Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(S(O[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]3[CH:40]=[C:39]([N:41]4[CH:46]=[CH:45][C:44](=[O:47])[NH:43][C:42]4=[O:48])[CH:38]=[C:37]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:36]=3[O:53][CH3:54])[CH:31]=2)[CH:26]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[CH3:56][S:57]([NH2:60])(=[O:59])=[O:58]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(OCC)(=O)C>[C:49]([C:37]1[C:36]([O:53][CH3:54])=[C:35]([C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:60][S:57]([CH3:56])(=[O:59])=[O:58])[CH:34]=[CH:33]3)[CH:40]=[C:39]([N:41]2[CH:46]=[CH:45][C:44](=[O:47])[NH:43][C:42]2=[O:48])[CH:38]=1)([CH3:51])([CH3:50])[CH3:52]
Reactant: CS(N)(=O)=O
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 236.8 %

Procedure:
A 450-mL, stainless steel Parr pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.167 g, 0.344 mmol) and milled potassium phosphate tribasic (6.69 g, 31.5 mmol). The flask was purged with argon for not less than 90 minutes. Ethyl acetate (80 mL) was taken in a 100-mL, round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (20.0 g, 22.9 mmol), methanesulfonamide (3.27 g, 34.4 mmol) and ethyl acetate (160 mL), purged with argon for not less than 60 minutes while stirring at 50° C. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 15 hours. The reaction mixture was allowed to cool down to the room temperature, filtered and rinsed with ethyl acetate (120 mL). Solid (26.76 g) was obtained after drying the solid for 2 hours on high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[I-].[Na+].C(N(CC)CC)C.[CH3:33][Si:34](Cl)([CH3:36])[CH3:35]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]([O:23][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (4.6 mmol), sodium iodide (9.3 mmol), and triethylamine (13.9 mmol) in 15 mL acetonitrile is added trimethylsilyl chloride (9.3 mmol). After stirring at RT for 2 hours it is quenched with 20 mL saturated NaHCO3 solution and extracted several times with EtOAc. The combined organic layers are dried over Na2SO4 and evaporated in vacuo yielding 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as a brown oil (95%). 1H NMR (CDCl3) 0.15 (s, 9H), 1.32 (t, 3H), 1.60 (s, 9H), 1.83-1.97 (m, 2H), 1.99-2.06 (m, 2H), 3.00 (t, 2H), 4.33 (q, 2H), 5.40 (t, 1H), 7.62 (s, 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH:13]([NH:12][CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:7]=2)[CH:18]=[CH:17][CH:16]=1)([CH3:15])[CH3:14]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 65 was coupled with tyramine following procedure F. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 363. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 7.5 (d, 2H), 7.2 (m, 2H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), 3.8 (m, 1H), 3.3 (m, 4H), 2.7 (m, 1H), 1.1 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][OH:28]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:26][CH2:27][OH:28])[N:3]=1
Reactant: OCCBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCCO)c(C#N)c1-c1ccc(O)cc1
Reaction time: 8 h

Procedure:
26.8 mg (0.1 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile are dissolved in 0.2 ml of dimethylformamide. 20 mg (0.238 mmol) of solid sodium bicarbonate are added, followed by a solution of 18.74 mg (0.15 mmol) of 2-bromoethanol in 0.06 ml of dimethylformamide. The reaction mixture is shaken overnight and, after filtration, purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][NH2:30])[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=2[N:7]=1>CN(C=O)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][NH:30][C:3]([NH:2][CH3:1])=[O:4])[N:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=2[N:7]=1
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)NCCn1c(CN)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Solvent: CN(C)C=O
Product: CNC(=O)NCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.2 %

Procedure:
Methyl isocyanate (322.9 mg, 5.66 mmol, 1.1 eq) was added to a solution of tert-butyl 2-(4-amino-2-aminomethyl-7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (2.38 g, 5.14 mmol, 1 eq) in DMF and stirred at ambient temperature for 2 days. The crude reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (on silica gel, 0-6% methanol in dichloromethane) and concentrated under reduced pressure to yield 2.73 g of tert-butyl 2-{4-amino-7-benzyloxy-2-[(3-methylureido)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[CH:15][C:3]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (4.30 g, 11.3 mmol) in THF (57 mL) at about 0° C. was added TBAF (1.0 M in THF, 12.6 mL, 12.6 mmol) dropwise and the reaction mixture was stirred at about 0° C. for about 1 h. The reaction was warmed to room temperature and stirred for about 30 min. The solvent was removed under reduced pressure and the resulting oil was partitioned between EtOAc and brine (100 mL each). The organic layer was dried over anhydrous Na2SO4, filtered and concd under reduced pressure. The residue was triturated with DCM and filtered to give ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.32 g, 52%) as an off white solid: LC/MS (Table 1, Method b) Rt=2.07 min; MS m/z: 225 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:13]2[CH2:14][N:10]([CH2:9][C:8]3[CH:28]=[CH:29][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11](=[O:27])[N:12]2[CH3:26])=[CH:19][C:20]=1[CH3:25])([CH3:38])[CH3:37])[CH3:36]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 50 °C
Yield: 87.9 %

Procedure:
1-(4-tert-Butyl-benzyl)-4-[3-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.060 g, 0.152 mmol) is dissolved in DMF (1.5 mL), to it is added ethyl 2-bromoisobutyrate (0.141 g, 0.760 mmol) followed by potassium carbonate (0.105 g, 0.760 mmol). After heating at 50° C. overnight, the reaction mixture is diluted with ethyl acetate (2 mL), washed with water (2 mL), the separated organic layer is passed through a chem elut tube, and the tube is washed with more DCM (50 mL). Evaporation of solvent followed by chromatography on silica gel, (gradient elution 0-40% ethyl acetate in hexane) to provide an oil (0.068 g, 88%). Mass [EI+] 510 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[NH:11]1[CH2:19][CH2:18][CH:14]([C:15](O)=O)[CH2:13][CH2:12]1.[OH-].[Na+]>>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][C:15]([CH:14]3[CH2:18][CH2:19][NH:11][CH2:12][CH2:13]3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1cc(Br)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Product: Fc1cc(Br)cc2nc(C3CCNCC3)oc12
Temperature: 195 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
2-amino-4-bromo-6-fluorophenol (1.7 g, 8.24 mmol) and isonipecotic acid (1.06 g, 8.24 mmol) were dissolved in polyphosphoric acid (28 g). This mixture was heated to 195° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with aqueous NaOH solution to pH 14. Solid that obtained was filtered and dried to obtain the title compound (1.3 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(=O)(O)[O-].[Na+].O.[C:16]([O:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]([CH3:37])=[CH:24][C:23]=1[CH3:38])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=2)[C:25]([CH3:37])=[CH:24][C:23]=1[CH3:38])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(C)c(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
Commercially available 2-amino-4,6-dichloropyrimidine (460 mg, 2.8 mmol), palladium dichloride-diphenylphosphinoferrocene dichloromethane complex (98 mg, 0.12 mmol), sodium bicarbonate (471 mg, 5.61 mmol), 1,4-dioxane (4.5 ml), and water (2.5 ml) were placed in a reaction vessel. The resulting mixture was stirred at 80° C. for 10 minutes. 2,4-Dimethyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid tert-butyl ester (620 mg, 1.8 mmol) obtained in Step 3 above that was dissolved in 1,4-dioxane (4.5 ml) was added dropwise to the mixture. The resulting mixture was stirred at 80° C. for 19 hours. The reaction solution was diluted with ethyl acetate (150 ml), and washed with water (80 ml) three times and then with a saturated aqueous sodium chloride solution (80 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (30 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=10:1 to 5:1) to yield 5-(2-amino-6-chloropyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (Compound 1-1) (422 mg) as a white solid material.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH3:36])[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([S:28](=[O:35])(=[O:34])[NH:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=4)[N:16]=3)=[CH:13][N:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CCOC(C)=O>C(O)C.[Pd]>[CH2:9]([C:10]1[N:11]([CH3:36])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:35])(=[O:34])[NH:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=3)[N:16]=2)=[CH:13][N:14]=1)[CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CCc4ccc(Cl)cc4)n3C)n2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CCc4ccccc4)n3C)n2)cc1
Reaction time: 72 h
Yield: 62.1 %

Procedure:
4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 117; 115 mg, 0.219 mmol) and triethylamine (34 μl, 0.241 mmol) was dissolved in ethanol (20 ml) and EtOAc (10 ml) and 30% palladium on charcoal catalyst (30 mg) added. The mixture was stirred for 3 days under an atmosphere of hydrogen. The catalyst was removed by filtration and filtrate evaporated. The residue was dissolved in DCM (20 ml), washed with water (2×5 ml), dried and the solvent removed by evaporation to give the title compound (67 mg, 63%) as a white solid. NMR: 2.88 (q, 2H) 3.05 (s, 4H) 3.16 (s, 3H) 3.28 (t, 3H) 3.90 (s, 3H) 7.21 (d, 1H) 7.28 (m, 5H) 7.69 (s, 1H) 7.70 (d, 2H) 8.44 (d, 1H) 9.94 (s, 1H); m/z 493.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([OH:34])=[O:33].C([O-])(O)=O.[Na+]>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([OH:34])=[O:33])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)C1CCCCN1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 27 %

Procedure:
Triethylamine (3.36 ml) was added to a stirred solution of 3-benzyloxybenzoic acid (5.0 g) and isobutyl chloroformate (3.13 ml) in THF (67 ml) under ice-cooling and the resulting mixture was stirred at the same temperature for 1 hour. A solution of 2-piperidinecarboxylic acid (4.14 g) and NaHCO3 (3.32 g) in water (40 ml) was added dropwise to the stirred mixture at the same temperature and the mixture was stirred at the same temperature for 2 hours and at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with 1N HCl (twice) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylic acid (2.01 g) as a amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1

Procedure:
A suspension of 4-chlorophenol (2.6 g, 20 mmol), chloroacetone (2.8 g, 30 mmol) and potassium carbonate (3.45 g, 25 mmol) in acetone (100 ml) is heated at reflux for 3 hours. The precipitating inorganic salts are filtered off and the filtrate is evaporated to dryness to give the 1-(4-chlorophenoxy)-propan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][OH:22])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1.[OH-].[Na+].[CH3:27]OS(OC)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21][O:22][CH3:27])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: COS(=O)(=O)OC
Reactant: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(N)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Yield: 19 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxybenzenecarboximidamide (222, mg, 0.6 mmol, 1 equiv.), 0.7 N NaOH solution (0.97 ml, 0.68 mmol, 1.13 equiv.) and dimethylsulfate (0.60 ml, 0.63 mmol, 1.05 equiv.) in THF (4 ml) was stirred at 0° C. for 6 h. The mixture was poured into H2O (40 ml) and the precipitant solid was filtered and washed with H2O (2×10 ml) and Et2O (2×10 ml) to give 43 mg (yield 19%) of the desired product. Purity 70% by HPLC (Gemini C18, 50×4.6 mm): m/z 384 [M+H]+, Rt=3.26 min. HPLC-MS analysis suggested also that there was 23% un-reacted starting material and 6% of the N-methylated by-product: 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxy-N-methylbenzenecarboximidamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=O)[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[S:36])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Yield: 91.7 %

Procedure:
N-[[(5S)-3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (180 mg, 0.47 mmol), Lawesson's Reagent (310 mg, 0.77 mmol) and dioxane (10 ml) are heated under reflux for 1 hr. After cooling, the solvent is evaporated and the residue chromatographed over silica gel (40 g) eluting with 2-4% methanol-chloroform gives the title compound as a foam (173 mg, 92%). HRMS(FAB): calcd for m+H=402.0957; Found: 402.0954.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:6][CH2:5]2.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:27][C:7]([CH3:25])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:26])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccc1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccccc2)=C(C)C1=O
Yield: 90.3 %

Procedure:
Oxidation as described in protocol B, using 102 mg (0.287 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-phenethylchroman-2-carboxamide and 355 mg CAN (0.647 mmol) yielded 95.8 mg of 2-hydroxy-2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>S(=O)(=O)(O)O.O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[NH:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:10][C:9]=3[C:19]=2[CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxane. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is added and the mixture is stirred at 80° C. for 6 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated, then slowly quenched with aq. NaHCO3 solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate, evaporated to dryness and purified by column chromatography to afford 2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
344 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] were subjected to N-alkylation with 406 mg of ethyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride as eluent, which separated the compound into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). Isomer A (in which the carbon attached to the phenethyl group had the R-configuration) was eluted first as an oily compound in a yield of 0.17 g.