Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CCc1nnc(CCl)o1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nnc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a 50 mL round-bottom flask was added (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) in DMSO (8 mL) followed by sodium tert-butoxide (102 mg, 1.059 mmol). The reaction mixture was stirred at room temperature for 10 minutes. 2-(Chloromethyl)-5-ethyl-1,3,4-oxadiazole (155 mg, 1.059 mmol) was then added to give an orange solution. After 1 hour, LC/MS indicated the reaction was complete. The reaction mixture was subsequently diluted with EtOAc and washed with aqueous saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (12 g SiO2 column, EtOAc (20-80%)/hexane gradient) to give the title compound as a pale yellow solid (165 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.58 Hz, 3H), 2.83 (d, J=7.33 Hz, 2H), 2.93-3.03 (m, 1H), 3.04-3.21 (m, 2H), 3.36-3.51 (m, 2H), 3.59-3.71 (m, 1H), 3.85-3.98 (m, 2H), 4.20-4.29 (m, 1H), 4.57-4.67 (m, 1H), 4.84-4.94 (m, 1H), 7.57 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C14H17ClN6O2, 337.78. found 337.2.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH:33]=[CH:32]1>C(C(C)=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.CO>[CH2:15]([O:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:16]1[O:18][CH2:17]1.[CH:1]([C:32]1=[CH:33][C:34]([O:36][C:31]1=[O:37])=[O:35])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)OCC1CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Solvent: CCC(C)=O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 70 °C
Reaction time: 10 h
Yield: 516.1 %

Procedure:
A monomer mixture comprising 600 g of styrene (hereinafter referred to as "St") and 70 g of glycidyl methacrylate (hereinafter referred to as "GMA") was dissolved in 1000 g of methyl ethyl ketone (hereinafter referred to as "MEK") in a four -necked flask fitted with a dropping funnel, a nitrogen inlet tube, a thermometer, a condenser and a stirrer and the solution was heated to 70° C. Another monomer mixture comprising 15 g of azobisisobutyronitrile (hereinafter referred to as "AIBN") as the polymerization initiator, 260 g of St, 70 g of maleic anhydride (hereinafter referred to as "MAH") and 280 g of MEK was stepwise dropped thereinto to initiate polymerization. After 10 h, the flask was cooled to room temperature arid the reaction mixture was immediately poured into a large quantity of methanol. The polymer thus precipitated was recovered by decantation, dried under reduced pressure in a vacuum drier axed Finely pulverized to give 870 g of styrene-maleic anhydride glycidyl methacrylate copolymer (3). According to GPC, the copolymer (3) had a number-average molecular weight (in terms of polystyrene ) of 15,000. The infrared absorption spectrum of the copolymer (3) is given in FIG. 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.C([O-])(O)=O.[Na+].[Br:24]Br>CO>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[C:3]=1[Br:24]
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(N)c(Br)c(=O)[nH]c2=O)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
300 g of 6-amino-1(p-methoxybenzyl)-uracil are taken up in 1200 ml of methanol and mixed with 105 g of NaHCO3. After cooling to 5° C., 66 ml of bromine are added dropwise with stirring. After the conversion is complete (about 2 hours) the resulting suspension is suction filtered, the residue is washed with methanol (2×100 ml) and the product is isolated in the form of bright yellow crystals (374 g, 95%) (melting point: 247° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:31][C:24]1[CH:25]=[C:26]([F:30])[CH:27]=[C:28]([F:29])[C:23]=1[CH2:22][N:10]1[C:9]([C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:8]=[CH:7][CH:6]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C#Cc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)c2)c1
Yield: 46.8 %

Procedure:
A solution of 3-(3-ethynylphenyl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.103 g, 0.24 mmol), ethyl 3-iodobenzoate (0.042 mL, 0.25 mmol), tetrabutylammonium acetate (0.108 g, 0.36 mmol) and 8.8 mg of tris-(dibenzylidineacetone)-dipalladium in 2 mL of dry DMF was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned with ethyl acetate and H2O. The organic phase was concentrated in vacuo and purified by flash chromatography (silica 60, CH2Cl2-hexane, 1:1) to give the title compound (0.065 g).
Reaction SMILES: ClC1C(C)=C(S(O[C@H:12]([CH3:31])[CH2:13][C:14]2[N:18]=[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[CH3:30])(=[O:22])=[O:21])[S:16][N:15]=2)(=O)=O)C=CC=1.[F:33][C:34]1[CH:35]=[C:36]([SH:40])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([S:20]([NH:19][C:17]2[S:16][N:15]=[C:14]([CH2:13][C@H:12]([S:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)[CH3:31])[N:18]=2)(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Fc1cccc(S)c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C[C@@H](C)OS(=O)(=O)c2cccc(Cl)c2C)ns1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C[C@@H](C)Sc2cccc(F)c2)ns1

Procedure:
(R)-2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-1-methylethyl 3-chloro-2-methylbenzenesulfonate (example 98), 3-fluorothiophenol (1 eq) and sodium carbonate (1 eq) in CH3CN were heated overnight. Standard work-up and purification yielded the desired product.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1.O=P(Cl)(Cl)[Cl:31].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1
Reactant: CCOC(=O)c1cncc(-c2nnc(O)c3c(-c4ccccc4)cccc23)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-(4-hydroxy-5-phenylphthalazin-1-yl)nicotinate (3.50 g, 9.42 mmol) in toluene (35 mL) was added POCl3 (26.4 mL, 283 mmol) followed by N,N-dimethylbenzenamine (1.5 mL, 9.42 mmol). The resulting mixture was heated in a sealed tube at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated NaHCO3 (2×50 mL) solution. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield ethyl 5-(4-chloro-5-phenylphthalazin-1-yl)nicotinate (3.50 g) as a yellow solid with LC-MS purity of 47% which was taken for the next step without further purification. LCMS (Condition 12): retention time 0.97 min, [M+1]=390.0.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:62]1[CH:63]=[C:64]2[C:68](=[CH:69][CH:70]=1)[N:67]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH:66]=[CH:65]2>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:74]([O:73][C:71]([N:67]1[C:68]2[C:64](=[CH:63][C:62]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:70][CH:69]=2)[CH:65]=[CH:66]1)=[O:72])([CH3:77])([CH3:75])[CH3:76]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.20 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 17 mg, tris(dibenzylideneacetone)dipalladium(0) 7 mg, palladium acetate 2 mg and cesium carbonate 0.48 g was added tert-butyl 5-bromoindol-1-carboxylate 0.55 g, and it was heated and refluxed for 8 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-((1-(tert-butoxycarbonyl)-1H-indol-5-yl)amino)-4-phenylbenzoate.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[OH:33].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:31]1\[CH:32]=[C:23]([CH3:22])[C:24](=[O:33])[C:25]2[C:30]\1=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: Cc1ccc2ccccc2c1O
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)c2ccccc2C1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 2-methyl-1-naphthol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: C(Cl)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[C:13](\[CH2:18][NH:30][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:28])=[O:29])/[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: COC(=O)/C(=C/c1ccc(Br)cc1)CNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 390 μL (5.46 mmol) of acetyl chloride in 10 mL of THF at 0° C. was added 1.41 g (5.20 mmol) of methyl 2-[(4-bromophenyl)(hydroxy)methyl]-2-propenoate and 870 μL (6.24 mmol) of TEA in 10 mL THF. After 2 hr at ambient temperature another 870 μL (6.24 mmol) of TEA and 390 μL (5.46 mmol) of acetyl chloride was added and the solution stirred at ambient temperature for an additional 1 hr. EtOAc was added and the organics washed with three 50 mL portions of H2O then 50 mL of brine. The organics were dried over Na2SO4 then concentrated. This residue was then taken up in 25 mL of DMF and 4.35 g (25.4 mmol) of 4-methylbenzenesulfonamide and 3.51 g (25.4 mmol) of K2CO3 were added. The mixture was stirred at 50° C. for 3 hr. To the mixture was added 100 mL of EtOAc which was then washed with three 50 mL portions of water, then brine. The solution was concentrated and the residue purified by silica gel chromatography (120 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes) to give 820 mg (37%) of methyl (2E)-3-(4-bromophenyl)-2-({[(4-methylphenyl)sulfonyl]amino}methyl)-2-propenoate as a beige glass. 1H NMR (400 MHz, CDCl3): δ 7.68-7.66 (m, 3H), 7.52 (d, J=7 Hz, 2H), 7.29-7.25 (m, 4H), 5.51 (t, J =6 Hz, 1H), 3.86 (d, J=6 Hz, 2H), 3.75 (s, 3H), 2.43 (s, 3H). ESI-LCMS m/z 425 (M+H)+.
Reaction SMILES: [C:1](=[O:15])(OC(Cl)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F-:16].[K+].C1OCCOCCOCCOCCOCCOC1>>[F:16][C:1]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:15]
Reactant: CCCCCCCCOC(=O)OC(C)Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: CCCCCCCCOC(=O)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A mixture of 10.6 g (0.045 mole) of previously distilled octyl 1-chloroethyl carbonate, 4.5 g (0.08 mole) of dry KF and 0.6 g (0.002 mole) of 18-crown-6 ether is stirred and warmed at about 85° C. (oil bath ) under a pressure of about 1.87 kPa. After 12 hrs., all the volatile acetaldehyde has evaporated. The mixture is cooled and distilled under reduced pressure. There is obtained 6.87 g of pure n-octyl fluoroformate (86%). b.p.: 74°-77° C. at 533 Pa (4 mmHg).
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[C:25](OC)[C:24]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])([CH3:22])[CH3:21]>O1CCCC1.C1C=CC=CC=1>[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[C:25]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:24]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])([CH3:21])[CH3:22]
Reactant: COc1c(C(=O)OC(C)C)c(C(C)C)cc(C(C)C)c1C(=O)OC(C)C
Reactant: Fc1ccc(Br)c(OCc2ccccc2)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)OC(=O)c1c(C(C)C)cc(C(C)C)c(C(=O)OC(C)C)c1-c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A dry flask containing freshly ground magnesium turnings (2.88 g, 120 mmol) and a crystal of iodine was heated until a dark purple iodine atmosphere had formed. The flask was cooled to ambient temperature and a solution of 2-bromo-5-fluorophenyl benzyl ether (33.8 g, 120 mmol, Example 166, Step A) in dry tetrahydrofuran (60 mL) was added in several portions over 40 minutes at a rate sufficient to maintain reflux. Reflux was continued for 45 minutes, then the reaction was cooled to room temperature. This solution of Grignard reagent was transferred via syringe to a second flask containing a solution of the intermediate from Step D (11.0 g, 30.2 mmol) in dry benzene (66 mL). The reaction mixture was held at reflux for one hour, quenched with 10% aqueous hydrochloric acid (300 mL) and extracted with diethyl ether (3×300 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a brown oil which was subjected to flash column chromatography on silica (80 mm×19.5″) using a stepwise gradient elution of dichloromethane:hexanes (1:3, 1:2, 1:1, 4L each). The fractions containing the product were combined and concentrated to afford an inseparable mixture of the product and an unidentified side product in about a 1:1 ratio as a pale yellow gum (5.3 g, 33% mass balance). This material was not fully characterized and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([O:19][CH:20]([CH3:24])[C:21](Cl)=[O:22])(=[O:18])[CH3:17]>CC(C)=O>[C:16]([O:19][CH:20]([CH3:24])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:22])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(C)=O
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 88.5 %

Procedure:
20.3 g (100 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 18.0 g (120 millimoles) of 2-acetoxypropionyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 28.1 g (88.6%) of 6-[p-(2-acetoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 198°-200° C. (dimethylformamide/water).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:8][C:9]#[N:10].[K+]>C(O)(=O)C.O>[C:2]1([NH:1][C:9]([NH2:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of aniline (2.51 g, 27 mmol) dissolved in glacial acetic acid (14 mL) and water (28 mL) was slowly added a solution of potassium cyanate (4.4 g, 54 mmol) dissolved in water (35 mL). The mixture stirred for 2 h at RT, filtered, washed with water and dried under reduced pressure to yield phenylurea as a white solid (1.85 g, 50% yield). 1H NMR (DMSO-d6): δ 8.47 (s, 1H), 7.38 (dd, J=8.4 Hz, 0.9 Hz, 2H), 7.2 (t, J=7.6 Hz, 2H), 6.88 (t, J=7.6 Hz, 1H), 5.81 (brs, 2H); MS (ESI) m/z: 137 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22](=[NH:30])[NH:23][O:24][C:25]([O:27]CC)=O)=[CH:12][CH:11]=2)[C:7]2[C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:2].N12CCCN=C1CCCCC2>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][O:24][C:25](=[O:27])[N:30]=3)=[CH:14][CH:15]=2)[C:7]2[C:31]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)ONC(=N)c1ccccc1-c1ccc(Cn2c(OCC)nc3cccc(C(=O)OC)c32)cc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
The crude crystals (4.0 g) obtained in Example (57b) was dissolved in ethyl acetate (50 ml). To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.2 g), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was partitioned between ethyl acetate (50 ml) and 1N HCl (20 ml). The organic layer was washed with water, dried and concentrated to dryness. The residue was crystallized from chloroform-ethyl acetate to afford the title compound as colorless prisms (2.1 g, 45%), which was in agreement with that obtained in Example (1d).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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]>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[CH:3][C:2]([NH2:24])=[CH:10][C:6]1=2
Reactant: Brc1ccc2ccsc2c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccc2ccsc2c1
Yield: 13.4 %

Procedure:
A mixture of 6-bromobenzo[b]thiophene (16.0 g, 76.0 mmol), benzophenone imine (16.6 g, 91.5 mmol), tris(dibenzylidineacetone)palladium(0) (0.72 g, 0.80 mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.3 g, 2.3 mmol) and sodium tert-butoxide (10.8 g, 112 mmol) in toluene is refluxed for 20 hours. The solvent is evaporated and the residue is chromatographed on silica, eluting with dichloromethane) to give the title compound (1.52 g, 11% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCc2ccc(C#N)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 68.1 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.52 mmol), 4-(2-aminoethyl)benzonitrile (0.09 g, 0.63 mmol) and TEA (0.07 g, 0.68 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 120° C. for 35 mins. 4-(2-Aminoethyl)benzonitrile (0.04 g) was added to the reaction mixture, and it was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was evaporated and the crude product was purified by flash column chromatography using hexane and EtOAc, 80:20-50:50, as eluant, to yield the title compound (0.14 g, 67%). 1H NMR (500 MHz, CDCl3): δ 1.57 (d, 6H), 2.63 (t, 2H), 3.15-3.19 (m, 2H), 4.37-4.43 (m, 1H), 5.46 (brm, 1H), 6.86 (d, 2H), 7.45-5.55 (m, 7H); 13C NMR (125 MHz, CDCl3): δ 20.4, 36.2, 44.5, 47.9, 107.8, 111.0, 118.9, 125.2, 129.1, 129.5, 130.1, 131.8, 132.7, 135.1, 143.1, 158.6; Mass Spectrum: M−H+ 394.
Reaction SMILES: C(OC(C)C)(C)C.[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11]>CC(C)=O>[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(C)(C)[C@@H](N)C(=O)O
Yield: 90 %

Procedure:
The filtrate obtained at dibenzoyl-d-tartrate salt stage (step.ii), was treated with a small amount of diisopropyl ether to remove any traces of dibenzoyl-d-tartaric acid and was concentrated under reduced pressure at 55° C. The residue obtained was stirred with small amount of acetone and filtered to obtain D-tert-leucine as a colorless solid (90% yield, 98.8% D-tert-leucine and 1.2% L-tert-leucine).
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:19][CH2:20][CH3:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:22])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:22])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([O:19][CH2:20][CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CCON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)OC
Yield: 84 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-ethoxy-N-(4-fluorobenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (84% yield); mp 61–62° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.28 (3H, t, J=7.1 Hz, CH3), 3.91 (3H, s, OCH3), 3.92 (2H, q, J=7.1 Hz, OCH2), 4.82 (2H, s, NCH2), 6.47 (1H, s, CH), 7.05 (2H, m, aromatics), 7.32 (2H, m, aromatics), 13.5 (1H, broad s, OH). Anal. calcd for C14H16FNO5: C, 56.56; H, 5.42; N, 4.71. Found: C, 56.67; H, 5.25; N, 4.64.