Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1CO
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of the product of step F (1.0 g, 3.7 mmol) in dichloromethane (20 mL) at 0° C. was added diisopropylethylamine (1.0 mL, 5.7 mmol) followed by acetyl chloride (0.32 mL, 4.4 mmol). The solution was stirred for 10 min at 0° C. followed by 45 min at ambient temperature. The reaction mixture was washed with NaHCO3 solution (3×15 mL) then NaCl solution (2×10 mL) and dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to afford the crude product which was purified by flash column chromatography (SiO2, 19:1 to 4:1, hexanes/ethyl acetate) to give tert-butyl 2-(acetoxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1-carboxylate (701 mg, 68%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 4.69-4.51 (m, 3H), 4.22-3.83 (m, 5H), 3.53-3.48 (m, 3H), 3.23-3.18 (m, 1H), 2.05-2.03 (m, 3H), 1.84-1.55 (m, 7H), 1.41 (s, 9H).
Reaction SMILES: CC(C)C(N[C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:28][C:29]1[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1)=[O:17])C1C(O)C(O)C(O)C(SC)O1.C1CC=CCC=1.CC[OH:50]>[Pd]>[CH2:34]([N:30]1[CH:31]=[CH:32][N:33]=[C:29]1[CH2:28][N:19]1[CH2:20][CH:21]([CH2:23][CH:24]=[CH:25][CH2:26][CH3:27])[CH2:22][CH:18]1[C:16]([OH:50])=[O:17])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCO
Reactant: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(Cc2nccn2Cc2ccccc2)C1
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CCC=CCC1CC(C(=O)O)N(Cc2nccn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an oven dried sealed tube, was added a solution of the above crude 1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (280 mg, 0.48 mmol) in anhydrous EtOH (5 mL), 10% Pd on carbon (560 mg) and 1,4-cyclohexadiene (1.5 mL). The reaction vessel was purged with N2, sealed and stirred at room temperature for 18 h. The reaction mixture was filtered through celite, washed several times with reagent alcohol, and the combined washings and filtrate were evaporated to dryness. The resulting residue was purified by silica gel chromotography (1:9 methanolic ammonia/CH2Cl2). The desired fractions were evaporated to dryness and lyophilized, to furnish the title compound for example 42 (29.3 mg, 18%): TLC Rf=0.7 (14% methanolic ammonia/CH2Cl2), KMnO4 visualization stain; MS (ESPOS): 499.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[NH:12][C:11]2=[O:31])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:43]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]([CH3:43])[C:11]2=[O:31])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1[nH]c(=O)n2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1n(C)c(=O)n2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 368D (250 mg) in anhydrous N,N-dimethylformamide (6 mL) was added sodium hydride (34.1 mg). The mixture was stirred at 50° C. for 30 minutes. Then, iodomethane (35.6 μl) was added and the mixture was stirred at 50° C. overnight. The reaction mixture was quenched with water (30 mL), then extracted with ethyl acetate. The solution was dried (MgSO4), filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.3 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (930 mg, 2.61 mmol), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (807 mg, 2.74 mmol), Bop-Cl (770 mg, 2.99 mmol), and triethylamine (2 mL) in dichloromethane (20 mL) was stirred for 4 days at room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed with 5% aqueous potassium hydrogen sulfate, water, phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residual solid was recrystallized from acetone-ethyl acetate to give 1.04 g of the title compound. The mother liquid was concentrated and the residue was purified by silica gel column chromatography with 0.3% acetic acid/ethyl acetate to give additionally 360 mg of the title compound. A total amount of 1.40 g of the title compound was obtained (85%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.75 g (2.1 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Next, hydrochloric acid (2.0 M) was added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 323.3 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N+:13]([O-:15])[CH3:14])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[O:15][N:13]([CH3:14])[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)([CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH2:22]2)=[CH:19][CH:18]=1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccco1
Reactant: C=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1OC(c2ccc(Cl)cc2)CC1(Cn1ccnc1)c1ccco1
Temperature: 25 °C

Procedure:
A solution of 7.60 g (0.037 mol) of 1-(2-furanyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (4) and 7.70 g (0.056 mol) of 4-chlorostyrene in 400 ml of toluene is refluxed for 48 hours under a nitrogen atmosphere. Upon cooling to ambient temperature, the crude cis- and trans-diastereomeric mixture of compound 6 (R=C6H4Cl--4) is concentrated in vacuo and flash-chromatographed on neutral silica gel using a 98:2 by volume mixture of chloroform and methanol to give 1.30 g (10%) of isomer A, melting point 99°-101° C. (ethyl acetate-hexane, 1:1 by volume). Anal. Calcd. for C18H18ClN3O2 : C, 62.88; H, 5.28; Cl, 10.31; N, 12.22 Found: C, 62.90; H, 5.39; Cl, 10.44; N, 12,13. Isomer B (1.10 g, 8.5%) has a melting point of 131°-133° C. (ethyl acetate-hexane, 1:1 by volume). Anal. Calcd. for C18H18ClN3O2 : C, 62.88; H, 5.28; Cl, 10.31; N, 12.22. Found: C, 62.82; H, 5.28; Cl, 10.46; N, 12.12.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(CN)ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Yield: 117.5 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (1.80 g, 6.00 mmol), DIPEA (3.096 g, 2.4 mmol) and pivaloyl chloride (1.2 mL, 9.0 mmol) in THF (20 mL) to afford 2.0 g of the title product. 1H NMR (300 MHz, DMSO d6): 8.16 (m, 1H), 7.65 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.25 (d, J=5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([CH2:12][C:13]([OH:15])=O)([C:9](O)=[O:10])[CH2:5][CH2:4]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][NH:32][NH2:33]>CN(C)C=O>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:9](=[O:10])[N:33]([NH:32][CH3:31])[C:13](=[O:15])[CH2:12]2)[CH2:5][CH2:4]1
Reactant: CNN
Reactant: CN1CCC(CC(=O)O)(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CNN1C(=O)CC2(CCN(C)CC2)C1=O
Reaction time: 1 h

Procedure:
In dimethylformamide (30 ml) was dissolved (1-methyl-4-carboxypiperidin-4-yl)acetic acid.hydrochloride (1.9g). To the solution was added dicyclohexylcarbodiimide (1.82 g), and the mixture was stirred for one hour, to which was added methylhydrazine (0.43 ml). The mixture was stirred at 60° C. for one full day. Precipitates were removed, and the solvent was evaporated off under reduced pressure. The residual oily product was subjected to a silica gel column chromatography [eluent; n-butanol:acetic acid:methanol:water=1:1:1:1 (V/V)]. To the solution containing the desired product was added 4 ml of 1N hydrochloric acid. Then, the solvent was evaporated off, and the residual solid product was recrystallized from ethanol to obtain 0.25 g of colorless solid, m.p. 235° to 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([NH:21][CH3:22])[C:16]([N+:23]([O-])=O)=[CH:15][CH:14]=1>>[NH2:23][C:16]1[C:17]([NH:21][CH3:22])=[C:18]([C:19]#[N:20])[C:13]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CNc1c(N)ccc(-c2ccc(Cl)cc2Cl)c1C#N
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from 2,4-dichloro-phenylboronic acid and 6-chloro-2-methylamino-3-nitro-benzonitrile according to the procedure for Example 1A. 1H NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), 7.24-7.31 (m, 2H), 6.89 (d, 1H, J=8.4 Hz), 6.78 (d, 1H, J=8.0 Hz), 3.67 (br s, 3H), 2.97 (s, 3H). MS (ES) [m+H] calc'd for C14H11N3Cl2, 292, 294; found 292, 294.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.O>CN(C)C=O>[CH3:19][O:13][C:11]1[N:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:16]=[CH:15][S:14][C:9]=2[N:10]=1
Reactant: CI
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g of 4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 80 ml of dimethylformamide is added 0.8 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 4.97 g of methyl iodide in 15 ml of dimethylformamide is added dropwise thereto at 10°C. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 160° - 161.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 256° - 257.5°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-phenyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystal having a melting point of 175° - 181°C (after recrystallization from ethanol).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:14]2[CH:13]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Yield: 100.4 %

Procedure:
A mixture of 1.5 g (3.8 mmol) of 1-[2-(4-chlorophenyl)-4-quinolinyl]-4-piperidinecarboxylic acid ethyl ester, 2.7 ml of 3N aqueous sodium hydroxide, and 50 ml of ethanol was heated on a steam bath for 0.5 hr. It was then cooled, acidified with acetic acid, and diluted with water to give 1.4 g of product, mp 245°-247°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[P:9](OC)OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([P:9]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccccc1P(OC)OC
Solvent: CCOCC
Product: COc1ccccc1P(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a stirred solution of dimethyl 2-methoxyphenylphosphonite (1.0 g, 5.0 mmol) in diethyl ether (40 mL) at 0° C. is added dropwise over 30 minutes a solution (1 M) of (4-chlorophenyl)magnesium bromide in diethyl ether (10.5 mL, 10.5 mmol). After allowing to warm to room temperature, the mixture is filtered and stripped to give an oil that is triturated with MeOH to give a white solid (0.98 g, 58%) 1H NMR (C6D6): δ 7.09 (m, 5H), 7.03 (m, 4H), 6.78 (m, 1H), 6.74 (m, 1H), 6.47 (d of d, 1H, J=8.2, 4.7), 3.16 (s, 3H); 13C NMR (C6D6): δ 161.47 (d, 1C, JCP=15.1 Hz), 135.88 (d, 2C, JCP=13.8 Hz), 135.52 (d, 4C, JCP=21.4), 135.30 (s, 2C), 133.74 (d, 1C, JCP=2.6 Hz), 130.86 (s, 1C), 128.99 (d, 4C, JCP=6.6 Hz), 125.60 (d, 1C, JCP=14.2 Hz), 121.47 (s, 1C), 110.64 (s, 1C), 55.15 (s, 1C); 31P NMR (C6D6) δ-16.54. Elemental analysis calculated for C19H15Cl2OP: C, 63.18; H, 4.19; 0, 4.43; P, 8.58. Measured: C, 63.31; H, 4.40.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[CH2:32]([SH:35])[CH:33]=[CH2:34]>>[CH2:32]([S:35][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:33]=[CH2:34]
Reactant: Cc1ccccc1B(O)O
Reactant: C=CCS
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3C)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-methylphenyl boronic acid. Bromination and coupling reaction with allyl mercaptan gave 35 mg of 4-allylsulfanylmethyl-2,2-dimethyl-6-o-tolyl-1,2-dihydroquinoline.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CNc1cnccc1I
Reactant: OB(O)c1cccnc1Cl
Product: CNc1cnccc1-c1cccnc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine and 2-chloropyridin-3-ylboronic acid after a reaction time of 5 hours at 90° C. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (82%). MS (EI): m/z=219 [M]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C=O)C>[C:3]([C:6]1[N:7]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1ccc[nH]1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.32 g, 33 mmol) in DMF (30 ml) was added at an ice bath temperature a solution of 2-acetylpyrrole (3.27 g, 30 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 15 minutes and cooled again. To the solution was added dropwise a solution of 4-fluorobenzylbromide (6.24 g, 33 mmol) in DMF (2 ml). The reaction solution was stirred at room temperature for 1 hour and poured into ice-water, and then extracted with ethylacetate. The ethyl acetate was washed with water and dried. The solvent was evaporated to give 2-acetyl-1-(4-fluorobenzyl)pyrrole (6.5 g) as an oil quantitatively.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:22])[CH:4]=1)#N.[OH-:23].[Na+].Cl.[OH2:26]>CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]([OH:26])=[O:23])=[CH:4][C:5]=2[CH3:22])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: O
Reactant: Cc1cc(C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Yield: 92 %

Procedure:
To a suspension of tert-butyl 4-(4-cyano-2-methylphenyl)piperazine-1-carboxylate (3.685 g, 12.23 mmol) in EtOH (Ratio: 1.000, Volume: 50 mL) and Water (Ratio: 1.000, Volume: 10 mL) was added Sodium hydroxide solution (8.48 mL, 162 mmol) at 23° C. Rinsed sodium hydroxide forward with Water (Ratio: 1.000, Volume: 2.5 mL) The reaction was stirred at 90° C. for 10 hr. The reaction mixture was cooled to 23° C., neutralized with 3N HCl (52 mL), filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid (3.588 g, 11.20 mmol, 92% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9 H) 2.29 (s, 3 H) 2.81-2.90 (m, 4 H) 3.42-3.53 (m, 4 H) 7.05 (d, J=8.08 Hz, 1 H) 7.70-7.77 (m, 2 H) 12.61 (br. s., 1 H). ESI-MS: m/z 321.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:13]1[S:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1ccc(Br)s1
Temperature: 100 °C
Yield: 94 %

Procedure:
2-Decylthiophene (52.8 g, 0.235 mol) prepared above and DMF (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. A solution of N-bromosuccinimide (hereinafter referred to as “NBS”) (44.0 g, 0.247 mol) in DMF (100 ml) was added dropwise to the solution at room temperature in an argon gas stream over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred with heating at 100° C. for about 2 hr. After the completion of the reaction, water (300 ml) was added to the reaction solution, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-bromo-5-decylthiophene as a yellow liquid (67.0 g, yield 94.0%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.61 (m, 2H), 2.73 (t, 2H, J=7.32 Hz), 6.52 (d, 1H, J=3.90 Hz). 6.83 (d, 1H, J=3.90 Hz).
Reaction SMILES: Cl[CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C:17]([NH2:19])=[S:18].CCOC(C)=O>CCO>[NH2:19][C:17]1[S:18][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:16]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N)nc1-c1ccccc1
Yield: 89 %

Procedure:
A solution of ethyl 2-chloro-3-oxo-3-phenylpropanoate (9.73 mmol) and thiourea (9.73 mmol) in EtOH (25 mL) was heated at reflux overnight. The resulting mixture was concentrated in vacuo, neutralized with 18M-NH4OH, and extracted with CH2Cl2. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford a yellow solid that was washed with MeOH (3 mL) and dried to afford the product in 89% yield as a pale yellow solid. MH+=249.1, Rf=0.29 (Hexanes:EtOAc=1:1). MH+=249.1, retention time (LC-MS)=2.37 min.
Reaction SMILES: [C:1]([C:5]1[C:13]2[S:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[C:13]2[S:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1SCC2(C)C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1SCC2(C)C

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzothiophene (4.0 g, 18.2 mmol) in glacial acetic acid (30 mL) is added dropwise 70% HNO3 (2.0 mL, 2.8 g, 31.8 mmol). The reaction mixture darkens to a deep green color over the course of the addition. The reaction is monitored by TLC (2% EtOAc/hexanes). Then the reaction mixture is partitioned between Et2O (50 mL) and H2O (2×50 mL). The ethereal layer is washed with saturated aqueous Na2CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid. Crystallization from hexane provides the title compound as orange prisms. A second crop yielded slightly less pure material which is combined with the former and used without further purification.