Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=CN=C([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=1.O[CH2:28][CH2:29][NH:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1C1(C2CCNCC2)CCN(C([O-])=O)CC1)=[O:32].C(N=C=NC(C)C)(C)C>O1CCOCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:36]3[CH:37]=[CH:38][C:33]([C:31]4[O:32][CH2:28][CH2:29][N:30]=4)=[CH:34][CH:35]=3)[CH2:9][CH2:10]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(NCCO)c1ccccc1C1(C2CCNCC2)CCN(C(=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: [Cu+2]
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C4=NCCO4)cc3)CC2)CC1

Procedure:
A solution of tert-butyl 1′-(4-{([(2-hydroxyethyl)amino]carbonyl}phenyl)-4,4′-bipiperidine-1-carboxylate (234 mg; 0.542 mmol) in dioxane (5 mL) was treated with N,N′-diisopropylcarbodiimide (68 mg; 0.084 mmol) and Cu(OTf)2 (10 mg; 0.027 mmol). The mixture was refluxed for 5 hr. The reaction was evaporated and chromatographed (PTLC; 40:1 CH2Cl2/MeOH), giving the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NS(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [Li+].[CH3:2][C:3]([O-:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>O1CCCC1>[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Cl
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Lithium tert-butylate (2.2 M in tetrahydrofuran, 6.2 mL, 13.6 mmol) was added to a solution of 2-chloro-4-nitrobenzoyl chloride (2.00 g, 9.09 mmol) in tetrahydrofuran (12 mL) at 0° C. The orange solution was kept at 0° C. for 1.5 h, then allowed to reach room temperature over 16 h, then partitioned between 1 M aq. sodium carbonate solution and isopropyl acetate. The organic layer was dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 88%) which was directly used in the next step. Brown oil, MS (EI)=257.1 (M+).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CCOCC>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccnc(N2CCNCC2)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)c1ccc(N2CCNCC2)nc1
Reaction time: 1 h

Procedure:
The amine (21 g), triethylamine (17.9 g) and methylene chloride (600 ml) are cooled to 0°. Di-t-butyl dicarbonate (25.8 g) in methylene chloride (200 ml) is added over 30 min at 0°. The reaction mixture is stirred at 0° for 1 hr and allowed to warm to 20-25°. The reaction mixture is washed with saturated sodium bicarbonate (3×200 ml), dried over potassium carbonate and the solvent removed under reduced pressure to give a solid. The solid is dissolved in ether, petroleum ether is added until the mixture is cloudy, the mixture is filtered thru celite and the filtrate is concentrated to give the protected piperazine compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:2]2[NH:28][CH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Yield: 88.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.85 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine (436 mg, 2.78 mmol) to afford the product (640 mg, 89%) as a white solid: ESI MS m/z 389 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC/C=C\CCCOc1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)O
Yield: 99.5 %

Procedure:
500 μL of 1 N sodium hydroxide solution (500 μmol) are added portionwise to 80 mg of 29 (263 μmol) in methanol (3 mL). The solution is refluxed for 24 hours. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 76 mg of a yellow oil are obtained, i.e. a yield of 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C[O-].[Na+]>CO>[CH3:13][N:14]1[CH2:15][CH:16]=[C:17]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1

Procedure:
5-Nitroindole (2.6 g) was dissolved in 100 mL anhydrous MeOH, followed by 5 g N-methyl-4-piperidone and NaOMe (5 g) powder. The mixture was heated to reflux under N2 overnight. The mixture was concentrated in vacuo, and was extracted between saturated NaHCO3 solution and EtOAc. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. This solid was washed with 5 mL EtOAc and 2 mL MeOH to afford a bright yellow solid. MS: 258 (M+1). Calc'd. for C14H15N3O2−257.29.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Yield: 84.7 %

Procedure:
A mixture of 5-(4-bromo-5-chloropyrimidin-2-yl)thiophene-2-sulfonyl chloride (164 mg, 0.45 mmol, 1.0 equiv.), tert-butyl hydrazinecarboxylate (119 mg, 0.9 mmol, 2.0 equiv.) and DIPEA (5 mL) was stirred in DCM at r.t. for 2 h, The reaction was extracted with EA and the combined layers were dried (Na2SO4), filtered. The filtrate was concentrated to afford tert-butyl 2-(5-(4-bromo-5-chloropyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (179 mg, 85%). LC-MS (m/z)=469 [M+H]+
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.C(Cl)Cl.[Br:13]Br>C(O)(=O)C>[Br:13][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C1NCc2ccsc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1NCc2cc(Br)sc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 116e (1.87 g, 13.5 mmol), methylene chloride (10 mL), acetic acid (30 mL). The mixture was cooled to 0° C. Bromine (2.30 g, 14.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 3 h at 0° C. and then at room temperature for 48 h. After that time, the mixture was partitioned between aqueous saturated sodium bicarbonate (100 mL) and a 20% (v/v) solution of methanol in methylene chloride (100 mL). The layers were separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 34% yield (1.01 g) of 116f as an off-white solid: mp 96-97° C.; 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H), 6.57 (br s, 1H), 4.37 (s, 2H); MS (ESI+) m/z 217.9 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].S(Cl)([Cl:35])=O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:35])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
The 3-halo-3-cephem esters represented by the above formula II when Y is chloro or bromo are also prepared with the 3-hydroxy-3-cephem esters as described by R. R. Chauvette et al., J. Amer. Chem. Soc., 96, 4986 (1974). For example, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate is reacted with thionyl chloride in dry DMF to yield p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13](O)=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.CS(Cl)(=O)=O.[NH3:21].Cl>N1C=CC=CC=1>[CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13]#[N:21])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(C(=O)O)(C3)C2
Reactant: N
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC12CC3CC(C)(C1)CC(C#N)(C3)C2
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 3,5-dimethyl-1-adamantanecarboxylic acid (2.51 g, 12.1 mmol) in dry pyridine (40 mL) at 0° C. was treated dropwise with methanesulphonyl chloride (1.4 g, 12.2 nmmol), stirred for 2 h, saturated with ammonia gas, stirred for 5 min and the excess ammonia removed in vacuo. The resulting suspension at 0° C. was treated with methanesulphonyl chloride (11.8 g, 102 mmol), stirred overnight at room temperature, poured into cold 1-M HCl (200 mL) and extracted with EtOAc (3×40 mL). The organic phase was washed with dilute HCl (50 mL), water (50 mL), dried (MgSO4), concentrated in vacuo and the residue purified by chromatography [SiO2; CH2Cl2] to give the product (1.97 g, 86%) as a pale brown oil: IR νmax (liquid film)/cm−1 2922, 2849, 2235, 1455, 1359 and 1098; NMR δH (400 MHz, CDCl3) 0.87 (6H, s), 1.19 (2H, s), 1.3-1.45 (4H, m), 1.55-1.75 (4H, m), 1.8-1.9 (2H, m) and 2.1-2.15 (1H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[Br:16][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(Br)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
To the solution of 21.8 g of methyl m-trifluoromethylphenylacetate in 450 ml of carbon tetrachloride a portion of 18.7 g of N-bromosuccinimide is added along with several drops of triethylamine and a pinch of azobisisobutyronitrile. The mixture is warmed to reflux with a 250 watt incandescent bulb and a precipitate is formed. Thereupon the reminder of N-bromosuccinimide is added, the light removed and the solution stirred for 3 hours. It is cooled in an ice bath and the solid formed removed by filtration. The filtrate is evaporated the residue dissolved in diethyl ether-water and the organic phase washed with aqueous sodium bicarbonate and water. It is dried, evaporated, the residue distilled and the fraction boiling at 85°-88°/0.4 mmHg collected, to yield the methyl α-bromo-m-trifluoromethylphenylacetate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CN(C)C=O.Br[CH:11]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][NH:13][C:12]1=[O:24]>C(OCC)(=O)C>[N:1]([C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][NH:13][C:12]1=[O:24])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NCC(c2ccccc2)CCC1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CC[C@@H](c2ccccc2)CNC1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
2.0 g of sodium azide were added to 20 ml of dimethylformamide containing 1.6 g of 3-bromo-6-phenylperhydroazepin-2-one (Isomer A) [prepared as described in step (e) above]. The mixture was stirred for 6 hours at 60° C. and then diluted with ethyl acetate, washed with water three times and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The crystalline residue was triturated in a 1:1 by volume mixture of methylene chloride and diisopropyl ether and then collected by filtration, to give 1.14 g of the title compound melting at 150°-152° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[CH:31][C:24]=12.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([C:32]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[N:30]=[CH:31][C:24]=34)=[O:20])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)ccc21
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3cnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Yield: 73.8 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)thiochromane-7-carboxylic acid (500 mg), 4-amino-1-triphenylmethylpyrazolo[3,4-b]pyridine (670 mg) synthesized according to a known method and 2-chloro-1-methylpyridinium iodide (496 mg), the objective (S)-4-(tert-butoxycarbonylamino)-N-(1-triphenylmethylpyrazolo[3,4-b]pyridin-4-yl)thiochromane-7-carboxamide (796 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[CH3:15][O:16][C:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[N:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([N:19]2[N:18]=[C:17]([O:16][CH3:15])[O:21][C:20]2=[O:22])=[CH:24][C:25]=1[O:30][CH3:31])=[O:8])=[O:5]
Reactant: COc1nn(-c2ccc(N)c(OC)c2)c(=O)o1
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nn(-c2ccc(NC(=O)NC(=O)c3ccc(F)cc3Cl)c(OC)c2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 0.39 g of 5-methoxy-3-(4-amino-3-methoxyphenyl)-3H-[1,3,4]oxadiazol-2-one hydrochloride and 0.2 ml of triethylamine in 5 ml of acetonitrile and the mixture is stirred at room temperature overnight. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:4][CH2:3]1.IC.[CH2:29](N(C(C)C)C(C)C)C>C(Cl)Cl>[O:26]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][N:15]([CH3:29])[CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCNCC3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.060 g, 0.00016 mol), iodomethane (0.015 mL, 0.00016 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.056 mL, 0.00032 mol) in DCM (2 mL) was stirred at rt for 3 h. The mixture was diluted with DCM and washed with water (3×) and satd. aq. NaCl. The separated organic layer was dried and concentrated. The residue was purified by FCC [7 N NH3/MeOH)/DCM] to give 0.010 g (16%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][NH:31]1)=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1>C(#N)C>[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][N:31]1[CH2:9][CH2:10][CH2:11][OH:12])=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1
Reactant: OCCCBr
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (0.2 mL, 1.38 mmol, 3 equiv), followed by 3-bromo-1-propanol (60 μL, 0.69 mmol, 1.5 equiv), were added to a stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (192.5 mg, 0.46 mmol, 1 equiv), prepared as in Example 10, in anhydrous acetonitrile (2 mL), under nitrogen. The resulting mixture was stirred at rt for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel with an eluent of 5% methanolic ammonia in dichloromethane. The desired fractions were pooled together, evaporated to dryness, and lyophilized to furnish the title compound as a white fluffy powder (13.5 mg, 6%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[N:18]=[N:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=3)[N:7]=2)[CH:3]=1.[Cl:41]N1C(=O)CCC1=O>>[Cl:41][C:5]1[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:18]=[N:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=2)[N:7]=[C:8]2[C:4]=1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9]2
Reactant: Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2c1
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Cl)c2c1

Procedure:
By treating 5-[2-(5-methyl-2H-indazol-2-yl)phenyl]-2-(triphenylmethyl)-2H-tetrazole as obtained in Reference Example 8, in the same manner as in Reference Example 4 by using N-chlorosuccinimide (1 equivalent amount) in place of N-bromosuccinimide, 5-[2-(3-chloro-5-methyl-2H-indazol-2-yl)-phenyl]-2-(triphenylmethyl)-2H-tetrazole was obtained.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].[CH3:19][C@@H:20]([CH2:32][CH3:33])[CH2:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)=[O:24].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:21][C@@H:20]([CH3:19])[CH2:32][CH3:33])=[O:24])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC[C@H](C)COC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC[C@@H](C)CC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
In 12 ml of methylene chloride were dissolved 107 mg of 4-[2-(S)-propoxypropanoyloxy]benzoic acid, 95 mg of 4-[(S)-2-methyl butoxycarbonyl]phenol, and 140 mg of dicyclohexylcarbodiimide, and a catalytic amount of 4-dimethylaminopyridine was added to the solution, followed by stirring at room temperature. After 5 hours, diethyl ether was added to the reaction mixture, and any insoluble matter was removed by filtration. The filtrate was washed successively with a 10% hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, water, and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The solvent was removed from the residue by distillation, and the resulting oily substance was purified by silica gel column chromatography to obtain 139 mg of the entitled compound as a transparent oily substance. This compound did not crystalize even when allowed to stand at room temperature or less for a long time. The structure of the compound was confirmed by NMR and IR spectra.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=2)[CH:30]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN1CCCC1=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][C:2]([C:3]([NH2:5])=[O:4])=[CH:30][C:29]=3[CH:32]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)c(C=O)c2)CC1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
5 ml of 1-methyl-2-pyrrolidone, 0.16 g of chloroacetamide and 0.25 g of potassium carbonate are added at 20° C. with stirring/under nitrogen to 0.5 g of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde. The mixture is stirred at 60° C. for 16 hours, cooled and then filtered, and the solvent is removed under reduced pressure. The residue is taken up in MTB ether, re-filtered and concentrated, and the residue is crystallized from toluene. The isolated yield is 0.34 g (60%).