Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(NN)=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(N2[C:31](=[O:32])[C:30]3[CH2:33][CH2:34][CH2:35][C:29]=3N2)=CC=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:31](=[O:32])[C:30]3[CH2:33][CH2:34][CH2:35][C:29]=3[NH:18]2)=[C:13]([F:19])[CH:12]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCC2
Reactant: NNc1ccc(Cl)cc1F
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2

Procedure:
By substituting 4-chlorophenylhydrazine in the former procedure for 4-chloro-2-fluorophenylhydrazine, 2-(4-chlorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one was prepared, m.p. 193.5°-195°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[C:24](O)=[O:25])=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN1CCCC1=O.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[C:24]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:25])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnoc1-c1ccc(Cl)cc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cnoc1-c1ccc(Cl)cc1)N1CCC(c2cccnc2)C1
Reaction time: 96 h

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added 3-(pyrrolidin-3-yl)pyridine (1.0 g, 6.7 mmol, source: ASDI Inc.) in 25 mL of N-methylpyrrolidinone (NMP). To this solution was added 5-(4-chlorophenyl)isoxazole-4-carboxylic acid (1.6 g, 7.1 mmol, source: CiVentiChem), 1-hydroxybenzotriazole (1.0 g, 7.4 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.6 g, 8.1 mmol), and the mixture was stirred at ambient temp. After ca. 4 days, water was added (ca. 150 mL) and the aqueous layer was extracted with EtOAc (3×75 mL). The organic extracts were combined, washed with water, sat'd NaHCO3, and brine. The organic layers were combined and dried over MgSO4, filtered and concentrated in vacuo. The crude material was absorbed onto silica gel and purified on a 120 g Isco Redi-sep® silica gel column using CH2Cl2 with 3% (2M NH3 in CH3OH) as the eluant to give the desired product. Mass Spec. m/z+ion=354.1, m/z negative ion=352.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][OH:24])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Ag]=O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:23][O:24][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:32])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: COC(=O)c1c(C=NO)cccc1Oc1nc(OC)cc(OC)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)ON=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 27 %

Procedure:
2.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-hydroxyiminomethylbenzoate, 3 ml of ethyl 2-bromopropionate and 0.9 g of silver oxide (I) were place in a 50 ml eggplant type flask, and were allowed to stand for one night at room temperature. 10 ml of acetone and 10 g of silica gel were added to the resultant reaction liquor, and the acetone was distilled off under reduced pressure. The resultant product was purified by column chromatography to obtain 0.7 g of the aimed compound (refractive index=1.5261) at a yield of 27%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]1=[O:24].[CH3:25][C:26]([CH3:44])([CH3:43])/[CH:27]=[CH:28]/[C@H:29]1[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]2[CH:37]([O:41][CH3:42])[C:38](=[O:40])[O:39][C@H:30]12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@H:6]1[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3](=[O:24])[C@@H:2]([NH:1][C:38](=[O:40])[C@@H:37]([C@H:31]2[C@H:30]([OH:39])[C@@H:29](/[CH:28]=[CH:27]/[C:26]([CH3:43])([CH3:25])[CH3:44])[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)[O:41][CH3:42])[CH2:8][CH2:7]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)N(Cc2cccnc2)C1
Reactant: COC1C(=O)O[C@H]2C1OC(C)(C)O[C@@H]2/C=C/C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Yield: 57.2 %

Procedure:
A solution of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one (1.84 g, 5.3 mmol), (4R,4aR)-4-((E)-3,3-Dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one (1.0 g, 3.5 mmol) and diisopropylethylamine (1.37 g, 11.0 mmol) in isopropanol (10 mL) is refluxed for 16 h. The solution is evaporated and chromatographed on silica (95% CH2Cl2/5% CH3OH) to give 1.27 g (57.0%) of (R)-N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a white solid. MS (ESI) 634.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)SC)[C:3]=1[NH2:4].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[C:3]=1[NH2:4]
Reactant: COc1cc(OC)nc(C(SC)c2cccc(Cl)c2N)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(Cc2cccc(Cl)c2N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To 10 ml of a methanol solution of 2-chloro-6-[1-(4,6-dimethoxypyrimidin-2-yl)-1-methylthiomethyl]aniline 0.6 g (1.84 mmol) and 0.88 g (3.68 mmol) of nickel(II) chloride hexahydrate, 0.28 g (7.37 mmol) of sodium borohydride was added at 0-10° C. and the reaction solution was stirred at room temperature for 2 hours. After the reaction solution was distilled off under reduced pressure, aqueous ammonia and dichloromethane were added and the insoluble matter was filtered off. The organic layer was separated and the water layer was further extracted three times with dichloromethane. After the organic layer had been washed with water and dried, dichloromethane was distilled off under reduced pressure and the obtained crystals were washed with n-hexane to obtain the objective 2-chloro-6-[(4,6-dimethoxypyrimidin-2-yl)methyl]aniline 0.48 g (yield 93%) as white crystals.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(C(F)(F)F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (79 mg, 80%), MS (ISP) m/z=397.4 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C1COCC1.N1CCNCC1>C(N(CC)CC)C>[CH3:19][CH:20]1[NH:21][CH:22]([CH3:26])[CH2:23][N:24]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:25]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CC(C)NC(C)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 2,6-cis-dimethylpiperazine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperazine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to a colorless solid (79 mg, 85%). 1H NMR (CDCl3) 1.03 (d, J=4.8, 6 H), 1.72-2.20 (m, 1 H), 2.29 (s, 3 H), 2.58 (br, 1 H), 2.78-2.90 (m, 2 H), 4.25 (br, 2 H), 7.24-7.26 (m, 1 H), 7.37-7.39 (m, 1 H). 13C NMR 7.9, 19.4, ˜50 (br obsc), 51.3, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2, 140.2, 155.1 (q, J=40), 157.9, 162.4. 19F NMR −63.2. LC/MS 4.43 min, [M+1]+374.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Ba].[H][H]>[Cr]([O-])([O-])=O.[Cu+2].C(O)C>[CH3:1][CH:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: [H][H]
Reactant: Cc1c2ccccc2cc2ccccc12
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: [Ba]
Solvent: CCO
Product: CC1c2ccccc2Cc2ccccc21
Temperature: 150 °C

Procedure:
9,10-Dihydro-9-methylanthracene was prepared by pressurizing a mixture of 2 g of 9-methylanthracene, 0.5 g of a barium-promoted copper chromite catalyst (Girdler G-22), and 3 ml of ethyl alcohol with hydrogen to 3000 psi at room temperature, followed by heating the mixture at a temperature of 150° C. for 1 hour with agitation. The product was characterized by nmr spectroscopy. The products of four such runs were combined, and the mixture was vacuum-distilled to give 9,10-dihydro-9-methylanthracene as a pale-yellow solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[NH:14]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[NH2:15].O>C(OCC)C.ClCCl.N1C=CC=CC=1>[CH2:19]([O:18][C:16]([NH:14][NH:15][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C(=O)NNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.80 g (54.4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl ether are added dropwise to a solution of 9.04 g (54.4 mmol) benzyl hydrazine carboxylate in 100 mL diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature and then combined with water. The precipitated solid is filtered off and washed with diethyl ether. White solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([NH2:13])=[N:11][C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9]2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]3[N:11]=[C:12]([NH2:13])[N:8]([C:4]4[CH:3]=[C:2]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:7]=[CH:6][N:5]=4)[N:9]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1cc(N2CCNCC2)ncn1
Yield: 64 %

Procedure:
A mixture of 1-(6-chloro-pyrimidin-4-yl)-N3-(4-morpholin-4-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine (0.11 g, 0.30 mmol), piperazine ((0.26 g, 3.0 mmol), and di-iso-propylethylamine (0.21 mL) in THF (100 mL) was stirred at reflux for 3 d, then cooled and evaporated. Purification by semi-preparative HPLC provided the title compound (0.13 g, 64% yield) as a pale yellow solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.Cl[C:9]1[N:18]=[C:17]2[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]2[CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[F:26]>C(#N)C>[OH:23][CH2:22][CH:14]=[C:13]1[CH2:5][CH2:4][N:3]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:6][CH2:7]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(=CCO)CC3)c(F)cc2c1=O
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A solution of amine 103 (256 mg, 1.06 mmol) and triethylamine (0.5 mL, 3.55 mmol) in acetonitrile (4 mL) was treated with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid (200 mg, 0.71 mmol) under nitrogen and the reaction mixture was allowed to stir for 16 h. The resulting mixture was concentrated in vacuo, and the residue was washed with water (3×10 mL) and allowed to dry overnight to afford the title compound 163 (105 mg, 40%). MS 374 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([CH:33]1[O:35][CH2:34]1)Br>CN(C=O)C>[O:35]1[CH2:34][CH:33]1[CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.89 g, 5.90 mmol), (prepared as described in Example 49), potassium carbonate (2.43 g, 17.6 mmol) and epibromohydrin (1.61 g, 11.7 mmol) in DMF (40 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The insoluble inorganic material was removed by filtration and the solvent was removed by evaporation. The residue was triturated with diethyl ether, filtered, washed with further diethyl ether and dried to give 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.97 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O-:17].[Na+]>CO>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([O:17][CH3:16])=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C[O-]
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2ccc(OC)nc2c1N

Procedure:
A solution of methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared according to the procedure in Example 10A (5 g, 21 mmol) and sodium methoxide (4.5 g, 82 mmol) in methanol (150 mL) was refluxed for 18 hours, concentrated and partitioned between ethyl acetate and saturated aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4) and concentrated, and the residue was chromatographed on silica gel with 5:1 hexanes/ethyl acetate to provide the title compound. MS (DCI/NH3) m/e 239 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:36][CH3:37])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]([CH:31]=O)[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:13]>>[CH2:36]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([CH:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:37]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=O)c1-c1ccccc1
Product: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 52.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (57 g, 0.27 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (120 mg) to give 78 mg (53%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[OH-].[NH4+:20].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Temperature: -50 °C

Procedure:
The solution from EXAMPLE 14 was charged into a flask fitted with overhead stirrer, nitrogen inlet, temperature probe and cooling bath. The solution was cooled down to −50° C. using an acetone/dry ice bath. Ammonium hydroxide (238 g) solution was slowly added to the reaction mixture through an additional funnel. The internal temperature was kept at about −40° C. HPLC showed the reaction was completed. The solution was cooled down to −60° C. 6 N HCl (600 g) was added to the reaction mixture slowly to keep the temperature under −35° C. The mixture was warmed up to room temperature. The layers were separated, and the organic layer was washed twice with 375 g of 4 N HCl. The organic layer was distilled down under vacuum with bath temperature from 40 to 50° C. Toluene (700 g) was added to the residue, and the mixture was stirred at room temperature for an hour. The mixture was filtered and washed with toluene to obtain the title compound.
Reaction SMILES: [CH2:1]([C@H:4]([C@@H:6]1[CH2:11][CH2:10][O:9][C@H:8]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@H:7]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:5])[CH:2]=C.[BH4-].[Na+].[Cl-].[NH4+].ClCCl.C[OH:43]>>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:20]=[C:15]([C@H:13]([O:12][C@@H:8]2[C@@H:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]([C@H:4]([OH:5])[CH2:1][CH2:2][OH:43])[CH2:11][CH2:10][O:9]2)[CH3:14])[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1
Reactant: CO
Reactant: C=CC[C@@H](O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H]([C@H](O)CCO)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
(2R,3R,4R,αR)-α-2-Propenyl-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-methanol (Description 31; 1.0 g, 2 mmol) was dissolved in dichloromethane/methanol (1:1, 30 mL), cooled to −78° C. and purged with nitrogen and then oxygen. Ozone was bubbled through the mixture for 15-20 minutes, until a blue coloration persisted. The mixture was purged with oxygen, then nitrogen, warmed to 0° C. and sodium borohydride (0.3 g, 8 mmol) was added in portions. The mixture was stirred at 0° C. for 30 minutes, aqueous ammonium chloride (10%, 40 mL) was added and the mixture was extracted with dichloromethane (2×75 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (50:50) to give the title compound as a colorless oil (0.5 g, 50%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:24])([F:23])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(C1CC1)#N>CN(C=O)C>[C:34]([C:35]1([NH:40][C:8](=[O:9])[C@@H:7]([NH:11][C@@H:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([F:15])([F:14])[F:16])[CH2:6][C:5]([F:23])([F:24])[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:37][CH2:36]1)#[N:39]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccccc1)C(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CC(F)(F)CC2CC2)N[C@@H](c2ccccc2)C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A stirred solution of (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid (150 mg, 0.4 mmol) in DMF (15 mL) was treated with HATU (253 mg, 0.5 mmol) and DIPEA (0.3 mL, 1.7 mL mmol). After 15 min, 1-cyanocyclopropane hydrochloride (61 mg, 0.5 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. Once the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate & washed with 1HCl solution and brine, dried over Na2SO4, filtered and was concentrated. The crude compound was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane followed by re-crystallization from DCM and pentane to provide (S)—N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide (65 mg, 37%) as white solid. 1H-NMR (500 MHz, DMSO-d6): 8.88 (1H, s, NH), 7.38 (5H, s, Ar—H), 4.23 (1H, m, CHCF3), 3.39 (1H, m, CH), 3.18 (1H, m, NH), 2.23 (2H, m, CH2), 1.94 (2H, m, CH2), 1.32 (2H, m, CH2), 0.82 (2H, m, CH2), 0.57 (1H, m, CH), 0.45 (2H, m, CH2), 0.12 (2H, m, CH2). 19F-NMR (500 MHz, CD3OD): −74.609 (CF2), −95.308, −95.507 (CF3). EIMS (m/z): 416 (M+H)1. HPLC: 97.37% (RT 16.39) Column used zorbax SB, C8, 250×4.6 mm, 5 uMobile Phase: ACN (B): 0.1% TFA in water (A) Flow rate: 1.0 mL/Min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
Ethyl 3-{4-[2-(4-Chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenyl}propionate (49 mg) was dissolved in a mixed solvent of 1 ml of ethanol and 1 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at 60° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, which was then adjusted to neutrality with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration, and washed in water, followed by drying, to produce 30 mg of 3-{4-[2-(4-chlorobenzenesulfonamido)-2(3-pyridyl)ethyl]phenyl}propionic acid. The spectrometric data supports the structure of [25] as follows.