Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:10])[CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)O.O>C(O)(=O)C.[Zn]>[Cl:1][C:2]([Cl:10])=[CH:3][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC(c1cccs1)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: ClC(Cl)=Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 36.3 g (0.555 mole) of zinc in 250 ml of glacial acetic acid, 64.2 g (0.277 mole) of 2,2,2-trichloro-1-(2-thienyl)ethanol was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 600 ml of cold water and the mixture extracted with three 250 ml portions of ethyl acetate. The combined organic extracts were dried with magnesium sulfate and filtered. The solvent was removed from the filtrate to give a liquid which was distilled under reduced pressure to give 2-(2,2-dichloroethenyl)thiophene; bp 60°-68° C./266 pa. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2SC)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 3.85 g. of ethyl 2'-mercapto-4-biphenylylglycolate is 40 ml. of water containing 0.65 g. of sodium hydroxide is added 2 ml. of dimethyl sulfate with stirring. The reaction mixture is gradually warmed to 40°C and stirred for 2 hours. The mixture is cooled and extracted with ether which is washed with water, dried and evaporated in vacuo. The residue is distilled to obtain ethyl 2'-methylthio-4-biphenylylglycolate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:34])[CH2:32][CH2:33]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl {1-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclopropyl}carbamate (27 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0° C. dropwise. After being stirred at room temperature for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (NH-silica gel: 10-100% chloroform in hexanes then 10% methanol in chloroform) gave the product (25 mg, quant.). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.07 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.49 (d, J=6.9 Hz, 2H), 7.38-7.20 (m, 7H), 7.14-7.07 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 1.06-1.00 (m, 2H), 0.99-0.93 (m, 2H). LCMS: 442 [M+H].
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH2:49]([Mg]Br)[CH3:50]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:6]([CH2:5][C:4](=[O:47])[CH2:49][CH3:50])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)C(CC(=O)N(C)OC)CC3c3ccc(OC)cc3)cc21
Reactant: CC[Mg]Br
Product: CCC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b by, 1.0 g of N-methoxy-2-[4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) in the presence of ethyl magnesium bromide are used to afford the title compound after flash chromatography (SiO2 60 F) as a colourless oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.13.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].O>CN(C=O)C>[CH2:4]([NH:16][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17])[CH2:5][CH:6]([CH3:14])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCNCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Anhydrous isopentylamine was bubbled into anhydrous DMF (200 mL) at 0° C. for 15 min. A solution of t-butyl 4-bromomethyl-3-nitrobenzoate (5.0 g, 15.8 mmol) (Int. J. Peptide. Res., 36, 31 (1990)) in DMF (10 mL) was added dropwise to the cold amine solution. The solution was stirred at 0° for 30 min and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, dried (sodium sulfate) and concentrated to give a yellow-brown oil. The oil was purified by chromatography over silica gel to yield t-butyl 4-(isopentylamino)methyl-3-nitrobenzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 81.7 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-isoleucine, 3.7 g of triethylamine, 150 ml of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example 1(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145°-149° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)Nc1nc2ccc(C(=O)CBr)cc2s1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2ccc(C(=O)CN3CCC(Cc4ccccc4)CC3)cc2s1

Procedure:
A solution of 2 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethanone and 1.5 g of 4-benzylpiperidin and 2.5 g of K2CO3 in 20 ml of DMF was heated at 35° C. for 2 hours.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17]N1CCNCC1)[CH3:14]>O>[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:7]1[CH2:6][CH2:5][N:4]([C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)[CH2:3][CH2:2]1)[CH3:14]
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: CCOC(=O)CN1CCNCC1
Solvent: O
Product: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2N)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 154.5 %

Procedure:
A neat mixture of 0.500 g (2.54 mmol) of 3-amino-2-chloro-6-trifluoromethylpyridine and 0.870 g (5.09 mmol) of piperazin-1-yl-acetic acid ethyl ester is heated to 150° C. and stirred for 20 h. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer is washed with water followed by brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material is purified by flash silica gel chromatography to provide 0.650 g (77.1%) of (3′-amino-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+]>C1COCC1.C(OCC)C>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:18][C:16]([CH3:19])([CH3:17])[CH3:15])=[CH:8][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A mechanically stirred solution of 4-(trifluoromethoxy)phenyl isocyanate (10.54 g, 51.9 mmol) in THF (200 mL) at 0° C. was treated with the dropwise addition of 1.0 M potassium tert-butoxide solution in THF (55 mL, 55 mmol). The solution was allowed to come to room temperature, and stirred overnight. The mixture was diluted with diethyl ether (300 mL), washed successively with saturated ammonium chloride solution (2×100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was combined with material from a previous reaction (5.4 g scale), and purified over silica gel, eluting with 10%-20%-50% ethyl acetate/hexanes to yield 20.0 g of an off-white solid as product. 1H NMR (400 MHz, DMSO) δ ppm 1.48 (s, 9 H) 7.26 (d, J=8.35 Hz, 2 H) 7.54 (d, J=8.79 Hz, 2 H) 9.56 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([OH:22])=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[C:13]3[C:18]([N:19]=[C:20]([CH3:21])[C:11]2=[C:10]([CH3:23])[N:9]=1)=[CH:17][C:16]([O:22][CH2:38][C:37]1[C:36]([F:35])=[CH:43][CH:42]=[CH:41][C:40]=1[F:44])=[CH:15][CH:14]=3
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2Cl)n2c1c(C)nc1cc(OCc3c(F)cccc3F)ccc12
Temperature: 130 °C
Reaction time: 3 h

Procedure:
1 g 1-(2-Chloro-phenyl)-3,4-dimethyl-7-hydroxy-imidazo(1,5-a)quinoxaline, 2.24 g Caesium carbonate, 50 mL N,N-dimethylformamide, and 6 mL water were stirred for 10 min followed by addition of 0.83 g 2,6-difluorobenzylbromide. After 3 h stirring at 130° C. the reaction mixture was given into 150 mL water, filtered off, washed with water, dried under reduced pressure, and purified with silica gel, dichloromethane/methanol=95/5.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:19][O:20][C:29](=[O:31])[O:21]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(Br)c(N(CC(O)CO)C(=O)C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-N-(2,3-dihydroxypropyl)-2,2-dimethylpropanamide (7.628 g, 21.130 mmol) in DCM (100 ml) and pyridine (3.407 ml, 42.26 mmol) at −78° C. under argon was treated with a solution of triphosgene (6.27 g, 21.130 mmol) in DCM (20 ml) over 5 min and the reaction was then allowed warm to rt and stirred at rt for 30 min. The reaction was then carefully treated with saturated sodium bicarbonate solution (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a white solid (5.722 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](O)(O)=[O:22].O1CCOCC1>O>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:22])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:20])=[CH:11][CH:12]=1)(=[O:17])=[O:18]
Reactant: O=[Se](O)O
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=O)C(=O)c2ccc(F)cc2)cc1

Procedure:
A mixture of ketone from step 3 (1 g, 3.5 mmol), selenious acid (H2SeO3) (550 mg, 1.25 equiv.), dioxane (10 ml) and water (1 ml) were heated to reflux for 4 hours and cooled. The mixture was filtered and the filtrate evaporated. The residue was triturated with cold methanol and filtered to give 620 mg (60%) of the dione: m.p. 174-175° C. Anal. Calc'd. for C15H11FO4S (M.W. 306.31): C, 58.82; H, 3.62; S, 10.47. Found: C, 58.70; H, 3.60; S, 10.70.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])=[CH:10][CH:9]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(Cl)(Cl)Cl>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: CC(NC1CC1)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CC(NC1CC1)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
Ethynyl(trimethyl)silane (80 mg), PdCl2(PPh3)2 (29 mg), CuI (16 mg), and TEA (0.25 g) were added to a chloroform (5.0 mL) solution of N-[1-(4-iodophenyl)ethyl]cyclopropylamine (0.23 g) as obtained in Example 14-(1), and the mixture was stirred in a nitrogen atmosphere for 24 hours at room temperature. Further, stirring was continued for 2 hours at 45° C., and then PdCl2(PPh3)2 (29 mg) was added. After the system was refluxed in a nitrogen atmosphere for 5 hours, the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=85/15) to obtain N-(1-{4-[(trimethylsilyl)ethynyl]phenyl}ethyl)cyclopropylamine (brown oil) (0.14 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of 4-methoxythiophenol (9.66 g), ethyl 4-bromobutyrate (13.5 g) and potassium carbonate (18.8 g) in DMF (200 ml) was stirred at room temperature for 4 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, into a solution of the residue in ethanol (200 ml) was added at room temperature a 1 N aqueous solution of sodium hydroxide (85 ml), and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to remove the ethanol and was then extracted with diethyl ether. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 4-[(4-methoxyphenyl)thio]butyric acid (13.09 g) as colorless crystals.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1([CH3:57])[CH2:56][O:55][CH2:54][CH2:53][NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][C:51]2([CH3:57])[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC1(C)COCCN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2(C)C)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylmorpholine and isolated as colorless gum (12.5 mg, 64%). MS(m/e): 415.4 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16](=[O:18])[N:21]([O:22][CH3:23])[CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: CNOC
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of Boc-D-cyclohexylglycine (10 g, 39 mmol) in DCM (200 mL), N,O-dimethylhydroxyamine HCl salt (4.6 g, 46 mmol), HOBT (7 g, 51 mmol), and TEA (11 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 10 g, 51 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added. The resulting solution washed with aqueous citric acid solution, aqueous NaHCO3 solution, and aqueous NaCl solution. The organic layer was separated, dried with MgSO4, and then evaporated to yield [cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:24])[N:10]=[N:11][C:12]=2[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:15]2[CH:14]=[C:13]([C:12]3[N:11]=[N:10][C:9]([NH2:24])=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: Nc1nnc(-c2cc(Cl)nc(C(F)(F)F)c2)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cc(N3CCC3)nc(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 19 %

Procedure:
6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (20.0 mg, 19%) was prepared from 5-phenyl-6-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.28 mmol) and azetidine according to the general procedure for Preparation 4a.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]#[CH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:19][OH:20].NC1C=C(C)C=CN=1>>[OH:20][N:19]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:8][C:9]#[CH:10])[C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: C#CCc1c(C)cc(=O)oc1-c1ccccc1
Reactant: NO
Agent: Cc1ccnc(N)c1
Agent: Cl
Product: C#CCc1c(C)cc(=O)n(O)c1-c1ccccc1
Yield: 76.9 %

Procedure:
1 g of 4-methyl-5-propargyl-6-phenyl-2-pyrone, 1.5 g of hydroxylamine hydrochloride and 3 g of 2-amino-4-methyl-pyridine were heated for 9 hours to 80° C. After the usual working up, there were obtained 0.82 g (77 %) of 1-hydroxy-4-methyl-5-propargyl-6-phenyl-2-pyridone melting at 200° C (Calc.: 5.9 % N, found: 5.8 % N).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[Cl:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:17])[F:19])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=3[Cl:36])[NH:2][S:38]([CH3:37])(=[O:40])=[O:39])=[O:28])[N:9]=2)=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl
Agent: Cl
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to Example 16, treatment of 76 mg (0.13 mmol) of the compound of Example 55A with methanesulphonyl chloride gave 59 mg (73% of theory) of the title compound.
Reaction SMILES: O=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(C2C=CC=CC=2)CCC[N:3]1[CH2:20]C(O)=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]3[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=3)[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:20]1[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:2][N:3]1[C:38](=[O:39])[CH2:37][N:33]1[CH2:34][CH2:35][CH2:36][C:31]([C:28]2[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:32]1=[O:41]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.00 (m, 14H), 4.69 (d, J=42.8, 2H), 4.32 (d, J=4.4, 2H), 3.86 (t, J=6.0, 1H), 3.67 (t, J=5.9, 1H), 3.52 (t, J=6.4, 2H), 2.88 (t, J=5.9, 2H), 2.72-2.56 (m, 2H), 1.92-1.76 (m, 2H); MS (DCI) m/z 425.1 (M+H)+.