Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH2:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH:37][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:36]
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 75.9 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.58 g, 1.75 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.36 g, 1.75 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow solid product, 0.66 g, 75.9% yield. MS: 497.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.44 (s, 1H), 10.90 (d, 1H, J=7.0 Hz), 8.12 (s, 1H), 7.93-7.90 (m, 2H), 7.73-7.71 (m, 1H), 7.40 (d, 1H, J=7.0 Hz), 6.16 (d, 1H, J=7.5 Hz), 4.23 (m, 1H), 3.38 (m, 2H), 3.05 (s, 3H), 1.38 (d, 3H, J=6.0 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1cscn1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 5.0 g (27 mmol) of ethyl 2-(1,3-thiazol-4-yl)propanoate from step A above in 25 mL of methanol was added dropwise to a mixture of 6.6 mL (33 mmol) of a 5 N aqueous NaOH solution, water (16 ml) and methanol (30 ml). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with a concentrated hydrogen chloride solution. The mixture was saturated with solid sodium chloride and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and treated with activated charcoal overnight. The mixture was filtered and evaporated to afford the title compound as an off-white solid 4.0 g (95%). 1H NMR (500 MHz, CDCl3) δ: 1.63 (d, J=7.3, 3H), 4.11 (q, J=7.3), 7.25 (d, J=1.8, 1H), 8.88 (d, J=1.8, 1H), 10.25 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NS(C)(=O)=O)cc3Cl)c2n1
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) was dissolved in pyridine (1.5 ml), and a solution of methanesulfonyl chloride (114 mg) in pyridine (0.5 ml) was added at room temperature. The mixture was refluxed under heating for 1 hr. Thereto was added a solution of methanesulfonyl chloride (114 mg) in pyridine (0.5 ml) at room temperature, and the mixture was left standing overnight at room temperature. The reaction mixture was concentrated under reduced pressure and ice water was added to the residue. The resulting product was extracted with chloroform. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the crystals were washed, filtrated and dried under reduced pressure to give the objective compound (101 mg) as pale-yellow crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C1COCC1>[CH2:42]([NH:49][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of heptylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 540.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OC(C)C)c(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)cc1CO
Temperature: 80 °C
Yield: 89 %

Procedure:
To methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 0.80 mmol) and 1,4-dioxane (1.895 mL) was added sodium hydroxide (2.1 mL of 1.0 M, 2.1 mmol) and the mixture was heated at 80° C. for 50 minutes. The solvent was evaporated under reduced pressure. The crude mixture was dissolved in water (10 mL) and was washed with ethyl acetate (3×10 mL) which was discarded. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 3-(hydroxymethyl)-4-isopropoxy-benzoic acid (89%) as a white solid. ESI-MS m/z calc. 210.2. found 211.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc(Br)cc1

Procedure:
A solution of 4-bromobenzenesulphonyl chloride (2.0 g) in THF (5 ml) was treated in two portions with aqueous methylamine (40%; 6 ml). The resulting exothermic reaction-was allowed to subside and the solution was diluted with water (10 ml) and extracted with dichloromethane (2×50 ml). The dried extract was evaporated to give the title compound as a white solid (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)CC)nc23)CC1
Yield: 281.7 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-butylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.058 mL (0.067 mMol) propionyl chloride, 0.062 gm (35%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+:27]>CCOC(C)=O>[Na+:27].[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:9]([O-:11])=[O:10])=[CH:22][CH:23]=1
Reactant: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C([O-])C(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
A solution of the acid 39 in EtOAc was treated with 1 eq. of 1N NaOH, and the resultant product was recrystallized from EtOAc/hexanes to afford white solid Na salt 141.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(#N)C.[OH:23][S:24]([O-:26])=[O:25].[Na+:27]>O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[S:24]([O-:26])(=[O:25])=[O:23])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1.[Na+:27]
Reactant: O=S([O-])O
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(C(O)S(=O)(=O)[O-])cc1)N1CCN(C2CC2)CC1
Temperature: 50 °C

Procedure:
A 100 mL flask was charged with 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (2.58 g, 10.0 mmol, 1.0 eq), acetonitrile (30 mL), and water (1.0 mL) under nitrogen atmosphere. The reaction mixture was heated to 50° C. A solution of NaHSO3 (1.14 g, 11.0 mol, 1.1 eq) in water (2.0 mL) was added dropwise over 5 min. The reaction mixture was then cooled to 17° C. The product was collected by filtration as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:22])([C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([F:13])([F:12])[F:11].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[O:22][C:9]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccccc2)(C(F)(F)F)O1
Yield: 40.8 %

Procedure:
A solution of 2-(2-amino-5-chlorophenyl)-4-phenyl-1,1,1-trifluoro-3-butyn-2-ol (2.0 g, 6.1 mmol) and 11.0 g (12.0 mmol) of 1,1'-carbonyldiimidazole in 300 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 200 mL of ether and 400 mL of water. The layers were separated and the aqueous extracted once more with ether. The combined ether extracts were washed with 2×200 mL 10% citric acid and then with brine before drying over MgSO4. Removal of the drying agent and solvent provided 1.5 g (70%) of the crude title compound as an oil. Trituration with ether-hexane afforded 875 mg of (±) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, partial melt at 137°, clear at 147° C. 1H-NMR (CDCl3): δ6.92 (d, J=8 Hz, 1H), 7.30-7.49 (m, 4H), 7.58-7.65 (m, 3H), 8.99 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O[CH:13]([C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>FC(F)(F)C(O)=O>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH:13]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1cccc(OC)c1C(O)Cn1ccnc1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(OC)cccc2OC)cc1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
20 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 1.38 g of methyl 4-mercaptobenzoate and 1.36 g of 1-[2-hydroxy-2-(2,6-dimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 2 hours. The reaction mixture was then treated and purified by the same method as described in Example 13, to give 2.02 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=2)=[N:19][CH:20]=1>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:28](=[O:29])[CH:27]([O:26][C:25]1[CH:32]=[CH:33][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:35])([F:34])[F:13])=[CH:20][N:19]=2)=[CH:23][CH:24]=1)[CH3:31])[CH3:2]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
3.4 g (0.046 mol) of diethylamine and 4.8 g (0.47 mol) of triethylamine dissolved in 10 ml of benzene are dropped into the solution of 15.6 g (0.045 mol) of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl chloride in 40 ml of anhydrous benzene at 0°-5° C. under stirring. After termination of the portionwise addition, the reaction mixture is stirred for additional 2 hours whilst it is allowed to warm to room temperature. The mixture is filtered off, the precipitate is washed with a little volume of ether, the filtrate is washed first with 5% hydrochloric acid and then with saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and finally evaporated to dryness. The crude product is purified by chromatography on a column filled with silica gel of 0.063-0.2 mm particle size by using a 4:1 mixture of n-hexane/acetone for elution.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH2:18]([Mg]Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide (5.0 g, 20 mmol) in THF (50 ml) was added phenethyl magnesium chloride (50 ml of 1.0M in THF) and the reaction was warmed to r.t. After 2 hr, the reaction was poured into 2N HCl and extracted with ether. The organic layer was dried (MgSO4), and concentrated and the product was purified by column chromatography (eluent 5% EtOAc/Hexane) to give 1-(2-fluoro-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one as a clear oil (4.8 g). MS (ES) m/z 297.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.CC(O)=O>O.O=[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC1CCNCC1
Reaction time: 72 h

Procedure:
4-pyridine acetic acid (50 g, 0.314 mole) was dissolved in H2O (50 mL), and HOAc (100 mL), PtO2 (1 g) was added and the mixture was hydrogenated at 55 psi for 72 h. An additional 1 g of PtO2 was added after 48 h. The solution was filtered through celite, the cake was washed with H2O and the filtrate was evaporated, using heptane to azeotrope off excess HOAc. The 4-piperidine acetic acid was obtained as a white solid. Rf (9:1 EtOH/H2O) 0.11.1H NMR (400 MHz, CD3OD) δ3.36 (bd, 2H), 330 (bt, 2H), 2.3 (d, J=7 Hz, 2H), 2.08 (m, 1H), 1.99 (bd, 2H), 1.47 (m, 2H). This solid was dissolved in H2O (200 mL), and dioxane (200 mL), treated with triethylamine (76 mL, 0.546 mole), and di-t-butyldicarbonate (59.5 g, 0.273 mole) and stirred for 96 h. After 72 h, an additional equivalent of triethylamine and 10 g of di-t-butyldicarbonate was added. The organic solvent was evaporated and the remaining aqueous solution was brought to pH 10 with saturated NaHCO3, washed with 3×50 mL EtOAc, acidified with 10% KHSO4 to pH 2-3, extracted with 3×100 mL EtOAc, dried with MgSO4, filtered and evaporated to give 4-(N-t-butyloxycarbonyl)piperidine acetic acid. Rf (9:1 EtOH/H2O) 0.68. 1H NMR (CDCl3) δ4.1 (bs, 2H), 2.7 (bt, 2H), 2.27 (d, J=7 Hz, 1.95 (m, 1H), 2.7 (bd, 2H), 1.45 (s, 9H), 1.18 (m, 2H). This acid was reduced with borane to yield 2-(4-N-t-butyloxycarbonylpiperidine)ethanol, 1-5, as an oil. 1H NMR (400 MHz, CDCl3) δ4.08 (bd, J=12 Hz, 2H), 3.7 (t, J=6.5 Hz, 2H), 2.4 (bt, 12 Hz, 2H), 1.67 (bd, 2H), 1.6-1.45 (m, 3H), 1.45 (s, 9H), 1.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Cl:14][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
The product from Step 2 (40.0 g, 229 mmol) was suspended in toluene (300 mL) and POCl3 (65 mL, 697 mmol) was added over 10 min, then the mixture was heated to relux for 6 h then cooled to 60° C. and allowed to stir overnight at that temperature. The heterogeneous mixture was cooled and concentrated, the residue was carefully made basic with aq. K2CO3 solution and extracted with EtOAc. The organic layers were combined, washed with H2O and brine, dried (Na2SO4), filtered and the filtrate was concentrated to give an oil. The crude oil was passed through a plug of silica gel (50% EtOAc in hexanes) to give the title compound (32.5 g, 74%) as an orange oil which solidified on standing. MS (ES+) m/e 194 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[C:19]1([C:25]2[C:29]3[CH:30]=[CH:31][C:32]([OH:37])=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=3[O:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH:11]([O:37][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][O:27][C:28]=2[C:33]=1[CH2:34][CH2:35][CH3:36])[CH3:12]
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: COC(=O)Cc1ccc(OCCCCBr)c(F)c1
Product: CCCc1c(OC(C)CCOc2ccc(CC(=O)OC)cc2F)ccc2c(-c3ccccc3)coc12

Procedure:
Using the method of Example 27, step A, using methyl 3-floro-4-(4-bromobutyloxy)-phenylacetate and 3-phenyl-6-hydroxy-7-propylbenzofuran (Example 5, Step B) as the starting material, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH:7]1([C:10]2[CH:11]=[C:12]([C:31]3[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=3)[CH:13]=[CH:14][C:15]=2[N:16]2[C:25]3[C:20](=[CH:21][C:22]([S:26]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:9][CH2:8]1
Reactant: Nc1ccon1
Reactant: O=c1ccc2cc(S(=O)(=O)Cl)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(-c2cc(F)cc(F)c2)cc1C1CC1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 3-aminoisoxazole (0.070 ml, 0.954 mmol) and 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.150 g, 0.318 mmol) in 3 mL THF was cooled to 0° C. and was treated with LiHMDS 1N in THF (0.636 ml, 0.636 mmol). The cooling bath was removed and the reaction mixture was allowed to stir for one hour. TFA (0.122 ml, 1.589 mmol) was then added, and the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.06, 0.115 mmol, 36.3% yield). m/z (ESI) 520.1 (M+H)+. The atropisomers were separated using supercritical fluid chromatography (SFC). The column used was Chiralpak OJ-H. The mobile phase was run under isocratic conditions; CO2 with 25% Methanol to afford product as an off-white solid. First atropisomer (peak 1): (M)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.015 g, 0.029 mmol, 9.08% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 472.0 (M+H)+. Second atropisomer (peak 2): (P)-1-(3-cyclopropyl-3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.016 g, 0.031 mmol, 9.69% yield). NMR (ACETONITRILE-d3) □: 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.80 (dd, J=8.9, 2.1 Hz, 1H), 7.65 (dd, J=8.2, 2.2 Hz, 1H), 7.35-7.42 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.95-7.04 (m, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 1.42-1.53 (m, 1H), 0.69-0.88 (m, 2H), 0.51-0.65 (m, 2H). m/z (ESI) 520.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:30]1[CH2:34][C@@H:33]([CH3:35])[C:32](=[O:36])[O:31]1)[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>>[OH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][NH:37][C:32](=[O:36])[C@H:33]([CH3:35])[CH2:34][C@H:30]([OH:31])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=2)[CH2:41][CH2:42]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Reactant: NCCN1CCC(O)CC1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCN2CCC(O)CC2)C(C)C)ccc1OC

Procedure:
102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16.