Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and commercially available 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (36 mg, 28%). MS (ISP) 483.5 [(M+H)+]; mp 262–264° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:66]=[C:67]1[CH:71]=[CH:70][C:69](=[O:72])[N:68]1[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([NH:80][NH2:81])=[O:79]>>[O:72]=[C:69]1[CH:70]=[CH:71][C:67](=[O:66])[N:68]1[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([NH:80][NH:81][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:79]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [Na].CO.[CH3:4][O:5][C:6](=[O:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][C:12](OC)=[O:13]>C1(C)C=CC=CC=1>[O:13]=[C:12]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:6]([O:5][CH3:4])=[O:16]
Reactant: COC(=O)CCCSCC(=O)OC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1SCCCC1=O
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a suspension of sodium (3.5 g, 0.15 mol) in dry toluene (300 mL) was added an excess of methanol (30 mL). After sodium was disappeared, the excess methanol was removed as the methanol-toluene azeotrope. When the distillation temperature had reached 105° C., Methyl 4-{[2-(methyloxy)-2-oxoethyl]thio}butanoate (28.3 g, 0.14 mol) in toluene (90 mL) was added over a period of ten mins. The methanol-toluene azeotrope was removed by distillation, after the distillation temperature rose to 106° C., the reaction mixture was cooled to room temperature. The reaction mixture was poured into a mixture of ice (100 g) and 12N HCl (20 mL). The organic layer was removed and the aqueous layer was extracted with three 60 mL portions of ether and the combined organic layers were dried over Na2SO4. After removing the solvent, 23.4 g of crude product was obtained (Yield: 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=1.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:22]=2[CH:21]=1.N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:23]1[C:22]2[CH:21]=[C:20]([O:18][C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([N:10]4[CH:11]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:8]=[N:9]4)[CH:13]=3)[CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: Oc1cccc(-n2cc(-c3cccnc3)cn2)c1
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2c3ccccc3c3ccc(Oc4cccc(-n5cc(-c6cccnc6)cn5)c4)cc32)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a dry Shlenck tube equipped with a magnetic stir bar was added 3-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)phenol 5 (475 mg, 2.0 mmol, 1.0 eq), 2-bromo-9-(pyridin-2-yl)-9H-carbazole (776 mg, 2.4 mmol, 1.2 eq), Cut (38 mg, 0.2 mmol, 0.1 eq), picolinic acid (49 mg, 0.4 mmol, 0.2 eq) and K3PO4 (819 mg, 4.0 mmol, 2.0 eq). The tube was evacuated and backfilled with nitrogen. The evacuation and backfill procedure was repeated another two times. Then solvent DMSO (10 mL) was added under nitrogen. The mixture was stirred in an oil bath at a temperature of 90-100° C. for 3 days and then cooled down to ambient temperature. Water was added to dissolve solid. The mixture was extracted with ethyl acetate three times. The combined organic layer was washed with water three times, dried over sodium sulfate, and then filtered. The solvent was removed under reduced pressure, and the residue was purified through column chromatography on silica gel using dichloromethane/methanol (50:1) as eluent to obtain the desired product Ligand ON13 as a brown-red solid 656 mg in 68% yield. 1H NMR (DMSO-d6, 400 MHz): δ 6.92 (dd, J=8.0, 2.4 Hz, 1H), 7.04 (dd, J=8.0, 1.6 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.33-7.40 (m, 3H), 7.45 (t, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.55 (t, J=2.0 Hz, 1H), 7.60 (dd, J=7.6, 1.6 Hz, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.98-8.03 (m, 2H), 8.16 (d, J=7.6 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.22 (s, 1H), 8.38 (dd, J=4.4, 1.6 Hz, 1H), 8.62 (dd, J=4.4, 1.6 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H), 9.08 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 102.54, 107.98, 111.12, 112.68, 113.27, 115.75, 119.02, 120.11, 120.19, 121.01, 121.27, 121.79, 122.11, 123.28, 123.87, 125.32, 125.99, 127.66, 131.06, 132.41, 138.90, 139.36, 139.49, 139.97, 140.78, 146.54, 147.62, 149.52, 150.48, 154.81, 158.56.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CO.[ClH:32].[H][H]>[Pd].CC(O)C>[ClH:32].[ClH:32].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][CH2:21][CH2:20][CH2:19][N:18]=1
Reactant: c1ccc(CN(CCCNc2ncccn2)CC2CCc3ccccc3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1ccc2c(c1)CCC(CNCCCNC1=NCCCN1)O2
Yield: 38 %

Procedure:
A mixture of 7.8 g of N-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl- N'-(2-pyrimidinyl)-1,3-propanediamine, 200 ml methanol and 10 ml of 2-propanol saturated with HCl was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (5%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the dihydrochloride salt in 2-propanol by adding 2-propanol saturated with hydrochloric acid. The salt was filtered off and dried, yielding 2.9 g (38.0%) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine dihydrochloride; mp. 227.0° C. (comp. 95).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.[CH3:13][O:14][C:15]1[CH:55]=[CH:54][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:51])[C@@H:30]([NH:31][C:32](=[O:50])[C:33]([C:37]4[N:38]=[C:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[S:40][CH:41]=4)=[N:34][O:35][CH3:36])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:52]Cl)=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([C:23]2[N:28]3[C:29](=[O:51])[C@@H:30]([NH:31][C:32](=[O:50])[C:33]([C:37]4[N:38]=[C:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[S:40][CH:41]=4)=[N:34][O:35][CH3:36])[C@H:27]3[S:26][CH2:25][C:24]=2[CH2:52][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:22])=[CH:54][CH:55]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: Sc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CSc3ccncc3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
To a solution of 4-mercaptopyridine (222 mg; 2 Eq.) in N,N-dimethylformamide (10 ml) keeping at 0° C. is added a solution of sodium methoxide in methanol (1.5 Eq.). To this mixture is added 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (652 mg; 1 mMol.), and the mixture is stirred for 10 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene:ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (3) (708 mg).
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[O:28][CH2:27][CH:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:35].[Na]>C1COCC1.CO.O>[Na+:35].[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[O:28][CH2:27][CH:26]([CH2:29][C:30]([O-:32])=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)OC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of methyl 2-(6-(4′-(5-cyclobutyl-1,3,4-oxadiazol-2-ylamino)biphenyl-4-yl)tetrahydro-2H-pyran-3-yl)acetate (43 mg, 0.10 mmol) in THF (0.5 ml) and MeOH (0.5 ml) was added a solution of 1N NaOH (0.29 ml, 0.29 mmol). The mixture was stirred at room temperature for overnight. Afterward, the reaction mixture was concentrated to dryness afford a white solid. The solid was taken up in water to form a slurry and was subsequently filtered. The filtercake was washed with water, dried to afford the title compound (36 mg, 81% yield) as a sodium salt. The ratio of cis to trans isomer was determined to be ˜1:1.2 by NMR studies. HR/MS [M+H]+: found 434.2071, calc. 434.2080. RT: 1.72 (Condition L). HR/MS [M+H]+: found 434.2077, calc. 434.2080. RT: 1.75 (Condition L).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][C:3]=1[S:11][CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([NH2:25])[CH3:24])=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([NH:25][CH2:7][CH:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11][CH3:12])[CH:4]=2)[OH:8])[CH3:24])=[CH:17][CH:16]=1
Reactant: CSc1cc(C2CO2)ccc1C
Reactant: COc1ccc(CCC(C)N)cc1
Solvent: c1ccccc1
Product: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(SC)c2)cc1
Temperature: 115 °C
Yield: 29.2 %

Procedure:
A mixture of 6 g of 4-methyl-3-methylthiostyrene oxide and 7 g of 3-(4-methoxyphenyl)-1-methylpropylamine was heated to 115° C. for 3 hours. After the reaction was over, the reaction mixture was dissolved in 100 ml of benzene and after washing twice each time with 200 ml of water, the benzene layer was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 3.5 g of amorphous α-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylthiobenzenemethanol.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH2:20].C(O)(C)C.CCOCC>CCOCC>[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH:20][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)=[S:17]
Reactant: CC(=O)N(C)N
Reactant: CCOC(=O)CN(C)c1ccc(N=C=S)cc1
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)CN(C)c1ccc(NC(=S)NN(C)C(C)=O)cc1

Procedure:
A solution of 1.25 g (5.0 mmol) of ethyl N-methyl-N-(4-isothiocyanatophenyl)glycinate and 0.44 g (5.0 mmol) of 1-methyl-1-acetylhydrazine in 40 ml of 1/1 isoproply alcohol/ether was left uncovered so the ether could evaporate over a 24 hr period. The product was collected and washed with isopropyl alcohol to give 1.32 g (3.9 mmol, 78%), mp 162° dec. Anal. C15H22N4O3S (338): Calcd.: C,53.24; H,6.55; N,16.56; S,9.48. Found: C,53.12; H, 6.45; N,17.05; S,8.90. MS(FD) m/z 338. 1H NMR(DMSO-d6)δ: 9.76,s,2H,NH; 7.11,d,2H,ArH; 6.58,d,2H,ArH; 4.15,s,2H,CH2—N; 4.05,q,2H,CH2—O; 2.93,s,3H,CH3—N; 1.92,s,3H,CH3CO; 1.14,t,3H,CH3—C.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH:14]=[CH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:18]=[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5ccc(=O)[nH]c45)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 446.2 (Exact Mass: 445.21).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[OH:18][C:15]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:19])[F:20])=[N:4][N:5]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: N#Cc1ccccc1Br
Product: N#Cc1ccccc1C1(O)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 24 %

Procedure:
A mixture of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 2-bromobenzonitrile was allowed to react by the method of Example 315 to give 2-[4-hydroxy-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzonitrile in 24% yield.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:15][C:16](OCC)=O)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)([O-])=O.CC[OH:23]>[Ni]>[O:12]1[C:8]2([CH2:13][CH2:14][C:5]3([CH2:15][CH2:16][NH:1][C:4]3=[O:23])[CH2:6][CH2:7]2)[O:9][CH2:10][CH2:11]1
Reactant: CCO
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Agent: [Ni]
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
To a solution of ethyl 2-(8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acetate (109 g, 379.38 mmol) in EtOH (600 mL) was added Raney Ni (10 g). The reaction mixture was stirred under H2 atmosphere at rt for 72 h and filtered. The filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filtrate was concentrated in vacuo and the residue was washed with a mixture of PE and EtOAc (10/1 (v/v), 800 mL) and filtered to give the product as a white solid (67 g, 83.8%).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][CH:3]=1.[Br:12]Br.O.[C:15]([OH:18])(=O)C>>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([O:18][CH3:15])=[CH:3][C:2]=1[C:1]([OH:11])=[O:10]
Reactant: CC(=O)O
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Product: COc1ccc(Br)c(C(=O)O)c1

Procedure:
To a three-necked flask equipped with a mechanical stirrer and condenser, 100 g of anisic acid and 600 ml of glacial acetic acid were added. A solution of 106 g of bromine in 300 ml of acetic acid was added, followed by the addition of water. The mixture was heated to boiling and allowed to cool. Approximately 130 g of 2-bromo-5-methoxybenzoic acid was obtained as fine needle crystals.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[OH2:28].[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Reactant: BrCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Oc1ccc2c(c1)nc(CC1CCN(CCSc3ccccc3)CC1)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 6.48 parts of [(2-bromoethyl)thio]benzene, 6.8 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazol-5-ol, 4.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred for 2 hours at reflux temperature using a water separator. After cooling to room temperature, the reaction mixture was poured into water. The layers were separated. The organic layer was washed with 500 parts of water, dried, filtered and evaporated. The residue was taken up in a mixture of trichloromethane and methanol (95:5 by volume) and 25 parts of silica gel. After stirring for 15 minutes, the whole was filtered, washed with the eluent and the filtrate was evaporated. The residue was boiled in 160 parts of 2-propanone. The mixture was stirred overnight at room temperature. The product was filtered off, washed with 2-propanone and crystallized from 280 parts of 2-propanone. The product was filtered off, washed with 2-propanone and dried in vacuo at 50° C., yielding 2.7 parts (27.8%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(phenylthio)ethyl]-4-piperidinyl]methyl]-1-H-benzimidazol-5-ol hemihydrate; mp. 193.8° C. (570).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH2:14][C:5]=2[CH:4]=[CH:3][N:2]=1>COC(OC)COCC(OC)OC.[Pd]>[CH:12]1[C:13]2=[CH:14][C:5]3[CH:4]=[CH:3][N:2]=[CH:1][C:6]=3[CH:7]=[C:8]2[CH:9]=[CH:10][N:11]=1
Reactant: c1cc2c(cn1)Cc1ccncc1C2
Agent: [Pd]
Agent: COC(COCC(OC)OC)OC
Product: c1cc2cc3cnccc3cc2cn1

Procedure:
1.6 g of 5,10-dihydro-pyrido[3,4-g]isoquinoline and 0.32 g of palladium-on-charcoal was dispersed and mixed in 100 cc of dimethoxyethyl ether, and refluxed for 15 hours under argon atmosphere. After the filtration of palladium-on-charcoal and solvent was evaporated to obtain crude pyrido[3,4-g]isoquinoline. The product was purified by preparative liquid chromatography (gel; R-055-15, S16SIL, YMC Ltd., developing solvent; ethyl alcohol/benzene=3/7). The yield of the compound was 1.3 g (95%) and its m.p. was 174° C. The compound was identified as pyrido [3,4-g]isoquinoline based upon the following elemental analysis.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].N([O-])=O.[Na+].[C-:22]#[N:23].[Na+]>O.Cl>[C:22]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17])#[N:23]
Reactant: [C-]#N
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nnc2ccc(C#N)cc2c1O
Temperature: 0 °C

Procedure:
A suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.164 g.) in water (10 ml.) and concentrated hydrochloric acid (1.0 ml.) was stirred at 0° C. in an ice-salt bath, and a solution of sodium nitrite (0.5 g.) in water (3 ml.) was added during 5 minutes, maintaining the temperature at 0°-5° C. The mixture was stirred at 0° C. for 10 minutes, and this mixture was then added dropwise to a stirred solution of cuprous cyanide (0.54 g.) and sodium cyanide (0.6 g.) in water (4 ml.), heated at 60°-70° C. on a steam bath. The mixture was heated under reflux for 30 minutes. The brown solid which was precipitated was filtered off, washed thoroughly with water and dried as much as possible on the filter. The crude product was extracted with boiling ethanol (2 × 100 ml.), and the combined extracts were filtered and the filtrate evaporated under reduced pressure. The residue was applied to a column of silica (30 g., Kieselgel 60). Elution with a mixture containing 15% v/v of ethanol and 85% v/v of chloroform yielded ethyl 6-cyano-4-hydroxycinnolin-3-yl carboxylate, m.p. 259°-261° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:20]([N:10]([C:11]([CH:13]1[CH2:14][CH2:15][C:16](=[CH2:19])[CH2:17][CH2:18]1)=[O:12])[C:9]1[CH:8]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:22])[CH3:21]
Reactant: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.126 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then 1N aqueous solution of LiOH.H2O (0.8 mL, 0.800 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (compound 28) (25 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.61 (d, J=7 Hz, 2H), 7.40-7.38 (m, 3H), 7.04 (s, 1H), 4.92 (m, 1H), 4.50 (d, J=7.6 Hz, 2H), 2.21-1.43 (m, 9H), 1.15 (bd, 3H), 0.93 (bd, 3H).