Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:30][CH2:29][CH2:28][CH:27]2[CH3:31])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:30][CH2:29][CH2:28][CH:27]3[CH3:31])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a solution of potassium tert-butoxide (0.68 g) in DMF (5 mL) was added dropwise a solution of 2-(benzyl{[3-chloro-5-(2-methylpyrrolidin-1-yl)pyrazin-2-yl]methyl}amino)ethanol (1.82 g) in DMF (5 mL) at 0° C., and the mixture was stirred for 1.5 hr. Water (10 ml) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→33% ethyl acetate/hexane) to give the title compound (1.38 g, 85%) as a pale-yellow oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9][CH2:8]1)(=O)=O.[C-]#[N:18].[K+].[CH2:20](O)[CH3:21]>>[O:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]([CH2:6][CH2:21][C:20]#[N:18])[CH2:8][CH2:9]1
Reactant: [C-]#N
Reactant: CCO
Reactant: CS(=O)(=O)OCC1CCOc2ccccc21
Agent: [K+]
Product: N#CCCC1CCOc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of chroman-4-ylmethyl methanesulfonate in ethanol (650 ml) was added potassium cyanide (9.23 g), and the mixture was stirred with heating under reflux for 15 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 3-chroman-4-ylpropionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1COCC1.Cl[C:47]([O:49][CH3:50])=[O:48]>O>[CH2:1]([O:3][C:4]([N:6]1[CH:11]([CH2:12][CH3:13])[CH2:10][CH:9]([N:14]([CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[C:47]([O:49][CH3:50])=[O:48])[C:8]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:7]1=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(c(C)nn2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1c2c(c(C)nn2C)C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3,5-Bis-trifluoromethyl-benzylamino)-6-ethyl-1,3-dimethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-b]pyridine-7-carboxylic acid ethyl ester (0.02 g, 0.04 mmol) obtained in step (vi), and K2CO3 (0.016 g, 0.12 mmol) were charged to a flask under a nitrogen atmosphere. Dry THF (5 mL) was added to this mixture, and the resulting mixture was stirred at room temperature for about 30 min, after which time methyl chloroformate (0.011 g, 0.12 mmol) was added dropwise. The reaction was stirred at room temperature overnight. Water was then added to the reaction mixture and the product was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum to provide a residue. This residue was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate in petroleum ether as eluent, to afford the title compound. Yield: 0.01 g (50%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22](O)=[O:23])[C:7]([C:10]2[C:11](C(O)=O)=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.Cl>O1CCCC1>[OH:23][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2CO)cc1
Reaction time: 19 h

Procedure:
3.6 g (10.83 mmol) 4,4′-Dinitro-1,1′-biphenyl-2,2′-dicarboxylic acid are dissolved in 25 ml tetrahydrofuran and added dropwise in a the course of 1 hours to 65 ml (65.02 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 19 hours at 25° C., 50 ml water are carefully added. After 1 h the solution is acidified to pH=1-2 with 10 ml 1N HCl solution and allowed to stirred for 30 min. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 4.2 g of 2,2′-bis(hydroxymethyl-4,4′-Dinitro 1,1′-biphenyl as white powder is used without further purification.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][C:36]1([CH2:42][OH:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:39]3[CH2:40][CH2:41][C:36]([CH2:42][OH:43])([CH3:35])[CH2:37][CH2:38]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(CO)CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(C)(CO)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with (4-methyl-piperidin-4-yl)-methanol trifluoroacetate and N-ethyldiisopropylamine in chloroform [α]D20=+24.1° (c=1.02, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([O:25]C)=[O:24])[CH3:22])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CO>CO.O>[NH:1]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of tBoc-Lys(Cbz)-Ala-OMe (6.4545 g, 13.86 mmol) 16 and LiOH (1.004 g, 41.8 mmol) in methanol/water (80/10 mL) was stirred at room temperature for 4 h. The reaction mixture was neutralized with 0.5 N citric acid and methanol was removed under reduced pressure. The resulting aqueous solution was diluted with water and extracted with dichloromethane and ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and dried under vacuum to obtain 17 as a white solid (3.445 g, 55%). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH:18]=[C:19]([C:23]5[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:25][C:24]=5[CH3:36])[NH:20]4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C1COCC1>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH:18]=[C:19]([C:23]5[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:25][C:24]=5[CH3:36])[NH:20]4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(-c3ccc4cc(-c5c(C)cc(CCC(=O)O)cc5C)[nH]c4c3)o2)cc1

Procedure:
A mixture of methyl 3-(4-{6-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-1H-indol-2-yl}-3,5-dimethylphenyl)-propionate (35 mg, 73 pmol) and IN NaOH (174 μL, 174 μmol) in 5 mL of 2:1 water/methanol and 5 mL THF was heated at 50° C. for 4 h. The solvent was removed under reduced pressure and the residue was stirred with water, and neutralized with 174 μL of 1N HCl. The precipitate was filtered, washed with water, and dried to the title compound. H1-NMR (DMSO-d6): δ ppm 12.17 (s, broad, 1H), 11.62 (s, 1H), 8.08 (m, 3H), 7.76 (m, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.06 (s, 2H), 6.46 (s, 1H), 3.88 (s, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.12 (s, 6H). MS: m/z 468.2 (M+1); Retention time=1.33 min (Method 10). High Res MS (M+H): theory 468.1923, measured 468.1918.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH:10]([CH2:12][O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-Boc-azetidin-3-yl)-methanol (1.06 g, 5.7 mmol), TEA (1.18 mL, 8.52 mmol) in CH2Cl2 at 0° C. was added MeSO2Cl (0.53 mL, 6.82 mmol) via a syringe. The reaction was warmed to RT over 2 h and stirring was continued at RT for 2 h. The white solid formed was removed by filtration and the filtrate was washed with 25 mL of H2O. The organic phase was dried over Na2SO4, and concentrated in vacuo to afford yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:15])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Product: COc1ccc(CN2CC(C)(C)N(C(=O)c3ccccc3)C2=O)cc1

Procedure:
Using 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (500 mg) described in Preparation Example 54 and benzoyl chloride (0.28 mL) and by the reaction and treatment in the same manner as in Preparation Example 55, the title compound (500 mg) was obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I-:1].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>CN(C=O)C.Cl>[I:1][C:19]1[CH:18]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: [I-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium iodide (3.32 g) then chloramine-T (5.91 g) were added to a stirred solution of 4-trifluoromethylphenol (3.0 g) in DMF (30 ml) at O° C. The mixture was warmed to RT, stirred for 1 h, diluted with dilute hydrochloric acid then extracted with diethylether. The organic layer was washed with aqueous sodium thiosulphate solution, dried and the solvent removed under reduced pressure. Yield 5.25 g
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15]([CH3:18])(=O)=O)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3]1.[CH:24]1[CH:29]=[CH:28]C(S)=[CH:26][CH:25]=1.[OH-:31].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][C:18]4[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3]1.[CH2:29]([O:31][C:11]1[N:10]=[CH:9][C:8]2[CH2:7][CH2:6][C:5]3[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3][N:2]([CH3:1])[C:14]=3[C:13]=2[N:12]=1)[CH3:24]
Reactant: [OH-]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(S(C)(=O)=O)nc1-2
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(OCC)nc1-2
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(Sc3ccccc3)nc1-2
Reaction time: 72 h

Procedure:
To a stirred suspension of ethyl 1-methyl-8-(methylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (46 mg, 0.137 mmol) and phenylthiol (16 μl, 17 mg, 0.15 mmol) in ethanol (1 mL), 1N sodium hydroxide (150 μl, 0.15 mmol) was added at room temperature under an argon atmosphere. After the mixture was stirred for 3 days, 1N hydrochloric acid (150 μl, 0.15 mmol) was added and the solvent removed under vacuo. By chromatography on silica gel (eluant: dichloromethane/methanol 97/3), 13 mg of ethyl 1-methyl-8-(phenylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate and 10 mg of ethyl 8-ethoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were isolated.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:16](=O)([O:20]CC)[O:17][CH2:18][CH3:19]>O1CCCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][C:16]([O:17][CH2:18][CH3:19])=[O:20])[N:11]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cccnn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
Lithium diisopropylamide (2M in tetrahydrofuran, 6.83 g, 63.7 mmol) was added dropwise to a stirred solution of 3-methylpyridazine (5.0 g, 53.12 mmol) in anhydrous tetrahydrofuran (80 mL) at −78° C. under a nitrogen atmosphere over a period of 20 min. The mixture was allowed to warm to room temperature. The mixture was stirred for 1 h at room temperature and cooled again to −78° C. Diethyl carbonate (12.57 g, 106.2 mmol) in anhydrous tetrahydrofuran (20 mL) was added at −78° C. over a period of 20 min. The reaction mixture was allowed to warm to room temperature, stirred for 16 h and partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified via column chromatography (100-200 mesh silica gel, 50-80% ethyl acetate in petroleum ether) to afford ethyl 2-(pyridazin-3-yl)acetate (600 mg). MS (ES+) (M+H) 167.1569.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:13]([NH+:15]([CH2:10][CH3:2])[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: CC[NH+](CC)CC
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
Using triethylamine. Terephthalic acid is reacted with two equivalents of triethylamine in a suitable solvent to form bis(triethylammonium) terephthalate:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].BrC[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Br:27])=[CH:22][CH:21]=1.O.[CH3:29]N(C=O)C>>[Br:27][CH2:26][C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][C:24]=1[CH2:29][S:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc2c(SCc3ccccc3CBr)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
In a 25 mL round-bottomed flask 7-trifluoromethyl-quinoline-4-thiol (1.0 g, 4.37 mmol) was dissolved in 10 mL DMF anhydrous and NaH (60% dispersion in oil, 184 mg) was added slowly. The reaction was stirred at RT for 10 min. In a 50 mL round-bottomed flask 1,4-bis-bromomethyl-benzene (1.27 g, 4.80 mmol) was dissolved in DMF anhydrous (10 mL) and the solution was stirred at 0° C. for 10 min. The first solution was added via syringe to this solution and the reaction was stirred at 0° C. for 15 min. The solution orange became pale yellow and the mixture stirred 1.25 h at RT. Water (50 mL) was added and the product extracted with diethyl ether (5×100 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL), dried with MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent cyclohexane:diethyl ether=7:3. 4-(2-(Bromomethyl)benzylthio)-7-(trifluoromethyl)quinoline 27 was obtained (205 mg, 12% yield) as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.N([O-])=O.[Na+].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([CH3:24])=[O:23]>O.C(#N)C.CCOCC>[CH3:24][C:22]([C:18]1[O:17][C:21]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: CC(=O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A mixture of 200 g (1.16 mole) of p-aminophenyl methyl sulfone, 405 ml of concentrated hydrochloric acid, and 150 ml of water was heated at 80° for 20 minutes and then cooled to 0°. A solution of 80 g (1.16 mole) of sodium nitrite in 270 ml of water was added dropwise while maintaining the temperature between 0°-5° by means of an ice bath. The near solution was kept at 0° for 15 minutes. A solution of 129 g (1.16 mole) of methyl 2-furyl ketone in 125 ml of acetonitrile was added followed by a solution of 30 g of CuCl2 .2H2O in 100 ml of water. The reaction, after stirring in the cold for one hour, was allowed to warm to room temperature at which time it became exothermic and was controlled below 55° by means of an ice bath. The reaction, after stirring overnight at room temperature, was treated with 500 ml of ether with a solid forming. The solid was filtered, washed with dilute NaOH solution, and refluxed in acetonitrile with the insoluble material being removed by filtration. The filtrate was again heated to reflux and water was added to the "cloud point". Upon cooling an oil formed from which the acetonitrile was decanted. The acetonitrile was again treated with water and the resulting solid was filtered and recrystallized from ethyl acetate/charcoal and airdried to yield 28 g (9%) of 5-(p-methylsulfonylphenyl)-2-furyl methyl ketone. An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 160°-164°.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][S:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:21][N+:18]1([CH3:6])[CH2:17][CH2:16][CH:15]([S:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1
Reactant: COc1ccc(CSC2CCN(C)CC2)cc1
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: COc1ccc(CSC2CC[N+](C)(C)CC2)cc1
Product: O=S(=O)([O-])F
Reaction time: 0.33 h

Procedure:
2.9 ml of methyl fluorosulfonate were added, whilst ice-cooling, to a solution of 8.95 g of 4-(4-methoxybenzylthio)-1-methylpiperidine dissolved in 300 ml of dry methylene chloride, and the mixture was stirred at the same temperature for 20 minutes and then at room temperature for 2.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed repeatedly by decantation with diethyl ether and dried under reduce pressure, to afford 12.76 g of the title compound as a colorless powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1.O>O1CCCC1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1
Reactant: COc1ccc(-c2nc3ccccc3s2)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccccc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a suspension of lithium aluminum hydride (90 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of N-(2-benzothiazol-2-yl-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide (300 mg) in tetrahydrofuran (1 ml) on an ice bath, and the solution was stirred for 4 hours at room temperature. To the reaction mixture were sequentially added tetrahydrofuran (10 ml), water (0.14 ml), an aqueous solution of 5N sodium hydroxide (0.14 ml) and water (0.42 ml) on an ice bath, the resulting suspension was filtered, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-chloroform system) to provide the title compound (120 mg).
Reaction SMILES: C=O.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][CH2:13][O-].[Na+].Cl>CN(C)C=O>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:6][C:7]2[C:12]3[C:13](=[CH:11][CH:3]=[CH:4][CH:5]=3)[CH2:9][CH:8]=2)=[CH:4]1
Reactant: C1=Cc2ccccc2C1
Reactant: CC[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(CC2=CCc3ccccc32)c2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Formalin (37% solution; 3.5 g, 43.1 mmol) was added to a mixture of indene (10.0 g, 86.2 mmol) and EtONa (2.9 g, 43.1 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 12 hours. A solution of HCl (1 M, 50 mL) was added. The mixture was extracted with CH2Cl2 (2×100 mL) and the organic phases combined, washed with a saturated solution of NaCl and then with water, dried over MgSO4, filtered and finally concentrated to yield a viscous brown liquid (89% yield by GC). Vacuum distillation yielded pure bis-(3-indenyl)methane as a yellow viscous oil (b.p. 160-180° C. at 1.2 mmHg, 3.65 g, 35% yield), which can be recrystallized from pentane.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+]>O1CCOCC1.O>[S:7]1[C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]1=2
Reactant: [C-]#N
Reactant: ClCc1cc2ccccc2s1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1cc2ccccc2s1

Procedure:
To a solution of 2-chloromethyl-benzo[b]thiophene (1 eq.) in dioxane/water (2/1) was added KCN (1.5 eq.). The reaction was refluxed for 4 h. The crude was partitioned between water and EtOAc. The organic layer was washed with water, then brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 95/5 to 90/10) to afford benzo[b]thiophen-2-yl-acetonitrile.