Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C
Yield: 61 %

Procedure:
To a stirred solution of tert-butyl 4-((5-chloro-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (4 g, 9.09 mmol) in acetonitrile (50 mL), cesium carbonate (5.9 g, 18.09 mmol) and methyl iodide (6.95 g, 48.94 mmol) were added; resulting reaction mass was heated at 80° C. for 12 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (2.2 g, 53%).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2].[O:24]=O>>[C:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])([OH:24])=[O:2].[CH:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:6][CH3:7])=[O:5])=[O:2]
Reactant: O=O
Agent: CCCCCCCCCCCCCCCCC(C=O)C(=O)OC
Product: CCCCCCCCCCCCCCCCC(C(=O)O)C(=O)OC

Procedure:
Friedrich in an article entitled "Oxidation of Methyl Formylstearate with Molecular Oxygen" at J. Am. Oil Chemists' Soc. 53, p. 125-129 (1976) reports the use of air or oxygen to form methyl carboxystearate from methyl formylstearate in an emulsion with a soluble rhodium complex. The reuse of catalyst in hydroformylation reactions is described by Awl in an article entitled "Hydroformylation with Recycled Rhodium Catalyst and One-Step Esterification-Acetalation: A Process for Methyl 9(10)-Methoxymethylenestearate from Olefic Acid" which is printed in J. Am. Oil Chemists' Soc. 53, p. 190-195 (1976).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][C:15](OC)=[O:16])[CH:9]=1.O>O1CCCC1>[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=1
Reactant: COC(=O)CCc1cc(C)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCCO)no1
Yield: 81.4 %

Procedure:
To a suspension of 7.6 g of lithium aluminum hydride in 250 ml of tetrahydrofuran was added a solution of 64.9 g of methyl 5-methyl-3-isoxazolepropanoate in 100 ml of tetrahydrofuran. The reaction mixture was stirred at reflux for three hours, then cooled and 15.2 ml of water in 30 ml of tetrahydrofuran added. The mixture was filtered and the filtrate concentrated in vacuo. The residue was distilled to give 44.1 g of 5-methyl-3-(3-hydroxypropyl)isoxazole, b.p. 84°-85° C. (0.1 mm).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:16]=O.C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:16]#[N:28]
Reactant: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1ncnc2cc(O)c(C#N)cc12
Temperature: 130 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde (310 mg, 1.34 mmol) is presented as an initial charge in acetic acid (7 mL, 81 mmol) and admixed with sodium acetate (366 mg, 3.3 mmol) and also hydroxylamine hydrochloride (186 mg, 2.68 mmol). The batch is stirred at 130° C. for 18 hours. After cooling to room temperature, the batch is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) of the residue gives the desired product in 38% yield (116 mg).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]C(=O)C)=[CH:7][CH:6]=1)(=O)C.C(O)(=[O:24])C.OO.[OH-:28].[Na+]>C(O)C.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:24])=[O:28])=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: [OH-]
Reactant: CC(=O)Nc1ccc(SCCCCCCOC(C)=O)cc1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)CCCCCCO)cc1
Yield: 61 %

Procedure:
A mixture of 145 g (0.47 mol) of (4-acetamidophenyl)-(6-acetoxyhexyl)sulfide and 600 mL of glacial acetic acid was heated at reflux with stirring, and 140 g (1.2 mol) of 30% hydrogen peroxide was added in small portions over 3 hours. The reaction mixture was poured on ice, and an oil separated. The mixture was extracted with dichloromethane and the extract was washed with water. The organic layer was dried (MgSO4) and the solvent was removed at reduced pressure to leave a tan oil. The oil was dissolved in a mixture of 100 g of sodium hydroxide, 260 mL of ethanol, and 140 mL of water, and refluxed with stirring for 16 hours. The product was extracted with ethyl ether and the extract was dried (MgSO4) and concentrated. A waxy solid was obtained which was recrystallized from 60% ethanol/40% water at -20° C. to provide 74 g (61%) of a tan solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.CO>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 58.5 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g), conc.hydrochloric acid (0.3 ml), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:27])([CH2:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:15]([OH:17])=[O:16].N1C=CC=CC=1.CCOCC>C1COCC1>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:14]([C:15]([OH:17])=[O:16])([CH3:27])[CH3:13])=[CH:21][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(CSc1ccc(O)cc1)C(=O)O
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C(=O)Oc1ccc(SCC(C)(C)C(=O)O)cc1)c1ccccc1
Reaction time: 144 h
Yield: 87.7 %

Procedure:
A solution of 2-phenylbutyryl chloride (1.19 g, 6.5 mmol) in 5 mL of THF was added to a stirred solution of 2,2-dimethyl-3-(4'-hydroxyphenylthio)-propionic acid (1.36 g, 6.0 mmol) and pyridine (1.03 g, 13.0 mmol) in 10 mL of THF under N2. After 6 days, 30 mL of ether was added and the reaction mixture filtered into a separatory funnel. The organic layer was washed with 0.5N HCl (2×15 mL), saturated NaCl (15 mL), 1:9 saturated NaHCO3 /H2O (2×15 mL), saturated NaCl (15 mL) and dried over anhydrous MgSO4. Filtration and evaporation provided 1.96 g (88%) of the desired ester. 1H NMR (CDCl3) δ0.974 (t, 3H, J=7.2 Hz), 1.27 (s, 6H), 1.82-1.96 (m, 1H), 2.13-2.28 (m, 1H), 3.13 (s, 2H), 3.67 (t, 1H, J=7.5 Hz), 6.90 (d, 2H, J=8.7 Hz), 7.30-7.38 (ArH, 7H), 11.9 (br s, --OH); 13C NMR (CDCl3) δ11.84, 24.30, 26.45, 43.73, 44.95, 53.27, 122.06, 127.58, 128.01, 128.88, 131.66, 134.27, 138.58, 149.65, 172.75, 183.22.
Reaction SMILES: S(=O)(=O)(O)O.[C:6](S)(=S)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)O.CC1C=CC2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:31])C=2C=1.CC1C=CC2C(=O)C3C(SC=2C=1)=CC=CC=3>O.C1(C)C=CC=CC=1>[CH3:6][C:7]1[C:8]2[C:20](=[O:31])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:27][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1C(=S)S
Reactant: Cc1ccc2sc3ccccc3c(=O)c2c1
Agent: Cc1ccc2c(=O)c3ccccc3sc2c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into an Erlenmeyer flask was charged 139 g of sulfuric acid, and 10 g of dithiosalicylic acid (Wako Pure Chemical Industries, Ltd.) was added thereto. After stirring at room temperature (about 25° C.) for 1 hour and then cooling in an ice bath, a cooled solution was obtained. Subsequently, 25 g of toluene was dropped slowly while the temperature of the cooled solution was kept at 20° C. or lower, and then the temperature was returned to room temperature (about 25° C.) and stirring was continued for additional 2 hours, so that a reaction liquid was obtained. While 815 g of water contained in a beaker was being stirred, the reaction liquid was added thereto slowly, and then a precipitated yellow solid was collected by filtration. The yellow solid was dissolved in 260 g of dichloromethane and 150 g of water was added. Moreover, 6.7 g of 24% aqueous KOH solution was added to make the aqueous layer alkaline, followed by stirring for 1 hour. Then the aqueous layer was removed by a separatory operation and the organic layer was washed with 130 g of water three times. Subsequently, the organic layer was dried over anhydrous sodium sulfate and then the solvent (dichloromethane) was distilled away, so that 8.7 g of intermediate (10) (yellow solid) was obtained. As a result of an analysis by 1H-NMR {300 MHz, DMSO-d6, δ (ppm): 8.4 (d, 1H), 8.2 (s, 1H), 7.8-7.7 (m, 2H), 7.7-7.5 (m, 3H), 2.4 (s, 3H)}, it was confirmed that intermediate (10) was a mixture (molar ratio 2:1) of 2-methylthioxanthone and 3-methylthioxanthone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[NH:39][C:38](=[O:41])[N:37]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH2:36]2>O1CCCC1>[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[NH:39][C:38](=[O:41])[N:37]([CH:42]1[CH2:47][CH2:46][N:45]([C:18]([NH:16][CH:4]([CH2:5][C:6]3[CH:7]=[C:8]4[C:12](=[C:13]([CH3:15])[CH:14]=3)[NH:11][N:10]=[CH:9]4)[C:3]([O:2][CH3:1])=[O:17])=[O:19])[CH2:44][CH2:43]1)[CH2:36]2
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C(N)Cc1cc(C)c2[nH]ncc2c1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Temperature: 0 °C

Procedure:
A stirred solution of 2-amino-3-(7-methyl-1H-indazol-5-yl)-propionic acid methyl ester (0.36 g, 1.54 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with carbonyl diimidazole (0.20, 1.1 equiv). The reaction was stirred for min at 0° C., warmed to room temperature, stirred 10 min, and treated with 8-fluoro-3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one (0.38 g, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 0.41 g (53%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.53-1.68 (m, 4H), 2.48 (s, 3H), 2.82 (m, 2H), 3.05 (m, 6H), 3.09 (dd, JAB=13.7, 6.1, 1H), 3.14 (dd, JAB=140.0, 6.1, 1H), 3.35 (bs, 1H), 3.68 (s, 3H), 3.88-4.02 (m, 2H), 4.22 (d, JAB=15.6, 1H), 4.25 (d, JAB=15.3, 1H), 4.44 (m, 1H), 4.71 (dd, J=6.1, 6.1, 1H), 6.78 (d, J=7.3, 1H), 6.84 (ddd, J=7.6, 7.6, 4.9, 1H), 6.88-6.95 (m, 2H), 7.28 (s, 1H), 7.91 (s, 1H). Mass spec.: 509.25 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([NH2:51])([CH3:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].CCN(CC)CC.[C:60](Cl)(=[O:62])[CH3:61]>C(Cl)Cl.O>[CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@@H:16]([CH2:47][C:48]([NH:51][C:60](=[O:62])[CH3:61])([CH3:49])[CH3:50])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)N)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)NC(C)=O)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
To a solution of 1.0 mmol of 2-[(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1,1-dimethyl-ethylamine, 3.0 mmol of Et3N in 10 ml of CH2Cl2 are added 1.5 mmol of acetyl chloride at 0° C. and the resulting mixture is stirred for 1 h. The reaction mixture is diluted with water and extracted with CH2Cl2. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on its Rf value.
Reaction SMILES: [N:1]1[C:2](=O)[NH:3][CH:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6]2.O(Cl)[Cl:17].[P+3]>>[Cl:17][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[N:1]=1
Reactant: ClOCl
Reactant: O=c1nc2c(c[nH]1)CCc1ccccc1-2
Agent: [P+3]
Product: Clc1ncc2c(n1)-c1ccccc1CC2

Procedure:
5,6-Dihydrobenzo[h]quinazolin-2(3H)-one (2.97 g) was heated at 100° C. in phosphorus (III) oxychloride (70 mL) for 2 h. The solvent was removed under vacuum and the residue was treated with ice, followed by 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with a mixture of ether and ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro-5,6-dihydrobenzo[h]quinazoline as a yellow solid; 1H NMR (CDCl3/MeOD4, 300 MHz) 8.86 (s, 1H), 8.16 (m, 1H), 7.25-7.35 (m, 2H), 7.15 (m, 1H), 2.85 (m, 4H) ppm; 13C NMR (CDCl3/MeOD4, 75 MHz) 162.83, 159.45, 157.40, 139.60, 132.35, 130.99, 128.38, 127.61, 127.20, 126.14, 27.39, 24.11; MS (ES) 217/219 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:17])=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:17][CH3:18])=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(S)c(C(F)(F)F)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cc2c(cc1C(F)(F)F)N(C(C)=O)CC2
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of the thiol (D5) (26 g, 99 mmol), anhydrous K2CO3 (15.12 g, 109 mmol) and iodomethane (18.6 ml, 300 mmol) in dry DMF (100 ml) was heated at 80° C. for 1 h. The reaction mixture was cooled, evaporated in vacuo and partitioned between water (200 ml) and dichloromethane (3×200 ml). The combined organics were washed with water (400 ml), dried (Na2SO4) and evaporated to yield the title compound (26.3 g, 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@@H:16]([OH:18])[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@H:16]([O:18][C:43]4[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=4)[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1[C@@H]2C[C@H](Oc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 6.6 %

Procedure:
To a solution of (7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (0.5 g) (1.67 mmol) (Preparation 2), Ph3P (0.44 g) (1eq.) and 4-bromophenol (0.29 g) (1 eq.) in 5 mL of dry THF at 0° C. was added DIAD (0.337 g) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. After evaporating the solvent, the residue was dissolved in DCM, washed with NaHCO3 solution, water, dried over MgSO4, and the solvent was evaporated under reduced pressure, to afford after SiO2 chromatography (eluent: DCM) the titled compound as a white solid (50 mg). Mp=116° C. NMR (DMSO, 200 MHz): 7.75 (1H, m), 7.5-7.4 (4H, d+d), 6.85 (2H, d), 5.1 (1H, m), 4.6 (1H, dd), 3.95 (1H, dd), 3.35 (1H, dd), 2.7-2.5 (1H, m), 2.25 (1H, bd).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>>[ClH:1].[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Product: Cl
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Yield: 53 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-nitroquinazoline was reacted with 5-aminoindole to give 4-(5-indolylamino)-6-nitroquinazoline hydrochloride in 53% yield, m.p. 300° C.;
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.[CH2:13]([I:15])[CH3:14]>>[I-:15].[CH2:13]([N+:8]1([CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:14]
Reactant: CCI
Reactant: CC1CCCC(N2CCCC2)C1
Product: CC[N+]1(C2CCCC(C)C2)CCCC1
Product: [I-]
Yield: 85 %

Procedure:
N-(3-methylcyclohexyl)pyrrolidine prepared in example 2 above was quaternized with ethyl iodide in a similar fashion to the procedure described in example 6 with the exception of using ethyl iodide in place of methyl iodide. The quaternization afforded the desired N-ethyl-N-(3-methylcyclohexyl)pyrrolidinium iodide in 85% yield. The resulting N-ethyl-N-(3-methylcyclohexyl)pyrrolidinium iodide salt was exchanged with Bio-Rad AG 1-X8 ion-exchange resin as described in example 4 to give N-methyl-N-(3-methylcyclohexyl)pyrrolidinium hydroxide in 88% yield (by titration).
Reaction SMILES: [F:1][S:2]([C:5]([F:10])([F:9])[C:6](F)=[O:7])(=[O:4])=[O:3].[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)=[CH2:12].N1C=CC=CC=1.Cl>C(Cl)Cl>[F:9][C:5]([F:10])([S:2]([F:1])(=[O:4])=[O:3])[C:6](=[O:7])[NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=1
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Reactant: C=Cc1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(NC(=O)C(F)(F)S(=O)(=O)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A 100 ml flask was charged with CH2Cl2 (24 ml) under nitrogen stream and stirred for 10 min at 0° C. and then 2-(fluorosulfonyl)difluoroacetyl fluoride (6.60 g, 37.6 mmol, 1.5 eq.) was added. After 20 minutes, the CH2Cl2 (12 ml) solution of 4-vinyl aniline (2.86 g, 24.4 mmol, 1.0 eq.) and pyridine (1.93 g, 24.4 mmol, 1.0 eq.) was added dropwise to the mixture over 10 minutes. The mixture was allowed to warm to RT and was stirred for 4 hours at RT. 1N HCl was added to the final reaction mixture and the lower layer was separated and washed with 1N HCl and brine. The solution was dried over MgSO4, filtrated and then CH2Cl2 was removed by an evaporator. The target compound was obtained as a white solid (6.57 g) in 96% yield. 1H NMR (400 MHz, CDCl3); delta=5.28 (d, J=10.9 Hz, 1H), 5.74 (d, J=17.6 Hz, 1H), 6.68 (dd, J=10.9, 17.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 8.04 (brs, 1H). 19F-NMR (376 MHz, CDCl3, C6F6 as standard) delta=41.27 (t, J=4.6 Hz, 1F), −105.26 (d, J=4.2 Hz, 2F).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([NH:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:43])[CH3:37])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: CN(C)CCCN
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1
Product: CN(C)CCCNc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)ccc2Cl)c1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 23 which is concerned with the preparation of starting materials, 4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with 3-dimethylaminopropylamine to give the title compound in 76% yield; NMR Spectrum: (DMSOd6) 1.62-1.74 (m, 2H), 2.12 (s, 6H), 2.27 (t, 2H), 3.08-3.13 (m, 4H), 3.18-3.22 (m, 2H), 3.69-3.74 (m, 4H), 6.58 (d, 1H), 6.67 (m, 2H), 7.15-7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H), 7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 599.