Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:21])([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:6][NH:7][C@H:8]([C:12]([O:14]C)=[O:13])[CH:9]([CH3:11])[CH3:10]>C1COCC1.O>[F:4][C:5]([F:21])([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: C=CCCCC(F)(F)CN[C@H](C(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCC(F)(F)CN[C@H](C(=O)O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (6 eq.) was added to a stirred mixture of methyl N-(2,2-difluorohept-6-en-1-yl)-L-valinate 73 in THF and water (2/1 v/v, 0.013 M) and the mixture was stirred at 60° C. After 1 h, it was cooled to RT and THF was evaporated under reduced pressure. Aqueous 1N HCl was added until pH=5, and the aq. phase was extracted with EtOAc. Drying over Na2SO4, filtration and evaporation under reduced pressure afforded the title compound that was used in the following step without further purification. MS (ES+) m/z 250 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.S(Cl)([Cl:14])=O>N1C=CC=CC=1>[Cl:14][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCO
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCl
Temperature: -3 °C

Procedure:
275 ml (1.46 mol) of 3,7-dimethyl-1-octanol were placed in a 1 l four-neck round-bottom flask fitted with dropping funnel, low-temperature condenser and magnetic stirrer bar and cooled to −3° C. 0.7 ml of pyridine were then added and 129 ml (1.77 mol, 1.2 eq) of thionyl chloride were added dropwise at such a rate that the temperautre did not exceed 15° C. (75 minutes). The HCl gas formed was trapped in Ca(OH)2/water in a wash bottle. The mixture was then heated to 130° C. over a period of 40 minutes. After two hours at this temperature, the mixture was cooled to 50° C., volatile constituents were distilled off by application of a vacuum of 100 mbar. The residue was then cooled to room temperature, diluted with 200 ml of n-hexane and washed first twice with 50 ml each time of 10% strength of NaOH solution in water, then with 50 ml of water and finally with 50 ml of saturated aqueous NaHCO3 solution. The solution was dried over Na2SO4, the solvent was removed by distillation on a rotary evaporator. The residue was purified by distillation under reduced pressure (13 mbar, 86-87° C.). This gave 178.9 g (1.01 mol, 69%) of 1-chloro-3,7-dimethyloctane as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[CH3:26].Cl>O1CCOCC1.O.O1CCOCC1.C(OC(=O)C)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])(=[O:24])=[O:23])=[CH:18][C:17]=1[CH3:26]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D-Valine (1.39 g, 11.9 mmol) was dissolved in 80 ml of dioxane/water (1:1) containing K2CO3 (3.3 g, 24 mmol). A solution of 4-fluro-3-methylphenyl-sulfonylchloride (10 mmol) in dioxane (4 ml) was dropped in with good stirring. The reaction mixture was stirred at room temperature for 30 min. Ethylacetate (80 ml), 1N HCl (50 ml) was added. The organic layer was washed with 1N HCl 2 times, and extracted with 5% K2CO3 (3×25 ml). The combined base extracts was acidified and extracted with ethylaceate (80 ml). The organic layer was washed with brine (2×), dried over Na2SO4. The solvent was removed on rotavap, and residue tritrated with hexane. The resulting solid was dried to give 2(R)-[(4-fluoro-3-methylphenyl-sulfonyl)]amino-3-methylbutyric acid.
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH:29]1([CH2:32]O)[CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:29]1([CH2:32][O:28][C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[CH3:17])[CH2:31][CH2:30]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: OCC1CC1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
3.15 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.73 g of 2,5-dimethyl-4-nitrophenol, 0.75 g of cyclopropylmethanol, 3.26 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 1.95 g of 1-cyclopropylmethoxy-2,5-dimethyl-4-nitrobenzene.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:8]([C:22](=[O:36])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](=[O:35])(=[O:34])[NH:32][CH3:33])=[CH:27][CH:26]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>O.CCO.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:13]3[C:9](=[C:8]([C:22](=[O:36])[NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:35])[NH:32][CH3:33])=[CH:27][CH:26]=4)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=3)[CH:10]=[N:11]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(S(=O)(=O)NC)cc2)c2cnn(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(C(=O)O)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylic acid ethyl ester (0.13 g, 0.26 mmol) in H2O (10 mL) and EtOH (20 mL) was added a 2 N solution of aqueous KOH (10 mL, 20 mmol). The mixture was warmed at reflux for 1 hour and cooled to room temperature. The mixture was acidified with 2 N aqueous HCl (pH=3-4) and diluted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether (10 mL) to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 mL) and THF (1 mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N2. After 30 mm of stirring, the reaction mixture was cooled to 0° C. and 2-chloro-N,N-dimethylacetamide (11 mL, 0.14 mmol,) was added. The reaction mixture was stirred for 5 min at 0° C. and then for 10 h at room temperature. The mixture was purified by preparative HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of Pd—C (10 mg). The mixture was stirred open to the atmosphere overnight at room temperature. The reaction mixture was filtrated and purified by preparative HPLC providing 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1
Reactant: ICC1CCCO1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of diisopropylamine (0.59 mL, 4.51 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (1.8 mL, 4.51 mmol). The reaction mixture was stirred at −78° C. for 15 min, after which time, a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (825 mg, 3.76 mmol) in tetrahydrofuran (3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 2-iodomethyl-tetrahydro-furan (798 mg, 3.76 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 25° C., where it was stirred for 14 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (501 mg, 44%) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0464.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[C:5]2[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[O:25])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]4[CH3:19])[C:5]4[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=4[N:7]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1S(=O)(=O)CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1S(=O)(=O)CC2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To solution of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (50 mg, 0.16 mmol), in 2.0 mL of DME/H2O (4/1, v/v) was added 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (59.7 mg, 0.20 mmol) and Na2CO3 (52.3 mg, 0.49 mmol). The mixture was degassed twice, and then catalytic amount of Pd(dppf)Cl2 (10 mg, 0.013 mmol) was added. The mixture was heated to 80° C. and stirred for 3 h under nitrogen. The resulting mixture was then cooled and diluted with EtOAc and H2O the aqueous layer was extracted with ethyl acetate and the combined organic layers were combined, washed by brine, dried over anhydrous Na2SO4, filtered, and then evaporated to give the crude which was purified by column chromatography on silica gel (eluent: CH2Cl2/ethyl acetate=30/1˜1/1) to provide 1-cyclopropyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl]phenyl]urea as a white solid, (30.0 mg, 41%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1.Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][C:24]=1[C:33]([O:35]C)=[O:34].[OH-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu].O.C(O)C.O>[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=2[C:33]([OH:35])=[O:34])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: CCCCCOc1cc(SC)ccc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCOc1cc(SC)ccc1Oc1ccc(C(=O)O)cc1C(=O)O
Temperature: 120 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
4.40 g (0.032 mole) of anhydrous potassium carbonate and then 0.16 g of powdered copper were added to a solution of 3.60 g (0.016 mole) of 4-methylthio-2-(n-pentyloxy)-phenol and 4.37 g (0.016 mole) of dimethyl 4-bromo-isophthalate in 40 ml of nitrobenzene and the mixture was heated with stirring at 120° C under nitrogen for 3 hours. After cooling the mixture to 100° C, a solution of 1.92 g of sodium hydroxide pellets in 50 ml of a 1-1 ethanol-water mixture was added thereto and the mixture was refluxed for one hour. The mixture was cooled and 100 ml of water were added. The mixture was extracted with 100 ml of ether and the aqueous layer was washed twice with 50 ml of ether and was then acidified with 10% hydrochloric acid. The mixture was extracted with ether and the ether extract was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain an off-white solid residue. The residue was triturated wth petroleum ether to obtain 5.3 g of 4-[4'-methylthio-2'-(n-pentyloxy)-phenoxy]-isophthalic acid. The IR spectrum showed a bonded hydroxy at 3500 to 2200cm-1 and carboxyl at 1700cm-1.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32]
Reactant: [H][H]
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CO
Product: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 98 %

Procedure:
A suspension of 1′-[3-(benzyloxy)propyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (6.27 g, 14.5 mmol) and 10% Pd/C (0.5 g) in MeOH (150 mL) was hydrogenated under the normal pressure of hydrogen overnight and filtered through a pad of celite. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ether to yield the title compound (4.82 g) as a white solid in 98% yield: 1H NMR (300 MHz, CDCl3) δ 7.38-6.93 (m, 4H), 6.49 (s, 1H), 6.10 (s, 1H), 4.87 (m, 1H), 4.63 (m, 1H), 4.01-3.81 (m, 2H), 3.62 (t, 2H), 2.89 (br, 1H), 1.99-1.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 156.0, 148.9, 142.4, 142.1, 132.3, 129.0, 128.9, 124.1, 123.9, 119.0, 108.6, 103.0, 101.5, 93.6, 80.4, 58.3, 37.8, 29.8; MS (ES+) m/z 340.2 (M+1).
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](CC3C=CC(OC)=CC=3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ccncn4)cc3C)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Yield: 96.3 %

Procedure:
A solution of the 4-({(1S,2R)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.15 g, 0.20 mmol) prepared in Example 143f, triethylsilane (0.16 mL) and trifluoroacetic acid (0.20 mL) in dichloromethane (2.0 mL) was stirred at 140° C. for 1 hour under microwave irradiation. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (90 mg, 94%) as a colorless solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH2:13]([O:15][C:16](=[O:30])[CH:17]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19](=O)[CH3:20])[CH3:14].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:13]([O:15][C:16]([C:17]1[CH:18]=[C:19]([CH3:20])[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=2)[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])[CH3:14]
Reactant: CN(C)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(N(C)C)c2)c1-c1ccccc1

Procedure:
N,N-Dimethyl-1,3-phenylenediamine dihydrochloride (5 mmol, 1.0 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), triethylamine (10 mmol, 10 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The crude material was purified over silica gel and yielded the named product (m.p. 111.7° C.-114° C.).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:16]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:17][C:18](O)=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:15])[C@H:16]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:17][C:18]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1CCOCC1
Yield: 92.3 %

Procedure:
3-(R)-(4-(S)-Benzyl-2-oxo-oxazolidine-3-carbonyl)-5-cyclohexyl-pentanoic acid (1.76 g, 4.53 mmol, 1.0 eq.) dissolved in DMF (10 mL) and treated with HATU (1.3 g, 5.0 mmol, 1.1 eq.), morpholine (680 μL, 7.77 mmol, 1.7 eq.) and DIPEA (870 μL, 5.0 mmol, 1.1 eq.). Alternatively an additional equivalent of morpholine can be used in the reaction and CH2Cl2 can be used as the reaction solvent. The reaction is monitored by LC/MS. The reaction mixture is diluted with ethyl acetate (50 mL) and extracted with 0.5 M HCl (2×10 mL), saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered and evaporated. The crude mixture is used in Step F directly or purified by normal-phase silica chromatography in a 20-50% ethyl acetate in hexanes gradient to provide 1-(4-(S)-Benzyl-2-oxo-oxazolidin-3-yl)-2-(R)-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-butane-1,4-dione as a white solid (1.91 g, 4.18 mmol, 92%): 1H NMR (CDCl3, 400 MHz) δ 0.80-0.91 (m, 2H), 1.09-1.27 (m, 6H), 1.44-1.53 (m, 1H), 1.61-1.73 (m, 6H), 2.12 (s, 2H), 2.35 (dd, 1H, J=17.2, 4.0 Hz), 2.49 (dd, 1H, J=13.6, 9.6 Hz), 2.71 (dd, 1H, J=17.6, 10.8 Hz), 3.03 (dd, 1H, J=13.6, 3.2 Hz), 3.48-3.72 (m, 8H), 3.87-3.97 (m, 3H), 4.43 (m, 1H), 6.90-7.10 (m, 5H), 8.02 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=O.Cl.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Reactant: CNC
Agent: Cl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)N(C)C

Procedure:
The carboxylic acid from Example 33 (0.07 g, 0.18 mmol) was reacted with dimethylamine hydrochloride (0.072 g, 0.88 mmol) according to the procedure in Example 7. The product was purified by flash chromatography on silica (eluant chloroform:methanol:acetic acid 98:1:1) to give a white solid; yield 0.08 g (11%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](I)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[O:23][N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:25]3[C:21]([CH3:20])=[N:22][O:23][C:24]=3[CH3:35])[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCI
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(C)noc2C)c2c(c1)[nH]c(=O)n2C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (40 mg, 0.11 mmol, 1 equiv.) were added 3,5-dimethylisoxazole-4-boronic acid pinacol ester (72 mg, 0.32 mmol, 3 equiv.), Cs2CO3 (141 mg, 0.43 mmol, 4 equiv.), PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) and DME-H2O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. After 1 hr, the reaction was complete. Following cooling, the reaction mixture was extracted with EtOAc and the organic solution was washed with water, saturated NH4Cl. After drying with MgSO4, it was filtered and concentrated to dryness. The resulting solid was washed with EtOAc. Purification of the residue was carried out by reverse phase HPLC to furnish the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:30]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=2[F:31])=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cc(F)ccc2F)cc1
Yield: 35.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2,5-difluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), 2,5-difluorophenylboronic acid (0.038 g; 0.242 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.019 g; 0.023 mmol), sodium carbonate (0.048 g; 0.460 mmol), sodium iodide (0.069 g; 0.460 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.035 g (35%) of the title compound as a white solid.