Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1)=[O:16].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[CH:28]=[C:27]([S:29]([CH3:30])=[O:9])[CH:26]=[CH:25][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1)=[O:16]
Reactant: CSc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: -15 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
3-Chloroperbenzoic acid (1.3 g) was added to a solution of 4-[2-chloro-4-(methylsulphenyl)benzoyl]-5-cyclopropylisoxazole (2.0 g) in dichloromethane whilst maintaining the temperature below -15° C. The mixture was stirred at -15° C. for 2 hours and allowed to warm to room temperature. The mixture was stirred for 2 hours and then recooled to -15° C. 3-Chloroperbenzoic acid (0.7 g) was added and the mixture was stirred at -15° C. for 1 hour and at room temperature for 1 hour. A solution of sodium metabisulphite was added. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica eluted with ethyl acetate and hexane (3:2) to give 4-[2-chloro-4-(methylsulphinyl)benzoyl]-5-cyclopropylisoxazole (1.3 g) as a white solid, m.p.117° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[C:24]([O:36]CC2C=CC=CC=2)[CH:23]=1)[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:36][C:24]1[CH:23]=[C:22]([CH2:21][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])[CH:27]=[CH:26][C:25]=1[OH:28]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a solution of (1R,2R)-2-acetyloxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (7) (2.0 g, 3.4 mmol) in 20 mL of methanol, 10% Pd—C (100 mg) pre-mixed with 10 mL of methanol was added under nitrogen atmosphere. The nitrogen was exchanged with hydrogen and the mixture stirred under the hydrogen atmosphere at room temperature for 4 h. After filtration and washing with methanol, the filtrate was concentrated to provide 1.4 g (100% yield) of the title compound (8). 1H NMR (400 MHz, CDCl3): δ 1.14 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 2.06 (s, 3H), 2.92 (dd, J=12.8, 6.4 Hz, 1H), 2.96 (dd, J=12.8, 6.4 Hz, 1H), 4.46 (dd, J=12.4, 6.4 Hz, 1H), 4.95 (m, 2H), 5.05 (d, J=8.8 Hz, 1H, NH), 6.65 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.73 (d, J=8.0 Hz, 1H). MS (ESI) m/z 434.1 (M+Na)+ and 410.1 (M−H)−.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:42])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:40][C:38]([F:39])([F:41])[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:43])=[O:5])[C:9]=3[CH3:42])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C2=NN(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ6benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.17 (d, 1H), 7.93 (t, 1H), 7.85 (t, 1H), 7.50 (m, 3H), 7.38 (m, 3H), 6.89 (dt, 1H), 6.59 (dd, 1H), 5.11 (bs, 2H), 4.52 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C26H19F4N3O5S—H: 560, observed: 560.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([O:17]CC)=[O:16])[CH3:2].C(O)C.O1CCCC1.[OH-].[Na+]>O>[CH2:21]([O:20][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([OH:17])=[O:16])[CH3:22]
Reactant: CCOC(=O)c1cc2c(n1CC(OCC)OCC)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(Cn1c(C(=O)O)cc2c1CCCC2)OCC
Temperature: 75 °C
Yield: 77.6 %

Procedure:
To a mixture of 121b (4.7 g, 15.2 mmol) in a mixed solvent of ethanol (20 mL), tetrahydrofuran (20 mL), and water (30 mL) was added sodium hydroxide (3.0 g, 75.0 mmol). The reaction was heated at 75° C. for two days and concentrated under reduced pressure. The residue was suspended in water and neutralized with diluted aqueous citric acid solution. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase was concentrated under reduced pressure to afford 121c (3.32 g, 78%). MS-ESI: [M-ethanol+H]+ 236.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][O:28][CH2:29][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[O:31])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C>[OH:31][CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=1)[CH2:29][O:28][CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:26]=1
Reactant: N#Cc1ccc(C(=O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium borohydride is added in portions to a solution of 1 mmol of 4-[2-(1-trityl-1H-imidazol-4-ylmethoxy)acetyl]benzonitrile in 12 ml of ethanol at 0° C. The reaction solution is stirred at room temperature for 12 hours, then poured into ice-water and stirred for 15 minutes. The mixture is adjusted to pH 5 by adding glacial acetic acid and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>C(N(CC)CC)C.[Cu]I.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]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:26]3[CH:27]=[CH:28][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:30])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc—hexanes) afforded 70.0 mg (73%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([NH2:40])=[O:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]([NH2:40])=[O:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: NC(=O)CBr
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCC(N)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
0.5 g (1.3 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved, under nitrogen atmosphere and magnetic stirring, in 5 ml of THF; 0.5 g (3.6 mmol) of K2CO3, 0.27 g (1.9 mmol) of 2-bromoacetamide and a small amount of KI were added. The reaction mixture was left overnight under magnetical stirring; the precipitate was filtered off and the residue dissolved in H2O and extracted with EtOAc; the organic layer was washed with sat. sol. NaCl, dried over Na2SO4 and evaporated in-vacuo to dryness. The crude product was triturated with hexane and then recrystallized form EtOH to yield 0.29 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (25 g, 136 mmol) in DMF (125 mL) was added K2CO3 (37.8 g, 273 mmol). Then dimethyl sulfate (48.2 g, 382 mmol) was added dropwise to the mixture at rt. The mixture was stirred at rt overnight. Then the reaction was quenched by the addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step A (26.8 g, 99.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10-8.18 (m, 2H), 7.97-8.03 (br, 1H), 6.95-7.03 (m, 1H), 4.00 (s, 3H).
Reaction SMILES: C(OCC[C:7]1([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][CH2:10][CH2:9][C:8]21[O:15]CCO2)(=O)C.C[C:22]([CH3:24])=[O:23].N(CCO)(CCO)[CH2:26][CH2:27][OH:28]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:27]([O:23][CH2:22][CH2:24][CH:11]1[CH2:10][CH2:9][C:8](=[O:15])[CH:7]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:28])[CH3:26]
Reactant: CCCCCC1(CCOC(C)=O)CCCC12OCCO2
Reactant: OCCN(CCO)CCO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCC1C(=O)CCC1CCOC(C)=O
Yield: 83.3 %

Procedure:
A mixture of 7.1 g of 2-acetoxyethyl-1,1-ethylenedioxy-2-n-pentyl-cyclopentane, 14.5 g of acetone and 0.0475 g of paratoluenesulphonic acid is brought to reflux during 1 hour. There is added thereto 0.08 mole of triethanolamine and the mixture is concentrated under reduced pressure on a water-bath. The residue is dissolved in 50 ml of benzene and washed with water until neutral. The distilled benzene solution yields 7 g of crude product which are rectified. There are obtained 5 g of 3-acetoxyethyl-2-n-pentyl-1-cyclopentanone (83.3% yield) having b.p.0.5 = 110°-113°C, nD15 = 1.4610.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCOCC1.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:42](=[O:43])[NH:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c(ccn5c(=O)[nH]nc45)cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30.0 mg, 0.0620 mmol) and CDI (40.4 mg, 0.249 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 15 h and then cooled to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase (H2O/0.1% TFAaq.-MeCN/0.1% TFAaq.) HPLC to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3(2H)-one (7-6) as a colorless solid.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][O:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:12]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:11][O:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOc1nonc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCOc1nonc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(3-butyloxy-1,2,5-oxadiazol-4-yl)pyridine (1.9 mmol) in acetone (10 ml) was stirred at room temperature for 18 h and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH3:10][N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:12]>C1(C)C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N+:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccn1
Reactant: ClCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cccc[n+]1Cc1ccc(Cl)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.1313 g (0.00706 mol) p-chlorobenzylchloride, 0.8623 g (0.00706 mol) dimethylaminopyridine, and approximately 10 mL toluene were added to a clean, dry 50 mL round bottom flask equipped with a stir bar, condensor, and drying tube. The reaction apparatus was then lowered into an oil bath at 110° C. The solution became miscible immediately and after 5 minutes a thick white precipitate formed. The reaction was allowed to continue overnight, and after 12 hours was cooled to room temperature. The solvent was removed via rotary evaporation. The resulting solid was recrystallized from ethanol/diethylether to give 1.790 g (89.5%). Calculated for C14H16N2Cl2: C, 59.3765%; H, 5.6944%; N, 9.8917%. Found: C, 57.63%; H, 5.88%; N, 9.59%. 1H NMR (D2O 300 MHZ): δ 3.02 (s 6H), δ 5.15 (s 2H), δ 6.71 (d 2H), δ 7.18 (d 2H), δ 7.30 (d 2H), δ 7.90 (d 2H). Melting point 208-210° C.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[C:18]([CH2:31][C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[S:17][C:16]2=[O:41])C=CC=CC=1.O>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:33]#[C:32][CH2:31][C:18]2([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[S:17][C:16](=[O:41])[NH:15][C:19]2=[O:20])=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Trifluoroacetic acid (0.32 mL, 4.07 mmol) was added to a room temperature, stirred suspension of N-(triphenylmethyl)-5-[3-(4-chlorophenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [(X), from Example 35, 1.29 g, 1.94 mmol] in CH2Cl2 (2 mL). Dissolution occurred immediately. After 1 h, the reaction mixture was added to water (200 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate phase was washed with water and brine and then concentrated. The crude product was purified by flash chromatography (95:5 CH2Cl2 :isopropanol) and then triturated in petroleum ether to provide the title compound as a off-white solid (0.52 g, 64%): mp 172°-174° C.; NMR (CDCl3): δ8.00 (s, 1H, NH) 7.85 (d, J=8.3 Hz, 2H, ArH), 7.41 (d, J=8.3 Hz, 2H, ArH), 7.26 (s, 4H, Ar'H), 3.65 (d, J=17.1 Hz, 1H, CH2), 3.33 (d, J=17.1 Hz, 1H, CH2), 2.49 (s, 3H, CH3); MS(CI); 420 (M+H, 58%), 422 (M+H, 24%), 265 (40%), 267 (26%),157 (100%); Anal. Calc. for C19H14ClNO4S2 : C, 54.35; H, 3.36; N, 3.36; Found: C, 54.74; H, 3.54; N, 2.98.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([NH2:46])[CH3:45])=[CH:40][CH:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:41]1[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=1)[CH3:45])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid (10.25 mg, 0.021 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.0085 mL, 0.063 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (12 mg, 0.025 mmol) and diisopropylethylamine (0.012 mL, 0.07 mmol) in 0.2 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide which was subsequently dissolved in 0.2 mL CH2Cl2 and 0.5 mL TFA. The reaction mixture was stirred for 1 h and concentrated. Lyophilization gave 3-((2-amino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide as the TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=8.0 Hz, 1H), 7.92 (app d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.18 (m, 2H), 7.05 (m, 2H), 5.25 (m, 1H), 4.70 (m, 2H), 3.44 (A of AB, d, J=10.1 Hz, 1H), 3.38 (B of AB, d, J=10.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.4 Hz, 1H), 2.50 (m, 2H), 2.18 (m, 2H), 2.03 (m, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:23][C@H:22]([OH:24])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C@H:20]3[CH2:21][C@H:22]([OH:24])[CH2:23]3)=[CH:18][CH:19]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: Nc1ccc([C@H]2C[C@H](O)C2)cc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Nc1ccc([C@H]2C[C@H](O)C2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4,5-trichloronitrobenzene and trans-3-(4-aminophenyl)cyclobutanol (step 4).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]2[C:7](=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:11]=2)[O:6][C:5]=1[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:29].[CH3:36][N:37]([CH3:42])S(Cl)(=O)=O.C1[CH2:47][O:46]CC1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[C:12]3[C:4]([NH:3][C:47](=[O:46])[N:37]([CH3:42])[CH3:36])=[C:5]([C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[O:29])[O:6][C:7]3=[N:8][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.004 g; 60% dispersion; 0.111 mmol) in THF (0.5 mL) at 0° C. was added a solution of 0.050 g 0.101 mmol) of the product from Example 26 (in THF (0.5 mL) and the reaction mixture was stirred at 0° C. for 30 minutes. Dimethylsulfamoyl chloride (9 μL; 0.101 mmol) was added dropwise and the reaction was then stirred at room temperature for an additional 5 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 50% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 564.9 (M+1), 566.9 (M+3); Rt=4.33 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.N1[C:20]2=[N:21][CH:22]=[CH:23][C:24]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:28][C:27]=3[F:50])=[C:19]2C=C1.Cl.O1CCOCC1.C[N:59]1[C:63](=[O:64])CCC1>O>[ClH:1].[C:63]([C:20]1[CH:19]=[C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:2]3[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=3)=[CH:28][C:27]=2[F:50])[CH:23]=[CH:22][N:21]=1)(=[O:64])[NH2:59]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Alpha Aesar, 2.08 g, 8.93 mmol) and 4-(4-amino-2-fluorophenoxy)picolinamide (2.0 g, 8.09 mmol, Compound C of Example 3) in NMP (10 mL) was added a solution of 4 N HCl in 1,4-dioxane (4 mL, 16 mmol). After stirring overnight, the reaction mixture was diluted with water (200 mL) and the resulting solid was filtered and dried in vacuo to give the desired product (3.6 g, 93%) as a white solid. MS(ESI+) m/z 444 (M+H)+.