Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].N1C=CC=CC=1.[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18].O>C(OCC)C>[Br:15][CH:16]([CH3:20])[C:17]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:18]
Reactant: CC(Br)C(=O)Br
Reactant: COC(=O)NCCO
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)NCCOC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of methyl 2-hydroxyethylcarbamate and 6.7 g of pyridine are dissolved in 70 ml of diethyl ether and cooled to 0°-5° C. 18.0 g of 2-bromopropionyl bromide, dissolved in 20 ml of diethyl ether are now added dropwise within 30 minutes and the mixture is stirred at ice temperature for a further 30 minutes and at room temperature for 1 hour. For the working-up, the mixture is poured into water and extracted with diethyl ether. The ether phase is washed twice with sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. There is obtained methyl 2-(2-bromopropionyloxy)ethylcarbamate as a yellow oil which is used without further purification.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23].N1C=CC=CC=1.[NH2:32][CH2:33][CH2:34][OH:35].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([NH:32][CH2:33][CH2:34][OH:35])=[O:3])=[CH:17][C:16]=1[C:22]([F:23])([F:24])[F:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCO)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
p-Nitrophenyl chloroformate (437 mg, 2.17 mmol) was added to a solution of 4-bromo-3-trifluoromethyl-aniline (400 μl, 1.67 mmol) and pyridine (202 μl, 2.50 mmol) in CH2Cl2 (6.2 ml) at 0° C. The mixture was stirred at 0° C. for one hour, and 2-amino-ethanol (150 μl, 2.50 mmol) was then added, followed by further stirring at 0° C. for two hours. Triethylamine (210 μl, 1.51 mmol) was added to the mixture, and the mixture was stirred at 0° C. for one hour. 1 N HCl was added to the reaction mixture, followed by extraction with CH2Cl2/AcOEt. The organic layer was washed with water (×2), and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2-MeOH) to give 1-(4-bromo-3-trifluoromethyl-phenyl)-3-(2-hydroxy-ethyl)-urea as a white powder (520 mg, 73%).
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9]([C:12]#[N:13])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.CC(C)=O>[C:12]([C:9](=[N:6]/[C:3](=[C:2](\[NH2:1])/[C:7]#[N:8])/[C:4]#[N:5])[CH3:10])#[N:13]
Reactant: CC(=O)C#N
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C#N)=N/C(C#N)=C(\N)C#N
Yield: 41 %

Procedure:
10.8 g of diaminomaleonitrile and 10.0 g of acetyl cyanide were added successively to a solution of 1.9 g of p-toluenesulfonic acid in 100 ml of dry diethyl ether. The resulting yellow powder was collected by filtration and dried. The crude product thus obtained was dissolved in 600 ml of acetone and any insoluble insoluble solids were removed by filtration. 900 ml of water was added to the filtrate to obtain α-cyanoethylidenediaminomaleonitrile in 41% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[I:21]I.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[I:21]
Reactant: II
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(I)c(F)c1
Temperature: -72 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
Under dry nitrogen, a solution prepared by dissolving 4-bromo-3-fluorotoluene (10 g) in THF (50 mL) was cooled to −72° C. Then, a 1.6 mol/L n-butyl lithium hexane solution (35 mL) was added at −72° C. to the solution such a rate that the inside temperature was not more than −65° C., followed by further stirring at −72° C. for 1 hour. A solution prepared by dissolving iodine (14.8 g) in THF (30 mL) was added at −72° C. to the resultant mixture such a rate that the inside temperature was not more than −60° C., and the temperature was slowly increased to room temperature. Then, a saturated aqueous ammonium chloride solution and hexane were added at room temperature to separate an organic layer, and the organic layer was washed with a 10% aqueous sodium sulfite solution two times and saturated brine in that order, and then dried with sodium sulfate. The sodium sulfate was filtered off, and the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.0 g of 3-fluoro-4-iodotoluene as a yellow liquid.
Reaction SMILES: C([O:3][P:4]([CH:9]([C:36]#[N:37])[CH2:10][C:11]([CH2:34][CH3:35])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:36]([CH:9]([P:4](=[O:3])([OH:5])[OH:8])[CH2:10][C:11]([CH2:34][CH3:35])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])#[N:37]
Reactant: CCOP(=O)(OCC)C(C#N)CC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)CC(C#N)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonic acid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of 10% TFA/CH2Cl2 (2 mL) and stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and purified by RP-HPLC to provide 9.5 mg (61%) of the desired product. This material was dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2 mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reaction solution was allowed stir at room temperature overnight before quenching with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.1 mg (65%) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.10 (t, 3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m, 1H), 3.05-3.20 (m, 1H), 3.48 (d, J=7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CD3OD) δ 14.18 ppm; MS (m/z) 394 [M−H]−, 396 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[O:34][C:35]=1[CH3:36])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[O:34][C:35]=3[CH3:36])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1oc2ccccc2c1C(=O)CCCCCBr
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2c(C)oc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-methyl-3-benzo[b]furyl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-methyl-3-benzo[b]furyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15](Br)[CH:16]([Br:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([O:34][CH3:33])[CH:16]([Br:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C1CN(c2ccc(C(Br)C(Br)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-(1,2-dibromo-2-phenylethyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (25 mg, 0.043 mmol) in MeOH/methylene chloride (1:1, 4 mL) is added NaOMe (0.17 mL, 0.086 mmol, 0.5M in THF). The solution is stirred at RT for 2 h and the solvent is removed under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([CH3:21])([C:17](=O)CCl)[CH:5](Cl)[CH:6]=[C:7]([Cl:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl.[CH3:23][OH:24]>>[Cl:15]/[C:7](/[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[CH:6]\[C:5]1([C:23]([OH:24])=[O:1])[CH2:21][C:4]1([CH3:3])[CH3:17]
Reactant: CO
Reactant: [OH-]
Reactant: CC(C)(C(=O)CCl)C(Cl)C=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Product: CC1(C)CC1(/C=C(\Cl)c1ccc(Cl)cc1)C(=O)O
Reaction time: 3 h

Procedure:
10 g (0.11 mol) of 45% strength sodium hydroxide solution are added dropwise at 20° to 25° C. during the course of 30 minutes to a suspension of 7 g (0.02 mol) of 4,4-di-methyl-1,3-dichloro-6-chloro-1-(4-chlorophenyl)-hex-1-en-5-one in 20 ml of methanol. The reaction is subsequently stirred for 3 hours at 35° to 40° C. After neutralization using concentrated hydrochloric acid, the main amount of methanol is removed by evaporation in vacuo. The solution remaining is adjusted to pH 3 using concentrated hydrochloric acid, extracted using toluene at 40° C. and the solvent is stripped off. 5.36 g (94% of theory) of cis/trans-3-(Z-2-chloro-2-(4-chlorophenyl)-vinyl-2,2-dimethylcyclopropanecarboxylic acid are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1.CCCCCC>[CH:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: CC(C)[C@H]1COC(c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)[C@H]1COC(c2ccc(C=O)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g of (S)-2-(4-bromophenyl)-4-isopropyl-2-oxazoline in 20 ml of absolute tetrahydrofuran is treated drop-wise with 5 ml of 1.6M butyllithium in hexane at -78° C. and while gassing with nitrogen, stirred at this temperature for 2 hours, then treated dropwise with 2 ml of absolute N,N-dimethyl-formamide and then warmed slowly to room temperature. The reaction mixture is poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases are washed twice with 100 ml of saturated sodium chloride solution each time, dried over magnesium sulphate, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) yields 0.8 g of pure (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]2(N2CCCC2)[O:8][N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)CC12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc2c1CN(C(C)=O)CC2

Procedure:
A mixture of 18.0 g (58 mmol) of 5-acetyl-7a-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) in 150 mL of DCM and 6.47 mL (87 mmol) of trifluoroacetic acid was heated to reflux for 8 h. After addition of 100 mL of water, the organic phase was dried over MgSO4 and the solvent removed under a vacuum. The remaining brown oil was purified by column chromatography (SiO2, EtOAc/EtOH 10:1). 12.5 g (90% of theoretical) of the desired product 5-acetyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (C) were obtained in the form of a brown-yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:9][CH2:8][O:7][C:6]2=[O:10])[CH2:4][CH2:3][O:2]1>O>[C:1](=[O:11])=[O:2].[O:2]1[CH2:3][CH2:4][CH:5]([C:6]([OH:7])=[O:10])[CH2:9][CH2:8]1
Reactant: O=C1OCCC12CCOC2=O
Solvent: O
Product: O=C(O)C1CCOCC1
Product: O=C=O

Procedure:
The 2,7-dioxaspiro[4.4]nonane-1,6-dione II can preferably be reacted in molten (m.p.: 108° to 109° C.) or dissolved form, together with the alcohol III or water and, if appropriate, an inert gas such as nitrogen, carbon dioxide or argon, to give tetrahydropyran-4-carboxylic acid and its esters I.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1)[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39](=[O:40])[N:31]2[CH2:29][CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCn1[nH]c2ccccc2c1=O
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 2-ethyl-1H-indazol-3(2H)-one were reacted to give 472. LCMS m/z: 534.3 (MH+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH2:25]O)=[O:24])=[CH:19][C:18]=1[CH3:27].[OH2:28]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:21]1[CH:22]=[C:17]([CH3:16])[C:18]([CH3:27])=[CH:19][C:20]=1[C:23](=[O:24])[CH3:25]
Reactant: O
Reactant: Cc1ccc(C(=O)CO)cc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 4,5-dimethyl-2-hydroxyacetophenone (220 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 120° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (34 mg, yield 22%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: COC(=O)Cc1ccc(O)cc1
Product: COC(=O)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
1-(Benzyloxycarbonyl)piperidin-4-ol and methyl 4-hydroxyphenylacetate were treated in the same manner as the one of Production Example 65 to thereby give the title compound as a pale green powder.
Reaction SMILES: [ClH:1].[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[OH-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>CC(C)=O>[Cl:1][C:5]1[CH:6]=[CH:7][C:18]([C:17]([N:3]2[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[O:19])=[CH:12][CH:4]=1
Reactant: Cl
Reactant: CC(=O)Cl
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid hydrochloride (10.00 g, 46.8 mmol) was added portionwise into a mixture of acetone (75 mL) and 2N NaOH (75 mL). To this solution was added dropwise acetyl chloride (8.75 mL, 50 mmol) in acetone (50 mL) followed with 2N NaOH at room temperature. The reaction mixture was maintained at a pH>10 and stirred for 1 hour. The acetone was removed by evaporation under reduced pressure and acidified the residue by adding 3N HCl. The separated solid was collected by filtration, washed several times with water, and dried to give 2-(4-chlorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as an enantiomeric mixture, 13.80 g (93.4%); mp 77-79° C.; 1H NMR (DMSO-d6) δ 2.92 (1H, dd, J=5.9 Hz and J=15.8 Hz, CH), 3.29 (1H, d, J=15.8 Hz, CH), 4.12 (1H, d, J=5.9 Hz, CH), 4.49 and 5.02 (each 1H, d, J=17.4 Hz, CH2), 7.09-7.17 (4H, m, 4×ArH), 7.40-7.58 (4H, m, 4×ArH); m/z 315.00 (M+H)+ Anal. Calcld. for C17H14ClNO3: C, 64.67; H, 4.47; N, 4.44. Found: C, 64.65; H, 4.46; N, 4.41.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]([CH:16]=O)[CH3:15].[CH3:18]OC(OC)N(C)C>N1CCCC1>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:18])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Solvent: C1CCNC1
Product: COC(=O)c1cc([N+](=O)[O-])c(C=CN(C)C)s1
Yield: 26.9 %

Procedure:
To a solution of 5-methyl-4-nitro-2-thiophene carboxylic acid (4.6 g, 24.6 mmol) in DMF (14.5 mmol) was added N,N-dimethylformamide dimethyl acetal (3.8 mL, 28.5 mmol) and pyrrolidine (2 drops). The mixture was refluxed for 3 h, concentrated in vacuo and the residue taken up in EtOAc (0.2 L). The organic phase was washed with water, saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed over silica gel (0 to 40% EtOAc/heptane over 60 min) to give methyl 5-(2-dimethylaminovinyl)-4-nitrothiophene-2-carboxylate as a dark red solid (1.0 g, 16%). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.10 (s, 1H) 7.31 (d, J=13.1 Hz, 1H) 6.56 (d, J=13.1 Hz, 1H) 3.87 (s, 3H) 3.07 (s, 6H). LCMS m/e 279 (M+Na).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=CC(OC[CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, MeOD) δ ppm 1.29 (t, J=7.33 Hz, 3 H) 2.32 (s, 3 H) 2.91 (t, J=5.31 Hz, 2 H) 4.34 (t, J=5.43 Hz, 2H) 7.07-7.14 (m, 2 H) 7.65 (d, J=2.02 Hz, 1 H) 7.82 (t, J=7.83 Hz, 1 H) 7.94-7.98 (m, 1 H) 8.02 (dd, J=7.33, 1.52 Hz, 1 H) 8.15 (t, J=1.64 Hz, 1 H) 8.20 (d, J=2.02 Hz, 1 H) [M+H] calc'd for C24H27N3O3S, 438; found, 438.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C(=O)Cl)cc1

Procedure:
First, 1.2 g (6.1 mmol) of 4-pentyl benzoic acid was mixed with 1.1 g (9.1 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 2 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 4-pentylbenzoyl chloride.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])[CH2:2][CH3:3].[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CCCOc1cccc(CN)c1
Reactant: O=C(Cl)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cccc(CNC(=O)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 3-propoxy-benzylamine in 50 mL of dichloromethane and add dropwise to a mixture of 3-bromophenylacetyl chloride (4.90 gm; 21.0 mmol) and triethylamine (3.60 gm; 35.9 mmol) in 250 mL of dichloromethane at 0° C. Allow the reaction to warm to room temperature and stir for 18 h. Pour the reaction into 100 mL of saturated brine, separate the layers and extract the aqueous layer with 100 mL of dichloromethane. Combine organic layers, wash with brine, dry (MgSO4), and concentrate. Purification by chromatography on silica gel with 40% EtOAc in hexanes gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cncc(Br)c1

Procedure:
A mixture of (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 4.54 mmol) and concentrated sulfuric acid (0.02 ml) in MeOH was refluxed for 13.5 h. The RM was concentrated, taken in EtOAc and sonicated. The organic layer was washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a brown oil. (HPLC: tR 2.21 min (Method A); M+H=230, 232 MS-ES)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Mg]Br)C>CCOCC>[CH3:17][C:10]1[C:15]([OH:16])=[C:14]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[OH:1])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1O
Reactant: OCc1ccccc1O
Agent: CC[Mg]Br
Solvent: CCOCC
Product: Cc1cccc(Cc2ccccc2O)c1O
Yield: 23.6 %

Procedure:
2-Hydroxybenzyl alcohol (18.6 g, 0.15 mol) and o-cresol (16.2 g, 0.15 mol) were dissolved in 150 ml of ether in a flask and a dry nitrogen atmosphere established. Ethyl magnesium bromide (100 ml of 3M solution in ether, 0.30 mol) was added dropwise with stirring. The ether was removed by evaporation under reduced pressure and 450 ml of benzene added. The resulting mixture was heated at reflux with stirring for 20 hours and then allowed to cool. Saturated aqueous ammonium chloride solution was added and the mixture extracted with 2-500 ml portions of ether. The combined ether extracts were dried over magnesium sulfate and the ether then removed by evaporation. The residue was chromatographed on a silica gel column eluting with an 80:20 mixture of hexane and ethyl acetate and dried in a vacuum oven at 100° C. to obtain 7.6 g (24 percent of theory) of (3-methyl-2-hydroxyphenyl) (2-hydroxyphenyl)methane as an oil.