Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC[NH:4]C(=S)NN.C(Cl)C1C=CC=CC=1.[OH:17][CH2:18][CH2:19][N:20]=[C:21]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:22][NH2:23].N([O-])=O.[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:17][CH2:18][CH2:19][N:20]1[C:21]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][N:23]=[N:4]1
Reactant: NNC(=NCCO)SCc1ccccc1
Reactant: NNC(=S)NCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: ClCc1ccccc1
Solvent: CO
Solvent: O
Product: OCCn1nnnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(2-hydroxyethyl)thiosemicarbazide (10.3 g), benzyl chloride (10.6 g), water (30 ml) and methanol (60 ml) was stirred for 20 hours at room temperature to give a homogeneous solution containing benzyl N-(2-hydroxyethyl)thiocarbazimidate. The solution was ice-cooled and thereto was little by little added sodium nitrite (5.24 g) with stirring and then dropwise added conc. hydrochloric acid (3.5 ml) over a period of 30 mimetes. The resulting mixture was stirred for an hour under ice-cooling. To the reaction mixture were added potassium carbonate (18 g) and water (30 ml). The mixture was stirred and then concentrated under reduced pressure. The concentrate was extracted with chloroform and the extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residual oil was subjected to column chromatography on silica gel. The fractions containing the object compound were collected to give an oil of 1-(2-hydroxyethyl)-5-benzylthio-1H-tetrazole (12.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[C:14]=3[F:21])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 89 %

Procedure:
To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and 3-chloro-2-fluorobenzaldehyde (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27](=O)[O:28]CC)=[C:18]([F:32])[CH:17]=1.C(O)(=O)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:18]([F:32])[CH:17]=1
Reactant: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.5 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 25 ml of absolute dimethylformamide is added dropwise while stirring at 0° C. during 5 minutes to a suspension of 2.5 g of a 55% sodium hydride dispersion in 25 ml of absolute dimethylformamide. The temperature rises to 20° C. and the mixture is subsequently stirred at this temperature for 30 minutes. Thereafter, 14.4 g of ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate are added, and the mixture is stirred at room temperature for 30 minutes and heated at 150° C. (bath temperature) for 2.5 hours. The reaction mixture is cooled to 50° C., neutralized with 3.5 ml of concentrated acetic acid and largely concentrated at 60° C. under reduced pressure. The residue is poured into a solution of 200 ml of water and 30 ml of 2N hydrochloric acid and the aqueous mixture is extracted twice with 150 ml of diethyl ether each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether-n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4-Benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-yl)-methanol (1.10 g) is dissolved in methylene chloride (10 ml), and thereto is added thionyl chloride (332 μl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give 4-benzyloxy-2-chloromethyl-5′-isopropyl-2′-methoxy-biphenyl (1.15 g). MS (m/z): 345
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1OC
Yield: 96 %

Procedure:
A suspension of 4-chloro-2-methoxybenzoic acid (5 g, 27 mmol) in MeOH (18 mL) and conc. H2SO4 (1.5 mL) was refluxed overnight. MeOH was evaporated and the residue was extracted to EtOAc and successively washed with water and brine, dried over MgSO4, filtered and evaporated to give methyl 4-chloro-2-methoxybenzoate as a white solid (5.17 g, 96%).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3]>CO.[Pd]>[NH:1]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 60.6 %

Procedure:
Boc-Ala-Pro-boroPro-pinacol was prepared by coupling Boc-Ala-Pro-OH to H-boroPro-pinacol. First, the dipeptide, Boc-Ala-Pro-OBzl, was prepared by the mixed anhydride procedure. Boc-Ala-OH (10 g, 52.8 mmoles) was reacted with N-methylmorpholine (5.8 ml, 52.8 mmoles) and isobutyl chloroformate (6.8 ml, 52.8 mmole) for 5 minutes in 50 ml of THF at -20°. The reaction mixture and additional N-methylmorpholine (5.8 ml) were added to H-Pro-OBzl.HCL (12.8 g, 52.8 mmoles) dissolved in 50 ml of cold chloroform. After the mixture was stirred for 1 hour at -20° C. and 2 hours at room temperature, it was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and washed sequentially with 0.2N hydrochloric acid, 5% aqueous NaCO3, and saturated aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to yield Boc-Ala-Pro-OBzl as an oil (14.1 g). The benzyl ester protecting group was removed by dissolving Boc-Ala-Pro-OBzl (35 g, 92.8 mmoles) in 200 ml of methanol and hydrogenating for 1 hour in the presence of 0.5 g of 10% Pd/C. The catalyst was removed by filtration and the solvent evaporated. The residue was crystallized from ethyl acetate to yield 16.1 g of Boc-Ala-Pro-OH (mp 153.5°-154.5° C.).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.C(OCC)(=O)C>C(N(CC)CC)C>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (3.55 ml) was dropped to the mixture of 6.37 g 2-amino indane hydrochloride, 60 ml of ethyl acetate and 10.4 ml triethylamine and the reaction mixture was stirred at room temperature for 15 hours. The solvents were evaporated in vacuo and the solid residue was digested with water, filtered and dried at 40° C. in vacuo.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>O>[Cl:5][C:6]1[C:11]([N:12]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Nc1cccnc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ncccc1-n1cccc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To 30 ml of acetic acid were added 5.0 g of 2-chloro-3-pyridinylamine and 5.6 g of 2,5-dimethoxytetrahydrofuran, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 6.5 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole of the formula:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[NH:18][CH:13]([CH2:14][CH2:15]2)[CH:12]=1.Br[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH:13]2[N:18]([CH2:20][CH2:21][OH:22])[CH:16]([CH2:15][CH2:14]2)[CH:17]=1
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Yield: 91 %

Procedure:
3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene (1.00 g, 4.25 mmol), 1.05 g (8.40 mmol) 2-bromoethanol, 1.70 g (12.6 mmol) K2CO3 and 57 mL of DMF are stirred at 80 C for 12 h. The reaction mixture is poured into 300 mL of cold H2O and extracted with 3×50 mL of EtOAc. The combined organics are washed with 3×100 mL of H2O, 1×100 mL of brine, dried over MgSO4, filtered, and the volatiles are evaporated to give 1.08 g (3.87 mmol, a 91% yield) of the title compound as a white solid. mp: 113-114° C.; MS (ES) m/z 280 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].N1C=CC=CC=1.[C:38](Cl)(=[O:42])[O:39][CH2:40][CH3:41]>ClCCl>[CH2:40]([O:39][C:38]([N:30]([C:28]1[CH:27]=[CH:26][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:17])=[O:18])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:25])=[C:2]([Cl:1])[CH:29]=1)[CH3:31])=[O:42])[CH3:41]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (278 mg) in dichloromethane (3 ml) were added pyridine (148 mg) and ethyl chlorocarbonate (129 mg) under ice-cooling, and the mixture was stirred for 24 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (126 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16]([C:18](=[CH:39][CH:40]=[CH:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=1)[N:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[CH3:14]>C(#N)C>[CH2:48]([C:45]1[CH:44]=[CH:43][C:42]([C:41]2[CH:40]=[CH:39][C:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])=[N:19][C:7]=2[C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[CH:47][CH:46]=1)[CH3:49]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=CC=Cc1ccc(CC)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 60 °C

Procedure:
General Procedure K. 4-(trifluoromethyl)benzaldehyde (153 mg, 1.88 mmol) was added to a stirred solution of 3-ethoxycarbonyl-1,1,1-triphenyl-6-(4-ethylphenyl)-2-aza-1λ5-phosphahexa-1,3,5-triene (Compound 46, 444 mg, 0.88 mmol) in dry acetonitrile (10 ml) and the solution was heated to 60° C. for 18 hours. The solution was concentrated in vacuo, and the crude product was passed through a silica gel column with 15% ethyl acetate in hexane as eluant to give the title compound as a yellow oil.
Reaction SMILES: [BH4-].[Li+].C(O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:10]([F:21])[CH:9]=1)(=O)C.[O:22]1CCC[CH2:23]1>>[F:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:23][OH:22])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOCOc1ccc(COC(C)=O)cc1F
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: COCCOCOc1ccc(CCO)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
2.4 g (107 mmol) of lithium borohydride is added in portions to a solution of 9.7 g (36 mmol) of [3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 1.5 h and then it is poured into 500 ml of ice and extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. 8.6 g (99%) of 2-[3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol is obtained in the form of a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O-:3])=[O:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([O-:3])=[O:2]
Reactant: N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 48.4 g of S-(o-nitrophenyl)-L-cysteine in 100 ml of 2N aqueous sodium hydroxide at 0° C. is added 28.8 ml of benzyl chloroformate and 50 ml of 4N aqueous sodium hydroxide simultaneously from two addition funnels. The mixture is mechanically stirred overnight at room temperature and then extracted with 150 ml of ether. The aqueous layer is separated and acidified to pH 1 with 12N aqueous hydrochloric acid. The resulting gummy yellow solid is stirred for 3 hr in 500 ml of water, collected by filtration, and dried overnight at 70° C. in vacuo to afford S-(o-nitrophenyl)-N-carbobenzyloxy-L-cysteine; m.p. 84°-88° C.; [α]D =+46.6° (c=1.25, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])=[CH:13][CH:12]=1
Reactant: NCCc1ccccc1Cl
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NCCc2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
1-Amino-2-(2-chlorophenyl)ethane (44.5 g) was dissolved in 140 ml of pyridine, and with stirring under cooling, 44.5 g of p-toluoyl chloride was added dropwise. The reaction was performed at room temperature for 3 hours. The reaction mixture was poured into ice water, and the crystals that precipitated were collected by filtration. The crystals were dissolved in benzene, washed successively with hydrochloric acid, water and saturated aqueous sodium chloride solution, and dried. The solvent was distilled off. The residue was recrystallized from benzene to afford 72 g of 1-(p-toluoylamino)-2-(2-chlorophenyl)ethane as colorless needles having a melting point of 106.0° to 108.5° C.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:4].[C:14](O)(=O)C(C)(C)C>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[C:7]([CH3:14])([CH3:8])[CH3:9])[CH3:4]
Reactant: CC(C)(C)C(=O)O
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Product: CSC(=O)OC(C)OC(=O)C(C)(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with pivalic acid in Step B affords O-(1-pivaloyloxyethyl) S-methyl thiocarbonate (5) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:17]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:10][N:9]=2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1nsc(=O)o1
Reactant: CCOC(=O)C#N
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2OC)ns1
Temperature: 150 °C
Yield: 19.1 %

Procedure:
To a solution of 5-(4-chloro-2-methoxyphenyl)-1,3,4-oxathiazol-2-one (1.32 g, 5.42 mmol) in 1,2-dichlorobenzene (5 ml) was added ethyl cyanoformate (2.20 ml, 21.67 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), the reaction mass was as such (direct loading) purified through flash chromatography (100-200 M silica, 5% EtOAc-Hexane) to get the desired product (0.31 g, 19%). LCMS: 299.29 (M+H)+, 98.99%.
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[OH:14])[CH3:2].CN(C)CCN(C)CCN(C)C.Br[CH:29]([CH3:40])[C:30]([O:32][CH2:33][CH2:34][O:35][C:36](=[O:39])[CH:37]=[CH2:38])=[O:31]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:15])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:37]([CH3:38])[C:36]([O:35][CH2:34][CH2:33][O:32][C:30](=[O:31])[CH:29]=[CH2:40])=[O:39])[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1O
Reactant: C=CC(=O)OCCOC(=O)C(C)Br
Agent: CN(C)CCN(C)CCN(C)C
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)C(C)ON1C(C)(CC)CC(O)C(C)C1(C)CC
Temperature: 10 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a stirred solution of 99.6 g (0.46 mol) of 2,6-diethyl-1-hydroxy-2,3,6-trimethyl-piperidin-4-one (prepared as described in U.S. Pat. No. 6,353,107 B1, example 2), 66.3 g (0.46 mol) of CuBr and 29.4 g (0.46 mol) Cupper in 1000 ml toluene 160 g (0.92 mol) of N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDTA) are added. The brown suspension is then cooled to 10° C. and 116 g (0.46 mol) of acrylic acid 2-(2-bromo-propionyloxy)-ethyl ester dissolved in 250 ml toluene are added dropwise while keeping the temperature below 15° C. The reaction mixture is stirred for another 12 h at room temperature and then filtered. The filtrate is washed with water (3×500 ml), then with a 10% solution of EDTA (3×500 ml), dried over NaSO4 and evaporated. The residue is chromatographed over Silica gel with hexane-ether (7:3) to afford 165 g of the title compound as slightly yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH3:17])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[CH:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[N:33]=1)([CH3:30])[CH3:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]([O:31][C:32]1[N:33]=[C:34]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH3:17])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:3]=2)[CH:35]=[CH:36][CH:37]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Oc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CNc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nnc(-c2ccc3c(c2)c(-c2cccc(OC(C)C)n2)cn3S(=O)(=O)c2ccc(C)cc2)o1
Temperature: 125 °C

Procedure:
A mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (210 mg, 0.42 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (145 mg, 0.55 mmol) (CombiPhos Catalysts Inc., Cat#BE177), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16 mg, 0.034 mmol, Strem), Pd2(dba)3 (15 mg, 0.017 mmol, Strem), and potassium phosphate (271 mg, 1.27 mmol) in dioxane (4 mL) and H2O (1 mL) in a sealed glass tube was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 20 min. The mixture was partitioned between 2 mL of 0.5 N NaOH and 10 mL of EtOAc. The organic layer was filtered through a pad of Celite and concentrated to give crude 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine that was used in next step without further purification. MS (ESI, pos. ion) m/z: 504.1 (M+1). A mixture of 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine and KOH (49 mg, 0.88 mmol) in 2 mL of dioxane and 1 mL of H2O was heated in a microwave at 105° C. for 15 min. It was partitioned between 15 mL of EtOAc and 3 mL of H2O. The organic layer was concentrated and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in AcCN] in [0.1% TFA in H2O] to afford 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine 2,2,2-trifluoroacetate (51 mg, 27% overall for 2 steps) as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 350.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br.), 8.99 (1H, s), 8.19 (1H, d, J=2.6 Hz,), 7.66 (2H, m), 7.56 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=7.4 Hz), 6.52 (1H, d, J=8.0 Hz), 5.49 (1H, m), 4.06 (1H, br.), 2.89 (3H, s), 1.44 (6H, d, J=6.1 Hz).