Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.S(Cl)(Cl)=O.C([O-])([O-])=[O:19].[K+].[K+].[NH:24]1[C:28]2=[N:29][CH:30]=[C:31]([NH2:33])[CH:32]=[C:27]2[CH:26]=[CH:25]1>C1C=CC=CC=1.C(#N)C>[CH3:4][C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[C:1]([NH:33][C:31]1[CH:32]=[C:27]2[CH:26]=[CH:25][NH:24][C:28]2=[N:29][CH:30]=1)=[O:19]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methyl-4-nitrobenzoic acid (2 g, 11 mmol) in benzene (40 ml) was added thionyl chloride (2 ml) and refluxed for 3 h. The reaction mixture was concentrated, diluted with dry acetonitrile (20 ml). To this solution was added dry K2CO3 (2 g, 14 mmol) followed by a solution of 1H-Pyrrolo[2,3-b]pyridin-5-ylamine (example c), 1.4 g, 11 mmol) in acetonitrile (20 ml) and the reaction mixture and stirred for 16 h at RT. Solvent was removed under reduced pressure, diluted with water stirred for 15 min and filtered. The solid residue was washed with EtOAc to get 2.4 g of crude title product. LC-MS: (m/z 297)
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:15]C(C)(C)C)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1.O.C(N(CC)CC)C>[C:11]([O:10][C:9]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Ketopiperidine hydrochloride (48.3 g) and di-tert-butyl carbonate (93.2 g) were dissolved in a dioxane-water equivolume mixture (1000 ml), and triethylamine (119 ml) was added to the resultant mixture. The mixture was stirred at room temperature for five hours and concentrated under reduced pressure. Water and ethyl acetate were added to the residue. After separation of the organic phase, the organic phase was washed with a saturated solution of potassium hydrogensulfate and water, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby obtain the title compound as a colorless solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].I[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.N1CCCCC1>[NH:10]1[CH2:9][CH2:8][CH2:3][CH:2]([C:6]2[CH:12]=[CH:11][C:9]([NH:10][CH2:12][C:6]#[CH:7])=[CH:8][CH:7]=2)[CH2:1]1
Reactant: Nc1ccc(I)cc1
Reactant: C#CCBr
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C#CCNc1ccc(C2CCCNC2)cc1
Temperature: 0 °C
Yield: 15 %

Procedure:
Under nitrogen gas, to a pre-cooled (0° C., ice-bath) flask containing 400 mL piperidine, a number of reagents were added, including 14.2 mL of propargyl bromide (80 wt. % solution in toluene, 127 mmol), 22.0 g of 4-iodoaniline (100 mmol), 1.4 g of tetrakis(triphenylphosphine)palladium O) (1.2 mmol) and 200 mg copper(I) iodide (1.05 mmol). The mixture was heated for 18 h (40-45° C., oil bath temperature). The reaction mixture was filtered through Celite and the solvent (piperidine) was removed. The crude solid was redissolved with 125 mL AcOEt. The acetate solution was extracted with water (2×450 mL) and dried with brine (2×250 mL). Flash column chromatography on aluminum oxide (Brockmann I, basic, Aldrich #19,944-3, CH2Cl2) supplied 4-(3-piperidinyl)-propargyl-aniline as a light yellow solid (3.1 g; yield: 15%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:21][CH:22]=O>>[N:1]1[CH:21]=[CH:22][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][O:15][C:14]3=[O:19])[C:2]=12
Reactant: Nc1ncccc1OCCCCN1C(=O)COC1=O
Reactant: O=CCCl
Product: O=C1COC(=O)N1CCCCOc1cccn2ccnc12

Procedure:
Using 6.63 g (25 mnmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]oxazolidine-2,4-dione and 25 ml of a 40% chloroacetaldehyde solution, the same procedure as in Reference Example 18 was followed, to yield 6.48 g (89.5%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Cl:22][C:13]1[C:12]2=[CH:19][N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[C:16]([F:17])=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(F)c2nn(-c3c(F)cccc3Cl)cc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Temperature: 70 °C
Yield: 40.1 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (7.2 g, 25.6 mmol) was suspended in DCE (130 mL) under an atmosphere of nitrogen and phosphorus oxychloride (7.2 mL, 77.0 mmol) was added. The reaction mixture was heated at 70° C. for 5 hours and then allowed to cool to room temperature. The resultant mixture was poured cautiously onto saturated aqueous sodium carbonate solution, with stirring, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (3.08 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=2.5 Hz, 1H), 8.22 (d, J=3.4 Hz, 1H), 7.86-7.78 (m, 1H), 7.76-7.66 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:29])[CH3:24])[CH3:19])(=O)=O>CN(C=O)C>[CH3:19][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:17][CH2:16][O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5]
Reactant: OCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOCC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
Under a nitrogen gas stream, 36.09 g (265.1 mmol) of pentaerythritol was dissolved in 210 ml of dry DMF, and 5.3 g (132.5 mmol) of 60% NaH was added little by little under ice cooling. The resultant was heated to room temperature and agitated for 1 hour, and 30.0 g (66.26 mmol) of phytanyl tosylate was added dropwise thereto, followed by washing with 55 ml of DMF. The resultant was heated to 80° C. and agitated for 4 hours, the resulting reaction solution was concentrated under reduced pressure, 500 ml of ether was added to the residual solution to perform extractive dissolution twice, the product was washed twice with saturated saline, and then it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated, purified by silica gel column chromatography to obtain 6.3 g of mono-O-(3,7,11,15-tetramethylhexadecyl)pentaerythritol, which was in colorless, transparent, and somewhat viscous liquid form. The purity of the product determined by HPLC analysis was not lower than 99.5%. The results of NMR analysis are as shown below.
Reaction SMILES: Br[C:2]1[C:11]2[O:10]C[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[Cl:20][C:21]1[S:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[ClH:20].[C:16]([C:4]1[CH:3]=[C:2]([C:24]2[S:25][C:21]([Cl:20])=[CH:22][CH:23]=2)[C:11]([OH:10])=[C:6]([CH2:7][NH:8][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)s2)c1O
Product: Cl

Procedure:
The title compound was prepared as a white solid using the procedure described in Example 1 from 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) and 5-chlorothiophene-2-boronic acid [purchased from Frontier Scientific].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:4]([NH:3][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[CH:21][CH:20]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-fluorophenyl)acetate dihydrochloride (I82) (325 mg, 0.92 mmol) in DCM (10 ml), were added triethylamine (386 μl, 2.78 mmol) and benzenesulfonyl chloride (142 μl, 1.11 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with 1M Na2CO3, water and then brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(phenylsulfonamido)acetate (150 mg; 39% yield).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:12]=4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+]>C(O)(C(F)(F)F)=O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C@@H:11]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:12]4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10-(4-Chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride (140mg) was dissolved in TFA (3 ml), cool to 0° C. and sodium cyanoborohydride was added portionwise (150 mg). The reaction mixture stirred two hours, was quenched with 2N NaOH, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The product was dissolved in EtOAc and 1N HCl in Et2O was added. The solvent was evaporated and solid recrystallized from EtOAc/MeOH to provide the title compound: 1H NMR (DMSO-d6) δ 1.31, 1.66, 2.21, 2.7, 2.91, 3.03, 3.27, 4.1-4.4, 6.88, 7.25, 7.52. HRMS (FAB) calcd for C18H21ClN2 (MH+) 299.1315, found 299.1321.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[NH4+]>CO.O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCNc1cc(C=NO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g; prepared as in Example 93) in hot methanol (100 ml) a solution of hydroxylamine hydrochloride (10 g) and ammonium acetate (10 g) in water (25 ml) is added, and the mixture is left for 3 days. Water (500 ml) is then added, and the resulting precipitate is collected by filtration, washed with water and dried in air. After recrystallization from a mixture of ethanol and 2-methoxyethanol, 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime is obtained with a melting point of 226°-228° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH:49][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[O:23][CH3:24])=[O:42])[CH3:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (140 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (55 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (83 mg, yield 57%).
Reaction SMILES: [C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([S:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:42])[CH:35]([CH3:41])[CH2:36][C:37]([O:39]C)=[O:38])=[CH:30][CH:29]=3)[CH:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:45][CH2:46][CH3:47])[C:5]=1[OH:48])(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[OH2:3].[C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([S:27][C:28]3[CH:29]=[CH:30][C:31]([C:34](=[O:42])[CH:35]([CH3:41])[CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:33]=3)[CH:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:45][CH2:46][CH3:47])[C:5]=1[OH:48])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(Sc3ccc(C(=O)C(C)CC(=O)OC)cc3)C(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCSc2ccc(C(Sc3ccc(C(=O)C(C)CC(=O)O)cc3)C(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of ester from Step A of this Example (760 mg) in THF (15 ml) and MeOH (1 ml) was added 2N NaOH (2.4 ml) and stirred overnight at room temperature. The reaction mixture was diluted with H2O (50 ml) and acidified with 2N HCl and extracted with CH2Cl2 (2×50 ml). The combined organic layers were washed with brine, dried over Na2SO4 and purified on a column of flash silica gel 230-400 mesh using toluene-dioxane-acetic acid (10:2:0.1) as eluant to give the title compound as a foam (580 mg, 79%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[OH:16][C@@H:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18](=[CH2:22])[C:19](O)=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[C:18](=[CH2:22])[C@@H:17]([OH:16])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=C(C(=O)O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)NCC(=O)OCC)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (3.75 mL, 0.027 mol, 1.2 eq) was added to a suspension of glycine ethyl ester hydrochloride (3.44 g, 0.024 mol, 1.1 eq) in anhydrous dichloromethane (60 mL) (see FIG. 4). The mixture was stirred for 15 min at room temperature and then cooled to 0° C. (ice bath). Compound 9a (4 g, 0.022 mol, 1 eq) and dicyclohexylcarbodiimide (5.09 g, 0.02469 mol, 1.1 eq) were added successively to the reaction mixture which was stirred at room temperature for 17 h. The precipitate (dicyclohexylurea and triethylamine hydrochloride) was collected by filtration. The filtrate was washed with a 1N aqueous solution of HCl (50 mL), brine (50 mL) and dried over sodium sulfate. Evaporation of the solvent afforded an oil which was purified by column chromatography (eluent: hexane/EtOAc=6:4). The desired product 10a was obtained as a yellow oil (3.51 g, 60%). Rf0.25 (hexane/EtOAc=4:6). 1H NMR δ (CDCl3) 1.25 (t, 3H), 3.63 (s, 1H), 4.02 (m, 2H), 4.17 (q, 2H), 5.49 (s, 1H), 5.58 (d, 1H), 5.96 (s, 1H), 6.86 (s, 1H), 7.65 (m, 5H).[M+H]+ 264.1,: tR=2.55 min; purity: 96%.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH:13]=[N+]=[N-])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:23]>O1CCCC1>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH2:13][Cl:23])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)C=[N+]=[N-]
Reactant: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CCl

Procedure:
Boc-TyrCHN2 (1.81 g, 5.92 mmoles) was dissolved in 30 mL of tetrahydrofuran, and the resulting solution was treated with 3.45N ethanolic HCl (1.72 mL, 5.92 mmoles) for 5 minutes at 0°. Solvent was removed by evaporation on a rotary evaporator without temperature regulation. The resulting residue was dissolved in ethyl acetate, and this solution was washed with 0.2N hydrochloric acid and saturated sodium chloride. The solution was dried over sodium sulfate, and solvent was evaporated to yield crystalline Boc-TyrCH2Cl. The crystals were isolated and washed with cold ether to yield 0.45 g (mp 110°-112°). In a second crop, 0.90 g (mp 110°-112°) was obtained. NMR in CDCl3 corresponded to that expected, except that methylene protons of --COCH2Cl appeared as a doublet at δ4.1.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27]C=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[O:31]1[C:35]2([CH2:40][CH2:39][CH2:38][CH:37](S)[CH2:36]2)[O:34][CH2:33][CH2:32]1>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[O:31]1[C:35]2([CH2:40][CH2:39][CH2:38][CH:37]([S:3]([C:2]3[CH:27]=[CH:28][C:23]([S+:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]4[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=4)=[CH:24][CH:25]=3)(=[O:6])=[O:4])[CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: SC1CCCC2(C1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccc([S+](c2ccccc2)c2ccccc2)cc1)C1CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 132.3 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution and 11.8 g of 1,4-dioxaspiro[4.5]decane-7-thiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was further shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 25.3 g of [4-(1,4-dioxaspiro[4.5]decan-7-ylsulfonyl)phenyl]diphenylsulfonium trifluoromethanesulfonate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=O)[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=[S:26])[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CN1C(=S)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 181.5 %

Procedure:
To a solution of (2S)-2-t-butyldimethylsilyloxymethyl 1-methyl-5-pyrrolidone (16 g) in tetrahydrofuran (160 ml) was added Lawesson's Reagent [2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetane-2,4-disulfide] (14.6 g) at ambient temperature. After stirring at 60° C. under nitrogen for 1 hour, the solvent was removed. The residue was chromatographed on silica gel eluting with a mixture of acetone and dichloromethane (1.9 V/V) to give (2S)-2-t-butyldimethylsilyloxymethyl-1-methyl-5-thioxopyrrolidine (17.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[Br:9]Br.C(N(CC)CC)C>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([Br:9])[C:3]1=[O:8]
Reactant: BrBr
Reactant: CN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To N-methyl maleimide (0.5 g, 4.5 mmol) in methanol (22.5 mL) was added bromine (0.52 mL, 10 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 hours. Solvent was removed in vacuo and the reaction mass was dissolved in tetrahydrofuran (20 mL) and triethylamine (0.8 mL, 5.85 mmol) added, then stirred for 24 hours at room temperature. The material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 7:3) to afford a pale white powder (0.761 g, 4.0 mmol) in 89% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>ClCCl.N>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: COc1ccc(N)cc1
Agent: N
Solvent: ClCCl
Product: COc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-methoxyaniline in dichloromethane and methanolic ammonia.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].Br.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([O:16][CH:28]3[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH2:27]3)[C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2cc(O)c([N+](=O)[O-])cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2cc([N+](=O)[O-])c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 2-isopropyl-6-hydroxy-5-nitrobenzimidazole and the HBr addition product (15 g), N-tert-butoxycarbonyl-4-hydroxypiperidine (17.7 g), PPh3 (23.1 g), and THF (150 mL) at room temperature was added DEAD (14 mL). After 4 hours, the solvent was removed in vacuo and the product recovered from the crude using chromatography (3% methanol/methylene chloride) to yield 2-isopropyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-nitrobenzimidazole (16.5 g).