Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:20][CH2:21][CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH3:31])=[CH:27][CH2:26]1)[CH3:24])(=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>C(Cl)Cl>[C:12]([O:20][CH2:21][CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]2([O:9][CH:27]2[CH2:26]1)[CH3:31])[CH3:24])(=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCC(=O)OCCC(C)C1CC=C(C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CCC(=O)OCCC(C)C1CCC2(C)OC2C1
Reaction time: 8 h

Procedure:
An 8.2g (0.04 mole) portion of 85% m-chloroperbenzoic acid was added portionwise over 15 min. to a stirred, cooled (0° C.) solution of 11.3g (0.04 mole) of succinic acid, 3-(4-methyl-3-cyclohexenyl)butyl methyl ester in 250 ml of methylene chloride. The temperature rose to 10° C. during the addition and to ambient after the cooling bath was removed. The reaction mixture was stirred overnight. Sufficient 5% sodium hydroxide was added to dissolve the precipitated acid, and the organic layer was separated, washed with 5% sodium hydroxide and with brine, dried over magnesium sulfate and concentrated. Obtained was 10.6g of succinic acid 3-(3,4-epoxy-4-methylcyclohexyl) butyl methyl ester as a clear, colorless liquid. The analytical determinations indicated that the product was pure and did not require further purification (See Table I).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:20][CH3:21])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[CH:11]1[CH2:19][CH:8]2[CH:9]=[CH:10]1)=[O:4].[OH-].[Na+]>CO>[CH3:21][O:20][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:14]([O:15][CH3:16])[C:13]([O:17][CH3:18])=[C:12]2[C:7]=1[CH:8]1[CH2:19][CH:11]2[CH:10]=[CH:9]1
Reactant: COC(=O)c1c(OC)c(OC)c2c(c1OC)C1C=CC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(OC)c2c(c(OC)c1C(=O)O)C1C=CC2C1
Yield: 100.1 %

Procedure:
To a solution of 14 (0.591 g, 2.05 mmol) in methanol (50 mL) was added a 4 N NaOH solution (50 mL), and the resulting reaction mixture was heated at reflux for 5 h. Methanol was removed under reduced pressure and a 3 N HCl solution was added to achieve pH 1. The reaction mixture was extracted three times with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to yield 0.567 g of 15 as a brown oil in nearly quantitative yield. 1H NMR (300 MHz, CDCl3): δ=2.18-2.27 (m, 2H, CH2), 3.86 (s, 3H, O—CH3), 3.89 (s, 3H, O—CH3), 3.92 (s, 3H, O—CH3), 4.19-4.22 (m, 2H, CH—CH(C)—CH2), 6.78-6.86 (m, 2H, HC═CH); 13C NMR (75 MHz, CDCl3): δ=47.6 (CH—CH(C)—CH2), 47.9 (CH—CH(C)—CH2), 61.6 (CH3), 62.1 (CH3), 62.5 (CH3), 68.5 (CH2), 117.9, 137.8, 142.4 (HC═CH), 142.9 (HC═CH), 144.2, 147.2, 147.6, 148.6, 170.6; ESI-MS calcd for C15H16O5 [M−H]−: 275.0920. found 275.0910.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].O=P(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:12])=[C:4]([CH:3]=1)[C:9]#[N:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc(Br)c[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cnc1Cl
Temperature: 25 °C

Procedure:
5-Bromo-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (33 g, 166 mmol) was added to a suspension of PCl5 (96.6 g, 464 mmol) in POCl3 (20 ml, 216 mmol). The mixture was stirred at reflux for 3 hours, cooled to room temperature and then poured slowly into ice/water. The resulting solid was fitered, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH:28]6[CH2:29][CH2:30][CH2:31][O:27]6)[CH:37]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cnn(CC3CCCO3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC4CCCO4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydrofuran-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.8 mg). LCMS (M+H)+: m/z=489.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]2[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 275.3 %

Procedure:
To a solution (100 ml) of ethyl 4-benzyloxy-1H-indole-2-carboxylate (12.0 g) in DMF was added sodium hydride (1.6 g) and the mixture was stirred at room temperature for 10 min. To this reaction mixture was added methyl iodide (2.2 g) and the mixture was stirred for one more hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13.2 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][C@H:5]([C:9]([N:11]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:60])[NH:39][C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[C:42]([O:55][C:56]([F:59])([F:58])[F:57])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:33]([O:37][C:38](=[O:60])[NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([C@@H:19]4[CH2:18][C:13]5([O:17][CH2:16][CH2:15][O:14]5)[CH2:12][N:11]4[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:32])[CH:6]([CH3:8])[CH3:7])[NH:21][CH:22]=3)=[CH:26][CH:27]=2)=[C:42]([O:55][C:56]([F:58])([F:59])[F:57])[CH:41]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(Br)cc3)c[nH]1)OCCO2)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(OC(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(-c4ccc(NC(=O)OC(C)(C)C)cc4OC(F)(F)F)cc3)c[nH]1)OCCO2)C(C)C
Yield: 133.9 %

Procedure:
To a solution of ((S)-1-{(S)-8-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (350 mg, 0.69 mmol) in dioxane (8 mL) and water (4 mL) was added [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethoxy-phenyl]-carbamic acid tert-butyl ester (334 mg, 0.83 mmol), sodium carbonate (148 mg, 1.4 mmol), and tetrakis(triphenylphosphine)-palladium(0) (81 mg, 0.07 mmol). The reaction mixture was stirred at reflux for 3 h under nitrogen. Ethyl acetate (50 mL) was added and the solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a yellow solid (650 mg). (m/z): [M+H]+ calcd for C34H49N5O8 704.28. found 704.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]4([CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[NH:15][CH2:14][C:13]4([CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 6′-morpholino-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-carboxylate (5.8 g, 15.45 mmol) in DCM (30 mL) was added TFA (23.80 mL, 309 mmol) and the reaction was stirred at rt for 3 h. After this time the reaction was evaporated under reduced pressure and dried under vacuum overnight. After this time the reaction was partitioned between EtOAc (80 mL) and 1.0M aqueous HCl (200 mL). The separated aqueous layer was washed with EtOAc (40 mL). The aqueous layer was then basified to pH 14 with aqueous NaOH and extracted with EtOAc (2×200 mL) and DCM (100 mL). The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] as a white solid. Mass Spectrum (ESI) m/e=276.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=S.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:10]1[S:9][CH2:15][C:13](=[O:14])[N:12]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccsc1CN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 3-methyl-thiophen-2-ylmethylamine (700 mg, 5.5 mmol) and rhodanine (732 mg, 5.5 mmol) in acetonitrile (30 mL) was added diisopropylethylamine (DIEA) (1.91 mL, 11 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.52 g, 5.6 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (200 mL) and ethyl acetate (250 mL). The filtrates were removed under the vacuum and the crude residue was dissolved in dichloromethane (150 mL) and washed with water and brine solution. After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in dichloromethane (10 mL) and diluted with hexanes (10 mL). After overnight storage in the refrigerator, the solids were collected by filtration and washed with dichloromethane. After drying in air, 390 mg (31.5% yield) of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one was isolated as a light yellow amorphous solid: EI-HRMS m/e calcd for C9H10N2OS2 (M+) 226.0235, found 226.0232.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S([O-])([O-])=O.[Ca+2:9].S([O-])([O-])(=O)=O.[Ca+2].[OH-].[Ca+2].[OH-]>>[N+:1]([O-:4])([O-:3])=[O:2].[Ca+2:9].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Ca+2]
Product: O=[N+]([O-])[O-]

Procedure:
In a second embodiment of the present invention, no wet scrubbing of the sulfur dioxide from the combustion gas stream is effected but rather removal of sulfur dioxide by dry calcium hydroxide injection is carried out, and the combustion gas stream substantially humidified prior to such treatment. As illustrated in FIG. 2, a combustion gas stream, containing sulfur dioxide and nitrogen oxides, is passed through a line 20 while water is injected into the gas stream through line 21 to substantially completely humidify the gas stream. Dry calcium hydroxide is then charged to the humidified gas stream in line 20 through line 22 from a source 23. The injected calcium hydroxide will react with sulfur dioxide present in the humidified gas stream to form calcium sulfite and/or calcium sulfate. The humidified combustion gas stream is then passed to a coronal discharge unit 24 where NOx present therein is converted to nitric acid. The combustion gas stream is discharged from the coronal discharge unit, as hereinbefore described, through line 25 and now contains calcium sulfite and/or calcium sulfate, as well as nitric acid. Additional dry calcium hydroxide is fed to line 25 from a source 26 through line 27, which additional calcium hydroxide reacts with nitric acid present in the combustion gas stream to form calcium nitrate. The combustion gas stream is then fed to a dry filtering device, such as a baghouse filter unit 26. In the baghouse filter unit 26, a mixture of calcium sulfite and/or calcium sulfate with calcium nitrate, and residual calcium hydroxide, is separated and discharged through line 29 to a collection device 30, while the combustion gas with sulfur dioxide and nitrogen oxides removed therefrom is discharged to the atmosphere through line 31. In order to maximize the use of the calcium hydroxide, a portion of the material from the collection device 30 may be returned to the dry calcium hydroxide sources 23 and 26 through lines 32 and 33 respectively.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([Cl:22])[N:16]=[C:15]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([O:35]CC)=[O:34]>O.C(O)C>[Br:3][C:4]1[C:8]2[CH:9]=[C:10]([CH2:13][N:14]3[C:18]([C:19]([OH:21])=[O:20])=[C:17]([Cl:22])[N:16]=[C:15]3[CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1

Procedure:
Sodium hydroxide (89 mg) in water (0.2 ml) was added to a suspension of the product of Example 51 (0.5 g) in ethanol (5 ml). The solution was heated under reflux for 16 h, cooled, then evaporated in vacuo. The residue was dissolved in water (5 ml), and HCl (2N; 1 ml) was added dropwise resulting in the precipitation of the title compound which was filtered off, washed with water (2×5 ml) and dried to give the title compound as a colourless solid (391 mg). m.p. 148°-152° C.
Reaction SMILES: [H-].[Na+].[C:3]1(C)[C:4]([S:9]([NH:12][CH2:13][CH2:14]OS(C2C(C)=CC=CC=2)(=O)=O)(=[O:11])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:27]COCC>O1CCCC1>[CH3:27][C:7]1[CH:8]=[CH:3][C:4]([S:9]([N:12]2[CH2:13][CH2:14]2)(=[O:10])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: Cc1ccccc1S(=O)(=O)NCCOS(=O)(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
118 mg (3 mmol) of sodium hydride (55 percent in oil) was placed in 3 ml of tetrahydrofuran and cooled to 0° C. 1 g (2.7 mmol) of N,O-bis-(toluenesulfonyl)-ethanolamine in 2 ml of tetrahydrofuran was added in 7 minutes (generation of gas). The reaction mixture was warmed to room temperature. Then 2 ml of ether was added and it was stirred for 50 minutes at room temperature.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[K+]>C(O)(C)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 105.3 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and tert-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 26% aqueous solution of potassium hydroxide (4.3 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 11.8 g of p-cyanobenzamide (yield 81%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[F:6][C@@H:7]([CH3:11])[C:8](O)=O.O=P(Cl)(Cl)Cl>O1CCOCC1>[F:6][C@H:7]([C:11]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1)[CH3:8]
Reactant: C[C@H](F)C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C[C@H](F)c1nnc(N)s1
Temperature: 0 °C
Yield: 70.4 %

Procedure:
A 350 mL sealable pressure vessel was charged with thiosemicarbazide (11.17 g, 122.5 mmol) and dry dioxane (100 mL), and the mixture was cooled at 0° C. under an N2 atmosphere. To this rapidly stirring mixture was slowly added a solution of (S)-2-fluoropropanoic acid (9.40 g, 102.1 mmol, from Fritz-Langhals, E., Tetrahedron Asymmetry, 981 (1994)) in dioxane (10 mL). To the resulting mixture was added POCl3 (11.22 mL, 122.5 mmol) dropwise, then the cooling bath was removed and the thick white slurry was stirred at room temperature for 1 h. The vessel was then sealed and the mixture was heated at 90-95° C. (oil bath temperature) for 5 h. The cooled mixture was stirred at room temperature for 14 h (Note: this was for convenience only and is optional) and then the supernatant (two-phase mixture) was decanted and concentrated under reduced pressure. The lower phase was slowly poured into ice water (250 mL) and then the concentrate was also added. This mixture was rapidly stirred until it was essentially a homogeneous (turbid) solution, and then it was basified to pH 9-9.5 using 40% aqueous NaOH. The resulting slurry was filtered and the filter-cake was washed with water (Note: LC of this beige solid showed that it contained only a trace of the desired product, so it was not further investigated). The combined filtrate was then extracted with EtOAc (×3) and the organic phase was dried (Na2SO4) and evaporated to give a cream solid (10.58 g, 70%) which was the essentially pure product according to LC and LCMS. This material was used as such without further purification. An analytical sample was purified by flash chromatography [Isco/0-20% (MeOH—NH4OH, 9:1)-DCM] to give a white solid. LC (Method B): 0.608 min. MS (ESI) calcd. for C4H6FN3S m/z: 147.03. found: 148.05 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.38 (s, 2H), 5.82 (dq, J=6.4, 48.0 Hz, 1H), 1.65 (dd, J=6.4, 24.0 Hz, 3H). Chiral LC: S:R=95:5.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[F:8][C:9]1[CH:10]=C2[C:15](=[CH:16][CH:17]=1)[NH:14]C(=O)C2=O>[O-2].[Cr+6].[O-2].[O-2].C(O)(=O)C>[F:8][C:9]1[CH:10]=[C:6]2[C:5]([O:4][C:1](=[O:3])[NH:14][C:15]2=[CH:16][CH:17]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
Acetic anhydride (90.0 mL), 5-fluoroisatin (20.62 g, 0.125 mmol, 1.00 eq), and acetic acid (90 mL) were added to a 250 mL, three neck flask fitted with a magnetic stir bar and a condenser. The flask was placed in a water bath and heated to 85° C. Chromium (VI) oxide (20.36 g, 0.204 mol, 1.63 eq) was added in small portions (0.5 g size) over 40 min to the red solution. The reaction mixture was stirred for an additional 15 min and cooled to 10° C. in an ice bath. The solid that formed was isolated by filtration. Washing with 400 mL of water removed most of the green color. The solid was taken up in 300 mL of 2:1 acetic acid/water, refiltered, and dried overnight in a 50° C. vacuum oven. The 5-fluoroisatoic anhydride was isolated as a bright yellow solid (14.45 g, 64%). ##STR5##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([CH3:13])=[N:10][C:11]=1[Cl:12])[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([Cl:12])=[N:10][C:9]([CH3:13])=[N:8][C:7]=1[NH:19][C:18]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=1[CH3:16])[CH3:2]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCOC(=O)Cc1c(Cl)nc(C)nc1Cl
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(Cl)nc(C)nc1Nc1c(C)cc(C)cc1C
Yield: 52.1 %

Procedure:
A mixture of (2-methyl-4,6-dichloro-pyrimidine-5-yl)-acetic acid ethyl ester (1.470 g, 5.9 mmol) and 2,4,6-trimethylaniline (2.56 ml, 17.7 mmol), in 15 ml of dimethylsulfoxide was heated at 120° C. overnight and 138° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a brown oil. The oil was purified through silica gel column chromatography to give 1.070 g (52%) of the title compound as a tan solid. 1H NMR (CDCl3) δ 1.30 (t, 3H), 2.14 (s, 6H), 2.32 (s, 3H), 2.37 (s, 3H), 3.79 (s, 2H), 4.23 (q, 2H), 7.00 (s, 2H), 7.02 (s, 1H) ppm.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>CO>[OH:13][CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]1[CH3:3]
Reactant: CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)c2ccccc2C1O
Temperature: 0 °C
Yield: 32.5 %

Procedure:
NaBH4 (566 mg, 14.91 mmol) was added to a stirring solution of 2-methyl-isoindole-1,3-dione (2.0 g, 12.42 mmol) in methanol (20 mL) at 0° C. Stirring at 0° C. was maintained for 1 hour, then the reaction was warmed to room temperature. Additional NaBH4 (566 mg, 14.91 mmol) was added in order to push the reaction to completion. The reaction was then quenched with acetic acid (5 mL) and partitioned between water and dichloromethane. The organic layer was washed several times with water and concentrated under vacuum to give 659 mg of the sub-title compound as a white solid. MS: ESI (positive): 164 (M+H).
Reaction SMILES: [Br:1]Br.[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH3:12])=[CH:6][C:5]=2[O:4]1.N1C=CC=CC=1>ClCCl>[Br:1][C:8]1[CH:9]=[C:10]2[O:11][CH2:3][O:4][C:5]2=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1ccc2c(c1)OCO2
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
3.2 ml (62 mmol) of bromine was dropwise added at 0° C. to a solution having 7.0 ml (58 mmol) of 3,4-(methylenedioxy)toluene and 5.5 ml (68 mmol) of pyridine dissolved in 110 ml of dichloromethane, followed by stirring for 30 minutes, and the temperature was raised to room temperature, followed by stirring for 22 hours. The mixture was washed with an aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 13 g (yield 99%) of 2-bromo-4,5-(methylenedioxy)toluene.