Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH:25]([S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[C:19]([F:40])[C:18]=2[F:41])=[C:15]([F:42])[C:14]([F:43])=[C:13](F)[C:12]=1[F:45].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:45])=[C:11]([F:10])[C:16]([C:17]2[C:18]([F:41])=[C:19]([F:40])[C:20]([CH:25]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:28])[S:33]([C:36]([F:37])([F:38])[F:39])(=[O:35])=[O:34])=[C:21]([F:24])[C:22]=2[F:23])=[C:15]([F:42])[C:14]=1[F:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(C(c1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCOc1c(F)c(F)c(-c2c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c2F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane (1.2 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 80° C.), and {4-(4-hexanoxy-2,3,5,6-tetrafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane was obtained at 94% yield (1.27 g, 1.88 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:36]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (9.66 mmol, 3.64 g) and Lawesson's reagent (6.0 mmol, 2.46 g, 0.62 equiv.) was added toluene (15 mL, which had been stored over 4 Å molecular sieves) at room temperature. The suspension was heated to 90-100° C. and was stirred for 24 h. Examination of the resulting clear solution by TLC failed to detect the presence of starting material. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic extract was dried (MgSO4) filtered and evaporated under reduced pressure. The crude compound was purified by careful silica gel column chromatography (hexane:ethyl acetate, 4:1 to 2:1) to obtain 1.52 g (40%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester as a yellow solid, mp 150-153° C. (triturated from diethyl ether/hexane 3:1 ratio). HRMS: Obs. mass, 393.0685. Calcd. mass, 393.0677 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:23](N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:34])[CH3:33].C(OCC)(=O)C>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1cccc(N)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)=O)c1)N2
Yield: 76.3 %

Procedure:
To a solution of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.97 mmol) in dichloromethane (10 mL) was added acetyl chloride (0.04 mL, 0.58 mmol) with ice cooling. The resultant mixture was kept 0° C. overnight. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.4) showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by Prep. Thin layer chromatography (petroleum ether:ethyl acetate=3:1) to afford 129 mg of methyl 2-(3-acetamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a off-white solid. Yield: 71.1%.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[NH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)#[N:8].[N:24]#[C:25]Br>C1COCC1>[Cl:14][C:13]1[C:9]([C:7]#[N:8])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:11]([C:25]#[N:24])[C:12]=1[Cl:15]
Reactant: N#CBr
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(Cl)c(Cl)n(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
Potassium t-butoxide (617 mg, 55 mmol) is added in portions to a solution of 3-cyano-4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole (1.52 g, 5 mmol) in anhydrous THF (20 mL). After 30 minutes, a solution of cyanogen bromide (583 mg, 5.5 mmol) in THF (1 mL) is added. The reaction mixture is stored at room temperature overnight. The solvent is removed in a rotary evaporator. The residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried (MgSO4). Evaporation and crystallization of the residue from ethyl acetate gives while crystals (1.07 g); mp 250.5°-252.0° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:3]=1.CCN(CC)CC.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32].Cl>C1COCC1.CCOC(C)=O>[OH2:32].[ClH:34].[CH3:1][C:2]1[NH:7][C:6]2[C:5]([N:10]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:8]=2)=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:19][CH2:18]2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(S(C)(=O)=O)CC2)c2nc(-c3ccccc3)cc-2[nH]1
Product: O
Temperature: 0 °C
Reaction time: 2 h
Yield: 144 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 2-methyl-6-phenyl-4-piperazinylpyrrolo[3,2-d]pyrimidine (Example 26) (400 mg, 1.36 mmol) was suspended in anhydrous THF (20 mL) and Et3N (0.4 mL, 2.8 mmol) was added. The mixture was cooled to 0° C. and methanesulfonyl chloride (Aldrich Chemical Company) (0.12 mL, 1.5 mmol) was added dropwise and allowed to warm to room temperature over 30 min. EtOAc (50 mL) was added to the mixture which was extracted with saturated NaHCO3 (3×50 mL). The organic layer was washed with saturated NaCl (75 mL), dried over MgSO4, filtered and evaporated in vacuo to give 450 mg (89% yield) as a light yellow solid. The free base (440 mg, 1.2 mmol) was dissolved in hot EtOAc (20 mL) and anhydrous ethereal HCl (1.18 mL, of a 1.0 M soln, 1.18 mmol) was added dropwise. The mixture was stirred for 2 h and allowed to cool to room temperature. The resulting solid was filtered and dried under high vacuum to give 460 mg (95.6% yield) of the title compound as a light yellow solid. Mp: 280-282° C. 1H NMR (DMSO-d6; 400 MHz); d 2.54 (s, 3), 2.88 (s, 3), 3.29 (s, 4), 4.13 (t, 4, J=4.62), 6.9 (s, 1), 7.51 (m, 3), 7.94 (d, 2, J=6.85). MS m/z: 372 (M+1); 370 (M−1). Anal. Calcd for C18H21N5O2S.HCl.H2O.: C, 50.46; H, 5.70; N, 16.35; Cl, 8.41. Found: C, 50.71; H, 5.60; N, 16.22; Cl, 8.45.
Reaction SMILES: [O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.Cl>[O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3]1
Reactant: O=S1(=O)CCC(CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)C2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of (1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-yl)-methanol (3.59 g), 4-toluenesulfonyl chloride (9.11 g) and pyridine 5.8 mL) in chloroform (50 mL) was heated to 60° C. and stirred overnight. The reaction mixture was cooled and diluted with 100 mL 1N HCl and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 4.012 g of toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[N:6]=1)([CH3:3])[CH3:2].[OH-:20].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13](/[CH:9]=[CH:10]\[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:20])[N:12]=2)[CH:8]=[C:7]([C:16]([F:18])([F:17])[F:19])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(OC(C)C)nc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
In a 50 ml capacity 3-neck round-bottomed flask attached with nitrogen bubbler, & magnetic stirrer 2-isopropoxy-4-(1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine (1 g), dissolved in 10 ml DMF at RT. Ethyl iodo acrylate (1.310 g) in DMF (1 ml) dropwise added in the reaction mixture. Then NaOH (0.291 g) added and stirred the reaction mixture for 12 h at 0° C. Completion of the reaction confirmed on TLC in 30% ethyl acetate/hexane mobile phase. Reaction gives two isomeric compounds (cis/trans). The reaction mixture was poured in ice water solution & extract with ethylacetate (3×50 mL). Organic layer dried over Na2SO4 & concentrate to give crude product (1.1 g). The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 1% to 5% ethyl acetate in hexane. Compound started eluting with 5% ethyl acetate in hexane. Fractions containing such TLC profile was collected together to obtain pure (Z)-isopropyl 3-(3-(2-isopropoxy-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39])[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[O:35][CH2:33][CH3:34])=[O:31]
Reactant: O=C(Br)CBr
Reactant: CCOc1ccccc1CN
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC(C)C)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH2:8]O)[CH:7]=1.[BrH:20].[C:21]1([PH+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br-:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:7]=1)[CH2:8][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Br
Reactant: COc1ccc(CCc2ccc(F)cc2CO)cc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(CCc2ccc(F)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Yield: 90.5 %

Procedure:
A solution of 5.95 g (22.86 mmol) of {5-fluoro-2-[2-(4-methoxyphenyl)ethyl]phenyl}methanol from Example 31A in 130 ml of acetonitrile is mixed with 7.45 g (21.71 mmol) of triphenylphosphonium hydrobromide and heated to reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is taken up and triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a drying oven at 50° C. overnight. 11.5 g (77% yield) of crystalline product are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]3[CH:5]=[C:4]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:3][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(-c3ccccc3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 16.9 %

Procedure:
To a stirred solution of 0.130 g (0.465 mmol) (2-amino-5-phenyl-thiophen-3-yl)-phenyl-methanone in 7 ml acetic acid was added 62 mg (0.491 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 110° C. for 20 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 29 mg (17%) cyclopropyl-(6-methyl-2,4-diphenyl-thieno[2,3-b]pyridin-5-yl)-methanone as a light yellow powder. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][NH2:15])[CH2:11][C@H:10]2[C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[O:8])=[CH:3][CH:2]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:15][N:14]=[C:12]1[CH2:13][N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:6][CH:5]=2)=[O:8])[C@H:10]([C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:17])[CH2:11]1)(=[O:36])[CH3:35]
Reactant: NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 8 h

Procedure:
A hydrazono pyrrolidine derivative obtained by the general method outlined in Example 17, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide (51 mg, 0.11 mmol) was dissolved in pyridine (1 mL). Acetic anhydride (3 eq, 32 μl, 0.35 mmol) was added, and the mixture was stirred overnight. The solvent was evaporated and the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (20:1) to collect the desired product, e.g. (2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 73% yield (98.4% purity by HPLC).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.[C:18](Cl)(Cl)=[O:19].Cl.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34]([C:36]3[CH:45]=[C:44]4[C:39]([CH2:40][CH2:41][NH:42][CH2:43]4)=[CH:38][CH:37]=3)[N:33]=[C:32]([NH2:46])[N:31]=2)[CH2:26][CH2:25]1>>[NH2:46][C:32]1[N:33]=[C:34]([C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][N:42]([C:18]([NH:17][C@@H:14]4[CH2:15][CH2:16][O:12][CH2:13]4)=[O:19])[CH2:43]3)=[CH:38][CH:37]=2)[CH:35]=[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]2)[N:31]=1
Reactant: O=C(Cl)Cl
Reactant: N[C@@H]1CCOC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H]3CCOC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from (3R)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (Fluka, Cat. #09440), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=438.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.CCN(CC)CC.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][C:25](=[O:27])[CH3:26])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (80 mg, 0.34 mmol, 1 equiv) in CH2Cl2 (10 ml) was added NEt3 (0.142 ml, 1.02 mmol, 2 equiv) and acetic anhydride (0.078 ml, 0.82 mmol, 2.4 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was then diluted with AcOEt (20 ml), washed with 2N aqueous HCl solution (20 ml), dried over MgSO4, and concentrated in vacuo to give 3-acetylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B50) (67 mg, 71%) as a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C@H:17]1[CH2:19][O:18]1
Reactant: Oc1cc(Br)ccc1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(Br)cc1OC[C@H]1CO1
Yield: 82 %

Procedure:
A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared using literature procedure [EP0238272] and (2R)-glycidyl 3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treated with potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (4.25 g) in 82% yield. 1H NMR (400 MHz, CDCl3): δ7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd, 1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7]([CH:9]([CH3:11])[CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])/[CH:6]=[C:7](\[CH:9]([CH3:11])[CH3:10])/[CH2:8][P:21]([O:24][CH3:25])([O:22][CH3:23])=[O:26])[CH3:2]
Reactant: C=C(C(C)C)C(O)C(NC=O)C(=O)OCC
Reactant: COP(OC)OC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(/CP(=O)(OC)OC)C(C)C)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of 3-methyl-2-methylene-butanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 15 to 2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[C:5]([C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](O)=[O:10])=[O:6].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C>CCCCCC>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:5]1([C:4]2[CH:20]=[CH:21][C:22]([N:24]([CH3:26])[CH3:25])=[CH:23][C:3]=2[N:2]([CH3:27])[CH3:1])[C:7]2[C:8](=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([Cl:17])[C:15]=2[Cl:16])[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(N(C)C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
A mixture of most of the 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid from part A of this example, N,N,N',N'-tetramethyl-m-phenylenediamine (0.82 g. plus 0.4 g.) and acetic anhydride was heated under reflux. Concentration of a toluene extract of the resulting product gave a tar, which was slurried in hexane, affording 3,3-bis(2,4-bis(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y2 =Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =Cl) (m.p. 195°-197° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH2:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>CC#N>[Br:14][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:13]
Reactant: COc1ccc2cc(N)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc2c(Br)c(N)ccc2c1
Yield: 74.4 %

Procedure:
6-Methoxy-2-naphthylamine (400 mg, 1.6 mmol) was suspended in 20 mL of MeCN with 12 mg of NH4OAc (0.16 mmol) and stirred in an ice bath. N-Bromosuccinimide (299 mg, 1.68 mmol) was dissolved in 6 mL of dry MeCN and added slowly over 1 hour (h). The reaction was stirred for an additional hour at 0° C., then adsorbed onto Celite, concentrated under reduced pressure and subjected to silica gel chromatography eluting with 0→60% EtOAc in heptanes to yield 300 mg of an orange solid. 7.94 (d, 1H); 7.55 (d, 1H); 7.18 (dd, 1H); 7.09 (d, 1H); 7.02 (d, 1H); 4.29 (br s, 2H); 3.89 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH3:13])=[C:7]([OH:9])[CH:8]=1.C(N(CC)CC)C.[I:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][C:26](=[O:33])/[C:25]/2=[CH:34]/OC.O>CN(C)C=O>[OH:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[O:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:1]/[CH:34]=[C:25]1\[C:26](=[O:33])[NH:27][C:28](=[O:32])[C:29]2[C:24]\1=[CH:23][C:22]([I:21])=[CH:31][CH:30]=2
Reactant: CCCOc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount of 5-(aminomethyl)-2-propoxyphenol) (60 mg, 0.33 mmol) is dissolved in N,N-dimethylformamide (2 mL). 0.137 m/(1.0 mmol) of triethylamine is added followed by 100 mg (0.30 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (5 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 54 mg of a white solid. MS (ESI) m/z 480.3 (M+1).