Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN>>[CH3:30][N:10]1[CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CNN
Product: Cn1cc(-c2ccncc2)c(-c2ccc(CCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting methyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2H), 8.06 (t, J=10.4 Hz, 2H), 7.77 (d, J=7.1 Hz, 1H), 7.70 (t, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J=9.1 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.24 (m, 3H), 7.20 (d, J=5.0 Hz, 2H), 3.97 (s, 3H), 3.31 (m, 2H), 3.18 (m, 2H); MS: (M+H m/z=391.0).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([O:17][C@H:14]2[CH2:15][CH2:16][C@@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:40])=[CH:37][CH:36]=1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](OC(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.24 g (0.001 mol) of cis-4-(4-dimethylaminomethylphenyl)-cyclohexanol, 0,34 ml (0.0025 mol) of triethylamine and 0.12 g (0.001 mol) of dimethylaminopyridine are dissolved in 20 ml of methylene chloride, mixed with 0.175 g (0.001 mol) of 4-chlorobenzoylchloride and stirred for 12 hours at ambient temperature. The reaction mixture is combined with water and adjusted to pH 12-13 using sodium hydroxide solution. The methylene chloride phase is separated off, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated saline solution, dried and evaporated down in vacuo. The residue is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/ethyl acetate=45:1) White crystals.
Reaction SMILES: [N:1]([C:4]1[C:9](Cl)=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16](C#N)=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3].N(C1C([Br:32])=CN=CC=1C=O)=[N+]=[N-].ClC1C=CC=C(Cl)C=1N>>[N:1]([C:4]1[C:9]([Br:32])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][CH:16]=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Reactant: [N-]=[N+]=Nc1c(Br)cncc1C=O
Agent: Nc1c(Cl)cccc1Cl
Product: [N-]=[N+]=Nc1c(Br)cncc1/C=N/c1c(Cl)cccc1Cl

Procedure:
Following the procedure described for 4-{[1-(4-azido-5-chloropyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile, 4-azido-5-bromopyridine-3-carbaldehyde and 2,6-dichloroaniline were reacted to afford the title compound as a beige solid that was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]([C:14](=O)[CH2:15]Br)[CH:4]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[C:24]([NH2:26])=[S:25])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:24]2[S:25][CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=3)[N:26]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH3:19]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(OC)cc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cc(OC)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-methoxy-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-methoxy-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][CH:19]2[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:28]([SH:30])[CH3:29].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:30][CH2:28][CH3:29])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCS
Reactant: CSC1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Reaction time: 1 h

Procedure:
To a solution of 11β-acetyloxy-9-fluoro-17-(methylthio)androsta-1,4-diene-3-one (632 mg) in dry dichloromethane (20 ml) containing dry ethanethiol (0.6 ml) is added boron trifluoride etherate (0.25 ml). After one hour, the mixture is added to a NaHCO3 solution and extracted with chloroform. The chloroform solution is washed with water, dried (MgSO4 anhydrous), and evaporated to afford the title compound (620 mg) contaminated with a small amount of 11β-acetyloxy-9-fluoroandrosta-1,4-diene-3,17-dione. This material is used in the next step without further purification. A specimen crystallized from acetone-hexane shows melting point 140°-142° C. and a consistent nmr spectrum.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Cn1cncn1)Nc1n[nH]c2cc(Cl)ccc12
Yield: 21.2 %

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile, 423 mg of 1,2,4-triazole and 283 mg of potassium carbonate. The reaction medium is refluxed for 4 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 120 mg of N-(6-chloro-1H-indazol-3-yl)-1H-1,2,4-triazole-1-acetamide in the form of a white powder melting above 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[C:31](C=O)[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(=O)=O>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]3[CH:30]=[C:31]([CH2:36][N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:15])[CH3:13])[N:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccc(C=O)cc3n2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc3nc(-c4cc(Cl)nn(COCC[Si](C)(C)C)c4=O)n(COCC[Si](C)(C)C)c3c2)CC1
Reaction time: 0.25 h

Procedure:
6-Chloro-4-(6-formyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one is dissolved in dichloro-methane. 4-Methylpiperazine and acetic acid are added. After 15 minutes, sodium triacetoxyborohydride is added in several portions over the course of 3 hours. After conversion is complete, saturated aqueous NaHCO3 solution is added and the reaction solution is stirred until no further CO2 evolution is observed. It is diluted with dichloromethane, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried with MgSO4, and the solvent is removed in a rotary evaporator.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:32])[C:11]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1COCC[Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:32])[C:11]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([CH3:30])([CH3:31])[C:28]#[N:29])=[CH:25][CH:26]=4)=[C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[C:5]2=[N:4][NH:3]1
Reactant: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)n(COCC[Si](C)(C)C)nc34)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)[nH]nc34)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a stirred solution of 2-{4-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-2-methyl-propionitrile (55 mg, 0.1 mmol) in DCM (2 mL), cooled in an ice bath, was added TFA (1.5 mL) at RT. After 16 h, the reaction mixture was evaporated to dryness, the resultant residue was dissolved in THF (3 mL) and benzyltrimethylammonium hydroxide solution (0.06 mL, 40% in MeOH) was added. The reaction mixture was stirred at RT for 1.5 h. EtOAc and water were added and the mixture was acidified by the addition of 1 M HCl (1 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, EtOAc) to afford the title compound (20 mg, 47%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.05 (s, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.46-7.38 (m, 5H), 7.33-7.22 (m, 5H), 1.73 (s, 6H). LCMS (Method E): RT=4.22 min, [M+H]+=423.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].C([O-])([O-])=[O:25].[K+].[K+].CN(C=O)C>>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][OH:25])=[CH:6][CH:7]=3)[O:14][C:15]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cc(C#Cc3ccc(OC(C)=O)cc3)oc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CCc1ccc(OCCO)cc1)C2
Reaction time: 2 h
Yield: 117.2 %

Procedure:
To a stirred solution of the product of Step A (0.05 g, 0.19 mmol) and K2CO3 (0.05 g, 0.36 mmol) in anhydrous DMF (5 ml) ethyl-bromo acetate (0.025 ml, 0.22 mmol) was added at room temperature. The mixture was stirred for 2 h and quenched with saturated NH4Cl solution, extracted in EtOAc (100 ml) and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.07 g; 100%), as pale oil. 1H-NMR (CDCl3) 7.10 (d, 2H, J=8.39 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.80 (t, 2H, J=8.36 Hz); 6.35-6.33 (m, 2H); 4.75-4.71 (m, 1H); 4.56 (s, 2H); 4.22 (q, 2H, J=14.36, 7.17 Hz); 3.72 (s, 3H, OMe); 3.2-3.13 (m, 1H); 2.79-2.69 (m, 3H); 2.0-1.87 (m, 2H); 1.26 (t, 3H, J=7.12 Hz).
Reaction SMILES: COC(=O)C(C1C=CC(SCC2C=CC(C3C=CC(C(F)(F)F)=CN=3)=CC=2)=C(OC)C=1)(C)C.[CH3:34][O:35][C:36](=[O:49])[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][C:45]([SH:47])=[CH:46][C:41]=2[O:40][C:39]1=[O:48].[F:50][C:51]([F:69])([F:68])[C:52]1[CH:67]=[CH:66][C:55]([CH2:56][O:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64]Cl)[CH:59]=2)=[CH:54][CH:53]=1>>[CH3:34][O:35][C:36](=[O:49])[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][C:45]([S:47][CH2:64][C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([O:57][CH2:56][C:55]4[CH:66]=[CH:67][C:52]([C:51]([F:50])([F:68])[F:69])=[CH:53][CH:54]=4)[CH:59]=3)=[CH:46][C:41]=2[O:40][C:39]1=[O:48]
Reactant: COC(=O)Cn1c(=O)oc2cc(S)ccc21
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Agent: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c(OC)c1
Product: COC(=O)Cn1c(=O)oc2cc(SCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc21
Yield: 25 %

Procedure:
Compound 76D was prepared analogously to compound 21D using the product prepared from compound 76C and 6B. Yield was 25% after flash column purification. MS m/z 504 (M+1). 400 MHz 1H NMR (DMSO-d6) δ 7.61-6.71 (m, 11H), 5.05 (s, 2H), 4.50 (s, 2H), 3.99 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: C=Cc1ncc(C(=O)OCC)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)s1
Yield: 100 %

Procedure:
To a solution of ethyl 2-vinylthiazole-5-carboxylate (400 mg, 2.18 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (267 mg, 0.25 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is concentrated to give ethyl 2-ethylthiazole-5-carboxylate (404 mg). HPLC retention time=0.60 minutes (condition B); MS (m+1)=186.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.3 Hz, 2 H) 1.39 (t, J=7.20 Hz, 2 H) 3.07 (q, J=7.58 Hz, 2 H) 4.35 (q, J=7.16 Hz, 2 H) 8.22 (s, 1 H)
Reaction SMILES: Cl[Si:2](Cl)([CH2:5][CH3:6])[CH2:3][CH3:4].[CH:8]([F:11])([F:10])[F:9].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[CH2:3]([Si:2]([CH2:5][CH3:6])([C:8]([F:11])([F:10])[F:9])[C:8]([F:11])([F:10])[F:9])[CH3:4]
Reactant: CC[Si](Cl)(Cl)CC
Reactant: FC(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC[Si](CC)(C(F)(F)F)C(F)(F)F
Yield: 44 %

Procedure:
A similar procedure to the one reported in EXAMPLE 2 was followed except dichlorodiethylsilane (5.12 g, 32.5 mmol, 1 eq) was used as the substrate along with 2eq each of CF3H and KHMDS to obtain pure diethyl bis(trifluoromethyl)silane 3.2 g, 44% yield. 1H NMR (400 MHz): δ 1.08 (m, CH2), 1.16 (m, CH3); 13C NMR (100.5 MHz): δ-1.10 (s, CH2), 5.55 (s, CH3), 128.6 (qq, 1JC—F=319 Hz, 3.35 Hz, CF3); 19F NMR (376.3 MHz): δ-60.2 (s); 29Si NMR (79.5 MHz): δ-2.43 (sept, 2JSi—F=39.4 Hz, 1 Si).
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCC1.N1CCCC1>>[N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:12][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(N2CCCC2)COC1
Reactant: O=C1CCC1
Solvent: C1CCNC1
Product: N#CC1(N2CCCC2)CCC1

Procedure:
The title compound, colorless liquid, MS: m/e=151.1 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and pyrrolidine.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Cl:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[ClH:14].[CH:17]1([NH:20][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: ClCc1ccc(C#Cc2ccccc2)cc1
Product: C(#Cc1ccc(CNC2CC2)cc1)c1ccccc1
Product: Cl

Procedure:
A solution of 0.9 g. (4 mmole) of 4-(phenylethynyl)-benzyl chloride in 3 ml. of cyclopropylamine is heated to refluxing for 2 hours and then is allowed to stand at room temperature for several days. Another 1 ml. of cyclopropylamine is added and the solution is heated to refluxing for 4 hours. After evaporation of the excess cyclopropylamine, the residue is triturated with ether and the precipitate removed by filtration. The ethereal filtrate is evaporated and the residual oil dissolved in benzene. This solution is shaken with 10 ml. of 3N hydrochloric acid. The white crystalline hydrochloride salt of the product precipitates. It is collected and recrystallized twice from absolute methanol to give N-cyclopropyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 210°-212°C. dec.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]2)=[C:8]([F:22])[C:7]=1[F:23])[CH2:2][CH2:3][CH3:4].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]2)=[C:8]([F:22])[C:7]=1[F:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: CCCCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Temperature: 30 °C
Yield: 97.7 %

Procedure:
The compound (10) (47.8 g), formic acid (87%; 67.0 ml) and toluene (200 ml) were mixed, and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (1,000 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the resulting residue was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was further purified by recrystallization from heptane to give 1-(4-butoxy-2,3-difluorophenyl)-cyclohexan-4-one (11) (40.4 g). The yield based on the compound (10) was 97.8%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.Br[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc2ccccc12
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1c1cccc2ccccc12

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromonaphtalene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([SH:22])=[N:10]2)=[CH:5][CH:4]=1.IC.Cl[CH2:26]Cl.O>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22][CH3:26])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(S)nn2-c2ccc(OC)cc2)cc1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nc(SC)nn2-c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol (470 mg, 1.5 mmol) in 1N sodium hydroxide solution (5 mL), was added iodomethane (0.934 mL, 15 mmol). The mixture was shaken overnight. Dichloromethane and water were added to the mixture and the organic layer was separated, washed with 0.1 N hydrochloric acid and sat sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure.The generated precipitate was isolated by filtration, washed with diisopropyl ether, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole (235 mg, 47.9% yield).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-phenoxy}-2-methyl propionic acid ethyl ester (345.2 mg, 0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield 226.2 mg (70%) as a white, crystalline solid: Rf=0.2 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.64-7.62 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 6.88-6.77 (m, 4H), 4.18 (t, J=6.4 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H), 2.44 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCc2cccs2)cc1
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 70.7 %

Procedure:
Sodium hydride (0.41 g, 20 mmol) was added to a solution of 2-thiophene methanol (2.0 g, 18 mmol) in THF (20 ml) at −40° C. The reaction was stirred at −40° C. for 25 min., then neat benzylbromide (3.6 g, 20 mmol) was added by syringe. The solution was stirred at −40° C. for 0.5 hr, then at room temperature for 1 hr. The THF was evaporated off and the remaining residue was taken up in ether (˜50 ml). The organic solution was washed with water (1×10 ml), brine (1×10 ml) and dried over MgSO4. Evaporation of solvents left an oil which was purified by column chromatography using 1% ether-hexanes to give 2.6 g of the thiophene as a pale yellow oil (78% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[O:29][CH3:30])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:33][CH3:32])[CH2:17][C:16]=3[CH:18]=[C:19]([F:31])[CH:20]=2)[CH:27]=1
Reactant: COc1ccc(Cl)cc1-c1cc(F)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.62 g, 38%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) and methylamine (0.139 g, 4.5 mmol). mp 189-190° C.