Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[C:9]#[CH:10])=[CH:4][CH:3]=1.[N:18]([CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[N+:19]=[N-:20].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O.C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:9]2[N:20]=[N:19][N:18]([CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)[NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)S(=O)N[C@@H](c1ccc(Br)cc1)c1cn(C[Si](C)(C)C)nn1
Reaction time: 24 h

Procedure:
To a solution of 1.5 g (4.8 mmol) N-[(1R)-1-(4-bromophenyl)prop-2-ynyl]-2-methylpropane-2-sulfinamide in 10 mL water and 10 mL t-butanol was added 0.62 g (azidomethyl)(trimethyl)silane, 0.48 mL (0.48 mmol) 1.0M aqueous ascorbic acid solution, and 0.05 mL (0.05 mmol) 1.0M solution of aqueous copper (II) sulfate pentahydrate. After 24 h at room temperature, the reaction mixture was quenched with water, extracted three times with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 25-100% EtOAc:hexane) afforded N-((S)-(4-bromophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.51-7.47 (m, 2H); 7.35-7.30 (m, 2H); 7.06 (s, 1H); 5.68 (d, 1H, J=2.65 Hz); 4.58 (d, 1H, J=2.48 Hz); 3.81 (d, 2H, J=3.84 Hz); 1.24 (s, 9H); 0.12 (s, 9H). ES-MS [M+1]+=444.94.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][C@@H:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
10% Palladium-carbon (2.63 g) was added to (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (9.267 g, 41.69 mmol) in ethanol (250 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 4.68 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 85%, b.p. 65° C. at 3 mmHg, optical purity 97.5% e.e., specific rotation [α]D20+ 10.84° (c=1,MeOH)).
Reaction SMILES: [CH:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(O)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>CCCCCCCC>[CH2:4]([O:3][C:1](=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)CCCCC(=O)O
Reactant: O=COCc1ccccc1
Solvent: CCCCCCCC
Product: O=C(O)CCCCC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 87 %

Procedure:
DOWEX® 50W-X2 (2 g), benzyl formate (10 mL, mol), and adipic acid (2 g, mol) were added to octane (10 mL). The mixture was refluxed for 4 hours at 100° C., and the crude product was purified via silica chromatography to yield a clear, colorless liquid (87% yield). 1H NMR (CDCl3) 1.59-1.78 (m, 4H, CH2CH2), 2.33-2.39 (m, 4H, CH2COOH), 5.09 (s, 2H, PhCH2), 7.25-7.30 (m, 5H, aromatic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (100 mg, 0.25 mmol) in a 1:1 mixture of THF/MeOH (5 mL/5 mL), was added 1M NaOH (2 mL). The mixture was heated in 60° C. bath for 1.5 hours, poured into 100 mL of water and acidified with 2M HCl (2 mL). The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as yellow solid. Yield: 90 mg, 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[N+:13]([O-])([O-:15])=[O:14].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:13]([C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2cc(Cl)ccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Cc1ccc2c([N+](=O)[O-])c(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
6-Chloroquinaldine (11 g) was dissolved in 15 ml of concentrated sulfuric acid and the solution was ice-cooled. Then, a solution of 7.1 g of potassium nitrate dissolved in 20 ml of concentrated sulfuric acid was added to the solution dropwise, during which operation the reaction temperature was maintained at 10° C. or less. After completion of addition the mixture was agitated at the same temperature as above for 1 hour and then poured onto 200 g of ice. Subsequently, the mixture was rendered alkaline with 10% sodium hydroxide, taking care that the internal temperature should not be raised to above 20° C., thus forming a pale yellow precipitate. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to obtain 12.3 g of 5-nitro-6-chloroquinaldine as pale yellow rhombic crystals having a melting point of 123° to 124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([OH:25])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:26]1(C)C=CC(S(O)(=O)=O)=C[CH:27]=1.C(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([O:25][CH2:26][CH3:27])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(O)C4)cc3c2c1C
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(OCC)C4)cc3c2c1C
Yield: 135.5 %

Procedure:
100 mg (0.29 mmol) of 6-(2-hydroxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is refluxed in 5 ml of toluene with 10 mg of p-toluenesulfonic acid and 52 mg (0.35 mmol) of triethyl orthoformate for 1.5 hours. After concentration, the mixture is chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1 thus obtaining 29 mg (27% of theory) of 6-(2-ethoxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[NH:36][C:35]([C@@H:37]5[CH2:41][C@H:40]([CH2:42][O:43][CH3:44])[CH2:39][N:38]5C(OC(C)(C)C)=O)=[N:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:8])=[O:4].Cl.[C:56]([O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:62])([CH3:59])([CH3:58])[CH3:57].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[NH:36][C:35]([C@@H:37]5[CH2:41][C@H:40]([CH2:42][O:43][CH3:44])[CH2:39][N:38]5[C:65](=[O:66])[C@H:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:57])([CH3:59])[CH3:58])[C:68]5[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=5)=[N:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 2 h
Yield: 59 %

Procedure:
(2S,4S)-tert-butyl 2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (289 mg, 0.39 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue was treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (98 mg, 0.39 mmol), COMU (186 mg, 0.39 mmol) and DMF (5 mL), then DIPEA (0.34 mL, 1.96 mmol) was added dropwise. After 30 min, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl (R)-2-((2S,4S)-2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (201 mg, 59%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[NH:10][CH:9]=1.CI.[CH2:20](OC(=O)C)C>CN(C=O)C.CCCCCC>[Br:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]([CH3:20])[CH:9]=1
Reactant: Clc1ccc2[nH]cc(Br)c2c1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cn1cc(Br)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 65 %

Procedure:
K2CO3 (1.39 g, 10.08 mmol) was added to a stirred solution of 3-bromo-5-chloro-1H-indole (775 mg, 3.36 mmol) in DMF (7.5 mL) and the resulting mixture was stirred for 30 minutes. This was followed by the addition of methyl iodide (572.5 mg, 4.03 mmol) at 0-5° C. and the stirring was continued for a further 2 hours at room temperature. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was partitioned between ice water and DCM. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (5% ethylacetate in hexane) afforded 530 mg of 3-Bromo-5-chloro-1-methyl-1H-indole (65% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:19][CH3:20]>CN(C)C=O>[CH2:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:15])([CH3:1])[C:3]1=[O:14])[CH3:20]
Reactant: CCBr
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of 3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (6 g, 29.10 mmol) in anhydrous N,N-dimethylformamide (DMF) (35 ml) was treated with sodium hydride. The resulting suspension was stirred for 1 h at 60° C. A solution of bromo-ethane (2.17 mL, 3.17 g, 29.10 mmol) in DMF (10 ml) was added. The mixture was allowed to cool to room temperature and stirred for 1 h. After removal of the solvent the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3×100 ml). The extract was dried over Na2SO4, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 5.94 g (87%) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.C([Li])CCC.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1.CCCCCC>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=2)([OH:32])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COCOCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Into a solution of 10 g of 4-bromophenethyl methoxymethyl ether in 200 ml of tetrahydrofuran was dropped 28 ml of a 1.6 M solution of n-butyllithium in hexane at −78° C. and the resulting mixture was stirred at the same temperature for 30 minutes. After heating to −20° C., a solution of 7.0 g of 1-benzyl-4-piperidone in tetrahydrofuran (10 ml) was added thereto. The mixture was reacted at the same temperature for 2 hours. After adding water, the resulting mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 7.6 g of the title compound was obtained as a yellow oily substance.
Reaction SMILES: CC1C=CC(S([N:11]2[CH:15]=[C:14]([CH:16]=O)[CH:13]=[N:12]2)(=O)=[O:9])=CC=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.O>[OH2:9].[NH:11]1[CH:15]=[C:14]([CH2:16][N:18]2[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]2=[O:28])[CH:13]=[N:12]1
Reactant: Nc1ccccc1CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2N1Cc1cn[nH]c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x58 (1.65 g, 6.6 mmol) is dissolved in a 1/1 mixture of THF/H2O (50 ml) and the solution containing (2-aminophenyl)acetic acid x96 (1 g, 66 mmol) is added. The pH is adjusted to 5 with acetic acid and the mixture is cooled to 0° C. Sodium triacetoxyborohydride (2.10 g, 10 mmol) is added and the mixture is stirred overnight at room temperature. Water is added and the aqueous phase is extracted three times with CH2Cl2. The combined organic phases are washed with brine, dried over MgSO4 and evaporated. Purification of the residue by preparative chromatography on silicagel and recrystallization from AcOEt affords 106 mg of pure 1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one hydrate 173.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[F:18][C:19]([F:25])([F:24])[C:20](OC)=[O:21]>C1COCC1>[Cl:9][C:5]1[C:4]([F:10])=[CH:3][C:2]([C:20](=[O:21])[C:19]([F:25])([F:24])[F:18])=[CH:7][C:6]=1[F:8]
Reactant: COC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(F)c1Cl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-bromo-2-chloro-1,3-difluorobenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the i-PrMgCl—LiCl (1.3M solution in THF) was added over about 1 minute—very slight exotherm noticed to ˜30° C. Reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 mL) over about 1 minute—slight exotherm to ˜40° C. Solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCl3) δ ppm: 8.05 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.C(OO)(=[O:18])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:13]([OH:18])=[N:12][CH:11]=[N:10][CH:9]=1
Reactant: N#Cc1nccc(-c2cncnc2)c1F
Reactant: CC(=O)OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: N#Cc1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a vial charged with 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.400 g, 1.998 mmol) in acetone (Volume: 11.89 ml) were added peroxyacetic acid (0.841 ml, 4.00 mmol) and sulfuric acid (0.222 ml, 4.00 mmol). The reaction mixture was refluxed for 1 h, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-25% MeOH in CH2Cl2 over 25 min, tr=16 min) gave the title compound (263 mg, 1.204 mmol, 60.3% yield) as a yellow solid. ESI MS (M+H)+=217.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH4+:15].[OH-]>C1COCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[S:11](=[O:13])(=[O:12])[NH2:15]
Reactant: [NH4+]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Temperature: 0 °C

Procedure:
2-Acetamido-4-methylthiazole-5-sulfonyl chloride (0.50 g, 1.96 mmol) was dissolved in THF (7 mL), cooled to 0° C., and concentrated NH4OH (0.7 mL) was added. After 3 hours the reaction was concentrated, diluted with water, and extracted with CHCl3/methanol. The organic layer was dried over Na2SO4. Filtration and concentration gave the product that was used EXAMPLE 11B.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[CH3:6][C:7]([S:10]([NH2:12])=[O:11])([CH3:9])[CH3:8]>O1CCCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:6][C:7]([S:10]([N:12]=[C:3]1[CH2:4][O:1][CH2:2]1)=[O:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1COC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of oxetan-3-one (600 mg, 8.33 mmol) and 2-methylpropane-2-sulfinamide (1.01 g, 8.33 mmol) in tetrahydrofuran (14 mL), titanium ethoxide (3.45 mL, 16.65 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was poured over brine. The suspension was filtered through celite and washed with ethyl acetate. The solution was partitioned between ethyl acetate and brine. The organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (0-70% ethyl acetate in hexanes) to afford 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (692 g, 3.20 mmol, 38% yield) as a clear oil. MS ESI: [M+H]+ m/z 176.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[N+:14]([O-])([OH:16])=[O:15].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[O:10])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(C)=O)cc1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Br
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a cold (5° C.) solution of 3.36 g (13.8 mmol) of 2-Bromo-4-acetaminoanisole in 5 mL of acetic anhydride and 10 mL of acetic acid, was added dropwise 0.9 mL (13.8 mmol) of concentrate nitric acid. The resulting solution was stirred at 5° C. for 3 h, poured into 90 mL of water, stirred, and filtered to collect the solid (the desired product). The solid was washed twice with cold water, dried under vacuo at 100° C., crystallized from chloroform to give 3.26 g (82% yield) of pure compound 6. 1H NMR (CDCl3) δ 10.2 (s, 1 H, NH), 9.09 (s, 1 H), 7.67 (s, 1 H), 3.95 (s, 3 H, OMe), 2.28 (s, 3 H, CH3).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=c1cc(Cl)cn[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cn[nH]1
Temperature: 100 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a mixture of 5-chloropyridazin-3(2H)-one [ES-A-454136 (1977)] (2.32 g, 17.8 mmol) and 4-trifluoromethylphenylboronic acid (4.06 g, 21.4 mmol) in anhydrous dioxane (20 ml) was added (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium (0.8 g, 1.09 mmol) and saturated aqueous sodium carbonate solution (18 ml). Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 24 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature and poured onto a mixture of ethyl acetate/ethanol/water (300 ml/30 ml/30 ml). The phases were separated and the aqueous phase was extracted two times more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flask column chromatography (50% ethyl acetate-iso-hexane) gave 5-[4-trifluoromethylphenyl]pyridazin-3(2H)-one (0.78 g) which was suspended in phosphorous oxychloride (5 ml, 54 mmol) and the mixture heated at 100° C. for 5 hours. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (50 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash column (50% ethyl acetate-iso-hexane) to yield the title compound (0.56 g, 12%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.Cl.[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][SH:17])[NH2:15].CCN=C=NCCCN(C)C.CN1CCOCC1>CC#N.CCOC(C)=O>[SH:17][CH2:16][C@H:14]([NH:15][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)[C@@H](N)CS
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/C(=O)N[C@@H](CS)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Separately, mono methyl fumarate (100 mg, 0.77 mmol) was taken up in 4 mL of CH3CN along with L-cysteine methyl ester hydrochloride (132 mg, 0.77 mmol), EDCI (245 mg, 0.77 mmol) and N-methylmorpholine (85 μL, 0.77 mmol). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford crude (R,E)-methyl 4-(3-mercapto-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate. This material was then taken up in 3 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (173 mg, 0.38 mmol) and stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 60 mg of (E)-methyl 4-((R)-3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (22%). MS (EI) calcd for C37H51N3O8S: 697.34. found: 698 (M+1).