Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+].O>CO>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-iodo-3-nitrobenzoic acid (3 g, 10 mmol) in methanol (30 ml) cooled to 0° C., sulfuric acid (3.4 g, 34.6 mmol) is added slowly. The reaction mixture is warmed to room temperature and then refluxed (˜70° C.) for 8 hours. After cooling, the reaction mixture is neutralized with solid NaHCO3 and the salts are filtered. The filtrate is evaporated under reduced pressure. To the residue obtained, water (30 ml) is added and the mixture extracted with MTBE (30 ml×2). The combined organic phase is washed with brine, dried using anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, 4-iodo-3-nitro-benzoic acid methyl ester is obtained as a yellow solid (2.67 g, 85% yield, 98% HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:20])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: O=C=NC(=O)c1ccccc1
Product: N#Cc1ccccc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminobenzonitrile and benzoyl isocyanate as a white powder (661 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.29 (t, 1H), 7.52-7.56 (t, 1H), 7.64-7.74 (m, 2H), 7.82-7.85 (dd, 1H), 8.02-8.04 (m, 2H), 8.22-8.24 (d, 1H). MS 266 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:38]=[N+:39]=[N-])(=O)=O)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13](=[N+:38]=[N-:39])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To methyl 3,5-bis(trifluoromethyl)phenylacetate (43.5 g, 160 mmol), in dry acetonitrile (250 ml), cooled to -5° C., was added 2,4,6-triisopropylbenzenesulfonyl azide (52.7 g). To the resulting solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (25.5 ml), and the mixture was stirred at -5° C. for 1 hour. The mixture was warmed to room temperature, and then stirred for 0.5 hour. The solvents were evaporated at reduced pressure and the residue chromatographed on silica (eluent 5% ether/60-80 bp petrol), to afford the the title compound (45.6 g, 91%) as yellow prisms. I.R (film, NaCl) n 1740, 2140 cm-1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[CH3:10]C1NN=C(N)C=1>>[CH3:10][C:5]1[NH:1][N:2]=[C:3]([NH:6][C:7](=[O:9])[CH3:8])[CH:4]=1
Reactant: CC(=O)Nc1cc[nH]n1
Reactant: Cc1cc(N)n[nH]1
Product: CC(=O)Nc1cc(C)[nH]n1
Yield: 70.4 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 1, replacing 1H-pyrazol-3-amine with 5-methyl-1H-pyrazol-3-amine. (ALDRICH, 1.01 g, 7.25 mmol, 70.4% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.89 (s, 1H), 10.16 (s, 1H), 6.22 (s, 1H), 2.16 (s, 3H), 1.94 (s, 3H). [ES+MS] m/z 140 (MH+).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([NH:14][CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:16]1
Reactant: c1ccc(CN2CCC(CNC3CC3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CC(CNC2CC2)CN1
Yield: 76.1 %

Procedure:
A mixture of 13.6 g (59.0 mmol) of 1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine, 0.5 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 6.3 g of N-cyclopropyl-3-pyrrolidinemethanamine, bp 88-90°/13 mm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20](O)=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.C(Cl)CCl.[CH3:27][NH2:28].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][NH:28][C:20]([C:18]1[NH:19][C:15]2[N:14]=[CH:13][N:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)[CH:7]=3)[C:16]=2[CH:17]=1)=[O:21]
Reactant: O=C(O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Reactant: CN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
A solution of 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (60 mg, 0.2 mmol), EDC (44.6 mg, 0.97 mmol) and DMAP (7.1 mg, 0.06 mmol) in dry DMF (1.5 mL) was stirred at room temperature under nitrogen for 30 minutes. Methylamine (0.5 mL, 0.97 mmol, 2M solution in THF) was then added and the mixture was allowed to stir overnight at rt. After this time, water (5 mL) was added to the mixture which was extracted with DCM (3×15 mL) and the combined organic layers washed with a saturated aqueous sodium chloride (5×10 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo and the resulting crude material purified by preparative TLC (5% MeOH in CH2Cl2) to yield 2.7 mg (4.3%) of N-methyl-1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxamide EXAMPLE 6. 1H NMR (400 MHz, CDCl3): δ=7.95 (br s, 1H), 7.73-7.71 (m, 1H), 7.57-7.42 (m, 6H), 6.59 (br s, 1H), 3.02 (d, J=5.2 Hz, 3H). MS (ES+): m/z 323.31 (100) [MH+].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:21][CH:22]=[C:23]([F:25])[CH:24]=2)=[O:18])=[CH:11][CH:10]=1)(C)(C)C.[ClH:35]>CO>[ClH:35].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:18])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[N:21][C:20]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[4-({[5-Fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (1.62 g, 3.44 mmol) (see Preparation 5) was dissolved in a 2.25 M solution of hydrochloric acid in methanol (100 ml) and the mixture stirred at room temperature under an atmosphere of nitrogen for 4 hours before removing the solvent in vacuo. The residue was dissolved in water (50 ml), the pH adjusted to pH higher than 8 by addition of sodium hydrogen carbonate and extracted with dichloromethane (3-fold 50 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to give N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide hydrochloride (1.25 mg) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(OOC(C)(C)C)(C)(C)C>ClCCCl>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:15][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:21]=2[CH:22]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)OOC(C)(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(Br)cc12
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (130 g, 0.6 mol), 4-bromophenol (311 g, 1.8 mol) and FeCl3.6H2O (19.5 g, 0.09 mol) in DCE (700 mL) was heated to reflux, and then 2-(tert-butylperoxy)-2-methylpropane (193 g, 1.32 mol) was added dropwise under nitrogen. After 6 hours of refluxing, the mixture was cooled to RT, quenched with saturated NaHSO3 and extracted with dichloromethane. The organic phases were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether/dichloromethane=15/1) to provide the crude product, which was crystallized from cold MeOH to provide ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (37 g, yield: 14.3%) as solid. 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.97˜8.01 (m, 2H), 7.37 (d, J=4.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.11 (t, J=8.0 Hz, 2H), 4.32˜4.38 (m, 2H), 1.36 (t, J=8.0 Hz, 3H). MS (M+H)+: 363/365.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:24][C:22]([F:25])([F:23])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:18]([F:19])([F:21])[F:20]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([O:25][C:26](=[O:38])[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>>[CH2:31]([O:30][C:28](=[O:29])[CH:27]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
2-Chloro-1,5-dinitro-3-(trifluoromethyl)benzene was treated with malonic acid dibenzyl ester in the presence of sodium hydride to obtain [2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid dibenzyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitrobenzene (1.757 mL, 16.02 mmol) and 3,5-difluoroaniline (2.069 g, 16.02 mmol) to give N-(3,5-difluorophenyl)-5-fluoro-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1H, s), 8.23 (1H, dd, J=9.4, 6.1 Hz), 7.05-7.17 (3H, m), 6.99 (1H, tt, J=9.4, 2.3 Hz), 6.84-6.91 (1H, m); LC-MS (ESI) m/z 267.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 225. NMR (400 MHz CDCl3): 2.68 (4H, m, CH2), 2.81 (3H, s, CH3), 3.30 (4H, m, CH2), 3.85-3.88 (6H, m, CH2), 4.00-4.03 (4H, m, CH2), 4.06 (3H, s, CH3), 4.09 (3H, s, CH3), 7.33 (1H, s, ar), 8.93 (1H, s, ar). MH+=536.30
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([O:11][CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:3]([OH:22])=[O:2])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)OC(C(=O)O)c1ccccc1
Yield: 88.8 %

Procedure:
Methyl((((4-chlorophenyl)amino)carbonyl)oxy)(phenyl)acetate (0.73 g) obtained in Example 3a) and 1 N sodium hydroxide (3.0 ml) were dissolved in methanol (10 ml) and THF (10 ml), and then mixed at room temperature for 15 hours. The reaction solution was then concentrated under reduced pressure, acidified by adding 1 N hydrochloric acid to the concentrated solution, and then the precipitate was collected by filtration and washed with water to obtain the title compound as pale brown powder (0.62 g, 89%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH2:40])[C:33]=1[C:42]([OH:44])=[O:43])(=[O:29])[CH3:28]>O1CCCC1.O>[C:27]([O:30][CH2:31][C:32]1[CH2:39][S:38][CH:37]2[N:34]([C:35](=[O:41])[CH:36]2[NH:40][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:33]=1[C:42]([OH:44])=[O:43])(=[O:29])[CH3:28]
Reactant: O=C(O)CCCn1cccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCn3cccc3)C2SC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
4-(1-Pyrryl)butanoic acid (0.05 mole) is dissolved in 50 ml of tetrahydrofuran (THF) and 0.05 mole of triethylamine is added. This mixture is cooled to -10° C. and 0.05 mole of isobutylchloroformate is added. The mixture is stirred for 0.5 hours at -5° C. and then 0.05 mole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 0.075 mole of triethyl amine in 50 ml of THF (precooled) is added. The mixture is stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture is diluted with water and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. The ethyl acetate extracts are combined, dried, filtered, and the solvent evaporated to give the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:23]([O:30][C:31]([NH:33][C:34]1([C:37]([OH:39])=O)[CH2:36][CH2:35]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:40]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([N:47]([C:37]([C:34]1([NH:33][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:32])[CH2:35][CH2:36]1)=[O:39])[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.0 g, 110 mmol) and 1-hydroxybenzotriazole (2.70 g, 20 mmol) were added to a dichloromethane (235 ml) solution of 1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylic acid (23.5 g, 100 mmol) and ethyl N-benzylglycinate (19.3 g, 100 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure and then the residue was diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=2:1 (v/v)] to give the title compound (35.7 g, 87%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NC1CCCC1
Product: N#CC(=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 71 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in cyclopentylamine (2 ml) at 80° C. for 2 h and at room temperature for 16 h under nitrogen. Work up as descriped in Example 1, 2) gave 305 mg (71%) of the title compound as pale yellow crystals. Mp 199-200° C. 1H NMR (300 MHz, CDCl3): δ=1.4-1.65 (m, 4H), 1.65-1.85 (m, 4H), 3.56 (sextet, 1H), 7.42 (s, 2H), 7.49 (d, 2H), 7.67 (s, 1H), 7.78 (d, 2H); MA calc for C22H18ClF6N3O2S: C, 49.12%; N, 7.18%.; Found: C, 48.93%; H, 3.31%; N, 7.58%.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:27])[CH:7]([CH2:13][C@H:14]1[CH2:18][C@@H:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]=[CH:15]1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.[Cl-].[Na+].O>[CH2:3]([O:5][C:6](=[O:27])[CH:7]([CH2:13][C@H:14]1[CH2:18][C@@H:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]=[CH:15]1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of KOH (0.19 g; 3.4 mmol) in ethanol (6 mL) was added to a solution of 2-(Cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid diethyl ester (1.15 g; 3.2 mmol) in ethanol (6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, concentrated and ice-water (400 mL) was added. The aqueous phase was washed with diethyl ether (the emulsion formed during the extraction was treated with brine in order to get good phase separation), acidified to pH 3 with 0.5 M HCl, and extracted with diethyl ether. The organic phase was dried and concentrated under reduced pressure to afford 2-(cis4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid monoethyl ester (0.86 g, 81%) as white crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]([CH3:48])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[N:18]=[C:17]1SCC1C=CC(OC)=CC=1)=[O:15]>ClCCl.C(OCC)(=O)C>[CH3:48][N:13]([CH3:12])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[NH:18][C:17]1=[O:6])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CSC2=NC(C)=C(C(=O)OC(C)C)C(c3cccc([N+](=O)[O-])c3)N2C(=O)N(C)C)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (3 eq, 2.0 mmol, 349 mg) was added to a solution of (-)-3,4-dihydro-3-[(dimethylamino)carbonyl]-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester in dry dichloromethane (6.7 ml) at 0° C. under a nitrogen atmosphere. The reaction was stirred overnight at room temperature, and a precipitate formed. The mixture was diluted with ethyl acetate (15 ml) and washed with 1N hydrochloric acid (twice), 1N sodium hydroxide (twice) and water. The combined organic layers were dried over magnesium sulfate, filtered, and reduced in vacuo to afford an oil, 390 mg. Flash chromatography on 39 g silica gel (2:1:ethyl acetate:hexanes) afforded the product as an oil. The oil was allowed to stand under ether for a 48 hour period, and was then triturated to produce a white crystalline solid, 144 mg (55%), melting point 152°-153° C. [α]D =-128.6° (c=1.2, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[C:3]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][NH:12]1.Cl[CH:17]([CH3:21])[C:18](=O)[CH3:19]>COCCO>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[C:3]=1[N:10]1[C:11]2=[N:12][CH2:13][CH2:14][N:15]2[C:18]([CH3:19])=[C:17]1[CH3:21]
Reactant: CC(=O)C(C)Cl
Reactant: Cc1cc(Br)c(N=C2NCCN2)c(Br)c1
Solvent: COCCO
Product: CC1=C(C)N(c2c(Br)cc(C)cc2Br)C2=NCCN21

Procedure:
5.0 gm (0.015 mol) of 2-(2,6-dibromo-4-methyl-phenylimino)-imidazolidine were refluxed for about 30 hours with 1.8 gm (110%) of 96% 3-chloro-2-butanone in 25 ml of glycol monomethyl ether. The reaction mixture was then evaporated to dryness in vacuo, and the oily residue was dissolved in 1 N hydrochloric acid. The hydrochloric acid solution was adjusted to a pH value of 7 with dilute NaOH and, starting from the pH value, was fractionally extracted with ether at increasing pH values (NaOH). The ether extracts which were uniform according to thin-layer chromatography were combined, dried over magnesium sulfate, and the ether was eliminated in vacuo. The residual oil crystallized out after a short time. Yield: 0.4 gm of the compound of the formula ##STR10## corresponding to 7% of theory. Melting point: 154°-156° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:21](=[O:22])[C:20]([CH3:24])=[CH2:19])[C:5]=2[CH:4]=1
Reactant: C=C(C)C(=O)Cl
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)N1c2ccccc2Sc2ccc(C(F)(F)F)cc21
Yield: 53.1 %

Procedure:
27 g of 2-trifluoromethyl-phenothiazine and 12 g of α-methylacryloyl chloride in 100 ml of toluene were 1 for 2 hours and the mixture was evaporated to dryness. The residue was chromatographed over silica gel and elution with a 1-- 1 benzene-cyclohexane mixture gave 18 g of 2-trifluoromethyl-10-(α-methyl acryloyl)-phenothiazine in the form of white crystals melting at 103°C.