Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=CC=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C([O:40]C(=O)N[C@H]1CCN(NCC2OC3C=CN=C(N)C=3C=2)C1=O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[O:40][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(N)c5c4)C3=O)cc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NCc2cc3c(N)nccc3o2)C1=O
Agent: Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cc5c(N)nccc5o4)C3=O)cc2c1

Procedure:
Using the procedure described in example 85j 150 mg of [l-((4-amino-furo[3,2-c]pyridin-2-yl)methylamino)-2-oxopyrrolidin-3-(S)yl]carbamic acid tert-butyl ester was transformed into 110 mg of the title compound. MS ESI+: 467 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.I[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([O:17][CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: CC(C)I
Reactant: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(OC(C)C)cc12
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To methyl [6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 23, Step 2, 130 mg, 0.4 mmol) in DMF (1.5 mL) at r.t. was added 2-iodopropane (300 μL, 3 mmol) and Cs2CO3 (300 mg, 0.92 mmol). The reaction mixture was stirred for 15 minutes, and was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (100 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=3[F:21])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cc(F)ccc1F

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2,5-difluoro-benzamide was prepared starting from intermediate D and 2,5-difluoro-benzoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (br. s., 1H) 8.28 (d, J=8.66 Hz, 1H) 8.00 (s, 1H) 7.53-7.79 (m, 5 H) 7.21-7.52 (m, 4H) 6.92 (d, J=1.81 Hz, 1H) 4.39 (d, J=5.64 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22]>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:22][CH2:21][CH:20]([CH3:19])[CH2:23][CH3:24])=[O:5]
Reactant: CCC(C)CN
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Product: CCC(C)CNC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1
Yield: 58 %

Procedure:
Prepared in a similar manner to Example 20 from 2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and 2-methylbutan-1-amine. Yield: 58%. 1H NMR (400 MHz, dMSO): δ 0.72-0.74 (d, 3H), 0.79-0.84 (m, 3H) 0.97-1.00 (m, 1H), 1.24-1.27 (m, 1H), 1.47 (m, 1H), 1.48 (s, 6H), 2.81-2.87 (m, 1H), 2.93-2.98 (m, 1H), 7.37-7.39 (t, 1H), 7.44-7.47 (d, 2H), 7.76-7.79 (d, 2H), 9.13 (s, 1H), 9.18 (s, 1H); MS+H (312.1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:13][C:12](=[CH2:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:17]1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][C:12]2([CH2:14][O:17]2)[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OO1
Reactant: C=C1CC(COCc2ccccc2)O1
Solvent: ClCCl
Product: c1ccc(COCC2CC3(CO3)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxymethyl-2-methyleneoxetane (0.19 g, 0.98 mmol) in dry CH2Cl2 (2 mL), was cooled to −78° C. Dimethyldioxirane (0.5M in CH2Cl2, 2 eq) was added dropwise to the stirred solution. The reaction mixture was stirred for 1 hour more, then quickly warmed to room temperature, and, subsequently, the solvent was removed in vacuo. 2-Benzyloxymethyl-1,5-dioxaspiro[3.2]hexane was isolated as pale yellow oil (0.19 g, 95%) and as a mixture of diastereoisomers (72:28). Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 5H), 4.83 (m, 1H), 4.67 (d, J=12.2 Hz, 1H), 4.62 (d, J=12.2 Hz, 3H), 3.71 (m, 2H), 3.06 (dd, J=12.6, 2.7 Hz, 1H), 3.04 (dd, J=12.6, 4.2 Hz, 1H), 2.93 (d, J=3.3 Hz, 1H), 2.71 (d, J=3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.2, 128.6, 127.9, 127.8, 89.0, 73.8, 73.5, 72.1, 51.4, 31.4. Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 5H), 4.70 (m, 1H), 3.71 (m, 2H), 3.19 (dd, J=12.6, 7.2 Hz, 1H), 2.94 (d, J=3.6 Hz, 1H), 2.88 (dd, J=12.7, 5.6 Hz, 1H), 2.75 (d, J=3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.2, 128.6, 127.9, 127.8, 88.2, 73.9, 72.6, 72.5, 51.3, 31.6.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10]2=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:20]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccccc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.34 g of NaH (80% suspension in mineral oil), 18.5 g of 1.5-diphenyl-4-imidazolin-2-one, 160 cc. of DMF, 18.5 g of 8-bromocaprylic acid methyl ester and 2.34 g of NaJ.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.C([C@@:35]1([C:44]([OH:46])=[O:45])[CH2:39][CH2:38][CH2:37][N:36]1[C:40](=[O:43])[CH2:41]Br)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:41][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:44]([OH:46])=[O:45])=[O:43])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15])[CH3:14]
Reactant: O=C(CBr)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.24 g, 0.0011 mole) in chloroform (10 ml) was added triethylamine (0.34 ml, 0.002 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.29 ml, 0.0023 mole) was added to the above solution dropwise, followed by benzyl bromoacetyl-L-proline (0.25 g, 0.0011 mole). The ice bath was removed and the mixture stirred at room temperature for 4 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil was vacuum dried to get 0.23 g (57%) of title compound, TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot at Rf =0.23.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To a solution of 4-bromophenylacetone (5.00 g, 23.5 mmol) in ethanol (100 mL) at 0° C., was added sodium borohydride (976 mg, 25.8 mmol) portionwise over 5 min. The mixture was stirred at rt for 15 h, then quenched with 5% citric acid. The volatile solvent was removed in vacuo. The mixture was diluted with water, the pH was adjusted to 4.5 with 1N HCl, then aqueous phase was extracted with CH2Cl2 (3×). The combined organic washed with brine, dried (Na2SO4), filtered through a pad of SiO2 (eluted with 10% EtOAc/CH2Cl2) and concentrated to afford 4.90 g of 77A as a colorless oil. MS (ESI) m/z 197.1 (M-OH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A mixture of methyl 3-bromo-5-(trifluoromethyl)benzoate (5.10 g, 0.0180 mol), zinc cyanide (1.26 g, 0.0107 mol) and tetrakis(triphenylphosphine)palladium(0) (0.910 g, 0.000787 mol) in DMF (50 mL) was subjected to MWI for 20 min at 230° C. The solvent was evaporated and the residue was suspended in EtOAc. The organic solution was and washed with 1N HCl, water and brine, dried and concentrated. The residue was purified by column chromatography to give methyl 3-cyano-5-(trifluoromethyl)benzoate (2.67 g, 64%) as white solid. 1H NMR (400 MHz, CDCl3) δ: 8.50-8.52 (m, 2H), 8.09 (m, 1H), and 4.03 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>O>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (20 g) in tetrahydrofurna (50 ml) was added a solution of thiourea (3.9 g) and sodium acetate (4.2 g) in water (50 ml), and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half of the original volume, which was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate and then washed with ethyl acetate. After the aqueous solution was further adjusted to pH 2.0 with 10% hydrochloric acid, the water was removed by decantation. The residual substance was dissolved in tetrahydrofuran (200 ml), followed by drying over magnesium sulfate. Removal of the solvent gave an oil, which was triturated with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (3.5 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][S:18][C:12]=3[NH:11][C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:10]1[N:11]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:12]2[S:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[N:9]1[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=c1[nH]c2sccc2c(=O)n1CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3ccsc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.9 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (3.2 g), potassium carbonate (2.9 g) and acetonitrile (150 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (4.8 g, 97%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:19])=[O:18])[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.75 h

Procedure:
The product from Example 18 is dissolved in trifluoroacetic acid (170 ml) and left at room temperature for 1 h 45 min. Subsequently, the mixture is codistilled five times with toluene and the product is dried in a desiccator over phosphorus pentoxide/potassium hydroxide for 24 h. Yield: 11.8 g (93%).
Reaction SMILES: C1(SC2C=CC(S([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=O)=O)=CC=2)CCCCC1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CN(C)C(=O)C>O>[N:35]1([CH2:34][CH2:33][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CNCCN1CCOCC1
Temperature: 60 °C
Yield: 57 %

Procedure:
The N-[[4-(cyclohexylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, from Example 5b (3.34 mmol, 1.145 g), dried 325 mesh K2CO3 (13.4 mmol, 1.84 g), N-(chloroethyl)morpholine (10 mmol, 1.86 g), and N,N-dimethyacetamide (13 mL) were combined and heated at 60° C. under an inert atmosphere for 16 hours, then an additional 4 hours at 80° C. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (100 mL, then 50 mL). The combined organic phases were dried (MgSO4), filtered through a silica plug, concentrated, and subjected to chromatography (ethyl acetate:toluene 1:1), to afford N-[[4-(cyclohexylthio)phenyl]phenyl]sulphonyl]-N-[2-(4-morpholinyl)ethyl]-glycine, 1,1-dimethylethyl ester (954 mg, 57%) as an oil. The structure was verified spectroscopically. MS MH+ calcd. for C24H38N2O5S2 : 499, found: 499. Elemental anal. calc'd for C24H38N2O5S2.0.25H2O: C, 57.29; H, 7.71; N, 5.57. Found: C, 57.32; H, 8.21; N, 5.27.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](OC4C=CC=CC=4)=[O:29])=[CH:23][C:22]=3[O:37][CH3:38])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[C:41]([NH2:45])([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:45][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:8]2[C:7]3[CH:39]=[CH:40][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]2=[O:17])(=[O:19])=[O:20])=[C:22]([O:37][CH3:38])[CH:23]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)NC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.7 g of the compound obtained in EXAMPLE 16 step A), 1 ml of tert-butylamine and 25 ml of DCM is stirred for 48 hours at RT. The solvent is evaporated off under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.41 g of the expected product after crystallization from an AcOEt/iso ether mixture (50/50; v/v). M.p.=237° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cnccc1C(=O)c1ccc(F)cc1

Procedure:
To a solution of pyridine-3,4-dicarboxylic anhydride (56.04 g, 0.38 mol) in 950 mL of fluorobenzene is added AlCl3 (126.67 g, 0.95 mol) over 45 min. from a powder addition funnel. The mixture is heated to reflux for 12 hours, then allowed to cool and quenched with ice water. Addition of a concentrated NaOH solution results in a solid precipitate which is filtered. The basic aqueous fraction of the biphasic filtrate is separated, washed with Et2O (3×150 mL), and acidified to pH 2.5 with concentrated HCl to generate a white solid which is collected by vacuum filtration. The solid is washed with several portions of hot MeOH to generate pure 3-(4-fluorobenzoyl)pyridine-4-carboxylic acid. M.P. 308.5° C. The combined methanolic filtrates are evaporated and recrystallized from MeOH to generate 4-(4-fluorobenzoyl)-pyridine-3-carboxylic acid. M.P. 231°-232.5° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:29][CH2:30][CH2:31][OH:32])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: OCCCBr
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCCCO)cc13)Sc1ccc(Br)cc1-2
Yield: 34 %

Procedure:
According to Example 34, the compound (147 mg) produced in Example 70 was reacted with 3-bromopropanol (42 μl) to obtain the title compound (57 mg; 34%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28](/[CH:30]=[C:16](/[C:15]2[CH:14]=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)\[OH:18])[CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Reactant: Cc1ccnc(Cl)n1
Product: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Yield: 85.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 3-(2,5-difluorophenylsulfonamido)benzoate (20.5 g, 62.7 mmol) and 2-chloro-4-methylpyrimidine (8.8 g, 68.9 mmol) the title compound was obtained (22.6 g, 85.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.40-13.50 (br s), 10.95-11.12 (br s), 8.72-8.80 (m), 8.57-8.63 (m), 7.77-7.82 (m), 7.36-7.72 (m), 7.22-7.30 (m), 6.43 (s), 4.52 (s); m/z (ES+): 424 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:30])=[O:29])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:30])=[O:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1(Cc2ccc(C3=CC(=O)N(C(C)(C)C)S3(=O)=O)cc2)CCC(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccc(C3CC(=O)N(C(C)(C)C)S3(=O)=O)cc2)CCC(=O)N1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Ethyl 2-[4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)benzyl]-5-oxopyrrolidine-2-carboxylate (24 mg, 0.055 mmol) was dissolved in ethanol (2.5 mL) and 10% Pd/C (10 mg, 0.09 mmol) was added. Hydrogen was added to a Parr shaker (58 psi) and shaken overnight. Purification by preparative LCMS gave the desired product as a colorless glass (23 mg, 95%). 1H NMR (400 MHz, CD3OD): δ 7.42 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.12 (t, J=8.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.30 (m, 2H), 3.22 (d, J=13.6 Hz, 1H), 3.13 (d, J=13.6 Hz, 1H), 2.38 (m, 1H), 2.21 (m, 2H), 1.92 (m, 1H), 1.61 (s, 9H), 1.28 (t, J=7.0 Hz, 3H); LCMS found for C21H29N2O6S (M+H)+: m/z=437.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:2]([CH3:1])([CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Yield: 84.3 %

Procedure:
A reaction mixture of ethyl 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g, 26.6 mmol) and Pd/C (0.283 g, 2.66 mmol) in MeOH (50 mL) was hydrogenated using an H-cube (settings: 50° C., 50 psi, 24 h). The mixture was filtered and the filtrate was concentrated. The crude material was purified on silica column chromatography (PE/EA=10:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.4) were combined and concentrated to yield a off white solid of ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7 g, 22.42 mmol, 84.0% yield): 1H NMR (400 MHz, CDCl3) δ: 6.98 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 8.4 Hz, 1H), 4.15 (q, J=6.8 Hz, 2H), 3.00 (s, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][C:22]4[CH:21]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:26]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)c1
Yield: 45.5 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.1, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2 hr and followed the same processes as in Example 1 to obtain 7.4 mg (44.8%) of the target compound.