Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[S:6].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH3:22])=[S:6]
Reactant: CO
Reactant: Cc1cc(C(O)=S)ccc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)c(C)c1
Reaction time: 4 h

Procedure:
A mixture of 3-methyl-4-phenylthiobenzoic acid (85 g), conc. sulfuric acid (20 ml) and methanol (1.2 liter) is refluxed with stirring for 4 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure. To the residue is added ethyl acetate (1.5 liter), and the mixture is washed with saturated aqueous sodium chloride solution (400 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 3-methyl-4-phenylthiobenzoate (80.33 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:20][N:21]([CH3:23])[CH3:22])=[O:15]
Reactant: CS(=O)(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Yield: 99.4 %

Procedure:
2.5 g of m-trifluoromethyl-α-methanesulfonylacetophenone and 1.4 g of N,N-dimethylformamide dimethylacetal were dissolved in 40 ml of toluene, and the resulting mixture was heated under reflux for 2 hours. The solvent was distilled away under reduced pressure. The residue was treated with column chromatography on silica gel, thereby obtaining 3 g of 1-(3-trifluoromethylbenzoyl)-1-methanesulfonyl-2-(N,N-dimethylamino)ethene (Compound 205).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])=[C:4]([F:18])[CH:3]=1.[ClH:19]>C(OCC)(=O)C>[Cl-:19].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH3+:10])[CH3:9])=[C:4]([F:18])[CH:3]=1
Reactant: Cl
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1F
Solvent: CCOC(C)=O
Product: C[C@@H]([NH3+])c1ccc(Br)cc1F
Product: [Cl-]

Procedure:
Tert-butyl(1R)-1-(4-bromo-2-fluorophenyl)ethylcarbamate (10.04 g, 31.55 mmol) was dissolved in ethyl acetate and treated with hydrochloric acid gas. A white solid precipitated and the suspension was concentrated under reduced pressure to yield (1R)-1-(4-bromo-2-fluorophenyl)ethanaminium chloride as a white solid that was used without further purification. Low resolution mass spectrometry: (M+H+−NH3)=201.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:16])[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=O)=[O:4].C1([SiH3])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([CH3:16])[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)C(=O)Nc2cc(Br)ccc21
Agent: [SiH3]c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CNc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
To a solution of 6-bromo-3-methyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester (200 mg, 0.7 mmol) in toluene under N2 were added Fe3(CO12) (14 mg, 0.028 mmol) and PhSiH3 (33 μL) and the mixture was stirred at 100° C. for 16 h. The resulting mixture was filtered through Celite (wash with EtOAc). The solvent was removed in vacuo to give the title compound (70 mg) as a colourless gum. MS: [M+H]+=270.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21]>C(OCC)(=O)C.O>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[Br:6])[CH3:21]
Reactant: Sc1ccccc1Br
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(CSc1ccccc1Br)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
A 500 mL round bottom flask was charged with anhydrous DMF (100 mL), 2-bromothiophenol (10.0 g, 52.88 mmol), potassium carbonate (11.0 g, 79.59 mmol) and bromoacetaldehyde diethyl acetal (8.35 mL, 55.5 mmol). The reaction was stirred at room temperature for 5 hours. Water (50 mL) and ethyl acetate (100 mL) were then added with mixing. The layers were separated and the organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-bromophenylthio) acetaldehyde diethyl acetal (13.78 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=C=NC(C)(C)C)=[O:5])[CH3:2].[F:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:28][CH3:29])[C:20]=2[C:24]([F:27])([F:26])[F:25])[C:15]=1[C:30]([N:32]([CH3:37])[CH2:33][C:34]([OH:36])=O)=[O:31]>C1COCC1>[CH2:1]([O:3][C:4]([NH:6][C:34](=[O:36])[CH2:33][N:32]([CH3:37])[C:30]([C:15]1[C:16]2[C:21](=[C:20]([C:24]([F:27])([F:25])[F:26])[C:19]([O:28][CH3:29])=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[F:13])=[O:31])=[O:5])[CH3:2]
Reactant: COc1ccc2c(C(=O)N(C)CC(=O)O)c(F)ccc2c1C(F)(F)F
Reactant: CCOC(=O)N=C=NC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)CN(C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
According to the procedure of O. M. Mitsunobu et al, Bull. Chem. Soc. Japan, 45, 3607 (1972), a solution of ethoxycarbonyl-t-butylcarbodiimide (0.436, 1.10 q) and N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine (0.838 g, 2.38 mmole) in anhydrous THF (13.5 mL) was heated to reflux under a dry nitrogen atmosphere for 10 hours. The reaction was cooled to room temperature and the organic solvent was removed. The solid was flash chromatographed (1:1 pertroleum ether:ethyl acetate, silica). The resultant foam was triturated with petroleum ether and dried to provide the title compound as a white solid (0.567 g, 50%), m.p. 130°-132° C.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:31]3[CH:36]=[N:35][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccc(Cl)cc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2ccc(Cl)cc21
Yield: 51.9 %

Procedure:
The title compound (16.6 mg, 52%) was prepared from 6D (23.2 mg, 0.0688 mmol) and 5A (22 mg, 0.0722 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.612 min; LCMS Found: (M+H)+=465.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
Chloroacetyl chloride (4 g, 35.4 mmol) was added to a stirred mixture of 3-aminobenzamide (4.0 g 25.9 mmol), K2CO3 (22 g, 159 mmol), water (40 ml), and dioxane (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and 25° C. for 16 hours, resulting in a solid precipitate. The precipitate was collected, washed, and dried to yield 4.1 g (75%) of the desired 3-chloroacetamidobenzamide, mp: 210 (D).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH2:32][C@H:33]1[O:35][CH2:34]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:32][C@@H:33]2[CH2:34][O:35]2)=[CH:16][N:15]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc(O)cn1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC[C@@H]2CO2)cn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 189 mg) in N,N-dimethylformamide (20 ml) was dropwise added 2-benzyloxycarbonylamino-5-hydroxypyridine (1.1 g) in N,N-dimethylformamide (12 ml) at 5° C., and the mixture was stirred at room temperature for 1 hour. To this one was added (2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.1 g) at 5° C., and the mixture was stirred at room temperature for 7 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=9:1) to give 2-benzyloxycarbonylamino-5-[(2S)-oxiranylmethoxy]pyridine (780 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:39]2[N:38]=[CH:37][N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:35]=2[CH:34]=[CH:33][C:32]=1[CH3:48].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.O>CCO.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>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:39]4[N:38]=[CH:37][N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:35]=4[CH:34]=[CH:33][C:32]=3[CH3:48])[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc2c(ncn2COCC[Si](C)(C)C)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)ccc3c2ncn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester. (20 mg, 0.044 mmol, Example 140: step a), 4-Iodo-5-methyl-1-(2-methylsilanyl-ethoxymethyl)-1H-benzoimidazole (21 mg, 0.054 mmol, Example 287: step b) and Pd(PPh3)4 in 1.2 ml of 1:1:2 EtOH/2M Na2CO3/toluene was stirred at 90° C. for 5 h, the cooled to RT. Treated with 3 mL of H2O, the mixture was extracted with EtOAc (3×5 mL)/Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (30% EtOAc/hexane) gave 21 mg (71%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 8.42 (s, 1H). 8.08 (s, 1H), 8.05 (s, 1H), 8.01 (ddd, 1H, J=7.2, 1.8, 1.7 Hz), 7.71–7.67 (m, 2H), 7.57 (d, 1H, J=8.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 5.64 (s, 2H), 3.57 (t, 2H, J=8.3 Hz), 2.61 (s, 3H), 2.33 (s, 3H), 1.51 (s, 9H), 0.95 (t, 2H, J=8.3), −0.03 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H40N4O5S3Si, 673.2, (M+H), found 672.9.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O=S(Cl)[Cl:19]>>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCc1ccccc1C(=O)Cl
Yield: 80 %

Procedure:
Heptylbenzoyl chloride (530 mg., 0.0022 M), obtained by reaction of heptylbenzoic acid with SOCl2, and 380 mg. of ##STR15## (0.002 M) in 5 ml. of pyridine are allowed to react at ambient temperature for 48 hours. Then the reaction mixture is poured into a solution of 5 ml. of concentrated H2SO4 and 50 g. of ice. The organic fraction is extracted with ether (3 times, 100 ml. total). The organic fraction is washed with water (3 times) and dried over anhydrous Na2SO4. The solvent is evaporated and the solid residue is treated by chromatography on silica with a benzene (50%) hexane (50%) mixture. The product is finally recrystallized twice from ethanol. The yield is above 80%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17][N:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19]2)[CH2:3]1.[NH2:26][C:27]1[C:28](=[O:38])[N:29]([CH2:35][CH2:36][CH3:37])[C:30](=[O:34])[NH:31][C:32]=1[NH2:33].CCN=C=NCCCN(C)C>CO>[NH2:33][C:32]1[NH:31][C:30](=[O:34])[N:29]([CH2:35][CH2:36][CH3:37])[C:28](=[O:38])[C:27]=1[NH:26][C:23]([C:21]1[CH:20]=[N:19][N:18]([CH2:17][CH:4]2[CH2:3][C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[CH2:5]2)[CH:22]=1)=[O:24]
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1cnn(CC2CC(=O)N(c3cccc(C(F)(F)F)c3)C2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(CC3CC(=O)N(c4cccc(C(F)(F)F)c4)C3)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 1-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (1 g, 2.83 mmol) and 5,6-Diamino-3-propyl-1H-pyrimidine-2,4-dione (521 mg, 2.83 mmol) in MeOH (40 mL) was added EDCI (813 mg, 4.24 mmol) under argon atmosphere. After stirring at overnight at room temperature the reaction mixture was quenched with water (10 mL) and white solid was precipitated out. The solid was filtered and washed with water to give the crude product which on purification by column chromatography (eluting with 5% MeOH:DCM) furnished the title compound as a white solid (1.3 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([C:10]2[N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(4-nitrobenzoyl) pyrrole (White et al., J. Org. Chem., 42 4284 [1977]; 2 g. 9.26 mM) in DMF (5 ml) was added dropwise to a stirred suspension of sodium hydride (0.42 g of a 60% dispersion in mineral oil, 1.05 mM) in DMF (15 ml). After 10 minutes, the mixture was cooled to 5° C. and 2-trimethylsilylethoxymethyl chloride (1.7 ml) was added dropwise and the mixture stirred for 10 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was poured into aqueous sodium carbonate solution and extracted into EtOAc. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography in dichloromethane, eluting with a gradient increasing in polarity from 2% to 5% MeOH/dichloromethane to give 2-(4-nitrobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole as an oil (2.3 g). MS: 347 (MH+) NMR: −0.1 (9H, s); 0.82 (2H, t) 3.5 (2H, t); 5.71(2H, s); 6.28 (1H, m); 6.84 (1H, m); 7.52 (1H, m), 7.92 (2H, d); 8.36 (2H, d).
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([OH:18])=O)=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH:27][CH2:28][C:29]1[CH:34]=[CH:33]C=CC=1>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([N:27]2[CH2:28][CH2:29][CH2:34][CH2:33]2)=[O:18])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)O)cc1[N+](=O)[O-]
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1c from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5]([F:15])[C:4]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19].BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1/C=C(\C)/C(O)=O>CC(C)=O>[F:15][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(F)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Agent: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(C)=O
Product: C/C(=C\C1=C(F)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 52 was prepared from 99d (0.097 g, 0.33 mmol) as described above for 39a to give 0.020 g (0.08 mmol, 23%) of the product as a yellow solid following flash chromatography (3:17 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes. (0.020 g E; 0.015 g E starting material; 0.023 g Z methyl ester)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][N:17]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2cccs2)cc1

Procedure:
14.8 g of 2-thiophenecarbaldehyde was added to a mixture of 25.2 g of p-chlorophenylhydrazine hydrochloride and 33.6 g of sodium acetate in 400 ml of 50% aqueous ethyl alcohol. The mixture was heated on a water bath for 30 minutes. After cooling, the precipitated solid was collected and crystallized from ethyl alcohol to give 1, as yellow needles, mp 137° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ncccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ncccn1
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (4.40 mL, 57.1 mmol) was added to a stirred solution of 2-hydroxymethylpyrimidine (6.28 g, 57.1 mmol) and triethylamine (9.50 mL, 68.5 mmol) in DCM (250 mL) at 0° C. After approximately 20 min, the reaction mixture was poured into water, the organic layer was separated and the aqueous phase was re-extracted twice with DCM. The combined organic extracts were washed with water, brine, dried (sodium sulfate), and concentrated in vacuo to afford the title compound i-2a. 1HNMR (500 MHz, CDCl3): δ 8.81 (d, 2H, J=4.8 Hz), 7.32 (t, 1H, J=4.9 Hz), 5.46 (s, 2H), 3.24 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=CC=CC=1.N[C@H](C(N1CCC[C@H]1C(OC)=O)=O)CCCCNC([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.[F:49][C:50]([C:53]([OH:55])=[O:54])([F:52])[F:51]>>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][CH2:4][C:9](=[O:54])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[F:49][C:50]([C:53]([OH:55])=[O:54])([F:52])[F:51]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(=O)OCc1ccccc1

Procedure:
Instead of H-Phe-Pro-OMe (1 equivalent) and TEA (1 equivalent) in (b), (c) H-Lys(Z)-Pro-OMe trifluoroacetate (1 equivalent) and TEA (2 equivalents) were used to obtain (c') oleoyl-Lys(Z)-Pro-OMe (SUAM 1197) as an oil, and (d) H-Glu(Bzl)-Pro-OMe trifluoroacetate (1 equivalent) and TEA (2-equivalents) were used to obtain (d') oleoyl-Glu(Bzl)-Pro-OMe (SUAM 1196) as an oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>C1COCC1>[CH2:1]([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)/C=C\C(=O)O

Procedure:
Allylamine reacts readily with maleic anhydride in THF to give N-allylmaleamic acid (VIII) in quantitative yield. VIII reacts with bisulfite in water to form 3-carboxy-3-sulfo-N-allyl propionamide (IX). At 160° C., (IX) cyclolyzes slowly to form N-allyl-sulfo-succinimide (X).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]([CH3:33])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: CNC
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 135 °C
Yield: 46 %

Procedure:
A mixture of 0.67 g (1 equivalent) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equivalent) of sodium iodide and 15 ml of 2M dimethylamine in tetrahydrofuran was heated at 135° C. for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated to give 0.50 g. The crude product was purified by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethylamine 6:4:0.1) to give 0.312 g (46%) of pure product. MP 218-219° C. mass spectrum (electrospray m/e): M+H=402.9.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][CH3:15])=[CH:3][CH:4]=1)([O-:23])=[O:22]
Reactant: CCCN1CCCC1Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCCN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Benzyl-1-propylpyrrolidine (0.90 g, 3.75 mmol) was dissolved in nitromethane (10 mL) and added to a mixture of concentrated H2SO4 (3.7 mL), concentrated nitric acid (0.3 mL) and water (0.6 mL) cooled to 5° C. After stirring for 2 h, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (0.95 g, 100%).