Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[C@@H:6]1[C@@H:10]([CH2:11][O:12]S(C)(=O)=O)[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(C)(=O)=O.[OH-].[Na+].O.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:24][C:23]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][OH:12])[CH:6]=[CH:7]2)[CH:25]=1
Reactant: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 79 %

Procedure:
In the above synthesis, 3′,5′-di-O-mesylthymidine is first treated with sodium hydroxide in refluxing water for 2 hours and the resultant 3,4-anhydrothymidine is treated with potassium t-butoxide in dimethyl sulfoxide (DMSO) at room temperature for 2 hrs. The reaction mixture is neutralized, evaporated to dryness and after a series of manipulations which included extraction, declourization, precipitation and recrystallization, gave Stavudine in 79% yield and an overall yield of 56%.
Reaction SMILES: O.Br[CH2:3][C:4]1[C:5]([Cl:22])=[CH:6][C:7]([Cl:21])=[C:8]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:9]=1.C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:15][C:14]1[C:10]([C:8]2[C:7]([Cl:21])=[CH:6][C:5]([Cl:22])=[C:4]([CH:9]=2)[CH:3]=[O:34])=[N:11][N:12]([CH3:20])[C:13]=1[O:16][CH:17]([F:19])[F:18]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Yield: 56.3 %

Procedure:
After addition of 100 ml water to a solution of 3-(5-bromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole (26.60 g, 63.3 mmoles) in 100 ml glacial acetic acid, hexamethylenetetramine (8.87 g, 63.3 mmoles) was added and reacted under reflux for 2 hours. Further, 40 ml conc. sulfuric acid was added and reacted under reflux for 13 hours. Then the reaction product mixture, poured into ice-cold water, was extracted with ethyl acetate. The extract solution was washed with 5% aqueous NaHCO3 and then with water, dehydrated, and concentrated. Purification of the residue by column chromatography gave the title compound (12.66 g), m.p. 138.2° C., yield 56.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([N:25]=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of the title compound of Example 45, the slower moving enantiomer of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.41 g, 1.74 mmol) in THF (200 ml) was added 2N hydrochloric acid (20 ml) slowly. The reaction mixture was stirred at ambient temperature for 1.5 hour after which time it was cooled to 0° C. An aqueous solution of potassium carbonate was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1 to 2:98:0.1) as the eluents to afford the title compound as a white solid (0.844 g, 1.59 mmol, 90% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: [OH-:1].[Na+].CS(C)=O.[CH:7]([N:10]1[C:14](S(C)(=O)=O)=[N:13][N:12]=[C:11]1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=1[O:32][CH2:33][O:34][CH3:35])([CH3:9])[CH3:8]>O>[CH:7]([N:10]1[C:11]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=2[O:32][CH2:33][O:34][CH3:35])=[N:12][NH:13][C:14]1=[O:1])([CH3:9])[CH3:8]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1C(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1C(C)C
Temperature: 95 °C
Yield: 78 %

Procedure:
At room temperature, aqueous sodium hydroxide (1.0 M aqueous solution, 9 mL) was added to a dimethylsulfoxide (11 mL) solution of 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-5-methyl sulfonyl-4H-[1,2,4]triazole (F63-05, 1.63 g, 3.82 mmol). The mixture was heated at 90-100° C. for 12 hours while stirring. After returning to room temperature, water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed twice with water and then with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain white solids. After suspension purification by diethyl ether, the solids obtained by filtration were dried under reduced pressure to obtain 4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one (F63-06, white solids, 1.09 g, 78%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[P:12](Cl)([Cl:15])([Cl:14])=[O:13].CCN(CC)CC>CCOCC>[P:12]([Cl:15])([Cl:14])([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2ccccc12
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Temperature: -78 °C

Procedure:
To 1-naphthol in Et2O (0.23 M) was added phosphorus oxychloride (1.0 eq.) and the solution was cooled to −78° C. Neat Et3N (1.0 eq) was added and the resulting solution was left to warm to RT overnight. The white slurry was filtered under an inert atmosphere and all volatiles were removed to yield the title compound as a colorless liquid that was used without further purification in the next step. 31P NMR (400 MHz, CDCl3): δ 3.93 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH2:23][CH2:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH2:23][CH2:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=Cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C=C(C(=O)O)CCC3)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.8 %

Procedure:
To methyl 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1245 mg, 3.10 mmol) dissolved in a mixed solvent of methanol (10 ml) and THF (10 ml) was added a 1N aqueous solution of sodium hydroxide (9.3 ml), and the resulting mixture was stirred at room temperature for 23 hours. The reaction mixture was mixed with 1 N hydrochloric acid (9.3 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water, and was dried under reduced pressure to obtain 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (1150 mg, 2.97 mmol, 96%).
Reaction SMILES: [ClH:1].C(C1C=CC(C(N)=N)=CC=1)CCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:34]([C:36]1[C:37](O)=[N:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)=[N:40][CH:41]=1)#[N:35].[P]>C(O)C>[Cl:1][C:37]1[C:36]([C:34]#[N:35])=[CH:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)[N:38]=1
Reactant: CCCCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: Cl
Agent: CCCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-pentylbenzamidine hydrochloride with α-ethoxymethylene- α -cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-pentylphenyl)-pyrimidine (melting point 199°-205° C) is treated with phosphorus oxychaloride to give 4-chloro-5-cyano-2-(4-n-pentylphenyl)-pyrimidine having a melting point of 96.0°-96.3° C.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[F:24])=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C-]#N.[K+].[OH:35][C:36](C)(C)C#N>CO>[CH:1]1[C:6]2[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]([O:35][CH3:36])=[O:21])=[CH:18][C:17]=3[F:24])=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)C#N
Reactant: O=Cc1ccc(C2=Nc3ccccc3Oc3ccccc32)c(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)c(F)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A mixture of compound 102 (0.59 g, 1.90 mmol), triethylamine (1.6 mL, 11.48 mmol), potassium cyanide (0.061 g, 0.93) and 2-hydroxy-2-methylpropanenitrile (1 mL, 10.93) in methanol (15 mL) was stirred at 40° C. for 24 h then solvent evaporated. The resulting crude residue was purified on ISCO (0-100% EtOAc in Hexanes) to afford title compound 103 (0.364 g, 56%) as a yellow solid. LRMS (ESI): (calc) 347.10 (found) 348.4 (MH)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Ta+5].C([Mg]Br)(C)C.C(C1([Li])C=CC=C1)C.C(C1CC=CC=1)C.C([Li])CCC.[CH2:32]([C:34]1([Ta:39]([C:42]2([CH2:47][CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43]2)(Cl)Cl)[CH:38]=[CH:37][CH:36]=[CH:35]1)[CH3:33].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>CCOCC.C1COCC1.O.C1(C)C=CC=CC=1>[CH2:47]([C:42]1([TaH3:39][C:34]2([CH2:32][CH3:33])[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:46]=[CH:45][CH:44]=[CH:43]1)[CH3:48]
Reactant: CCC1([Ta](Cl)(Cl)C2(CC)C=CC=C2)C=CC=C1
Agent: [Ta+5]
Agent: CC(C)[Mg]Br
Agent: CCC1=CC=CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC1([TaH3]C2(CC)C=CC=C2)C=CC=C1
Temperature: -70 °C
Reaction time: 17 h
Yield: 10.1 %

Procedure:
75.0 g (209 mmol) of tantalum pentachloride was suspended in 1,200 ml of ether, and 335 ml (228 mmol) of isopropyl magnesium bromide (0.68M THF solution) was added thereto. A solution of 41.9 g (419 mmol) of ethylcylopentadienyl lithium prepared from ethylcylopentadiene and butyl lithium in THF (240 ml) was added, followed by refluxing for 1 hour. The solvent was distilled away, and the residue was dried at 80° C. in vacuo for 8 hours to obtain a dark brown solid containing bis(ethylcyclopentadienyl)dichlorotantalum (Ta(EtCp)2Cl2). 1,060 ml of toluene was added to this dark brown solid, and the resulting mixture was ice-cooled. 187 ml (623 mmol) of a toluene solution (65 wt %) of sodium bis(2-methoxyethoxy)aluminum hydride was added dropwise to the mixture, and temperature was returned to room temperature, followed by stirring for 17 hours. 107 ml of water was added to the mixture, followed by stirring until foaming does not occur. Insoluble contents were filtered out, and the solvent was distilled away from the filtrate. 590 ml of hexane was added to the residue, the insoluble contents were filtered out. When the filtrate was cooled to −70° C., a white solid was formed. The supernatant was removed, and the solid was washed with 24 ml of cold pentane two times to obtain a solid. The solid obtained was distilled in vacuo at 2.5 Pa/100° C. to obtain 7.79 g (yield: 10.1%) of a colorless liquid. When this liquid was cooled to room temperature, white crystals were formed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:37])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:25]3[CH2:24][C:23]([C:18]4[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=4)([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=3)=[CH:29][C:30]=2[CH3:37])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Cl)n1
Yield: 68.8 %

Procedure:
In a solution of 0.10 g of 2-amino-6-chloropyridine and 0.16 g of pyridine in 5 mL of dichloromethane, a solution of 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 5 mL of dichloromethane was added at room temperature with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH:1]([C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Nc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(Nc2ccccc2)c1
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution (22 mL) of methyl 3-anilinobenzoate (2.13 g, 9.37 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.36 g, 9.37 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hrs. Sodium sulfate 10 hydrate (9.1 g, 28.1 mmol) was gradually added to the reaction mixture and the mixture was stirred at room temperature for 5 hrs. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (1.12 g, yield 60%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Reaction time: 0.08 h

Procedure:
A solution of diethyl p-nitrobenzylphosphonate (2.73 g) in ethanol (10 mL) was added to a solution of sodium (0.245 g) in ethanol (20 mL). The resulting mixture was stirred for 5 min, and then a solution of 4-fluorobenzaldehyde (1.24 g) in ethanol (10 mL) was added. The reaction mixture was stirred for 1 h. a yellow precipitate (1.444 g) was isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH:10]([CH3:15])[C:11]([O:13]C)=[O:12].Cl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)C(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1cccc(F)c1)C(=O)O
Temperature: 80 °C
Yield: 42 %

Procedure:
To a solution of m-fluorophenol (24.2 g, 0.22 mol) in 79.2 ml of 2.5% aqueous sodium hydroxide heated to 45° C. with an oil bath was added 29.5 ml (0.26 mol) methyl 2-chloropropionate. The reaction mixture was heated to 80° C. for 17 hours and then allowed to cool. When the temperature reached about 40° C., concentrated HCl (25 ml) was added and the reaction mixture was allowed to cool to room temperature. The reaction mixture was extracted twice with 100 ml ethyl ether. The organic layers were combined and washed with 200 ml of 1.5M aqueous sodium carbonate. The aqueous layer was separated and acidified to pH 1, by pH test paper, by adding concentrated HCl. The acidified aqueous layer was extracted with 200 ml ethyl ether. The organic layer was separated, dried with MgSO4 and filtered. The solvent was removed in vacuo to yield 17 g (41% yield) of 2-(3'-fluorophenoxy)propionic acid as a yellow solid (m.p. 72.5°-74° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 4.5 h
Yield: 92.9 %

Procedure:
(S)—N′-(1-tert-Butyl-but-3-enyl)-hydrazinecarboxylic acid tert-butyl ester (2.34 g, 9.65 mmoles) was dissolved in methanol (50 mL) in a Parr bottle. 10% Pd/C (70 mg) was added as a slurry in water (1.6 mL), and the mixture was shaken on a Parr hydrogenator for 4.5 h with a starting pressure of 55 psi. The pressure dEcREase was monitored as a measure of the reaction progress, indicating that the reaction was likely complete after 30 minutes. The catalyst was allowed to substantially settle, and the supernatant was removed with a pipette, passed through a 0.45 micron syringe filter, and analyzed by TLC. Solvent was removed in vacuo to yield 2.19 g (92.7%) of (S)—N′-(1-tert-butyl-butyl)-hydrazinecarboxylic acid tert-butyl ester as a faintly pale yellow oil. Rf=0.48 (5:1 hexanes:ethyl acetate, I2 visualization), 1H NMR (400 MHz, CDCl3).6.0 (br, 1H), 4.0 (br, 1H), 2.5 (d, 1H), 1.5 (s, 9H), 1.1 (m, 2H), 1.6 (br, 2H), 0.94 (s, 9H), 0.94 (t, 3H).
Reaction SMILES: BrC1C(O)=C([C:9]2([C:12](N)=[O:13])[CH2:11][CH2:10]2)C(C#N)=C(C)C=1C1C=CC=CC=1.C1(C(O[C:30]2([NH2:46])[C:35]([C:36]#[N:37])=[C:34]([CH3:38])[C:33]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:32]([Br:45])[CH2:31]2)=O)CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:45][C:32]1[C:33]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[C:34]([CH3:38])[C:35]([C:36]#[N:37])=[C:30]2[C:31]=1[O:13][C:12]([CH:9]1[CH2:11][CH2:10]1)=[N:46]2
Reactant: CC1=C(C#N)C(N)(OC(=O)C2CC2)CC(Br)=C1c1ccccc1
Reactant: Cc1c(C#N)c(C2(C(N)=O)CC2)c(O)c(Br)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(Br)c2oc(C3CC3)nc2c1C#N
Yield: 85.7 %

Procedure:
Next, a mixture of (2-bromo-5-cyano-3-hydroxy-6-methylbiphenyl-4-yl)cyclopropanecarboxamide/4-amino-2-bromo-5-cyano-6-methylbiphenyl-4-yl cyclopropanecarboxylate mixture (160 mg, 0.426 mmol), p-toluenesulfonic acid monohydrate (24 mg, 0.128 mmol) and toluene (13 ml) was heated under reflux for 1.5 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (129 mg) as a colorless solid.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[F:15][C:16]1[C:21]([C@@H:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C:26](=[O:31])[C:25]2=[O:32])[CH3:23])=[CH:20][CH:19]=[C:18]([F:33])[N:17]=1.[OH-].[Na+].OO.S(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O.C1(C)C=CC=CC=1.C1COCC1>[F:15][C:16]1[C:21]([C@@H:22]([N:24]2[CH2:29][CH:28]([CH3:30])[O:27][C@H:26]([OH:31])[C:25]2=[O:32])[CH3:23])=[CH:20][CH:19]=[C:18]([F:33])[N:17]=1
Reactant: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S([O-])O
Agent: OO
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1CN([C@@H](C)c2ccc(F)nc2F)C(=O)[C@@H](O)O1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A 1 M solution of lithium tri-sec-butylborohydride in THF (20 mL) was added dropwise to a solution of (S)-4-[(S)-1-(2,6-difluoropyridin-3-yl)ethyl]-6-methylmorpholine-2,3-dione (4.5 g) in THF at −50° C. or less, and the reaction solution was stirred for two hours. A 5 N sodium hydroxide solution (1.66 mL) and 30% aqueous hydrogen peroxide (6.78 mL) were added dropwise to the reaction solution at −10° C. or less, and the reaction solution was stirred for one hour. Sodium bisulfite (520 mg) was added to the reaction solution, which was then stirred for 30 minutes. Brine and 50% toluene-THF were added to the reaction solution, and the organic layer was separated. The aqueous layer was washed with 50% toluene-THF. The organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (heptane:ethyl acetate=1:1 to 0:100) to obtain 4.52 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].O.OP([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.CC(O)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:32])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4CNC(=O)CO4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C1COC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)CN1
Temperature: 0 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
To a solution of 6-chloro-5-[4-(5-oxomorpholin-2-yl)phenyl]-1H-indole-3-carbaldehyde (150 mg, 0.42 mmol) in acetonitrile (5 mL) and t-BuOH (5 mL) was added 2-methyl-2-butene (2.9 g, 42 mmol). The mixture was cooled to 0° C. with ice bath. Sodium chlorite (1.15 g, 12.7 mmol) and sodium phosphate monobasic hydrate (1.75 g, 12.7 mmol) were dissolved in water (5 mL). The aqueous was added to the organic solution and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 48 hours. A solution of sodium sulfite was added slowly to the stirring mixture. The reaction mixture was allowed to stir 1 hour. Then the organics were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. The residue was purified by reverse phase HPLC to give the title compound (40 mg, 26% yield) as an off-white solid. MS (ES+) 371.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 4.65 (m, 1H), 4.22 (s, 2H), 3.46 (m, 2H).