Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]2[CH2:18][CH2:17][O:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[O:16]1[CH2:17][CH2:18][CH:14]([O:13][C:12]2[CH:19]=[CH:20][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:15]1
Reactant: c1ccc(COc2ccc(OC3CCOC3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(OC2CCOC2)cc1

Procedure:
3-(4-Benzyloxy-phenoxy)-tetrahydro-furan (1.80 g, 6.66 mmol) was dissolved in 30 ml ethyl acetate and stirred with 200 mg Pd/C 10% under hydrogen atmosphere for 16 hours. The catalyst was filtered off and the solvent evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→20:80 gradient). The desired compound was obtained as a light brown solid (900 mg, 75%) MS (m/e): 179.1 (M−H+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][Cl:17])[N:13]=[CH:12][C:11]=2[C:18]#[N:19])=[CH:6][C:5]1=[O:20])[CH:2]=[CH2:3].C[Al](C)C.Cl>ClCCl.CCCCCC.[OH-].[Na+]>[NH2:19][C:18]1[C:6]2[C:5](=[O:20])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:8][C:7]=2[N:9]=[C:10]2[N:14]([CH2:15][CH2:16][Cl:17])[N:13]=[CH:12][C:11]=12
Reactant: C=CCN1CC(Nc2c(C#N)cnn2CCCl)=CC1=O
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CCN1Cc2nc3c(cnn3CCCl)c(N)c2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 5-[N-(2-propenyl)-2-oxo-3-pyrrolin-4-yl]amino-1-(2-chloroethyl)-4-cyanopyrazole (19.60 g.) in dry dichloromethane (200 ml.) was cooled to 0° under nitrogen with stirring, while a solution of trimethylaluminium in hexane (57 ml. of 25 wt. % solution) was added dropwise. Gas evolved. The resulting clear yellow solution was warmed to room temperature and allowed to stir under nitrogen for three days. After cooling to 0° and introducing a vigorous stream of nitrogen, 3N aqueous HCl was added cautiously until gas evolution ceased. The mixture was then diluted with aqueous NaOH (400 ml. of 20% w/v solution) and dichloromethane (500 ml.) and the phases were separated. The aqueous layer was further extracted twice with dichloromethane (250 ml. each time) and the organic extracts were combined. These were washed with aqueous NaOH (250 ml. of 10% w/v solution), and then with brine (400 ml.), and finally dried (Na2SO4) Evaporation gave a yellow solid which was recrystallized from a minimum of EtOAc to give 4-amino-1-(2-chloroethyl)-6,7-dihydro-6-(2-propenyl)pyrazolo[3,4-b]pyrrolo[3,4-e]pyridin-5(1H)-one as a light yellow powder, 15.71 g.: m.p. 197.5°-199°.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([O:18]C)[CH:14]=[CH:13][N:12]=3)[NH:8][C:4]=2[CH:3]=1>Br>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]3[C:16]([CH3:17])=[C:15]([OH:18])[CH:14]=[CH:13][N:12]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccnc(CSc2nc3ccc(F)cc3[nH]2)c1C
Agent: Br
Product: Cc1c(O)ccnc1CSc1nc2ccc(F)cc2[nH]1
Yield: 61 %

Procedure:
A solution of 5-fluoro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]benzimidazole (5.5 g) in aqueous 47% HBr (50 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure. The residual oily substance was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, to which was added ethyl acetate (50 ml) to give 5-fluoro-2-[(4-hydroxy-3-methyl-2-pyridyl)methylthio]benzimidazole (3.2 g, 62%). Recrystallization from ethanol afforded colorless needles, mp 232°-233° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22]
Reactant: C/C(=C\C(C)c1ccc(C)cc1)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](C)[C@@H]2C[C@@]2(C)CO)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 5.3 g, 6.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (2.26 g, 12.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 10 minutes, and then cooled to −20° C. At the same temperature, (E)-2-methyl-4-(4-methylphenyl)pent-2-en-1-ol (0.60 g, 3.2 mmol) was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (2.5 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.24 g, 1.18 mmol, 36% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.013 g, 0.064 mmol, 2% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41](=O)[NH:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH:30]=1.[C:54]1([C:60]([NH2:63])([CH3:62])[CH3:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[I:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][C:41]([NH:63][C:60]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([CH3:62])[CH3:61])=[N:40][N:39]=3)[CH:36]=2)[N:31]([S:44]([C:47]2[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=2)(=[O:45])=[O:46])[CH:30]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.5 %

Procedure:
BOP (455 mg, 1.029 mmol) was added to a stirred mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (450 mg, 0.935 mmol), 2-phenylpropan-2-amine (0.442 mL, 3.27 mmol) and diisopropylethylamine (0.33 mL, 1.87 mmol) in DMF (5.0 mL). The mixture was stirred at RT for 14 h. It was treated with BOP (300 mg) and 2-phenylpropan-2-amine (0.3 mL) and heated to 65° C. for 3 h. The mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification (eluting with 20-70% EtOAc in Hex) afforded 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-amine (103.6 mg, 19%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 601.0 (M+1).
Reaction SMILES: N[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.N([O-])=O.[Na+].C(OCC)(=O)C.O.[ClH:24]>O1CCCC1>[Cl:24][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: Cl
Reactant: COC(=O)c1nc(Cl)cnc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a mixture of 14 mL of 12 mol/L hydrochloric acid and 14 mL of tetrahydrofuran was suspended 8.0 g of methyl 3-amino-6-chloro-2-pyrazinecarboxylate. After adding 5.9 g of sodium nitrite at 5-12° C., the mixture thus obtained was stirred at an ice-cooled temperature for 50 minutes. Then, 8.4 g of cuprous (I) chloride suspended in 6 mol/L hydrochloric acid was added and stirred at the same temperature as above for 10 minutes. The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and 100 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with 50 mL of water and 50 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=6:1] to obtain 6.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate as a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16](O)[CH3:17])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[Cl-:19].[Ca+2].[Cl-].Cl.[Cl-].[Na+]>C1(C)C=CC=CC=1.[Cu]I.[Cu]>[Cl:19][CH:16]([CH3:17])[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:2]([F:1])=[C:3]([CH:10]=1)[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: [Cl-]
Reactant: COC(=O)NCc1cc(C#CC(C)O)ccc1F
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C#CC(C)Cl)ccc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
0.53 g of methyl N-[2-fluoro-5-(3-hydroxy-1-butynyl)benzyl]carbamate was dissolved in 10 ml of toluene. This solution was added at 0° C. to a mixture comprising 0.11 g of calcium chloride, 0.08 g of copper(I) iodide, 0.01 g of copper and 10 ml of concentrated hydrochloric acid, followed by stirring at 0° C. for 5 hours. The reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.25 g of methyl N-[5-(3-chloro-1-butynyl)-2-fluorobenzyl]carbamate as white crystals.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Yield: 50.1 %

Procedure:
A mixture of 955 mg of 3-carboxymethylrhodanine, 516 mg of sodium acetate, 10 ml of acetic acid and 637 mg of benzaldehyde was heat-refluxed for 2 hours. To the reaction mixture was added 20 ml of water, and the precipitated crystals were filtered. The resulting crystals were recrystallized from ethanol to obtain 699 mg of the titled compound.
Reaction SMILES: [CH2:1]([C:5]1[N:21](CC(=O)C2C=CC=CC=2)[C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.CO.[Zn]>[CH2:1]([C:5]1[NH:21][C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1CC(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2[nH]1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
4 g(0.010 mole) of the compound obtained in step 8 was dissolved in a mixture of 40 ml of acetic acid and 40 ml of methanol and to the resulting solution was added 13.1 g(0.0002 mole) of zinc powder. The resultant was stirred under ultrasonification for 4 hours, filtered and washed with acetic acid(10 ml×3). To the filtrate was added 50 ml of saturated aqueous ethylene diamine tetraacetic acid solution and then the resultant was stirred for 10 minutes. After adding 100 ml of ethyl acetate, the solution was filtered and washed with 100 ml of aqueous 10% NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography(CH2Cl2 → 10% MeOH/CH2Cl2) to obtain 2.4 g of the title compound(yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:15]=[C:14]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[C:4]([O:25][CH3:26])[CH:3]=1.[NH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:15]=[C:14]([C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:8]=2[C:9]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=2)=[O:10])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (152.1 mg, 0.10 mmol), tert-butyl 4-aminobenzoate (21.26 mg, 0.11 mmol) and HATU (41.83 mg, 0.11 mmol) in DMF (0.5 mL) was added N-methylmorpholine (24.18 μL, 0.22 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, evaporated and taken up in dichloromethane (0.25 mL). TFA (0.25 mL, 3.245 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The mixture was diluted with MeOH, filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) containing HCl as a modifier to give 4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]benzoic acid (27) (5.16 mg, 10%) as a white solid. ESI-MS m/z calc. 499.07, found 500.3 (M+1)+; Retention time: 1.82 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.84 (s, 1H), 7.94 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.52 (d, J=7.9 Hz, 1H), 7.40-7.27 (m, 1H), 7.16 (dd, J=10.6, 2.8 Hz, 1H), 6.98-6.82 (m, 1H), 6.77 (s, 1H), 3.73 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[N:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:46][CH2:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1c(-c2cccc(C(=O)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2cccc(C(=O)NCCCN3CCOCC3)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(3-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-morpholin-4-ylpropylamine (31 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (93 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[N:7][CH:8]=1.Cl[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[NH2:9][C:6]1[C:5]([NH:10][C:14](=[O:15])[O:16][CH3:17])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cnc1N
Solvent: c1ccncc1
Product: COC(=O)Nc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-trifluoromethylpyridin-2,3-diamine (1.2 g) and pyridine (20 ml), methyl chloroformate (0.63 ml) was added under ice-cooling. The mixture was heated to room temperature, stirred for 8 hours, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 628 mg of methyl (2-amino-5-trifluoromethylpyridin-3-yl)-carbamate.
Reaction SMILES: C(OC(NC1C(=O)N2C(C)(C(O)=O)CCC2=NC=1)=O)C1C=CC=CC=1.C([O:30][C:31]([C:33]1([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)=[O:32])(C)(C)C>>[CH2:54]([C:33]1([C:31]([OH:32])=[O:30])[N:37]2[C:38](=[O:53])[C:39]([NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[CH:40][N:41]=[C:36]2[CH2:35][CH2:34]1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccccc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: O=C(Nc1cnc2n(c1=O)C(Cc1ccccc1)(C(=O)O)CC2)OCc1ccccc1
Yield: 95.2 %

Procedure:
According to the procedure for the preparation of intermediate 19b, intermediate 21a (149 mg, 0.313 mmol) was deproteted to afford 125 mg (95%) of intermediate 21b. MS (ESI) 420.4 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1.[H-].[Na+]>C1COCC1>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: CC1(C)CCC(O)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2nccc3c([N+](=O)[O-])cccc23)CC1
Yield: 62.4 %

Procedure:
The title compounds were prepared following the procedure described in step-1, Intermediate-10 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 200 mg, 0.96 mmol) and 4,4-dimethylcyclohexanol (135 mg, 1.05 mmol) and NaH (42 mg, 1.05 mmol, 60% in mineral oil) in THF (10 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.65 (d, J=7.8 Hz, 1H), 8.47 (d, J=7.8 Hz, 1H), 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=6.3 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 5.33 (m, 1H), 2.04-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.43-1.39 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:43])[CH:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:43])[CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH:29]=1)[O:19][P:16]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: COC(=O)C(O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(OP(=O)(O)C(NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: -5 °C
Reaction time: 0.42 h
Yield: 90.2 %

Procedure:
Following a procedure reported by Hoffmann, M., Synthesis (1986), 557A, a solution of (R)-1-(benzyloxycarbonyl)amino-2-methylpropylphosphonic acid (691.0 mg, 2.41 mmol) in 8 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this solution was added thionyl chloride (0.21 mL, 2.88 mmol) and stirred at −5° C. for 25 minutes. Racemic 2-hydroxy-2-(3-(t-butoxycarbonylamino)phenyl)ethanoic acid methyl ester (683.4 mg, 2.43 mmol) was added as a solution in 2 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 4 days (total reaction time 87 hrs), the reaction had almost gone to completion (95%). To this reaction mixture 5 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), acidified to pH 2 with concentrated HCl, and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a mixture of product and starting material. Purification via SiO2 gel flash column chromatography (CH2Cl2, then methanol) provided 1.1966 g (90%) of 2-(3-(t-butoxycarbonylamino)phenyl)-2-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester; as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>[Pt].O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
A mixture of 32.25 gm (124 mMol) N-(4-fluorobenzoyl)-4-nitroaniline and 3.2 gm platinum on carbon in 500 mL tetrahydrofuran was hydrogenated at room temperature for 18 hours with an initial pressure of 60 p.s.i. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure to give 22.45 gm (79%) of N-(4-fluoro-benzoyl)-4-aminoaniline.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:20][CH2:21][N:22]([CH2:30][CH2:31]Cl)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[H-].[Na+].[I-].[K+]>>[C:17]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:15][CH:14]=2)[CH2:31][CH2:30][N:22]([C:23]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:29])[CH2:21][CH2:20]1)#[N:18]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 53 %

Procedure:
The title compound (1.8 g, 53%) was prepared using [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile, tert-butyl bis(2-chloroethyl)carbamate, sodium hydride and potassium iodide similarly to the procedure used for intermediate 56. LRMS APCI+ m/z 414 [MH]+ and m/z 245 [SMH]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:27][C:23]2[N:22]([CH3:21])[CH:26]=[CH:25][N:24]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cn1ccnc1CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ccnc1COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperazine (556 mg, 2.0 mmol, 1.0 eq.), (1-methyl-1H-imidazol-2-yl)-methanol (448 mg, 4.0 mmol, 2.0 eq.), triphenylphosphine (1.04 g mg, 4.0 mmol, 2.0 eq.) and THF at 0° C. under nitrogen was added DEAD (0.629 mL, 4.0 mmol, 2.0 eq.) slowly so that temperature of the reaction does not rise above 10° C. After addition was complete, the ice bath was removed and the mixture was stirred at r.t. overnight. Methanol was added, and the mixture was stirred for about 15 minutes and then concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient 0-8% 2.0 M NH3 in MeOH/CH2Cl2 for 25 minutes and 8% 2.0 M NH3 in MeOH for 7 minutes) afforded the title compound (279 mg, 0.75 mmol, 37%). LRMS (ESI+): 373.3 (M+1).