Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].O[CH:4]=[C:5]1[C:15](=O)[C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[CH2:8][CH2:7][CH2:6]1>CO>[CH3:14][N:13]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3[CH:4]=[N:2][NH:1][C:15]=3[C:10]=2[CH:11]=[N:12]1
Reactant: Cn1ncc2c1CCCC(=CO)C2=O
Reactant: NN
Solvent: CO
Product: Cn1ncc2c1CCCc1cn[nH]c1-2
Yield: 96 %

Procedure:
Hydrazine (0.5 ml) was added slowly to a warm solution of 3 g of 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H)-cycloheptapyrazolone in 90 ml of methanol. The reaction was heated at reflux for 30 minutes and the solvent was removed under reduced pressure. The residue was triturated in warm ether to give 4,5,6,7-tetrahydro-7-methyl-1H-cyclohepta[1,2-c:3,4 c']dipyrazole as a tan powder (96% yield) melting at about 153°-155° C.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC12CCC(C(=Cc3ccc(O)cc3)C1=O)C2(C)C

Procedure:
A mixture of 172 g of 3-(p-methoxybenylidene)-bornan-2-one and 344 g of dry pyridine hydrochloride is heated under gentle reflux for 2 hours. After cooling, the reaction mixture is poured into 1 liter of water; the resulting solid precipitate, which is beige in colour, is filtered off, washed copiously with water and drained; it is then crystallised from 700 ml of isopropanol. 136 g of compound no. 2, which melts at 220°, are thus collected.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([NH:19][CH3:20])=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[N:7]=[CH:8][C:9]([N:19]([CH3:20])[C:36](=[O:37])[C:35]2[CH:34]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:11]=1
Reactant: CNc1cnc(N(C)CCOC)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of N2-(2-methoxyethyl)-N2,N5-dimethyl-4-o-tolylpyridine-2,5-diamine (32 mg, 0.11 mmol) and DIPEA (43 μL, 0.25 mmol) in CH2Cl2 (1 mL) was treated with 3,5-bis-trifluoromethylbenzoyl chloride (46 mg, 0.17 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 25% EtOAc in n-hexane afforded the title compound as a yellow solid (19 mg, 33%). MS (ESI): m/z=526.2 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][N:14]=[C:13]1[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc([N+](=O)[O-])n1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc([N+](=O)[O-])n1CCN=[N+]=[N-]

Procedure:
To 10 parts of sodium azide is added a solution of 32 parts of 2-(5-nitro-2-methyl-1-imidazolyl)ethyl methanesulfonate (Ger. Pat. No. 2,030,314) in 250 parts of warm N,N-dimethylformamide. The resultant mixture is stirred at approximately 50° for 6 hours, then diluted with 1000 parts of cold water. Sufficient potassium carbonate is added to insure basicity. The mixture thus obtained is extracted with toluene. The toluene extract is washed with water, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation, affording 1-(2-azidoethyl)-2-methyl-5-nitroimidazole as a yellow oil which is further purified by crystallization from ether. Isolated by filtration, washed with a 1:1 mixture of ether and hexane, and dried in air the purified product melts at 53°-54°. It has the formula ##SPC6##
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.[N:30]1(C(C)CC2CCN(C3C=CC(N)=CC=3)CC2)[CH:34]=[CH:33][N:32]=[N:31]1>>[N:30]1([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH:34]=[CH:33][N:32]=[N:31]1
Reactant: CC(CC1CCN(c2ccc(N)cc2)CC1)n1ccnn1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Product: O=[N+]([O-])c1ccc(N2CCC(CCCn3ccnn3)CC2)cc1

Procedure:
Following the procedure of Example 7(1), the 4-tosyloxypropyl-N-(4-nitrophenyl)piperidine obtained in Example 11(2) was used instead of 4-tosyloxyethyl-N-(4-nitrophenyl)piperidine, thereby obtaining 4-[2-(1,2,3-triazol-1-yl)-propyl]-N-(4-aminophenyl)piperidine (69%) as a yellow solid.
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH3:3].O>CC(O)=O>[CH2:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:1])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1ccc(CO)cc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
35 ml of a 33% solution of HBr in AcOH are cooled to 0° C., 5 g of 4-ethylbenzyl alcohol are added dropwise and the reaction mixture is stirred for 30 minutes at 0° C. and then overnight at RT. It is poured into 200 ml of iced water, the mixture is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution and with saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated off under vacuum to give 5.6 g of the expected product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][CH:42]=[C:16]23)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:43][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][C:42]([F:43])=[C:16]23)[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2c(F)cnn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.76 g) in acetonitrile (15 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.1 g), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.24 g, 13%).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:34][C:35]([O:37][CH3:38])=[O:36])[CH2:20][C@@H:21]3[O:29][C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1>CC(C)=O.S(=O)(=O)(O)O>[CH3:33][O:32][C:30]([O:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([O:34][C:35]([O:37][CH3:38])=[O:36])[CH2:20]1)=[O:31]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
In 5 ml of acetone was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregn-5,7-diene, followed by addition of one drop of concentrated sulfuric acid, and the mixture was refluxed in an atmosphere of argon gas for 3 hours. The reaction mixture was poured in ice-water and extracted with ether. The extracts were pooled and washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, followed by concentration under reduced pressure. Finally the concentrate was purified by recrystallization from ether. The procedure yielded 55 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=2[N+:20]([O-])=O)[C@@H:6]1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2].[CH2:27](O)CC>[Ni]>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:12]3[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=3[N:20]=[CH:27]2)[C@@H:6]1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])CCC[C@H]1OC(C)=O
Reactant: CCCO
Agent: [Ni]
Product: CC(=O)O[C@H]1[C@H](n2cnc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(±)-(1R*,2S*,3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclohexanediyl diacetate (part a of this example, 5.65 g, 13.9 mmol) in n-propanol (250 ml) was shaken with Raney nickel (Aldrich, ca. 0.50 g) under hydrogen (50 psi) for 2 h. Filtration through Celite and evaporation of solvent left the 5,6-diaminobenzimidazole intermediate. Triethylorthoformate (250 ml) and 4 drops of methanesulfonic acid were added and the solution stirred at room temperature for 2 days. Volatiles were evaporated in vacuo and the residual material chromatographed on silica gel. Title compound eluted with 2% methanol-ethyl acetate as off-white solid (1.87 g, 35%), m.p. 163-165° C. Anal. Calcd. for C17H18Cl2N2O4: C, 53.00; H, 4.71; N, 7.27; Cl, 18.41. Found: C, 52.85; H, 4.72; N, 7.17; Cl, 18.35.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[Cl:40]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][C:34]([Cl:33])=[C:39]([Cl:40])[CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)c(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 9) and 3,4-dichlorophenylboronic acid (130 mg, 0.68 mmol). Yield 100 mg (50%).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>O1CCCC1>[N:25]1[CH:26]=[CH:27][C:28]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:29][CH:30]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccncc1
Reaction time: 0.08 h

Procedure:
Methyl (triphenylphosphoranylidene)acetate (3.4 grams) and 4-pyridine-carboxaldehyde (10.00 grams) were refluxed in tetrahydrofuran under nitrogen overnight. The reaction was evaporated in vacuo, and the residue was suspended in hexane (400 mL), heated to boiling on a steam bath for 5 minutes, and filtered through a filter aide. The filter cake was rinsed with hot hexane (2×200 mL), and the rinses and filtrate were combined and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (1500 mL) using 3:7 ethyl acetate:methylene chloride. The resulting waxy solid was suspended in a minimum amount of cyclohexane to yield the product as a white crystalline solid. Yield: 7.06 grams (46%).
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[S:11].CCOCC>CN(C=O)C>[CH3:8][N:9]([CH3:13])[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[S:11]
Reactant: CN(C)C(=S)Cl
Reactant: Oc1cccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C(=S)c1cccnc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a solution in DMF (50 mL) of 3-hydroxypyridine (4.76 g, 50 mmol) was added 1,1-diazabicyclo[2.2.2]octane (6.80 g, 150 mmol) and dimethylthiocarbamoyl chloride (18.5 g, 150 mmol) and the reaction mixture was stirred for 0.5 hours at ambient temperature and 18 hours at 55° C. The reaction mixture was cooled to ambient temperature and poured into ether. The ethereal solution was washed with aqueous 2N sodium hydroxide (2×), water (2×) and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (1:1 ethyl acetate-hexane) gave 3-dimethylthiocarbamoylpyridine (5.46 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH3:19].S(=O)(=O)(O)O.C(O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH3:19])([O-:3])=[O:2]
Reactant: CC(=O)c1ccccn1
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(=NNc1ccccc1[N+](=O)[O-])c1ccccn1
Yield: 84.9 %

Procedure:
A mixture of (2-nitrophenyl)hydrazine (2.00 g), 1-(pyridin-2-yl)ethanone (1.67 g), sulfuric acid (0.73 mL) and ethanol (50 mL) was heated under reflux for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (2.84 g, 85%) as brown crystals. melting point 145-146° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:11][C@H:10]([N:12]([C:17]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)[CH2:3][O:4][CH3:5].CO.[ClH:43]>>[ClH:43].[ClH:43].[OH:1][CH:2]([C@H:6]1[CH2:7][NH:8][CH2:9][C@@H:10]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:17]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]=2)=[O:18])[CH2:11]1)[CH2:3][O:4][CH3:5]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2CC(C(O)COC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(O)COC)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) was dissolved in 10-20%-hydrogen chloride methanol solution (10 ml), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give the to object product (140 mg).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1COCC1>[C:18]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: Cc1cc(=O)c(O)co1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2cccnc2)co1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Allomaltol (1.266 g, 10 mmol) was dissolved in 40 mL of anhydrous THF. The mixture was cooled to 0° C. Triethylamine (1.8 mL, 13 mmol) was added. Nicotinoyl chloride hydrochloride (1.988 g, 11 mmol) was added portionwise. Cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was neutralized with ammonia hydroxide then extracted with EtOAc. The organic phase was washed with brine 2 times then dried over Na2SO4 and concentrated. The crude product was purified with flash chromatography using DCM/MeOH to give the desired product as an off-white solid (1.35 g, 58%). MP (148° C.). 1H NMR (CDCl3) δ (ppm): 2.27 (d, 3H, J=0.9 Hz), 6.26 (d, 1H, J=0.9 Hz), 7.42 (dd, 1H, J=4.8, 8.1 Hz), 7.95 (s, 1H), 8.37 (td, 1H, J=1.8, 7.8 Hz), 8.79 (br s, 1H), 9.28 (br s, 1H). 13C NMR (CDCl3) δ (ppm): 19.8, 115.3, 123.8, 124.7, 138.2, 140.8, 148.1, 151.3, 154.1, 162.4, 166.4, 172.4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[N:9]=[C:10]([CH2:12][CH3:13])[N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[N:5]2[N:9]=[C:10]([CH2:12][CH3:13])[N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2cc(Cl)nc(O)n2n1
Product: CCc1nc2cc(Cl)nc(Cl)n2n1

Procedure:
In analogy to Example 11A, 285 mg (80% of theory) of the product are obtained from 312 mg (1.57 mmol) of 7-chloro-2-ethyl[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 102A) by reaction with phosphoryl chloride.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Br:16][C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:14]=1[Br:15]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(Br)c(Br)c3c(O)c(C(=O)NCC(=O)O)ncc32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 512 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:28][S:29]([O:20][CH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:18]2)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)CN(CCCc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(CCCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.835 g (6.863 mM) of 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethanol and 1.43 ml (10.3 mM) of triethylamine in 50 ml of tetrahydrofuran was added 0.64 ml (8.24 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethyl methanesulfonate thus obtained was dissolved in 60 ml of N,N-dimethylformamide, followed by addition of 1.40 g (7.55 mM) of potassium phthalimide, and the mixture was stirred at 100° C. for 4 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic solution was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=3/1 to 2/1) to provide a mixture of the objective compound and phthalimide. This product was dissolved in ethyl acetate and the solution was washed serially with aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate (Na2SO4) and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][O:9][C:10](=[O:12])[CH:11]=2)[CH:2]=1.[N:13]([O-])=[O:14].[Na+]>O.C(O)(=O)C>[N:13](=[C:11]1[C:10](=[O:12])[O:9][N:8]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:14]
Reactant: O=N[O-]
Reactant: O=c1cc(-c2cccnc2)[nH]o1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1ON=C(c2cccnc2)C1=NO
Reaction time: 4 h

Procedure:
A suspension of 57 g of 3-(pyrid-3-yl)isoxazol-5-one in 50 ml of water and 350 ml of glacial acetic acid is treated dropwise at 15° C. with a solution of 27 g of sodium nitrite in 60 ml of water. After 4 hours, the precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]1([C:40]2[C:41]([Cl:48])=[N:42][C:43]([CH2:46]Br)=[CH:44][CH:45]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(#N)C.CO>[ClH:48].[C:34]1([C:40]2[C:41]([Cl:48])=[N:42][C:43]([CH2:46][N:22]3[C:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=4)=[CH:24][N:20]=[CH:21]3)=[CH:44][CH:45]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: Clc1nc(CBr)ccc1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccc3)c(Cl)n2)cc1
Temperature: 65 °C

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (88.4 mg, 0.208 mmol) in acetonitrile (1 mL) was added 3-phenyl-2-chloro-6-bromomethylpyridine (53.5 mg, 0.189 mmol) and the mixture heated at 65° C. for 16 hours. The residue was dissolved in methanol (3 ml) and heated at reflux for 2 hours, cooled and evaporated to dryness. The residue was partitioned between sat. aq. Na2CO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2.5-3% MeOH in CH2Cl2) to afford the free base which was converted to the HCl salt by treatment with one equivalent of HCl in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:18]([NH:17][CH2:13][CH2:14][CH2:15][CH3:16])[NH:1][C:2]=2[CH:7]=1
Reactant: CCCCN=C=S
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CCCCNC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and butyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 267-269° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (t, 3H, CH3), 1.24-1.60 (m, 4H, CH2CH2), 3.21 (q, 2H, NHCH2), 7.2-7.4 (m, 3H, ArH+NH), 7.68 (d, 1H, ArH), 10.55 (br.s, 1H, NH); MS: m/e 287-289 (M+); (C11H14N3Cl1O2S1) calc. C, 45.91; H, 4.91; N, 14.60; found C, 45.92; H, 5.12; N, 14.46.