Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1[NH:19][CH:20]1[CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[C:10](=[O:23])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:19]([CH:20]2[CH2:21][CH2:22]2)[C:24]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Yield: 46.4 %

Procedure:
A solution of N-benzyloxy-4-chloro-2-cyclopropylamino-5-fluoro-benzamide (Example D-3, 3.00 g, 8.96 mmol) in 1,4-dioxane (50 mL) was reacted with a 20% solution of phosgene (7.00 mL, 9.86 mmol) in toluene in a sealed tube. The mixture was heated to reflux for 24 hours, then cooled and quenched with H2O. The mixture was extracted three times with ethyl acetate, the organic layers combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 1.5 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]1Br.[I-].[Na+]>CC(C)=O>[O:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1(Br)Oc2ccccc2OC1Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=COc2ccccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Stir for 3 hours, at room temperature and under a nitrogen atmosphere, a mixture of 16 g (43.7 mmol) of ethyl 2,3-dibromo-1,4-benzodioxin-2-carboxylate and 24 g (160 mmol) of sodium iodide in 80 cm3 of anhydrous acetone. The reaction mixture is then concentrated under reduced pressure, hydrolysed with 80 cm3 of water, and subsequently extracted with diethyl ether. After treatment with an aqueous sodium thiosulfate solution followed by drying over magnesium sulfate, the ethereal phase is concentrated to dryness under reduced pressure and the crude product is purified by chromatography on a silica column (eluant:petroleum ether/diethyl ether, 40:60). Ethyl 1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 85%.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6]([Cl:15])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(CC=C(Cl)Cl)C(=O)O
Solvent: c1ccccc1
Product: CC(C)C(CC=C(Cl)Cl)C(=O)Cl
Yield: 79 %

Procedure:
To 2.1 g of α-(3,3-dichloroallyl)isovaleric acid were added 3.0 g of thionyl chloride, as well as 10 g of benzene, and the mixture was refluxed for 5 hours. Then, the reaction mixture was distilled to remove the low-boiling fraction. By this procedure there was obtained α-(3,3-dichloroallyl)isovaleroyl chloride. This chloride was dissolved in 30 g of dry benzene, followed by the addition of 2.0 g of 3-phenoxybenzyl alcohol. Then, 2.0 g of pyridine were added added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with diethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The residual viscous oil was purified by column chromatography to recover 3.1 g of 3-phenoxybenzyl α-(3,3-dichloroallyl)isovalerate (Compound [5]) having the following properties [yield: 79% based on α-(3,3-dichloroallyl)isovaleric acid].
Reaction SMILES: [C:1]([CH:3]([C:13]([C:15]1[C:16]2[CH2:29][S:28][C:27]3[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:26]=3[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:14])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:39]([CH2:38][CH2:37][C:36]([O:35][CH2:34][C:30]1[C:27]2[S:28][CH2:29][C:16]3[C:15]([C:13](=[O:14])[CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:5])=[N:19][N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]=3[C:26]=2[CH:33]=[CH:32][CH:31]=1)=[O:42])([OH:41])=[O:40]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1c(CO)cccc1-2
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1c(COC(=O)CCC(=O)O)cccc1-2
Temperature: 45 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
2-Cyano-3-(1,4-dihydro-6-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.2 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45° C. for 20 hours. After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH2Cl2 /isopropanol yields 0.95 g of 3-[6-(3-carboxy-propanoyloxymethyl)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)(=O)C.CO.C([O-])([O-])=O.[K+].[K+]>O>[F:20][C:17]([F:18])([F:19])[CH2:16][N:13]1[CH2:12][CH2:11][C:10]2[C:15](=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][CH:9]=2)[CH2:14]1
Reactant: CC(=O)OCc1cccc2c1CN(CC(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCc1cccc2c1CN(CC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 5 dram vial, added 7-4 (21.7 mg, 0.076 mmol) to methanol (504 μl) and water (252 μl). Added K2CO3 (52.2 mg, 0.378 mmol) and allowed to stir at RT. After 1 h at RT, LCMS showed complete consumption of SM to desired product. Partitioned reaction contents into 10 mL EtOAc+5 mL H2O. Separated layers, back-extracted aqueous with 3×5 mL EtOAc. Dried combined organics over Na2SO4, filtered, concentrated to give 7-5 as a pale yellow oil. Carried crude material forward to subsequent step.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[C:1](=[O:12])([S:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-pentanethiol as starting materials to give the aimed compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[O:33])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)(Br)C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCNCC3)ccc1OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 2 (0.244 g, 0.594 mmol), 2-bromo-2-methylpropionamide (0.494 g, 2.976 mmol) and Cs2CO3 (0.774 g, 2.376 mmol) in CH3CN (15 mL) was heated at 120° C. for 2 h using microwave irradiation. The crude mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) to give 0.261 g (89% yield) of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide as a colorless foam. A portion of the resulting residue (28 mg) was further purified by column chromatography (C18, gradient 15-55% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording the title compound (13 mg). LCMS: RT 2.92 min [M+H]+ 496.1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH3:7].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH2:6]([O:8][C:9]1[C:10]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][C:12]2[C:13]([CH3:21])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH3:7]
Reactant: CCC(=O)Cl
Reactant: CCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(=O)CC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Propionyl chloride (1.44 mL, 16.6 mmol) was added to a stirring solution of 3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (Intermediate 2, 3.5 g, 15.1 mmol) in dichloromethane (100 mL), and the solution was cooled to 0° C. Aluminum trichloride (2.21 g, 16.6 mmol) was added over two to three minutes, the ice-bath was removed, the yellow solution was stirred for 1 h at room temperature. The solution was poured over ice in a separatory funnel, and the products were extracted three times with ether. The combined organic layers were washed with 10% aqueous sodium hydroxide, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2].S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:29]([O-:31])=[O:30])=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2]
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77 %

Procedure:
A solution of 2-(2-ethoxyphenyl)-8-n-propylpyrido-(3,2-d]pyrimidin-4(3H)-one (Preparation 8; 0.80 g, 0.0026 mol) in a mixture of concentrated sulphuric acid (5.4 ml) and concentrated nitric acid (0.20 ml) was stirred at ambient temperature for 4.5 hours. The mixture was then poured cautiously into stirred ice/water (50 g) and the resulting mixture extracted with a methanol:dichloromethane mixture (1:9, 3×50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum, and the residue crystallized from ethyl acetate:methanol to give the title compound as an off-white solid (0.71 g, 77%), m.p. 257-259° C.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]#[N:23].C1C=CC=CC=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[C:22]#[N:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: N#CC(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1Cl
Temperature: -5 °C
Reaction time: 10 h

Procedure:
To a solution of 39 parts of potassium hydroxide in 39 parts of pyridine is added a solution of 17 parts of 1-chloro-4-nitrobenzene in 46 parts of pyridine. The whole is cooled to -5° C and there is added dropwise a solution of 22 parts of 2,4-dichlorobenzeneacetonitrile in pyridine, while still cooling at -5° C. Upon completion, stirring is continued for 10 hours at 0° C. After the addition of 90 parts of benzene, the product is precipitated. It is filtered off, washed on the filter with benzene and taken up in water. The aqueous mixture is treated with acetic acid, whereupon the product is separated as an oil. The latter is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of methanol, 2,2' -oxybispropane, petroleumether and trichloromethane, yielding 2,4-dichloro-α-(4-nitrophenyl)benzeneacetonitrile; mp. 81°- 82.5° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N:32]([Si](C)(C)C)=[N+:33]=[N-:34].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]2[NH:34][N:33]=[N:32][N:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=1[Cl:23])=[CH:10][CH:9]=2)=[O:5])[CH3:31]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCN(CC)C(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1
Yield: 46.9 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid diethylamide (0.078 g, 0.17 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.066 mL, 0.50 mmol) and dibutyltin oxide (0.012 g, 0.050 mmol). The reaction mixture was heated to reflux and stirred under argon at reflux temperature for 40 h. The solution was cooled and the toluene removed under reduced pressure. Methanol was then added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.040 g, 47%). MS(ES) m/e 501.2 [M +H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH:9]=[CH:8]1)=[O:5])[CH3:2].[H][H]>C(O)C>[CH2:15]1[C:10]2([CH2:26][CH2:27][CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9]2)[CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: CCOC(=O)C=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CC1CCC2(CCNCC2)CC1

Procedure:
9.6 g (26.0 mmol) of the protected spiro compound from Step B were dissolved in 400 ml ethanol, and the solution was filled into a hydrogenation vessel followed by 2 g Pd(II) hydroxide on charcoal. The reaction was carried out at 40° C. and 1 atm hydrogen, and it was complete after about 40 hours. The catalyst was removed by filtration through silica gel, and the filtrate was concentrated under reduced pressure. The remaining oil was treated with dry ether, filtered, and the filtrate was acidified with ethereal hydrochloric acid. The hydrochloride of the title compound was collected by filtration, washed two times with ether, dissolved in water, and the solution was made alkaline with 2 N aqueous sodium hydroxide solution. After extraction with dichloromethane the organic layer was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:7][OH:8])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)C[C@H](N)CO
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1

Procedure:
A mixture of (L)-leucinol (1.13 g, 9.67 mmol) and 4-fluorobenzaldehyde (1.20 g, 9.67 mmol) was dissolved in benzene (30 mL) and heated at reflux for 1 hour, using a Dean-Stark apparatus to remove water. (S)-2-[(4-Fluorobenzylidene)-amino]-4-methylpentan-1-ol was isolated by concentration in vacuo, and was used immediately without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](=[O:14])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:12]1[CH:13]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[C:10]([Br:15])[C:11]1=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Cc2ccccc2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(Cc2ccccc2)cn1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 5-benzyl-3-bromopyridin-2(1H)-one 4 (3.5 g, 13.5 mmol) in dry DMF (100 mL) was added NaH 60% suspension in mineral oil (0.5 g, 16.2 mmol) and stirred for 30 min, followed by the addition of benzyl bromide (0.1.36 g, 7.9 mmol) and mixture further stirred for 1 h at RT. DMF was distilled off and the residue redissolved in EtOAc (250 mL), washed with brine solution (2×100 mL), dried over anhydrous Na2SO4 and EtOAc distilled off to give a yellow syrup, which was purified by column chromatography on silica gel (EtOAc:Hexane, 4:6) to give 5. Yield 3.8 g (83%), yellow solid, mp 89-90° C. 1H NMR (CDCl3, 500 MHz): δ 3.69 (s, 2H, CH2), 5.18 (s, 2H, CH2), 7.11 (d, 1H, CH, J=2 Hz), 7.12-7.39 (m, 10H, Ar—H), 7.60 (d, 1H, CH, J=2 Hz), 13C NMR (CDCl3, 125 MHz): δ 37.4, 53.5, 117.1, 119.1, 126.9, 128.2, 128.2, 128.3, 128.3, 128.6, 128.8, 128.8, 128.9, 128.9, 134.6, 135.8, 138.7, 143.0, 158.3. HRMS (M+H)+ calcd for C19H17BrNO 354.0494, found 354.0455.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH:8]=[CH:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(CC=CC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1

Procedure:
A mixture of 4-11 (95 mg, 0.22 mmol) and 10% Pd/carbon (50 mg) in EtOH (3 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration, evaporative removal of the solvent gave 4-12 as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:43]2[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(F)ccn1
Reactant: COC(=O)c1cc(N)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(F)ccn2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A solution of 4-fluoropicolinic acid (1.0 g, 6.4 mmol), HATU (2.9 g, 7.6 mmol), and N-methylmorpholine (0.84 mL, 7.6 mmol) in N,N-dimethylformamide (12 mL) was stirred at 0° C. for 30 minutes. Methyl 4-aminothiophene-2-carboxylate (990 mg, 7.0 mmol) was added, the reaction was stirred for 30 minutes at 0° C., then warmed to room temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/H2O (1:1) and the solids were isolated by filtration, washed with water, acetonitrile, then dried to afford methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate as a white powder (1.0 g, 56% yield). M+1=281.1.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C(Cl)(Cl)Cl>[C:6]([O:5][C:1](=[O:4])[NH:2][N:3]1[C:13](=[O:14])[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:15])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Yield: 80.2 %

Procedure:
To a mixture of tert-butyl carbazate (5.15 g, 38.97 mmol) and phthalic anhydride (5.77 g, 38.97 mmol) was added CHCl3 (70 mL). The reaction mixture was refluxed for 18 h. Removal of the solvent under reduced pressure yielded 8.20 g (80%) of the title compound as a white solid. MH+263.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44]>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: C[C@H](O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-β-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2)N1CCOCC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a suspension of 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl chloride (0.027 g, 72.6 μmol) in DCE (1 mL) was added morpholine (15.97 μL, 182 μmol) and pyridine (350 μL). The reaction was heated to 70° C. and stirred at that temperature for 16 hours. LCMS analysis of the reaction mixture indicated complete consumption of starting material. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 0-60% EtOAc to provide (4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)(morpholino)methanone (21.8 mg, 49.3 μmol, 88% yield for 2 steps) as off-white solid. LCMS (+ESI) m/z=423.5 [M+H]−.