Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]2[S:15][CH:14]([CH2:16]O)[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OCC1CSC[S:21]1>>[C:1]1([CH:11]2[S:15][CH:14]([CH2:16][SH:21])[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CSCS1
Reactant: OCC1CSC(c2cccc3ccccc23)S1
Product: SCC1CSC(c2cccc3ccccc23)S1

Procedure:
The same method was followed as in Example 1 except that 2-(α-naphtyl)-4-hydroxymethyl-1,3-dithiolane produced in Example 3 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-(α-naphtyl)-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-7).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH:23]=O)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH2:23][N:29]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: C1CCCNCC1
Reactant: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2csc(CN3CCCCCC3)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Yield: 10.6 %

Procedure:
3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.072 mmol), hexahydro-1H-azepine (71.4 mg, 0.720 mmol, 10 eq), acetic acid (0.4 μL, 0.007 mmol, 0.1 eq) were dissolved in DMSO (2 mL) in a 5 mL A-vial reaction tube. The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (309 mg, 0.72 mmol, 10 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined and concentrated in a Glas-Col evaporator, giving 3.8 mg (9.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=1)[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:35](=[O:36])[C:34]3[CH:38]=[C:30]([CH3:29])[CH:31]=[N:32][CH:33]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: Cc1cncc(C(=O)O)c1
Product: Cc1cncc(C(=O)N(Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)C(C)C)c1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 5-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.2 (s, 1H)) 8.7 (s, 1H) 8.4 (s, 1H) 8.3 (m, 2H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 7.0 (d, 1H) 5.6 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 2.4 (s, 3H) 1.2 (d, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21][C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Product: O=c1cc(Sc2ccccc2)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and benzenethiol afforded 5-phenylsulfanyl-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded the lithium salt of 3-cyclopentyl-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionic acid as a white solid (98 mg, quantitative for the final step); ES+-HRMS m/e calcd for C18H20N2O3SI [M+H+] 345.1268, found 345.1268. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93-1.19 (m, 2H), 1.29-1.76 (m, 7H), 1.86-2.00 (m, 1H), 2.05-2.21 (m, 1H), 5.24 (dd, J=10.9, 3.9 Hz, 1H), 5.94 (d, J=2.1 Hz, 1H), 7.53-7.64 (m, 3H), 7.63-7.73 (m, 2H), 7.91 (d, J=2.1 Hz, 1H), 13.02 (br. s., 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=2.C(N(CC)CC)C>O1CCCC1>[Cl:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([OH:18])=[C:8]([NH:7][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cc(Cl)ccc2c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cnc2cc(Cl)ccc2c1O
Temperature: 25 °C
Yield: 59.2 %

Procedure:
Under a nitrogen atmosphere, butyryl chloride (0.76 mL, 7.3 mmol) was added dropwise to a mixture of 3-amino-7-chloro-4-hydroxyquinoline (1.3 g, 6.7 mmol), triethylamine (3.0 mL, 21.5 mmol) and anhydrous tetrahydrofuran (20 mL). The reaction mixture was maintained at ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with water followed by tetrahydrofuran, and then vacuum dried to provide 1.05 g of N-(7-chloro-4-hydroxyquinolin-3-yl)butanamide as a tan powder.
Reaction SMILES: [Br:1]Br.[BrH:3].[C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5].CCOCC>C(Cl)Cl>[BrH:1].[Br:3][CH2:5][C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CBr)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
7.9 g of bromine are added rapidly at RT to a suspension of 14 g of 4-acetyl-4-phenylpiperidine hydrobromide in 200 ml of DCM and the reaction mixture is stirred overnight at RT. It is diluted by the addition of 200 ml of ether and the precipitate formed is wrung and washed with ether to give 16.7 g of the expected product after drying under vacuum.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1.[CH2:19]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH2:21].CN1C(=O)CCC1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:21]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1)[CH:20]=[CH2:19]
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Yield: 74 %

Procedure:
Methyl 4-iodo-2-(2-methylphenyl)benzoate (10.0 g, 28.4 mmol), allyltributyl tin (11.3 g, 34.1 mmol), and dichlorobis(triphenylphosphine)palladium (II) (1.0 g, 1.42 mmol) were combined in 50 mL toluene and 20 mL NMP and heated at 125° C. for 18 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and chromatographed (5% EtOAc in hexanes) to provide the title compound in 74 % yield. MS m/e 284 (M+NH4)+.
Reaction SMILES: [CH:1]1([C:5]2[C:6](=[O:21])[NH:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41]([N:43]1[C:47]([CH2:48]O)=[N:46][CH:45]=[N:44]1)[CH3:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:5]2[C:6]([O:21][CH2:48][C:47]3[N:43]([CH2:41][CH3:42])[N:44]=[CH:45][N:46]=3)=[N:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCn1ncnc1CO
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1C1CCC1
Reaction time: 6 h
Yield: 57.9 %

Procedure:
6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (50 g, 0.18 mmol), triphenylphosphine (120 mg, 0.44 mmol) and (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (60 mg, 0.44 mmol) were suspended in dry tetrahydrofuran (1.5 ml). Diethyl azodicarboxylate (70 μl, 0.44 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 48 hours before purification by preparative tlc (60% EtOAc/hexanes) to afford a colourless oil which crystallised upon the addition of diethyl ether. The white solid was collected by filtration and stirred in diethyl ether for 6 hours and collected by filtration to afford 6-cyclobutyl-5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,3-triazolo[1,5-α]pyrimidine (41 mg; 59%) as white needles, m.p. 188-191° C.; δH (360 MHz, CDCl3) 1.42 (3H, t, J=7.3 Hz, NCH2CH3), 1.89-1.94 (1H, m, CH(CH2)3), 2.04-2.15 (3H, m, CH(CH2)3), 2.36-2.43 (2H, m, CH(CH2)3), 4.25 (2H, q, J=7.3 Hz, NCH2CH3), 5.65 (2H, s, OCH2), 7.19-7.31 (2H, m, ArH), 7.36-7.42 (1H, m, ArH), 7.92 (1H, s, triazole CH), 7.99 (1H, td, J=7.5 and 1.7 Hz, ArH), 8.59 (1H, d, J=1 Hz, pyrimidine CH); m/z (ES+) 394 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH3:21])[CH:19]=[CH:20][C:13]=12
Reactant: Cn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reaction time: 8 h

Procedure:
195 mg (0.68 mmol) of N-(2-fluoro-4-nitrophenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 10 ml of a mixture of ethanol/THF. (1:1). 15 mg (0.07 mmol) of platinum(IV) oxide are added, and the mixture is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The suspension is then filtered through Celite, the Celite is washed with a little ethanol and the solvent is removed under reduced pressure.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[C:7]2[S:16][CH:15]=[CH:14][C:8]=2[C:9]([CH3:13])=[N:10][C:11]=1[OH:12]>C(O)(=O)C>[OH:12][C:11]1[N:10]=[C:9]([CH3:13])[C:8]2[CH:14]=[CH:15][S:16][C:7]=2[C:6]=1[NH:5][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: Cc1nc(O)c(N)c2sccc12
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(O)c(NC(N)=O)c2sccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Sodium cyanate (0.50 g, 7.69 mmol) was added to a solution of crude 7-amino-4-methylthieno[3,2-c]pyridin-6-ol (1.26 g, 7.00 mmol) in acetic acid (30 ml) and an off-white solid precipitated. This mixture was stirred for one hour at room temperature. The solid was collected by filtration, washed with acetic acid, triturated with refluxing MeOH, then refluxing Et2O, and dried in vacuo to give the urea (0.798 g, 51% yield); mp 294°-297° C. (dec); IR (KBr) 1525, 1620 and 2300-3100 cm-1 ; mass spectrum m/z 223 (M+); 1H NMR (TFA) δ3.02 (s, 3H, 4-CH3), 7.63 and 7.77 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][CH:9]2[OH:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1.S(=O)(=O)(O)O.C(O)(C)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)C=CC1O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCc1cc(Br)ccc1C1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone (10.14 g, 0.036 mol) in acetone (150 ml) at 5° C. is added chromium trioxide in concentrated sulfuric acid (24 ml, 0.039 mol, 1.64M solution), at such a rate as to maintain a temperature between 10° C. to 15° C. The reaction mixture is further stirred at room temperature for 30 minutes, followed by the addition of isopropanol (150 ml) and additional stirring at room temperature for 2 hours. The green suspension is partitioned between ethyl acetate (200 ml) and water (300 ml), and the organic layer is separated. After drying over anhydrous magnesium sulfate, solvents are removed in vacuo to afford 2-(4-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione as an orange gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@@:8]2([CH3:28])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[C:11]([CH3:27])([CH3:26])S[CH2:9]2)[CH:7]=1.O[O:31][S:32]([O-:34])=O.[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@@:8]2([CH3:28])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[C:11]([CH3:26])([CH3:27])[S:32](=[O:34])(=[O:31])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)SC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(CN2C(=O)C(C)(C)S(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-2,2,5-trimethylthiomorpholin-3-one (2.45 g, 5.08 mmol, Eq: 1.00) in methanol (60 ml) was added at 23° C. Oxone® (6.24 g, 10.2 mmol, Eq: 2.00). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was carefully quenched by addition of water at 0° C. 10 ml of a diluted NaHSO3 solution, sat. NaHCO3 solution and ethyl acetate were added. Vigorous stirring was continued for 10 min. The organic layer was separated and washed with water, then dried over Na2SO4, filtered and evaporated to give the crude and nearly pure (R)-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-one (2.47 g, 4.80 mmol, 94.5% yield) as orange foam. MS (ISP): m/z=514.2 [M+H]+ and 516.3 [M+2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH:10]([C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH:10]([C:22]([N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=3[CH3:25])[CH2:34][CH2:35]2)=[O:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(C(=O)OC(C)(C)C)CCN3c3ccc(F)cc3C)CC2)c1

Procedure:
4-(4-fluoro-2-methyl-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS Reg. No.: [499780-10-8]) (100 mg) in DMF (2.5 mL) was treated with 1-(2,5-dimethylphenyl)piperazine (62 mg), 2-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro phosphate (HBTU) (123 mg) and triethylamine (124 μL) at ambient temperature for 5 h. Water was added, the phases were separated and the inorganic phase was extracted with tert-butyl-methyl ether (TBME). The combined organic phases were washed with water and brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 2:1) gave 3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (143 mg), MS: 511.5 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[CH:18]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[O:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26](=[O:29])[CH:27]([OH:28])[C:18]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:32]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a magnetically stirred solution of 2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine 13a (2.55 g, 10.71 mmol) and ethyl glyoxylate toluene solution (11.79 mL, 54.62 mmol) in toluene (130 mL) under Ar atmosphere was added p-toluenesulfonic acid monohydrate (60.9 mg, 0.32 mmol). The reaction mixture was equipped with a dean-stark trap and refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.72 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 1.15 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 3.83 (s, 3H), 4.13 (m, 1H), 4.24 (m, 1H), 5.75 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]([OH:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[C:3]1([C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
To a suspension of 0.78 g of sodium hydride (55% w/w dispersion in mineral oil) in 300 cc of dimethylformamide was added a solution of 2 g of 3,5-diphenyl-phenol in 10 cc of dimethylformamide. The mixture was stirred for 5 hours at room temperature until effervescence had stopped. 2.2 g of ethyl 6-bromohexanoate was then added and the resultant mixture stirred at room temperature overnight. The mixture was then heated for 20 hours to 40° C. After cooling, the resultant mixture was poured into 100 cc of cold water and extracted with ethyl acetate (3#100 cc). The combined extracts were washed with water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was flash chromatographed on silica gel (30-60 mm; eluent: 92:8 n-hexane/ethyl acetate) to give 1 g of ethyl 6-(3,5-diphenyl-phenoxy)hexanoate as a oil, used without further purification in the next step.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:5])[CH3:4].[C:6]1([C:16](Cl)=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>>[C:6]1([C:16]([O:5][CH:3]([CH3:4])[C:2]#[CH:1])=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C#CC(C)O
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: C#CC(C)OC(=O)c1cccc2ccccc12
Temperature: -10 °C

Procedure:
A suspension of 5.3 g of 1-butyn-3-ol and 5 g of 1-naphthoyl chloride is cooled to -10° C. and 3.1 ml. of 35% sodium hydroxide are slowly added dropwise. The mixture is warmed to room temperature and stirred until it is neutral. The mixture is poured into ice-water and then extracted with ether. The ether solution is washed with 10% sodium hydroxide and with water and dried. After the ether is distilled off, the residue is recrystallized from methanol to yield 1-methyl-2-propynyl 1-naphthoate, m.p. 66°-68° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:37][C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
0.9 g (0.0028 mol) of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 5) and 0.7 g (0.0043 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 80 ml of dimethylformamide are stirred at 60°-70° C. for five hours. To 0.4 g (0.004 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 40 ml of dimethylformamide cooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 3 ml (0.022 mol) of triethylamine. After thirty minutes the mixture is allowed to reach room temperature and is stirred for an additional two hours. The mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, and mixture is cooled and filtered to give 0.78 g of 4-oxo-2-phenyl-N-1H-tetrazol-5-yl-4H-pyrido[ 1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 324°-328° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Cl:14])[CH:8]=2)[N:5]=[N:4][C:3]=1C(OCC)=O.[OH-].[Na+].Cl>>[Cl:14][C:9]1[CH:8]=[C:7]([NH:6][C:2]2[CH:3]=[N:4][NH:5][N:1]=2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CCOC(=O)c1nnn(-c2ccc(F)c(Cl)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(Nc2cn[nH]n2)cc1Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Ethyl 5-amino-1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate 4a (120.0 mg, 0.4 mmol) was suspended in aqueous NaOH (4.00 mL of 2 M, 8.00 mmol) and the solution heated to reflux and stirred for 3 h. The solution was allowed to cool and acidified with 1M HCl and then extracted into EtOAc and the organic layer concentrated. The residue was dissolved in DMSO (2 mL) and heated to 110° C. for 3 h. The mixture was allowed to cool and purified by FractionLynx to afford the title compound I-13 as a white solid (56.8 mg, 64%). 1H NMR (500 MHz, d6-DMSO) δ 8.74 (1H, brs), 7.48-7.50 (1H, m), 7.31 (1H, s), 7.20-7.24 (1H, m), 7.10-7.13 (1H, m). MS m/z: 212.9 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccns1
Reactant: c1nc[nH]n1
Product: c1ccc(C(c2ccccc2)(c2ccns2)n2cncn2)cc1
Yield: 28 %

Procedure:
Following the procedure of Example 1, 1.5 g of α,α-diphenyl-5-isothiazolemethanol were converted to the corresponding chloro compound and treated with 1.5 g of 1,2,4-triazole to provide 0.5 g of the title product, m.p. 235°-240° C.