Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18]>ClCCl>[CH2:15]([Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])[CH2:14][CH3:13].[C:1]([NH:9][C:10]([NH2:12])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CO[Si](CCCN)(OC)OC
Solvent: ClCCl
Product: CCC[Si](OC)(OC)OC
Product: NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a 250 mL 3-neck RBF equipped with a condenser, magnetic stirrer, thermo-probe, nitrogen purge and pressure-equilibrated addition funnel was added benzoyl isothiocyanate (25.0 g, 0.150 mol) followed by dichloromethane (100 mL). The reaction mixture was cooled in an ice-water bath to a temperature below 5° C., at which point 3-aminopropyl trimethoxysilane (27.7 g, 0.150 mol) and dichloromethane (100 mL) were added slowly over a period of time of 30 minutes. The ice-water bath was removed and the reaction mixture was stirred at room temperature under a nitrogen purge overnight. The reaction mixture was then concentrated in vacuo at a temperature of 40° C. to provide a clear red liquid. The liquid was dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr in a 97% yield.
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])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.O[C:36]1[CH:41]=[CH:40][CH:39]=C[C:37]=1[C:42]#[N:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:39]=[CH:40][CH:41]=[CH:36][C:37]=2[C:42]#[N:43])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccccc1O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Oc4ccccc4C#N)cc3)c2cc1OC
Yield: 6.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-hydroxyphenyl cyanide (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (5 mg, yield 6%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].Cl.C[N:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[C@H:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:19]1>C1C=CC=CC=1>[C:35]1([C@H:20]2[C@@H:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)[CH2:22][CH2:23][N:18]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:19]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.46 g of anhydrous potassium carbonate and 0.5 ml of 2,2,2-trichloroethyl chloroformate are added under nitrogen to a solution of 1.11 g of the free base of cis-1-methyl-3-phenyl-4-(4-trifluoromethylphenoxy)piperidine of Example 22 in 10 ml of dry benzene. After 1 hour at room temperature the mixture is refluxed 18 hours. Another 0.045 ml of 2,2,2-trichloroethyl chloroformate is added, the mixture is again refluxed 18 hours, then cooled and partitioned between ether and water. The organic phase is washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil. This material is dissolved in benzene and filtered through a column of silica gel, then is further purified by preparative chromatography on five 2 mm silica preparative plates, using 3:1 petroleum ether as solvent. A nearly colorless glass of cis-3-phenyl-1-(2,2,2-trichloroethoxycarbonyl)-4-(4-trifluoromethylphenoxy)piperidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]2[CH2:8][CH:7]([C:10]#N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:12].[K+].[OH2:14]>C(O)C>[Cl:1][C:2]1[C:9]2[CH:8]=[C:7]([C:10]([OH:14])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: N#CC1Cc2c(Cl)cccc21
Agent: [K+]
Solvent: CCO
Product: O=C(O)C1=Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g of 3-chloro-1-cyanobenzocyclobutane (prepared according to the process described in Patent EP 119,107) are added to a solution of 6.0 g of potassium hydroxide in 58 ml of ethanol The mixture is stirred at room temperature overnight. 7.5 ml of water are then added and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off to dryness. The residue is taken up with water and the aqueous phase is washed with ethyl ether, then acidified (pH 1) with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is dried, filtered and evaporated to dryness.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8].[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(O)(C)C>[Cl-:10].[CH3:1][N+:2]([CH3:9])([CH2:11][C:12](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCCNC=O
Solvent: CC(C)O
Product: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Product: [Cl-]

Procedure:
In a manner similar to that described above in 1a, and using 14.2 parts of N-(3-dimethylaminopropyl)formamide, 20.0 parts of 2-chloro-4'-nitroacetanilide, and 78 parts of isopropyl alcohol there was obtained 27.4 parts of N,N-dimethyl-N-(4-nitrophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride as a white solid which melted at 195°-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].N1C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:29])[CH3:26]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)OC1=C(c2ccc(C)cc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A solution of 1.50 g (6.14 mmol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 10 ml of chloroform was cooled in ice and 1.94 g (24.56 mmol) of pyridine added followed by 2.00 g (12.28 mmol) of 2-ethylhexanoyl chloride. The mixture was stirred for 2 hrs. at room temperature, then refluxed for 12 hrs. The mixture was worked up exactly as described in Example I above to give 1.58 g of a slightly yellow, viscous oil. This material was chromatographed through 75 g of silica gel (0.063-0.2 mm) using a gradient ranging from 98:2 to 90:10 hexane-ethyl acetate. The chromatography gave 1.15 g (51%) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',4'-dimethylphenyl)-2-cyclohexenone as a clear colorless oil which showed one spot on a thin layer chromatogram (70:30 hexane-ethyl acetate) at Rf=0.52.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:12]([NH:20][C:7](=[O:10])[CH:8]=[CH2:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCCCCCCCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
A 500 ml four-necked flask equipped with a thermometer, mechanical stirrer, calcium sulfate-filled drying tube, and pressure-equalizing addition funnel is charged with a solution of 45.3 g of acryloyl chloride (0.5 mole) in 180 g of dichloromethane. The solution is cooled to 0° C. and to it is then slowly added a mixture of 66.6 g of n-octylamine (0.5 mole), 50.6 g of triethylamine (0.5 mole), and 125 g of dichloromethane, over a period of 2.5 hrs., at such a rate that the temperature does not exceed 5° C. Upon completion of the addition, the mixture is allowed to warm gradually to ambient temperature. The product is then stored at -15° C. overnight to complete crystallization of the byproduct triethylamine hydrochloride. After removal of the salt by filtration, the filtrate is washed successfully with 250 g of deionized water. The product is then dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to afford 85 g of N-(n-octyl)acrylamide, bp. 119°-120° (3 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:29])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH3:28])[C:24]([O:26]C)=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:29])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH3:28])[C:24]([OH:26])=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@H](C)C(=O)O)ccc12)c1ccc(Cl)cc1

Procedure:
(R)-Methyl 2-(5-((S)-2-(4-chlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)propanoate (0.23 g, 0.00050 mol) was stirred with lithium hydroxide (0.03 g, 0.001 mol) in tert-butyl alcohol (4 mL, 0.04 mol) and water (2 mL, 0.1 mol) at 0° C. for 1 hour. 1 N HCl was added until pH<7 and the reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and gave a light yellow solid. 1H NMR δ (CDCl3) δ: 8.05-8.01 (m, 1H), 7.89-7.62 (m, 2H), 7.38-7.29 (m, 5H), 6.89-6.80 (m, 1H), 6.04-5.94 (m, 1H), 5348-5.39 (m, 1H), 3.86 (d, J=6.6 Hz, 1H), 3.03-2.88 (m, 6H). MS m/z 399.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)=[CH:35][C:33]=2[CH:34]=1>C1COCC1>[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:1]3[C:9]4[C:8](=[CH:7][C:6]([O:10][C:11]5[C:12]6[CH2:19][NH:18][CH2:17][C:13]=6[N:14]=[CH:15][N:16]=5)=[CH:5][CH:4]=4)[CH:3]=[CH:2]3)=[O:41])=[CH:35][C:33]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Reactant: Cc1cc2cc(NC(=O)Oc3ccccc3)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (152.2 mg, 0.432 mmol) is suspended in THF (5 mL), flushed with nitrogen and cooled to 0° C. NaH (33 mg, 0.825 mmol, 60% in mineral oil) is added and mixture is stirred for 10 minutes. Phenyl 2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) is added neat and the reaction is allowed to stir to room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The solution is then diluted with ethyl acetate and the product is extracted (2×100 mL ethyl acetate). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath upon which 10 mL of TFA is added. The TFA is removed and ethyl acetate is added to the residue and ammonium hydroxide is added to quench the remaining TFA. The solution is concentrated and dissolved in DMSO and is purified via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide. MS (ESI) m/z 426.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.53 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.15-8.20 (m, 1H) 7.88-7.92 (m, 1H) 7.58 (ddd, J=6.13, 3.98, 2.27 Hz, 1H) 7.39-7.46 (m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.46 (s, 1H) 4.19 (d, J=9.35 Hz, 4H) 2.45 (s, 3H).
Reaction SMILES: CS(O[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH:18]3[N:22]([CH2:23][CH2:24][C:9]1=2)[CH2:21][CH2:20][CH2:19]3)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+].O>CN(C)C=O>[N:32]([CH:6]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH:18]3[N:22]([CH2:23][CH2:24][C:9]1=2)[CH2:21][CH2:20][CH2:19]3)=[N+:33]=[N-:34]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(F)cc2)CCN2CCCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(F)cc2)CCN2CCCC12
Yield: 7.1 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethyl methanesulfonate (400 mg, 0.9 mmol) and sodium azide (88 mg, 1.3 mmol) in dimethylformamide (10 mL) was stirred at RT for 18 h. The reaction mixture was diluted with ice cooled water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase HPLC to yield 7-(2-azido-2-(4-fluorophenyl)ethyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (25 mg). 1H NMR (CD3OD, freebase) δ (ppm): 7.32 (m, 3H), 7.26 (s, 1H), 7.13 (m, 2H), 7.09 (d, 1H), 5.09 (t, 1H), 4.8 (m, 1H), 4.32 (m, 2H), 3.44 (m, 2H), 3.3 (m, 1H), 3.1 (m, 1H), 3.0 (d, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 2.4 (s, 3H), 2.18 (m, 2H), 2.0 (m, 1H). Separation by chiral HPLC provides diastereomers V-23a-d.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccc(Br)c(Cl)[n+]1[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)ccc(C)[n+]1[O-]

Procedure:
step b—A solution of 357a (0.5 g) and 0.5 M NaOMe/MeOH (4.9 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue loaded on a SiO2 column and eluted with 5% MeOH/DCM to afford 3-bromo-2-methoxy-6-methyl-pyridine 1-oxide (357b).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH:35]O.Cl>O.C(#N)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:35])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.7 g (14.7 mmol) of NaClO2X4H2O (79% purity) in 7 ml of water is added dropwise to a stirred mixture of 4′-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxaldehyde (2.5 g, 4.5 mmol) in 10 ml of acetonitrile, 0.16 g of NaH2PO4 in 2 ml of H2O and 2.5 ml of 30% H2O2 at the temperature 10° C. pH of the mixture is adjusted to pH=2 with concentrated HCl and stirring is continued for 1.5 h at room temperature. Reaction mixture is poured into 120 ml of water, stirred for 15 minutes, filtered, washed with 2×10 ml of water and dried in vacuo. Yield: 2.34 g (90.6%)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: Clc1nccc2ncnn12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nccc2ncnn12
Reaction time: 1.5 h

Procedure:
A solution of 155 mg (1 mmol) of 5-chloro[1,2,4]triazolo[1,5-c]pyrimidine [D. J. Brown and K. Shinozuka, Aust. J. Chem., 33, 1147 (1980)] in 6 mL of dry ethanol was added gradually to a vigorously stirred solution of 198 mg (204 mg, 4 mmol) of hydrazine monohydrate in 2 mL of dry ethanol. A white precipitate separated during the addition. After 1.5 h, the solid was collected on a filter. It was suspended in 2 mL of concentrated ammonium hydroxide and agitated for a few minutes. The solid was then collected on a filter and washed with some additional concentrated ammonium hydroxide, then with some ethanol, and finally with a large volume of diethyl ether. After drying, the title compound was obtained as a white solid, mp 245-246° C. (decomposition). LC-MS 151 (M+1).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH2:8]([S:15][C:16]1[N:21]=[C:20]([NH:22]S(C)(=O)=O)[CH:19]=[C:18]([NH:27][C@H:28]([CH3:31])[CH2:29]O)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:32](N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:8]([S:15][C:16]1[N:21]=[C:20]([NH:22][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH:19]=[C:18]([NH:27][C@H:28]([CH3:31])[CH2:29][CH3:32])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](CO)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(N[C@H](C)CC)nc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Propane-1-sulfonyl chloride (0.14 g) in DCM (1 ml) was added to a solution of the subtitle product of Example 3 step (0.2 g) in DCM (3 ml) and N,N-diisopropylethylamine (0.14 g) at 0° C. The reaction mixture was stirred for 24 h at room temperature. To the reaction mixture more N,N-diisopropylethylamine (0.14 g) was added and the reaction mixture was stirred for an additional 24 h. The DCM was removed under reduced pressure and the residue dissolved in THF (2 ml). To this mixture sodium hydroxide (10%, 2 ml) was added and stirred overnight. The reaction mixture was diluted with EtOAc (50 ml). The organic layer was separated from the aqueous layer and evaporated to dryness. To the residue was added aqueous hydrochloric acid (1M, 30 ml) and THF (10 ml). This was stirred at room temperature for 3 h. The mixture was extracted with EtOAc (2×50 ml). The organics were washed with brine (30 ml). The combined organic layers were dried (MgSO4) and concentrated. This material was purified by reverse phase HPLC (90% to 5% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)N)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:12]1[CH2:11][CH2:10][N:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of (S)-1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:6]([O:8][CH2:9][C:10]([N:19](C(OC(OC(=O)C(C)C)C)=O)[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH3:12])=[O:7].[OH2:39]>>[CH3:38][O:37][C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:34]=1[O:35][CH3:36])[C:6]([O:8][CH2:9][C:10]([NH:19][CH2:20][C:9]([O:8][CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[CH:3][CH:4]=1)=[O:39])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:11][CH3:12])=[O:7]
Reactant: O
Reactant: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1ccccc1)N(C)C(=O)OC(C)OC(=O)C(C)C
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NCC(=O)OCc1ccc(OC)cc1)c1ccccc1

Procedure:
10 ml water is added to the mixture. The product is extracted with ethyl acetate (3 times 10 mL) then the organic phase is washed successively with water and a saturated solution of sodium chloride (15 mL). The organic phases are dried over Na2SO4, filtered then concentrated to dryness in order to produce a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 85/15) in order to produce 105 mg of the expected product (S) 2-[(1-isobutyryloxy-ethoxycarbonyl)-methyl-amino]-2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate in the form of a colourless oil (yield=15%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:9][C:8]([C:6]1[C:5]([F:11])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1nc(Cl)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1nc(Cl)ccc1F

Procedure:
To a solution of 6-chloro-3-fluoropyridin-2-carboxylic acid (250 mg) in methanol (3 ml), 0.3 ml of concentrated sulfuric acid was added, and the reaction solution was heated to reflux for 2.5 hours. The reaction solution was cooled, and then the solvent was distilled off under reduced pressure. To the residue obtained was added 1N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a white solid.