Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[C:9](=[O:22])[CH:8]=2)[CH2:3][CH2:2]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:19]([C:15]1[S:14][C:13]([N:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:8][C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 17% yield: mp 172-174° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 7.37-7.26 (m, 5H), 6.16 (dd, J=8.1, 2.5 Hz, 1H), 6.09 (t, J=5.6 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.68 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.89-0.72 (m, 1H), 0.52-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.2, 162.1, 153.6, 152.1, 137.7, 131.3, 128.8, 127.9, 127.7, 122.2, 104.1, 96.6, 69.1, 44.1, 33.6, 17.3, 7.5, 4.2; MS (ES+) m/z 410.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]2[CH:46]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[N:38]=[C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]4[CH:46]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1cccc2nc(CCl)cn12
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5c(C)cccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 77 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.8 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.22 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes upon which 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (218 mg, 1.2 mmol) was added. The mixture was heated at for 4 h (the reaction was monitored by TLC) upon which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (280 mg, 77.7%,) as a light yellow solid. 1H NMR: 500 MHz, DMSO-d6: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=455.6. HPLC: (97.3%, Condition-A).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]([F:15])([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10]>CN(C)C=O>[F:7][C:8]([F:15])([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:4])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCC(F)(F)C(=O)O
Solvent: CN(C)C=O
Product: C=CCC(F)(F)C(=O)Cl
Reaction time: 2 h
Yield: 86 %

Procedure:
Add oxalyl chloride (17.6 mL, 201.8 mmol) to compound 8c (25 g, 183.7 mmol) and dimethylformamide (3 drops) under neat conditions at room temperature. Observe gas evolution for approximately 2 h. After 5 h, treat the reaction mixture with an additional 0.08 eq of oxalyl chloride (1.2 mL) and stir for 18 h. Use fractional distillation (88°-91° C.) to obtain 24.4 g, 158 mmol of the title compound 8a as an oil in 85% yield. 19F NMR (CDCl3) δ -101.9 (t); 13C NMR (CDCl3) δ 167.3 (t, CO2H), 125.5 (s, C=C), 123.1 (s, C=C), 115.6 (t, CF2), 38.3 (t, CH2); 1H NMR (CDCl3) δ 2.90 (m, 2H), 5.33 (d, 1H), 5.36 (s, 1H), 5.74 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@@:23]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:24]([S:26][C@@H:27]1[CH2:32][O:31][C@@H:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37](OC)=[O:38])=[CH:35][CH:34]=2)[O:29][CH2:28]1)[CH3:25]>>[Cl:10][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[NH:1][C:37](=[O:38])[C:36]1[CH:41]=[CH:42][C:33]([C@H:30]2[O:29][CH2:28][C@H:27]([S:26][C@H:24]([CH3:25])[C@:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])([OH:49])[CH2:43][N:44]3[CH:48]=[N:47][CH:46]=[N:45]3)[CH2:32][O:31]2)=[CH:34][CH:35]=1
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c(Cl)c3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-2-chlorobenzonitrile (182 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (167 mg, yield 90%) as a colorless oil which was recrystallized from ethyl acetate-isopropyl ether to give white powdery crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:26]([O:28]C)=[O:27])[C:10]3[NH:11][C:12]4[CH:13]=[C:14]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:16][C:17]=4[C:18]=3[N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:23]([O:22][C:20]([C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[C:9]([C:26]([OH:28])=[O:27])[C:10]=3[NH:11][C:12]=2[CH:13]=1)=[O:21])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)OC(C)C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.9 %

Procedure:
A solution of 7-isopropyl 4-methyl 2-phenyl-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (380 mg, 0.978 mmol) in a mixture of THF (5.6 mL), MeOH (1.9 mL) and 1 N aqueous sodium hydroxide solution (2.0 mL, 2.0 mmol) was stirred at 25° C. for 15 min. The reaction was treated with 1 N aqueous HCl (0.52 mL) and the organic solvents were removed. The residue was diluted with water and acidified to about pH 3.0 with 1 N aqueous HCl to give an yellow gel-like precipitate. This was chilled in an ice bath and the precipitate was collected by filtration, washed with water and dried to leave impure 7-(isopropoxycarbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylic acid (395 mg). MS (ESI) m/z 375.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.88 (1H, s), 8.35-8.50 (3H, m), 8.25 (2H, d, J=7.94 Hz), 7.83-7.96 (1H, m), 7.56 (2H, t, J=7.78 Hz), 7.46 (1H, t, J=7.17 Hz), 5.22 (1H, quin, J=6.26 Hz), 1.40 (6H, d, J=6.10 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(Cl)(Cl)[Cl:21].Cl>CO.[Pd]>[ClH:21].[NH2:1][C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: ClC(Cl)Cl
Reactant: O=c1cc(-c2nnn[nH]2)oc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Reaction time: 4 h

Procedure:
Following the process described in example 1 (point B), by hydrogenating for 4 h 8-nitro-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran (0.896 g, 3.46 mmol) with 5% palladium-on-charcoal (91 mg) in a mixture of methanol (65 ml), chloroform (20 ml) and concentrated hydrochloric acid (2 ml), the title compound was prepared as its corresponding hydrochloride (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.CN.[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][CH3:18])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 117.1 %

Procedure:
A 50-mL round bottom flash was charged with 8-amino-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (200 mg, 1.025 mmol), methylamine hydrochloride (138 mg, 2.05 mmol), HATU (467 mg, 1.23 mmol), TEA (0.5 mL), and DMF (5.0 mL). The reaction mixture was stirred at room temperature for 15 h. It was then purified by reverse-phase Combi-Flash eluting with 0.1% NH4HCO3 in water/CH3CN to afford the title compound as red oil (250 mg, 88%). LCMS: ESI (3 minute run), m/z=209.1 [M+1]+; Retention time: 1.53 minute.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[O-:26])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONC1CCCCC1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: COc1cc(C=[N+]([O-])C2CCCCC2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-benzyloxy-3-methoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 97.9% yield as a solid, m.p. 154.1° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[O:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2cccc(OCC[C@@H]3CCCCN3)c2)cc1
Yield: 89 %

Procedure:
A solution of the product (0.250 g, 0.629 mmol) from step 1 in 4N HCl in dioxane (1.57 mL) was stirred at ambient temperature for about 1 h and then concentrated in vacuo. The residue was triturated with ether and dried in a 55° C. vacuum oven to afford the desired product as a white solid (0.187 g, 89%): 1H NMR (400 MHz, DMSO-d6): δ 8.98 (br s, 2H), 7.40 (m, 2H), 7.28 (t, 1H, J=8.4 Hz), 7.15 (tt, 1H, J1=7.6 Hz, J2=1.2 Hz), 7.02 (m, 2H), 6.73 (ddd, 1H, J1=8.4 Hz, J2=2.4 Hz, J3=0.8 Hz), 6.57 (m, 2H), 4.09 (m, 2H), 3.21 (m, 2H), 2.85 (td, 1H, J1=12 Hz, J2=2.8 Hz), 2.13 (m, 1H), 1.93 (m, 2H), 1.59 (m, 5H). MS; m/z 298 (MH+).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=2[CH3:27])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][C:24]1[CH:23]=[C:22]([O:5][C@H:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[CH:21]=[C:20]([CH3:27])[C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][OH:11])[CH:14]=1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 54 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (520 mg, 3.13 mmol), 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (714 mg, 3.13 mmol, prepared by a method disclosed in Chinese patent application CN101616913) and cesium carbonate (3.10 g, 9.39 mmol) were dissolved in 30 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 7 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 1c (500 mg, yield 54.0%) as a colorless oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][SH:5].[CH3:6][O:7][C:8]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>CO>[CH3:6][O:7][C:8]1[N:17]=[C:16]([S:5][CH3:4])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CS
Reactant: COC(=O)c1ccc(Cl)nc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(SC)nc1OC

Procedure:
To 10 ml of a 1 N methanolic sodium methoxide solution are added dropwise 3 ml of a 3.5 N methanolic methylmercaptan solution. To the resultant methylmercaptide solution is added a solution of 2.01 g (0.01 mole) of methyl 2-methoxy-6-chloronicotinate (cf. Example 6 a)) in 30 ml of methanol. The reaction mixture is refluxed for 5 hours and the solvent is thereafter evaporated in vacuo. The residue is treated with 30 ml of saturated potassium carbonate solution and 150 ml of methylene chloride and separated in a separating funnel. The methylene chloride solution is dried over sodium sulphate and subsequently evaporated to dryness in vacuo. The crystallised residue is recrystallised from pentane and yields the methyl 2-methoxy-6-(methylthio)-nicotinate with a melting point of 71°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[C:8]=2[NH:12][C:22](=[O:23])[CH2:21][CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: O=C(O)CCC1CCCCC1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12

Procedure:
Prepared according to the method of example 62(a), using 2,6-dichloroquinolin-5-amine (example 1(d)) (0.5 g) and cyclohexanepropionic acid (1.2 mL). The resulting precipitate was filtered and washed with acetone. The precipitate was further washed with water and then ether to give the sub-title compound as a solid (0.248 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:22](I)([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[N:18][N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: c1ccc(COc2ccc(-c3nn[nH]n3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
5-(4-Benzyloxyphenyl)-2H-tetrazole (500 mg) was added to a suspension of sodium hydride (96 mg) in dimethylformamide (5 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hour. After addition of isopropyl iodide (405 mg) thereto, the mixture was stirred at 60° C. for 2 hours under heating. The reaction mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (571 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:27])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:30][CH2:2][CH2:3][CH2:4][N:5]([CH3:27])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCO)nn23)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCCl)nn23)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To 2.8 g of N-(3-hydroxypropyl)-N-methyl-3-(4-methoxy phenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-amine (the compound of example 32) dissolved in chloroform (30 ml) are added a few drops of N,N-dimethylformamide and then 1.1 ml of thionyl chloride in chloroform (5 ml). The mixture is refluxed for about 5 hours. After cooling to room temperature, the mixture is concentrated to dryness and the residue is taken up with cold aqueous sodium bicarbonate. The product of the title is collected after filtration and crystallized from ethanol. Yield 85%. M.p. 113°-115° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with ethanesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give ethanesulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow oil. MS: 433.4 ([M+NH4]+)
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:10]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C1CCNC1
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and pyrrolidine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][NH:16][CH3:15])[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC(=O)c1ccc(F)cc1
Reactant: CNN
Solvent: CCO
Product: CNN=C(CS(C)(=O)=O)c1ccc(F)cc1
Yield: 31.9 %

Procedure:
To a 50 ml volume three-necked flask, 1-(4-fluorophenyl)-2-methylsulfonylethan-1-one (7-2-3) (5.0 g), methylhydrazine (14-a) (1.2 g), and ethanol (17.1 ml) were added under a nitrogen atmosphere, and heated to reflux for 4 hours. After the mixture was cooled, the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added hot hexane to be dissolved. The mixture was left to cool. Then, the precipitated crystals were collected by filtration, washed, and dried under reduced pressure. The crystal was purified by recrystallization (methanol) to give 1.8 g of 1-[1-(4-fluorophenyl)-2-methylsulfonylethylidene]-2-methylhydrazine (5-2-4).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Cl:13])(Cl)=[O:11].[CH2:14]([NH:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH2:14]([N:20]([CH3:21])[C:10]([Cl:13])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCNC
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCCCCN(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 0.35 ml of (i-Pr)2NEt in 10 ml of diethyl ether at 0° C. was added phosgene (1.06 ml, 1.93 M solution in toluene) and N-hexylmethylamine (0.31 ml, 2.05 mm). The reaction mixture was allowed to warm up to 25° C., and further stirred at 25° C. for 14 h. The mixture was filtered, and the solvent was removed under vacuum. The product was used for the next step reaction without further purification. 1H NMR (CDCl3): δ3.42 (m, 2H), 3.07 (s, 3H), 1.59 (m, 2H), 1.31 (m, 6H), 0.90 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:20])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1.Br[C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1>C(O)C>[CH3:27][N:26]1[C:22]([NH:1][CH2:2][CH:3]([OH:20])[CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:8]=2)=[N:23][N:24]=[N:25]1
Reactant: NCC(O)CCOc1cccc(CN2CCCCC2)c1
Reactant: Cn1nnnc1Br
Solvent: CCO
Product: Cn1nnnc1NCC(O)CCOc1cccc(CN2CCCCC2)c1
Yield: 55.6 %

Procedure:
A solution of 1-amino-4-[3-(1-piperidinylmethyl)phenoxy]-2-butanol (1.39 g) and 5-bromo-1-methyl-1H-tetrazole (0.82 g) in absolute ethanol (10 ml) was heated in an autoclave at 125° for 18 h. The solution was evaporated and the residue dissolved in 1M hydrochloric acid (25 ml). The acidic solution was washed with ethyl acetate, basified with excess sodium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a solid which was triturated with dry diethyl ether to give a white solid (1.0 g). This solid was recrystallised from methyl acetate-light petroleum (b.p. 60°-80°) to give the title compound (0.6 g) as white crystals, m.p. 138°-9°.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)=[O:28])[CH3:25].CO.C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:31]2[CH2:32][CH2:33][CH2:34][C@@H:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:30]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1CCCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (500 mg, 2 mmol) was combined with (R)-piperidine-3-carboxylic acid ethyl ester (0.51 g, 3.2 mmol) in methanol (10 mL, 200 mmol) and acetic acid (9.2 μL, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmol) was then added and the reaction was stirred overnight at room temperature. The reaction was then quenched with water and extracted three times with ethyl acetate. Organics were combined and dried over MgSO4. Solids were removed via filtration and 10 g of silica gel was added. All solvent was then removed and the resulting silica gel was loaded onto a 24 g column and the product was eluted using a gradient of 0-60% ethyl acetate/hexanes and then dried under vacuum to give the title compound as a colorless oil. EDI-MS: 438.1 (M+H)+.