol). Then the mixture is heated to reflux for 8 hours. After cooled to −5° C., the precipitate is collected by filtration, washed with water, and dried under vacuum to give the title product (1.39 g, 48.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)C(O[C:40]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:41]=1[F:50])=O>CN(C=O)C>[F:46][C:45]1[C:40]([O:24][C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=3)=[O:25])=[C:41]([F:50])[C:42]([F:49])=[C:43]([F:48])[C:44]=1[F:47]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 32 (0.154 g, 0.44 μmol) in DMF (5 mL) in the presence of DIEA (93 ml, 0.53 mmol) was added dropwise pentafluorophenyl trifluoroacetate (92 μl, 0.53 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. HPLC showed that the reaction was completed. The solvent was then evaporated to dryness, and the residue was carefully washed with ether to give compound 33 in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH2:57])=[CH:54][CH:53]=1>CN(C=O)C>[F:21][C:2]([F:1])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([NH:57][CH2:56][C:55]1[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=1)=[O:13]
Reactant: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.15 g, 0.45 mmol) in DMF (3 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (216 mg, 0.68 mmol) and N-methylmorpholine (0.01 ml, 0.9 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (67 mg, 0.54 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 15% acetone/hexane) affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-thiazole-5-carboxylic acid amide (example 14) (93 mg, 0.21 mmol, 47%). [M+H]+ 441.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[NH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([Cl:13])[N:7]=1.C(O)C>C(N(CC)CC)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:4][CH2:3][CH2:2][OH:1])[CH:9]=[C:8]([Cl:13])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCCO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCCO)n1
Yield: 59.6 %

Procedure:
To 2-hydroxyethylamine (2.6 g, 42.7 mmol) were added 2-amino-4,6-dichloropyrimidine (7.0 g, 42.7 mmol), ethanol (150 ml) and triethylamine (6.6 ml), and the mixture was refluxed for one day. The solvent was distilled away under reduced pressure and the residue was washed with water, which was followed by recrystallization from chloroform to give yellow prism crystals (4.8 g, 59.6%), m.p. 143-146° C. (chloroform).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C=O>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
0.75 g (0.00741 mol) of 4-hydroxy-piperidine were dissolved in 40 ml of dimethylformamide and cooled to 0°. 3.0 g (0.00926 mol) of 2-nitro-benzyl bromide and 2.87 ml (0.0204 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 1.22 g (56%) of 1-(2-nitro-benzyl)-piperidin-4-ol were obtained as a yellow oil. MS: me/e=237 (C12H17N2O3+).