Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21].C1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:20]([Cl:22])=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reaction time: 2 h

Procedure:
A solution of proline t-butyl ester (10.0 g; 0.058 mol) and triethylamine (8.56 ml; 6.22g; 0.0614 mol) in dry THF (60 ml) was added to a cold (0° C.) solution of phosgene (12.5%) in benzene (61 ml; 0.070 mol) over 1 hour. An additional 50 ml of dry THF was added and stirring was continued for 2 hours. The reaction mixture was filtered and evaporated, giving N-chlorocarbonyl-(L)-proline t-butyl ester (1) as a dark-red oil (13.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1
Yield: 66.9 %

Procedure:
A mixture of 4-chlorophenol (2.00 g, 15.56 mmol), 1-fluoro-2-nitrobenzene (2.20 g, 15.56 mmol) and potassium carbonate (2.15 g, 15.56 mmol) in DMF (10 mL) was stirred under reflux for 1 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 1-(4-chlorophenoxy)-2-nitrobenzene (2.6 g, 67%) as a yellow oil which solidified upon standing at room temperature (mp 33-35° C. from EtOH) and was used in the next step without further purification. Rf: 0.77 (DCM) 1H NMR (270 MHz, CDCl3) δ 696 (2H, AA′BB′), 699 (1H, m), 7.22 (1H, m), 7.31 (2H, AA′BB′), 7.52 (1H, m) and 7.96 (2H, dd, J=8.2, 1.7 Hz)
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:27][OH:28]>C(O)C.O>[OH:28][N:27]=[C:17]([C:14]1[S:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:16][CH:15]=1)[NH2:18]
Reactant: NO
Reactant: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(C(N)=NO)s2)cn1
Yield: 97.2 %

Procedure:
To a solution of Example 81A (343 mg, 1.3 mmol) and triethylamine (0.9 ml, 6.5 mmol) in ethanol/water (95:5, v/v, 10 mL) was added hydroxylamine hydrochloride (228 mg, 3.25 mmol). The reaction was heated at reflux for 15 minutes and concentrated on a rotary evaporator. The residual solids were dissolved in dichloromethane (50 mL), and washed with water (50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 30% ethyl acetate in hexanes to provide 372 mg of the title compound (96%) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.25 Hz, 6H) 5.11-5.33 (m, 1H) 6.03 (s, 2H) 6.84 (d, J=9.19 Hz, 1H) 7.61 (s, 1H) 7.78 (dd, J=9.01, 3.13 Hz, 1H) 8.22 (d, J=2.94 Hz, 1H) 9.71 (s, 1H); MS (ESI) m/z 295.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 92 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform, 62 mg (43%) of the desired compound (Rf 0.16, 10% methanol in chloroform) as an off-white solid, m.p. 122°-124° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A mixture of (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (40 mg, 0.068 mmol), 2-fluorophenylboronic acid (18 mg, 0.128 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3.9 mg, 0.005 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, 0.204 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone, which was used in step 5 without further purification.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:27]([C:28]([NH2:30])=[O:29])=[CH:26][NH:25][N:24]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C:31]([CH:33]=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)#[N:32].O>CN(C=O)C>[C:28]([C:27]1[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[N:24][N:25]([C:34]2([CH2:33][C:31]#[N:32])[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:38][CH2:39]2)[CH:26]=1)(=[O:29])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C(N)=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cc3)n2)CC1
Temperature: 50 °C

Procedure:
DBU (0.118 mL, 0.785 mmol) was added 3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate 34-2) (200 mg, 0.714 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (Intermediate 19-1) (317 mg, 1.43 mmol) stirred in DMF (3 mL) and the mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to 23° C., water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S-:33].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([S:33][CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of tert-butyl(6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.24 g, 0.5 mmol), sodium thiomethoxide (0.080 g, 1.1 mmol) and N,N-dimethylformamide (4 mL) was stirred at 85° C. for 1 h, and the reaction mixture was poured into water (50 mL) and extracted twice with ethyl acetate (25 mL). The extracts were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl[2-isobutyl-6-(methylsulfanyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.17 g, 73%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH3:24]>CN(C=O)C>[CH3:1][C:2]1[N:7]([CH2:23][CH3:24])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCCn1c(=O)[nH]c(C)c([N+](=O)[O-])c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c([N+](=O)[O-])c(C)n(CC)c1=O
Temperature: 80 °C

Procedure:
To a mixture of the nitro derivative, 6-methyl-5-nitro-3-propyl-1,3-dihydropyrimidine-2,4-dione prepared in Example 5 (1.56 g) and K2CO3 (3.0 g) in DMF was added iodoethane. The reaction mixture was heated at 80° C. for 3 h. After completion of the starting material, K2CO3 was filtered and DMF was distilled off. The residue was dissolved in ethyl acetate, washed with water, brine and dried over Na2SO4 Removal of solvent furnished the product as yellow oil, which was purified using flash chromatography. Elution with 30% ethyl acetate/hexane furnished the material as white solid, which was characterized by using NMR and mass.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:4][CH:3]=1.COC1C=CC(NC2C=CC(C(F)(F)F)=CC=2)=C(C=1)CN1C(C)(C)C(=O)N(C2C=CC(C#N)=C(C(F)(F)F)C=2)C1=O>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:9]([NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[C:10]([CH:33]=1)[CH2:11][N:12]1[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:30])([F:31])[F:29])[CH:21]=2)[C:13]1=[O:32]
Reactant: COc1ccc(Nc2ccc(F)cc2)c(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c1
Agent: COc1ccc(Nc2ccc(C(F)(F)F)cc2)c(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c1
Product: COc1ccc(Nc2ccccc2)c(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c1

Procedure:
The compounds of example 7, 4-{3-[2-(4-fluorophenylamino)-5-methoxybenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 526.16 (C27H22F4N4O3); retention time Rt=2.19 min. [B]; MS (ESI): 527.13 (MH+), and of examples 8, 4-{3-[5-methoxy-2-(4-trifluoromethylphenylamino)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 576.15 (C28H22F6N4O3); retention time Rt=2.30 min. [B]; MS (ESI): 577.15 (MH+),
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][NH:5][C:6]([C@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)=[O:7].C[O-].[Na+]>C(O)C>[C:6]1(=[O:7])[C@H:8]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]2[C:3](=[O:17])[CH2:4][NH:5]1
Reactant: COC(=O)CNC(=O)[C@H]1Cc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(=O)N2c3ccccc3C[C@H]12
Temperature: 25 °C

Procedure:
methyl{[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate (390 mg) was mixed with 100 mg of NaOMe in 5 mL of Ethanol. The mixture was refluxed for 2 hours and cooled to RT. The crude material was purified by flash chromatography to give the desired (10aR)-2,3, 10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:15][C:16]1[CH:21]=C(C(C)(C)C)C(O)=[C:18](C(C)(C)C)[CH:17]=1.CC(=C)CCO>O.C1CCCCC1>[CH3:2][C:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH:16]([CH3:21])[CH:17]=[CH:18][O:3]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)c1ccccc1
Agent: C=C(C)CCO
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Product: CC1C=COC(C)(c2ccccc2)C1
Temperature: 94 °C

Procedure:
Into a one-liter three neck flask equipped with stirrer, condenser, Barrett Trap, thermometer, addition funnel and heating mantle is placed 288 gms (2.4 moles) of acetophenone, 150 ml cyclohexane, 1 g of concentrated sulfuric acid and 1 g of Ionol®. The resulting mixture is heated to reflux temperature (94° C.). Then 208 gms (2.4 moles) of 3-methyl-3-buten-1-ol is added, dropwise from the addition funnel, to the reaction mass with stirring while maintaining the reaction mass at reflux. Water of reaction formed is azeotroped over into the Barrett Trap. The reaction mass is heated for a period of 10 hours, during which time 24 ml water collected. At the end of the 10 hour period, the reaction is cooled to room temperature and 2 gms of a 50% sodium hydroxide solution are added. The reaction mass is then rushed over using a 2 inch splash column after adding thereto 10 gms Primol® and 0.1 gms Ionol®. Fractions collected and fractionation data for this rush over is as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH2:25]([P:27]([O:30]C)[O:28][CH3:29])[CH3:26]>C(#N)C>[CH2:25]([P:27]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:30])[O:28][CH3:29])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CCP(OC)OC
Solvent: CC#N
Product: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, 1.5 g (4.14 mmol) of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene, 0.81 g (6.6 mmol) of dimethyl ethylphosphonite and 3 ml of acetonitrile are reacted together to give methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)([CH3:29])([CH3:28])[CH3:27]>[N+](C)([O-])=O.O>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of (E)-N-methyl-2-(2-phenoxyphenyl)2-methoxyiminoacetamide (300 mg) in nitromethane (3 ml), aluminium chloride (423 mg) and t-butyl chloride (147 mg) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with diethyl ether. The solvent was dried and evaporated, and the residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate to give 375 mg of the objective compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][C@@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=1.P([O-])([O-])([O-])=O>CS(C)=O.C(OCC)(=O)C>[OH:1][C@@H:2]([CH2:24][C@@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=1
Reactant: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)OCC)cs1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCC[C@H](C)C[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCSc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of the compound 29 (142 mg) in dimethylsulfoxide (7.00 mL)/phosphate buffer (7.00 mL) was added esterase from porcine liver (0.850 mL) and the solution was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with an aqueous saturated ammonium sulfate solution, 1N hydrochloric acid, water and brine. The reaction solution was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate), to give the title compound (88.0 mg) having the following physical data.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][OH:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][OH:40])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq) was dissolved in THF (0.07M). Then MeOH (2.5× the volume of THF) was added, followed by a 1N NaOH solution (2 eq). The reaction was stirred overnight and the solvent was then removed. The resulting residue was dissolved in water and 1N HCl was added until solution was acidic. The resulting white precipitate was collected by filtration and it was the title compound in 76% yield. m/z (M−1) 557.6
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O
Temperature: 120 °C
Yield: 55 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (250 mg, 0.8443 mmol) was dissolved in dry DMF and 4 Å molecular sieves were added to maintain dryness. 4-fluorophenyl-tri-n-butylstannane (392 mg, 1.013 mmol) and bis(triphenylphosphine)palladium(II) dichloride (71 mg, 0.1013 mmol) were added sequentially and the reaction heated to 120° C. in an oil bath. Upon completion, the reaction was cooled and diluted with ethyl acetate. The solution was washed with water then brine and the organic phase dried over sodium sulfate. The crude material was purified by medium pressure liquid chromatography (15 to 45% ethyl acetate in hexanes) to give the desired material in 55% yield as a thick yellow oil. 1H NMR (200 MHz, CDCl3): δ ppm=11.88 (s, 1H), 8.83 (s, 1H), 8.41 (d, 1H), 8.05 (s, 1H), 7.93 (d, 1H), 7.66 (m, 2H), 7.18 (t, 2H), 4.57 (q, 2H), 1.52 (t, 3H.)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[O:13][CH3:14])([O-])=O.[NH4+].[Cl-]>O.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[O:13][CH3:14]
Reactant: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: COc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
0.500 g (2.52 mmol) of compound 2,6-dinitroanisole was suspended in 40 mL of water together with 2.310 g (35.3 mmol) of Zn and 0.530 g (10.1 mmol) of NH4Cl. The solution was boiled for 2.5 h. After cooling to room temperature, the solution was extracted with ethyl acetate. The organic solution was dried with anhydrous Na2SO4 and distilled in vacuo to obtain 0.330 g (95%) of clean 2,6-diaminoanisole as a red oil. 1H NMR (CDCl3) δ 6.73 (t, J=7.9 Hz, 1H, Ar—H), 6.19 (d, J=7.9 Hz, 2H, Ar—H), 3.78 (s, 3H, O—CH3), 3.73 (br. s, 4H, Ar—NH2). 13C NMR (CDCl3) δ 140.3, 134.9, 125.2, 106.6, 58.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][Si](C(C)(C)C)(C)C)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(Cl)cn2)c2ccc(O[Si](C)(C)C(C)(C)C)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccc(Cl)cn2)c2ccc(O)cc2O1
Temperature: 0 °C

Procedure:
To a solution of the compound obtained in (2) described above (2 g) in tetrahydrofuran (20 mL) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (10 mL) under stirring at 0° C. and the mixture was stirred at the same temperature for 3 hours. The reaction solution was diluted with an aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the titled compound (1.5 g) as a brown powder, which was used in the next step without further purification.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1>C1COCC1>[CH2:20]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)[CH2:8][O:22]1)[CH3:21]
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC1(c2ccc(F)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl) propan-1-one (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.