Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2C=CC=CC=2Cl)[N:6]=1.C(O)(=O)C.[CH2:23]([C:27](OCC)(OCC)[O:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26]>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1=[N:6][N:7]([CH3:11])[C:8](=[O:10])/[C:9]/1=[C:27](\[O:28][CH2:29][CH3:30])/[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(OCC)(OCC)OCC
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Temperature: 70 °C

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 0.80 g) in acetonitrile (5 mL), glacial acetic acid (21 μl 0.1 equiv.) and BuC(OEt)3 (3 eq.) was heated at 70° C. for 1 h 15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl[(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.0 g, quantitative yield). MS (ESI+): 283.4; MS (ESI−): 281.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(-c3ccccc3)c2c1

Procedure:
Similar procedure as described in example 61g was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), phenylboronic acid, tetrakis(triphenylphosphine)palladium(0), and sodium carbonate solution to give 3-cyano-4-phenyl-quinoline-6-carboxylic acid ethyl ester. LC-MS m/e 303 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CCCCCC(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: CCCCCC(=O)Nc1nc(-c2ccccc2)c(-c2noc(C)n2)s1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and hexanoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@H:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:31](OC)([N:33]([CH3:35])[CH3:34])[CH3:32]>C1(C)C=CC=CC=1>[CH3:34][N:33]([CH2:31][CH:32]=[N:28][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C@H:14]1[CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)[CH3:35]
Reactant: NC(=O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)CC=NC(=O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Temperature: 120 °C

Procedure:
To a solution containing 3-[trans-N-benzyloxycarbonyl-3-aminocyclobutyl]indol-5-yl acetamide (4.68 g 13 mmol) in toluene (10 ml) was added N,N-dimethyl acetamide dimethyl acetal (40 ml). The mixture was then heated at 120° C. for 2 hours under Dean & Stark conditions. The solution becomes very dark. The solvent is evaporated under vacuum to give N-[(dimethylamino)ethanylidene]-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]-1H-indol-5-ylacetamide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[CH2:14]([N:16]([CH2:31][CH3:32])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:29]=O)=[CH:23]2)[CH3:15].N1CCCCC1.Cl>C(O)C>[O:13]=[C:8]1[C:7](=[CH:29][C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][N:16]2[CH2:31][CH2:32][CH2:15][CH2:14]2)=[CH:28][CH:27]=3)[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-carboxy-2-oxindole (35 mg, 0.2 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (51 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 6 hours. The reaction was acidified with 1N HCl and the precipitate was collected by vacuum filtration, washed with 1N HCl, water and ethanol, dried to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OCC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: O=C(N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1)OCc1ccccc1
Agent: Cl
Solvent: O
Product: N[C@H]1CCCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
To benzyl (4S)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (0.100 g, 0.166 mmol) was added 2.0 M Hydrogen chloride in Water (10.0 mL). The reaction was stirred for 18 h at 100° C. The reaction was concentrated then submitted to HPLC purification to give 248 (6.9 mg, 11% yield). ESI MS m/z=386.1 (M+1). 1H NMR (500 MHz, DMSO) δ 9.22 (s, 1H), 9.19 (s, 1H), 8.95 (s, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.57-7.51 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 3.80-3.70 (m, 2H), 3.60-3.55 (m, 2H), 2.95-2.85 (m, 1H), 2.10-1.96 (m, 2H), 1.86-1.56 (m, 3H), 1.40 (m, 1H)
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Reactant: O=S(Cl)Cl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCl

Procedure:
A solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.300 g, 1.1 mmol) (Example 6d) in thionyl chloride (3 mL) is refluxed overnight. The volatiles are removed in vacuo to give 4-(5-chloromethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one, which is redissolved in methanol (10 mL). The solution is injected in an H-Cube™ using a Pd on carbon cartridge at 0.5 mL/min, 100 bar H2 and 50° C. The solution eluting from the cartridge is collected and concentrated in vacuo. The residue is purified by semi-preparative reverse phase HPLC to give 3,3-dimethyl-4-(5-methyl-imidazol-1-yl)-isochroman-1-one as a white solid; MS (ESI) m/z 257.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 3 H), 1.58 (s, 3 H), 2.38 (br. s, 3 H), 5.18 (br. s, 1 H), 6.92 (s, 1 H), 7.17 (br. s, 1 H), 7.35 (br. s, 1 H), 7.58 (t, J=7.6 Hz, 1 H), 7.62-7.68 (m, 1 H), 8.26 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [NH3:1].Cl.[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([C:16](Cl)=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]#[N:20])=[CH:6][CH:5]=1>ClCCl>[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([C:16]([NH2:1])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]#[N:20])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)nc1SCc1ccc(Cl)cc1
Reactant: N
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(N)=O)nc1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Dry ammonia gas was bubbled through a solution of 6-(4-chlorobenzylthio)-5-cyanopicolinoyl chloride hydrochloride 81 (60 mg, 0.17 mmol) in dichloromethane (10 ml) for 5 min at 0° C. The mixture was stirred for 1 hr at ambient temperature and concentrated in vacuo. The crude product was purified by recrystallization in ether to afford 25 mg (48%) of the desired product 83. 1H NMR (600 MHz, DMSO-d6) δ 8.37 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.4 Hz), 7.49-7.47 (m, 2H), 7.38-7.37 (m, 2H), 4.74 (s, 2H). MS: m/z Calcd 303.8 Found MH+ 304.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:14][C:15]([F:32])([F:31])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([C:19]4[CH:20]=[N:21][C:16]([C:15]([F:31])([F:14])[F:32])=[CH:17][CH:18]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1Cl
Temperature: 80 °C

Procedure:
1.18 g of commercially available 3-Chloro-4-cyano-benzenesulfonyl chloride were dissolved in 30 ml dichloromethane. Then 880 mg 5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-1H-indole were added followed by 15 ml pyridine and 407 mg 4-dimethylaminopyridine. The mixture was stirred at 80° C. for thirty minutes. The mixture was diluted with 100 ml of dichloromethane and washed with 100 ml water and 100 ml saturated NaHCO3 solution. The organic layer was then separated and dried over MgSO4. The solvent was removed in vacuo to obtain 1.49 g 2-Chloro-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C(#N)C>[OH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 19.2 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (10 mL) was added potassium carbonate (155 mg, 1.124 mmol) and 3-bromo-2,2-dimethyl-propan-1-ol (141 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:27])OC3C=CC=CC=3)=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29].[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:41][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)(=[O:39])=[O:40])=[O:27])=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCNC(=O)Oc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3[N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a stirred solution of phenyl 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate (step 2, 10.0 g, 24.6 mmol) and p-toluenesulfonamide (6.3 g, 36.8 mmol) in DMF (100 mL) was added sodium hydride (2.0 g, 50 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate/toluene (v/v, 2:1, 2×300 mL). The organic extracts were washed with water (100 mL) and brine (200 mL), then dried (Na2SO4). Removal of the solvent gave crude product. Recrystallization from ethyl acetate gave 9.6 g (81%) of the title compound as brown solids. The mother liquor was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.9 g (16%) of the title compound as brown solids.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][N:33]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:34][CH2:35]3)[CH:21]3[CH2:22][CH2:23][N:24]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCNCC2)C2CCNCC2)n1
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCN(S(C)(=O)=O)CC2)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 36 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(1-piperazinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine with methane sulfonyl chloride in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 36% yield; mp (CH2Cl2/MeOH) 246-250° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.94 and 7.89 (2d, J=8.3 Hz, 1H), 7.73 and 7.70 (2t, JHF=53.0, 52.9 Hz, 1H), 7.44 and 7.40 (2t, J=8.4, 8.2 Hz, 1H), 6.97 (dd, J=8.0, 3.3 Hz, 1H), 4.68-4.51 (m, 1H), 3.98 (s, 3H), 3.81-3.69 (m, 10H), 3.59-3.48 (m, 2H), 3.12-3.10 (m, 2H), 3.06-3.02 (m, 2H), 2.94 and 2.92 (2s, 3H), 2.90-2.78 (m, 2H), 2.87 and 2.83 (2s, 3H), 2.55-2.39 (m, 6H), 1.92-1.75 (m, 6H); Anal. Calcd. for C30H44F2N10O6S2.0.25H2O: C, 48.2; H, 6.0; N, 18.7. Found: C, 48.1; H, 6.0; N, 18.7%.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:13][C:14]([F:19])([F:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C(OCC)C>[C:1]12([CH2:11][O:12][C:15](=[O:16])[C:14]([Br:13])([F:19])[F:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)C(F)(F)Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)Br
Temperature: 0 °C
Yield: 95 %

Procedure:
Into a 50-L reaction vessel, 476 g (3.18 mol, 1.11 eq) of 1-adamantanemethanol and 5.5 kg of diethyl ether were added. The resulting solution was suspended by stirring, followed by adding thereto 615 g (2.86 mol, 1.0 eq) of bromodifluoroacetyl chloride. The suspended solution was cooled down to 0° C. Then, 578 g (5.72 mol, 2.0 eq) of triethylamine was slowly dropped to the cooled suspended solution. This reaction solution was left, while stirring, until it reached room temperature. The reaction solution was further stirred for 1 hour at room temperature. Subsequently, the reaction solution was washed with 5 kg of water. The thus-obtained organic layer was washed with 5 kg of saturated sodium hydrogencarbonate solution, with 5 kg of saturated sodium chloride solution, and then, with 5 kg of water. The washed organic layer was dried with magnesium sulfate and subjected to solvent distillation. With this, 878 g of target bromodifluoroacetic acid adamantane-1-ylmethyl ester was obtained (yield: 95%, purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 14.9 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 3,4,5-trichloropyridine (216 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (35 mg), a white solid, in 15% yield.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C(O[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.O1CCOCC1.CCCCCC>CCN(CC)CC.CCOC(C)=O>[CH3:13][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)OC=Cc1ccccc1
Reactant: Cc1ccccc1-c1ccccn1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C=Cc2ccccc2)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 40 h
Yield: 97 %

Procedure:
A Teflon-coated magnetic stirring rod was placed in a 4 mL pressure proof screw vial, dried with heating, then, N2 gas was allowed to flow through the reaction apparatus for several minutes to purge the whole reaction apparatus with nitrogen. The reaction vessel was left to cool to room temperature, then, under a nitrogen flow, into the reaction vessel was added Ru(cod)(cot) complex (0.05 mmol, 15.08 mg), 2-o-tolylpyridine (1 mmol, 169 mg), styryl acetate (3 mmol, 486.6 mg) and dioxane (1.0 mL), and the reaction vessel was sealed. The mixture was heated at 100° C. by an oil bath and reacted for 40 hours. 40 hours after, the reaction solution was left to cool to room temperature, then, an internal standard was added, and the product was quantified by gas chromatography. Isolation of the product was carried out by silica gel column chromatography (i.d.=30 mm; length=170-250 mm; hexane:EtOAc:Et3N=8:1:0.1; 25 mL each). A subject substance 2-(2-methyl-6-styrylphenyl)-pyridine was obtained with a yield of 97%.
Reaction SMILES: C(S[C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[N:10][C:8]=2[N:9]=1)C.ClC1C=C(C=CC=1)C(OO)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.O1CCOCC1>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[N:10][C:8]=3[N:9]=2)[CH2:42][CH2:41]1
Reactant: CN1CCNCC1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde (5-4a) (1.0 g, 2.69 mmol) in CH2Cl2 (30 mL) was added m-chloroperoxy benzoic acid (0.660 g, 3.0 mmol). The solution was stirred for 1 hr then quenched with sat. NaHCO3 and 10% Na2S2O3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2, extracted, dried with MgSO4, and filtered. A portion of the resulting sulfoxide (0.700 g, 1.81 mmol) was dissolved in dioxane (7 mL) with methyl piperazine (181 mg, 1.81 mmol) and heated to 100° C. for 20 min. in a microwave reactor. The mixture was concentrated under reduced pressure and the residue was purified by HPLC (Phenomenx Synergi column; 20-85% acetonitrile/water+0.1% TFA) to give the title compound (5-5a). 1H-NMR (500 MHz, d4-CD3OD) δ 10 (s, 1H), 9.48 (s, 1H), 8.65 (s, 1H), 7.88 (d, 2H), 7.64 (d, 2H), 7.46 (m, 6H), 7.33 (m, 3H), 7.26 (m, 3H), 3.6-3.4 (m, 8H), 3.00 (s, 3H) LRMS m/z (M+1) Calcd: 410.5, found 410.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH2:40][CH2:41][CH3:42])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CCCCI
Product: CCCCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Yield: 62 %

Procedure:
In a manner similar to the method described in Example 36-2, using 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using iodobutane in place of iodoethane, 203 mg (yield: 62%) of the captioned compound was obtained as a diastereomer mixture.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](N(OC)C)=[O:38])[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:44][Mg]Br.Cl>O1CCCC1>[CH3:28][C:26]1[N:27]=[C:19]2[N:18]([C@H:29]3[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37](=[O:38])[CH3:44])[CH2:33][CH2:34]3)[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2nc(C)nn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 1.7 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 60%).