Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13](=[O:19])[C:14]([O:16]CC)=O.Cl.[CH2:21]([NH2:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(O)C.C(N(CC)CC)C.C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][NH:2][C:13]([C:14]([NH:39][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:16])=[O:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Into a 100-ml flask equipped with a stirrer were charged 5.2 g of tyramine hydrochloride and 40 ml of actonitrile, and 7.6 g of triethylamine was added under ice-cooling. Then, 4.1 g of ethyl chloroglyoxylate was added dropwise over a period of 30 minutes, and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a mixture of 100 ml of diluted hydrochloric acid and 15 g of ice, followed by two times of extraction with ethyl acetate. The combined organic layer was washed successively with diluted hydrochloric acid, distilled water and a saturated aqueous sodium chloride solution. The washed organic layer was dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The oil thus obtained was dissolved in 300 ml of ethanol, followed by adding thereto 8.2 g of octadecylamine, and the resulting mixture was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, after which the crystals precipitated were collected by filtration to obtain 8.8 g of the desired compound. Melting point: 167° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([C:15]([OH:17])=[O:16])[OH:14])([O-:3])=[O:2].[C:24]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO[CH:43](OC)[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=1[O:52][CH3:53].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:24][O:16][C:15]([CH:13]1[O:14][CH:43]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=2[O:52][CH3:53])[N:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:12]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Reactant: O=C(O)C(O)C(NSc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)C1OC(c2ccc(OC)cc2OC)N(Sc2ccccc2[N+](=O)[O-])C1c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A hot solution of 6.6 g N-(2-nitrobenzenesulfenyl)-3-phenylisoserine in 100 ml of dry benzene is added with 0.5 g of pyridinium p-toluenesulfonate and 5.3 g of 2,4-dimethoxybenzaldehyde dimethylacetal. The solution is refluxed for 4 hours, then left to cool to room temperature. After that, 10 ml of a NaHCO3 saturated solution are added and the phases are separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over Na2SO4 and evaporated under reduced pressure. The residual yellow oil is purified by chromatography (silica,hexane-ethyl acetate 5:1 with 2% triethylamine) to give the desired product in 74% yield.
Reaction SMILES: C[CH:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[NH:12][C:13](=[O:16])[N:14]=[CH:15][C:10]=2[CH2:9][CH2:8][O:7]1>[OH-].[Na+]>[NH4+:6].[C:17]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[NH:12][C:13](=[O:16])[N:14]=[CH:15][C:10]=2[CH2:9][CH2:8][O:7]1)([OH:19])=[O:18]
Reactant: CC(CCCN1OCCc2cnc(=O)[nH]c21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCN1OCCc2cnc(=O)[nH]c21
Product: [NH4+]
Reaction time: 2 h
Yield: 112.7 %

Procedure:
1-(4-Methylcarboxybutyl)-3,4-dihydro-8H-pyrimido[4, 5-c][1,2]oxazine-7-one (13.5) (0.42 g, 1.57 mmol) was dissolved in 1M aqueous sodium hydroxide solution (10 ml) and stirred for 2 hours. The mixture was applied to an ion exchange column of Dowex 50 WX8-200. This was eluted with water and the product recovered using 2M aqueous ammonia solution. The solution volume was reduced and then freeze-dried to yield a white solid (0.24 g, 60.4%). The product appeared as a single spot when analysed in the following thin-layer chromatography systems: Silica gel eluted with chloroform:methanol (7:3) and butan-1-ol: water, glacial acetic acid (12:5:3); Silica gel impregnated with ODS eluted with methanol:water:glacial acetic acid (80:20:1); Cellulose eluted with butan-1-ol:water:glacial acetic acid (12:5:3). The structure was confirmed by mass spectroscopy and proton NMR.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[NH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[NH:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1c[nH]c(C(=O)O)c1
Yield: 88.9 %

Procedure:
Preparation C8, Step 1: Ethyl 4-tert-butyl-1H-pyrrole-2-carboxylate (from C7, Step 1) (38 mg, 1.95 mmol, 1 eq), 1.000 N NaOH (39 mL, 39 mmol, 20 eq) and MeOH (50 mL) were mixed and refluxed for 1 hour. The mixture was acidified with 1.0 N HCl, (1.0 N), the MeOH stripped, and the remaining aqueous extracted with ethyl acetate (2×). The organic layers were combined, dried (MgSO4), and stripped to yield 290 mg of an off-white solid. NMR (CDCl3+2 drops DMSO-D6) δ 6.50 (s, 1H); 6.46 (s, 1H); 0.95 (s, 9H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9](=[O:25])[NH:10][C:11]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>C(OCC)(=O)C.O1CCOCC1>[CH:1]([N:4]1[C:8]2[C:9](=[O:25])[NH:10][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl 1′-isopropyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (100 mg, 0.29 mmol) in 4 mL ethyl acetate was added 4 N HCl in dioxane (2 mL). After stirring 30 minutes at room temperature, methanol (1 mL) was added and the resultant solution was stirred for 5 hours at room temperature. The volatiles were removed under reduced pressure and the resultant colorless solid triturated with 1:1 acetonitrile/dichloromethane to yield 71 mg of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.72 (br. s., 2H), 8.05 (s, 1H), 7.37 (s, 1H), 5.36 (m, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.78 (s, 2H), 1.78 (m, 4H), 1.33 (d, J=6.6 Hz, 6H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:42])[C@H:11]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31])(=[O:21])=[O:20])[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:42])[C@H:11]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=1[CH3:28])(=[O:20])=[O:21])[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NOCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NO)c(C)c1
Reaction time: 6 h
Yield: 44.8 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide (580 mg, 0.94 mmol) in a 3:1 mixture of ethanol/tetrahydrofuran (30 ml) was added 10% palladium on charcoal (60 mg). The reaction mixture was placed under a hydrogen balloon and stirred for 6 hours. The material was filtered through a short plug of silica, rinsing with ethanol (200 ml). The filtrate was condensed on the roto-evaporator and the residue was purified by preparative thin layer chromatography using 8.5% methanol-methylene chloride as eluant providing N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide as a tan powder (223 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[O:21])[NH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)([OH:3])=[O:2].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33].O>CN(C=O)C>[CH2:35]([O:34][C:32]([O:2][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[O:21])[NH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)=[O:3])=[O:33])[CH:36]([CH3:38])[CH3:37]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCC(=O)O)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCC(=O)OC(=O)OCC(C)C)cc1
Yield: 74.6 %

Procedure:
A solution of 820 mg (2.6 mmol) of 5-(4-carboxypropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (prepared as described in Example 2 above), 750 μl (5.38 mmol) of triethylamine, and 15 ml of DMF is cooled in an ice-water bath while stirring under N2. A solution of 540 mg (3.9 mmol) of isobutyl chloroformate in 5 ml of DMF is added dropwise. After 4 hr of stirring at 0°C., the reaction mixture is poured into water (75 ml), and extracted with EtOAc (2×50 ml). The combined EtOAc extracts are washed with water, dried (MgSO4), filtered and the solvent removed to leave 800 mg of 5-(4-isobutyloxycarbonyloxycarbonylpropoxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a tan-colored solid. 1H-NMR (CDCl3) δ1.00 (d, 6H); 1.60 (m, 1H); 2.16 (m, 2H); 2.50 (s, 3H); 2.70 (t, 2H); 4.10 (m, 4H); 6.93 (d, H); 7.20 (d, 2H); 7.80 (s, 2H).
Reaction SMILES: [OH2:1].[OH-:2].[K+].[C:4]([C:6]1[C:11]2[CH2:12][C:13](=[O:23])[C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)#N>C(O)C>[C:4]([C:6]1[C:11]2[CH2:12][C:13](=[O:23])[C:14]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=3[S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:2])=[O:1]
Reactant: O
Reactant: COc1ccc2c(c1)C(=O)Cc1c(C#N)cccc1S2
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)Cc1c(cccc1C(=O)O)S2

Procedure:
To the mixture of 1ml of water and 600mg of potassium hydroxide in 9ml of ethanol was added 200mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and the resulting mixture was heated under reflux overnight. Water was added to the mixture, which was washed with benzene. Aqueous layer was acidified with hydrochloric acid, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated therefrom and there was obtained 130mg of 9-carboxy-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin having a melting point of 157°-160° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:12][O:11][C:4]1[C:3]([NH:2][C:46](=[O:47])[C:45]2[CH:49]=[C:41]([CH2:40][C:34]3[C:35](=[O:39])[C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[C:32](=[O:55])[C:33]=3[CH3:54])[CH:42]=[CH:43][C:44]=2[O:50][C:51](=[O:53])[CH3:52])=[CH:8][CH:7]=[C:6]([O:9][CH3:10])[N:5]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.5 %

Procedure:
3-Amino-2,6-dimethoxypyridine hydrochloride (0.306 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.160 g, 0.313 mmol, 59%).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12](Br)[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:23][C:24](I)([F:26])[F:25]>[Cu].CN(C)C=O>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([C:24]([F:26])([F:25])[F:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: FC(F)(F)I
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(Br)c1
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl α- hydroxy-γ-(3-bromo-4-cyclohexylphenyl)butyrate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140°C, cooled and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl α-hydroxy-γ-(3-trifluoromethyl-4-cyclohexylphenyl)butyrate.
Reaction SMILES: C([N:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5]1=[O:26])C=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1COCC1.O>C([O-])(O)=O.[Na+].C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C@@H:8]3[NH:4][C:5](=[O:26])[CH2:6][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: C=CCN1C(=O)CC[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)N1
Temperature: 25 °C

Procedure:
Under argon, (5R)-1-allyl-5-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]-2-pyrrolidinone (XVII-1) (0.41 g, 1.14 mmol) is initially charged in a Schlenk tube together with Pd[PPh3]4 (131.7 mg, 0.114 mmol) and p-toluenesulphonic acid hydrate (0.52 g, 2.74 mmol), and THF (2 ml, degassed) and 1 ml of H2O are added. The yellow suspension is heated under reflux for 3 h. For work-up, the mixture, which was cooled to room temperature, is diluted with NaHCO3 solution and admixed with ethyl acetate and filtered through kieselguhr. The combined organic phases are dried (Na2SO4) and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:17]=O.CC([O-])=O.[Na+].Cl.[NH2:25][OH:26]>CO>[F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:17]=[N:25][OH:26]
Reactant: O=Cc1ccc2c(ncn2C2CCCCO2)c1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 148 (7.7 g, 0.031 mol) in dry MeOH (120 mL) was added NaOAc (3.31 g, 0.0372 moles) and hydroxylamine hydrochloride (2.57 g, 0.0372 mol). The reaction mixture was stirred at RT for 16 h. The solution was concentrated in vacuo, the residue taken up in water and extracted with DCM. The combined organic extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 5.8 g (71%) of 4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde oxime (150) as a white solid which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][NH:11]C)=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[C:18]([O-])(O)=O.[Na+]>C1COCC1>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH:10]([NH:11][C:1](=[O:3])[CH3:2])[CH3:18])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TEA (0.28 mL, 2.0 mmol) followed by acetylchloride (96 L, 1.3 mmol) were added to 4-chloro-methyl-3-nitrobenzylamine (0.27 g, 1.3 mmol) in THF (5 mL) at rt. The mixture was stirred at rt for 3.5 h and additional acetylchloride (20 L, 0.27 mmol) was added. After 1 h at rt, NaHCO3 (aq, 5%) was added and the mixture extracted with EtOAc.
Reaction SMILES: C(O[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([CH3:26])[CH2:20][CH2:19]2)CCCCCCCCCCCCC.[CH3:27][OH:28].[CH2:29]([Cl:31])Cl>>[Cl:31][C:29]1[CH:18]=[CH:17][C:16]([CH2:27][O:28][C:24]2[CH:25]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][N:21]([CH3:26])[CH2:20][CH2:19]3)=[CH:25][CH:24]=1
Reactant: ClCCl
Reactant: CCCCCCCCCCCCCCOc1ccc2c(c1)CCN(C)C2
Reactant: CO
Product: CN1CCc2cccc(OCc3ccc(Cl)cc3)c2C1

Procedure:
MS: 286 (M+ -1, 27), 162 (51), 125 (65); Rf : 0.43 (8% MeOH/CH2Cl2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1nccs1
Product: CNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g) with N-cyano-N', S-dimethylisothiourea (7.75 g) by a procedure similar to that described in Example 3(a) afforded N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°- 122.5° , following chromatography on silica gel with acetonitrile as eluant, and recrystallisation from isopropyl alcohol, (Found C, 42.3; H, 5.1; N, 27.2; S, 25.3, C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:20]2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].S(OC)(O[CH3:39])(=O)=O.N12CCCN=C1CCCCC2.O>CN(C)C=O>[CH3:39][N:13]([C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:20]2)[CH2:16][CH2:15]1)[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN([C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Nitro-N-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-yl)benzenesulfonamide (250 mg, 0.481 mmol) from Example 299 and dimethyl sulfate (0.138 mL, 1.444 mmol) were combined in N,N-dimethylformamide (3 mL) at 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.145 mL, 0.962 mmol) was added dropwise. The reaction mixture was stirred for 0.5 hours, water was added, and the precipitate was collected by filtration. The resultant crude material was purified using a 12 g silica gel cartridge eluting with a gradient of 0-60% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.15 (dd, J=12.1, 4.7, 3H), 7.94 (d, J=8.3, 2H), 7.88 (dd, J=7.7, 1.3, 1H), 7.68 (dtd, J=19.1, 7.5, 1.3, 2H), 4.29 (dt, J=10.8, 7.0, 1H), 3.63 (dd, J=9.9, 1.5, 1H), 3.21 (dd, J=9.7, 2.3, 1H), 2.90 (s, 3H), 2.89-2.81 (m, 2H), 2.58-2.39 (m, 2H), 1.83-1.72 (m, 1H), 1.68-1.58 (m, 1H), 1.50 (qd, J=11.8, 7.3, 1H), 1.21 (ddd, J=19.4, 12.4, 7.1, 1H); MS (ESI+) m/z 551 (M+NH4)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].O>[Fe].CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(SCc2ccccc2)cc1N

Procedure:
2.4 G. of 1-acetamido-2-nitro-4-benzylthiobenzene is treated with 2.4 g. iron powder and 1.2 g. ferrous sulfate in a mixture of 60 ml. water and 240 ml. methanol, at reflux for 4 hours. The mixture is then filtered, the filtrate concentrated and the residue recrystallized from benzene. Pure 1-acetamido-2-amino-4-benzylthiobenzene is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li][N:38]([Si](C)(C)C)[Si](C)(C)C>CCOC(C)=O.Cl>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CC(C)(O)c1ccc(Cl)nc1
Agent: Cl
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(N)nc1
Temperature: 90 °C
Yield: 95.4 %

Procedure:
In a flame-dried seal tube reaction vial, under argon atmosphere, add 2-(6-Chloro-pyridin-3-yl)-propan-2-ol (750 mg, 4.375 mmol), 2-(dicyclohexylphosphino)-biphenyl (307 mg, 0.875 mmol) and then add LiN(TMS)2 (1M in THF, 13.5 mL, 13.5 mmol). Seal the tube and heat it up to 90° C. for 18 hours. The dark reaction mixture was then diluted with EtOAc (10 mL). HCl (2M) (10 drops) was added with stirring. The reaction mixture was then concentrated and loaded onto ISCO separation column and eluted with 5% MeOH/(1/1 EtOAC/Hex) to afford 2-(6-Amino-pyridin-3-yl)-propan-2-ol as solid (635 mg, yield 95%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([C:9]4[CH:10]=[C:5]([C:2](=[O:4])[CH3:3])[CH:6]=[CH:7][C:8]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:12]=3[NH:19][C:18]=2[CH3:20])=[O:22])[CH2:25][CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available acetyl chloride the title compound is obtained as colorless solid.