Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:44][O:45][NH2:46]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:46][O:45][CH3:44])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of the carboxylic acid (6b, 965 mg, 3.49 mmol) of Example 9 or 16 in tetrahydrofuran (20 mL) were added triethylamine (1.95 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (802 mg), 1-hydroxybenzotriazole.monohydrate (658 mg), and O-methylhydroxylamine hydrochloride (363 mg), followed by agitating to room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/10) to afford 773 mg of the title compound (yield 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1c[nH]c2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-3-carboxylic acid were combined to provide N3-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-3-indolecarboxamide as a white powder, m.p. 225.5-227.4° C. 1H NMR (300 MHz, DMSO-d6) δ11.50 (broad s, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.06 (d, J=10.2 Hz, 1H), 7.95-7.89 (m, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.20-7.05 (m, 3H), 6.48 (broad s, 2H), 4.58 (t, J=7.2 Hz, 2H), 3.80 (t, J=6.6 Hz, 2H), 3.33 (m, 2H), 3.24-3.18 (m, 5H), 1.88 (m, 2H), 1.70 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ165.0, 152.0, 151.0, 145.1, 136.4, 132.6, 127.8, 126.8, 126.6, 126.4, 122.1, 121.5, 121.4, 120.6, 120.3, 115.1, 112.1, 111.0, 70.5, 58.4, 45.1, 38.2, 27.7, 27.5, 27.0; MS (EI) m/e 456.2282 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:35][CH2:34][C:9]2[C:10]3[C:15]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:21]=[CH:20]5)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:8]=2[CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:26]([N:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:15]3[C:10]4[C:9]5[CH2:34][CH2:35][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][C:8]=5[S:33][C:11]=4[N:12]=[CH:13][N:14]=3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC1CCc2c(sc3ncnc(Nc4ccc5c(cnn5Cc5ccccc5)c4)c23)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1CCc2c(sc3ncnc(Nc4ccc5c(cnn5Cc5ccccc5)c4)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of THF (100 mL) was added 4.50 g (9.04 mmol, 1 equiv) of [4-(1-Benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-acetic acid ethyl ester. A 1M solution of diisobutylaluminum hydride in THF (45.2 mL, 45.2 mmol, 5 equiv) was added to the solution at 0° C. and the reaction was stirred for 30 min before warming up to rt and stirring for 2 h. The reaction mixture was quenched with Rochelle's salt followed by EtOAc. The solution was separated and the aqueous layer discarded and the organic layer was washed with brine (200 mL) and water (100 mL). The resulting crude material was purified by flash chromatography eluting with 95/5 CH2Cl2/MeOH yielding 850 mg (21%) of Example 203 as a white solid. 1H-NMR (CD2Cl2) δ 8.36 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.01 (s, 1H), 7.46–7.19 (m, 8H), 5.60 (s, 2H), 3.77 (q, J=4.4 Hz, 2H), 3.21–2.96 (m, 3H), 2.56 (m, 1H), 2.11 (m, 2H), 1.67 (m, 3H), 1.45 (t, J=4.4 Hz, 1H). LCMS RT=2.68 min; [M+H]+=456.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[OH:25])#[N:2].N1C=CN=C1.[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:35]([O:25][CH:6]1[C:5]2[C:22](=[CH:23][CH:24]=[C:3]([C:1]#[N:2])[CH:4]=2)[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7]1)([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(C#N)ccc1O2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2

Procedure:
To a solution of 15.1 g of tert-butyl 6-cyano-4-hydroxy-spiro[chroman-2,4′-piperidine]-1′-carboxylate in DMF were added 3.6 g of imidazole and 7.95 g of TBSCl at rt, and the reaction mixture was stirred at rt for 1d. To this reaction mixture was added 598 mg of imidazole and 1.3 g of TBSCl at rt, and the reaction mixture was stirred at rt for 1d. The reaction mixture was poured into ice-cold brine, and the aqueous mixture was extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane and AcOEt (100/0-80/20) as eluent to give the intended compound.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][CH:5]=1.O1CCCC1.C([Li])CCC.O>CCCCCC>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]#[CH:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CCc1ccc(C=C(Br)Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(CC)cc1
Temperature: 25 °C

Procedure:
1,1-Dibromo-2-(4-ethylphenyl)ethylene (1.1 g., 3.69 mmol.) is dissolved in 20 ml. of dry tetrahydrofuran and maintained under a nitrogen atmosphere. The solution is cooled to -78° and 3.9 ml. of a 1.9 M solution of butyl lithium in hexane is added with stirring. The reaction mixture is stirred one hour at -78°, then warmed to ambient temperature and stirred an additional hour. Water is added, the mixture is extracted with petroleum ether, the extracts are combined, dried (MgSO4) and concentrated to give 4-ethylphenylacetylene.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:3]=1[CH2:4][N:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[NH2:6].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:21]([O:20][CH2:19][C:15]1[C:3]2[C:2]([CH:18]=[CH:17][CH:16]=1)=[N:6][N:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[CH:4]=2)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1CN(N)c1ccc(C#N)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc2nn(-c3ccc(C#N)cc3)cc12
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of (C3) in dry toluene (0.28 M) was added sodium tert-butoxide (1.5 eq.), followed by dppf (0.075 eq.) and Pd(OAc)2 (5% mol). The reaction mixture was heated to 80° C. for 35 min. After cooling down, the reaction mixture was directly loaded to a silica gel column and purified by flash column chromatography on silica (EtOAc/Petroleum ether 1:9) to yield (68%) the title compound as yellow powder. 1H NMR (300 MHz, CDCl3, 300K) δ 8.59 (1H, s), 8.07 (2H, d, J=8.7 Hz), 7.83 (2H, d, J=8.5 Hz), 7.64 (1H, d, J=8.7 Hz), 7.32-7.28 (1H, m), 7.05-7.03 (1H, m), 4.99 (2H, s), 0.96 (9H, s), 0.13 (6H, s). MS (ES+)C21H25N3OSi required: 363, found: 364 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][NH:18][C:17](=[O:21])[N:16]=2)[CH2:11][CH2:10]1.CC1C=CC(S(O[CH2:33][N:34]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[N:35]2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[CH:19][N:18]([CH2:33][N:34]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[N:35]3)[C:17](=[O:21])[N:16]=2)[CH2:13][CH2:14]1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3F)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCn2ccc(C(F)(F)F)n2)cc1
Product: O=c1nc(N2CCN(c3ccc(F)cc3F)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Yield: 7.3 %

Procedure:
The synthesis was performed using 4-[4-(2,4-difluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (189 mg, 0.65 mmol) synthesized in Reference Synthesis Example 86 and [3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl 4-methylbenzenesulfonate (413 mg, 1.29 mmol) synthesized in Reference Synthesis Example 15 in a similar manner to Synthesis Example 1 to obtain the title compound (21 mg, yield: 7.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][NH:17]1>CS(C)=O>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][N:17]1[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2
Reactant: C1=Cc2ccccc2CN1
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Solvent: CS(C)=O
Product: O=C1Cc2c(OCCN3CCc4ccccc4C3)ccc(F)c2N1
Yield: 45 %

Procedure:
4-(2-Chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one was reacted with dihydroisoquinoline in anhydrous dimethyl sulfoxide in the same manner described for intermediate 16 to afford the title compound in 45% yield. The fumarate salt was made in ethanol: mp 230°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Cl)CC1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%.
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:25]([F:28])([F:27])[F:26])=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[CH:18]3)[CH:13]=2)[NH:8][C:7]1=[O:29])(=[O:4])=[O:3].Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][N:32]([CH3:33])[C:22]([C:20]1[N:19]=[CH:18][N:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:25]([F:26])([F:28])[F:27])[NH:8][C:7](=[O:29])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3=[O:16])[CH:21]=1)=[O:24]
Reactant: CNC
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(=O)O)c3)cc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid (120 mg, 0.277 mmol) in 10 ml of dimethylformamide is treated with dimethylamine hydrochloride (46 mg, 0.554 mmol), N-3-dimethylaminopropyl-N′-ethyl-carbodiimide hydrochloride (60 mg, 0.305 mmol), N-hydroxybenzotriazole (11 mg, 0.08 mmol) and triethylamine (0.1 ml, 0.72 mmol). The solution is heated to 100° C. for 1 hour, cooled to room temperature, evaporated in vacuo and the residue chromatographed over silica gel to give 22 mg (0.048 mmoles, 17%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H -imidazole-4-carboxylic acid dimethylamide, m.p. 284 -286° C., ES-MS: m/z 461 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3CCNC(=O)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 72.5 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B) (1.00 g, 4.00 mmol) and 2-piperazinone (0.801 g, 8.00 mmol) were dissolved in 50 mL of toluene and 25 mL of acetonitrile with stirring. TEA (1.40 mL, 9.97 mmol) and HOAc (0.34 mL, 5.9 mmol) were added via syringe. Sodium triacetoxyborohydride (2.12 g, 10.0 mmol) was added in four equal portions over 1 h. The reaction was allowed to stir overnight and quenched by the addition of approximately 50 mL of 1N NaOH solution and 50 mL of MeOH. The mixture was stirred for 10 min and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.970 g (73%) of the title compound of step A. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=9.5 Hz, 1H), 7.68 (br. s., 1H), 6.55 (dd, J=9.5, 2.4 Hz, 1H), 6.46 (d, J=2.56 Hz, 1H), 4.07-3.94 (m, 2H), 3.86 (s, 3H), 3.07 (br. s., 2H), 3.00 (s, 2H), 2.97-2.86 (m, 2H), 2.66-2.37 (m, 3H), 1.87-1.75 (m, 2H), 1.48-1.32 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[Se:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N+:14]([O-])=O)[CH:6]=1)=[O:4].Cl.[Cl-].[NH4+]>O.CO.[Fe]>[CH3:13][O:12][C:10]([C:8]1[Se:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[NH2:14])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(=O)OC)[se]1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)c(C(=O)OC)[se]1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of methyl 5-(methoxycarbonyl)-3-nitroselenophene-2-carboxylate (8.0 g, 27.3 mmol) in a mixture of water (20 mL) and methanol (150 mL) was added conc. hydrochloric acid (2.75 mL, 27.3 mmol). To the above solution was added iron powder (7.64 g, 136.5 mmol) followed by ammonium chloride (7.3 g, 136.5 mmol) at rt. The reaction mixture was refluxed for 3 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (4×200 mL) and the combined organic layer was washed with brine, dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluent to give the product as pale yellow color solid (5.8 g, 41%), mp 144-146° C. IR (neat) vmax. 3449, 3339, 1673, 1604, 1556, 1285, 1217, 1125, 1023 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.55 (1H, s, H-4), 5.57 (2H, s, —NH2), 3.86 (3H, s, —COOCH3), 3.82 (3H, s, —COOCH3); LC-MS (negative ion mode): m/z 264, 262 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[C:13](=S)=[S:14].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[SH:14][C:13]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(CO)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCc1ccc(-c2nnc(S)o2)cc1

Procedure:
To a solution of 4-(Hydroxymethyl)benzoic hydrazide CAS [58855-42-8] (1.4 g, 8.4 mmol) in ethanol (14 mL) were added carbon disulfide (1.12 mL, 18.5 mmol) and triethyl amine (1.3 mL, 9.3 mmol). After heating to reflux for 16 h with stirring, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 10% HCl solution and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (65% ethyl acetate in hexanes) gave 1.62 g of [4-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl]methanol as a colorless solid.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:56])([F:55])[CH2:46][O:47][C:48]1[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:51]3[CH:52]=[N:53][C:48]([O:47][CH2:46][C:45]([F:44])([F:55])[F:56])=[CH:49][CH:50]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(OCC(F)(F)F)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=454.2 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)CCCC2
Reactant: [H][H]
Product: c1ccc2ccccc2c1

Procedure:
In practice tetralin together with the catalyst to be tested is introduced into a small unstirred autoclave. No hydrogen is added to the autoclave. The autoclave is heated to an elevated temperature, and the tetralin dehydrogenates as the equilibrium shifts towards a new value characteristic of the elevated temperature used. The rate at which the system moves towards equilibrium and hence the quantity of naphthalene produced in a given time depends upon the activity of the catalyst. The quantity of naphthalene produced is determined by GLC or by 1H-nuclear magnetic resonance (1H-nmr). The quantity of naphthalene produced is then expressed as a percentage of that produced when using a fresh unused catalyst to obtain a measure of the catalyst activity.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].Cl[C:21]([O:23][CH:24]1[CH2:26][CH2:25]1)=[O:22]>N1C=CC=CC=1>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][C:21]([O:23][CH:24]3[CH2:26][CH2:25]3)=[O:22])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Reactant: O=C(Cl)OC1CC1
Solvent: c1ccncc1
Product: C#CCN1CCC(OC(=O)OC2CC2)N(c2nnc(S(C)=O)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and cyclopropyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-cyclopropoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])S(C1C=CC=CC=1)(=O)=O>C1COCC1>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:15]=[N:25]/[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(c1cccc(Cl)c1Cl)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/N=C/c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
4.42 g (32.0 mmol) of potassium carbonate were dried in the heat under high vacuum and then cooled to RT under an atmosphere of argon. 52 ml of anhydrous THF and 2.22 g (5.33 mmol) of the compound of Example 21A were added. The reaction mixture was then stirred at reflux temperature for 16 h. After cooling to RT, the reaction mixture was filtered through Celite. The solid was washed with a little THF. The combined filtrates were freed from the solvent on a rotary evaporator and the residue was dried under high vacuum. This gave 1.38 g (94% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9]I.[Cu](C#N)[C:21]#[N:22].[Br-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:21]#[N:22]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#CI)c(F)c2)CC1
Reactant: N#C[Cu]C#N
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(C#CC#N)c(F)c2)CC1
Reaction time: 5 h

Procedure:
To a solution of 10 mmol of 3-fluoro-4-iodoethynyl-1-(trans-4-propylcyclohexyl)benzene in 3 ml of tetrahydrofuran were added 11 mmol of copper cyanide and 3 mmol of lithium bromide, and the solution was stirred for 5 hours under reflux. To the reaction solution were added 10 ml of 6N hydrochloric acid saturated solution of ferric chloride and the solution was stirred at room temperature for one hour. After completion of the agitation, the reaction solution was extracted with toluene, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentratred under reduced pressure. The resulting brown, oily product was isolated and purified by a silica gel column chromatography to afford a colourless oily substance which was recrystallized from ethanol to afford colourless crystal. This was identified as the title compound by analytical results.