Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
To a 2 mL heavy-walled tube was added (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (127 mg, 0.471 mmol), 4-(4-chlorophenyl)-4-oxobutanoic acid (91 mg, 0.428 mmol), Na2CO3 (136 mg, 1.284 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (3.03 mg, 4.28 μmol), dioxane (1 mL), and water (0.15 mL). The tube was sealed and heated to 150° C. for 10 min under microwave irradiation. The mixture was purified by preparative HPLC to give the title compound as a white solid. LCMS m/z=366.1 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.3 Hz, 0.4H), 1.37 (d, J=6.3 Hz, 2.6H), 1.54-1.65 (m, 1H), 1.90-2.05 (m, 2H), 2.18-2.26 (m, 1H), 2.62 (t, J=7.8 Hz, 2H), 2.95-3.10 (m, 2H), 3.16-3.30 (m, 3H), 3.38-3.68 (m, 4H), 7.46 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H), 9.34 (bs, 1H).
Reaction SMILES: [H-].[Na+].C1(C([C:11]2[C:16]([CH2:17][O:18][CH2:19][C:20]3[C:25]([C:26]4C(=CC=[C:31]([OH:33])[CH:32]=4)O)=CC=CC=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=CC(=CC=1)O)O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH3:43])[CH2:41][CH3:42]>CN(C)C=O>[CH3:43][CH:40]([CH2:41][CH3:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:33][C:31]1[CH:32]=[CH:26][CH:25]=[CH:20][C:19]=1[O:18][CH2:17][C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCC(C)CCCCCBr
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)CCCCCOc1ccccc1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A 100-ml 4-neck flask was charged with 3.74 g of NaH (containing 50% of oil) and 50 ml of N,N-dimethylformamide, and a solution of 15.46 g of hydroquinone monobenzyl ether in 30 ml of N,N-dimethylformamide was added under a nitrogen current over a period of 20 minutes in an ice water bath. After 20 minutes, 16 g of optically active 1-bromo-6-methyloctane was added over a period of 45 minutes, and reaction was carried out at room temperature for 6 hours. The reaction mixture was extracted with ether. The ether layer was washed with water, 5% NaOH, water and a saturated aqueous solution of sodium chloride in sequence and dried, and the organic solvent was distilled under reduced pressure to obtain a crude product. The crude product was purified to obtain 24.37 g of an ether compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:27][CH3:28])[C:17]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[O:6]CC1C=CC(OC)=CC=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:27][CH3:28])[C:17]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[OH:6])[CH3:2]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(O)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-(4-methoxy-benzyloxy)-acetic acid ethyl ester (58 mg, 0.115 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (58 μL). The reaction mixture was stirred for 2 h at room temperature and then quenched carefully with sat. NaHCO3. The aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water, dried (Na2SO4), concentrated and purified by flash column chromatography to give desired (23 mg).
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:12]([Cl:15])(=[O:14])[CH3:13]>C(#N)C>[ClH:15].[C:12]([O:10][CH2:9][CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: OCCNc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(=O)OCCNc1ccccc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
2-Anilinoethanol (137 g, 1.0 mol) was mixed with acetonitrile (300 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was evaporated to dryness. The residue was dissolved in acetonitrile (1000 ml); acetyl chloride (89 ml, 1.25 mol) was added and the reaction mixture was stirred at room temperature (22° C.) for 16 hours. The mixture was evaporated to dryness under reduced pressure and the resulting solid was triturated with ethyl ether (1000 ml). The solid was removed by filtration and dried to yield 197 g (91.3%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:10](I)=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].[CH3:15][N:16]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:10]([C:15]#[N:16])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13]
Reactant: COC(=O)Cc1c(Cl)cc(Cl)cc1I
Reactant: CN1CCCC1=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)Cc1c(Cl)cc(Cl)cc1C#N
Temperature: 110 °C

Procedure:
A mixture of 2,4-dichloro-6-iodophenylacetic acid methyl ester (0.95 mmol), Zn(CN)2 (0.95 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) in 1.5 mL anhydrous NMP was degassed and heated under argon in a closed vial to 110° C. for 2.5 h. The reaction mixture was cooled to RT, quenched with 10% aq Na2CO3 solution and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (9/1) gives the desired product as yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCCO
Reactant: O=Cc1cc2ccccc2cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(C3OCCO3)ncc2c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of 3-isoquinolinecarboxaldehyde (7 g, 44.5 mmol), 5.5 g (88 mmol) of ethylene glycol, 400 ml of toluene and 1.1 g (4.4 mmol) of p-toluenesulfonic acid was refluxed for 16 h while separating the water formed. The mixture was cooled to room temperature and washed with sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate, and concentrated in vacuo to afford 8 g (89.9%) of 3-(1,3-dioxolan-2-yl)isoquinoline (Formula XII: R2 =R7 =H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with 3-nitrophenylboronic acid (4.2 g, 25 mmol), dry molecular sieves (5 g), copper acetate (1.95 g, 12.5 mmol) and dry dichloromethane (150 mL). Triethylamine (8.7 mL, 62.5 mmol) is added followed by the addition of 4-fluoro-3-nitroaniline (2.27 g, 12.5 mmol). The resulting mixture is stirred at ambient temperature for three days. The mixture is filtered through celite and washed with EtOAc. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=1:3) to give the desired product: 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 7.82 (m, 1 H), 7.79-7.37 (m, 1 H), 7.73-7.70 (m, 1 H), 7.56-7.49 (m, 4 H); LC-MS: 278.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[CH3:11][O-:12].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: C[O-]
Reactant: Cc1cc(C)c(Br)c(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C)cc(C)c1Br

Procedure:
A mixture of 3-bromo-2-chloro-4,6-dimethylpyridine (2.97 g) and sodium methoxide (11.0 mL, 28% solution in methanol) was stirred in a DMF solvent (30 mL) at 80° C. for 36 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (2.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.C([Li])CCC.CON(C)[C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=2)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:19]([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=3)=[O:20])[CH:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)C#Cc3cc(Cl)cc(Cl)c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the 1,3-dichloro-5-ethynylbenzene (185 mg, 1.08 mmol) in anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (750 μL, 1.18 mmol). After 5 minutes, a solution of the intermediate from step E (320 mg, 1.3 mmol) in THF (5 mL) was added. The reaction was gradually warmed to room temperature over 30 minutes and quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 20% ethyl acetate-hexanes to afford the product as a light yellow solid. 1H NMR (500 MHz, CDCl3): 9.54 (d, J=2.3 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.62 (d, J=2.0 Hz, 2H), 7.5 (m, 2H), 7.34 (dd, J=2.5, 8.9 Hz, 1H), 4.04 (s, 3H). LC-MS: 3.92 min; (M+H)=356.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=C)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:32].[Na+]>[Os](=O)(=O)(=O)=O.O1CCOCC1.O>[CH2:29]([O:28][C:26]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:32])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:27])[CH3:30]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(Oc2ccc(N3CCCC3(C(=O)OCC)C(=O)OCC)cn2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
A mixture of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (4.8 g, 11.3 mmol), sodium metaperiodate (4.8 g, 22 mmol), osmium tetroxide (10 mg) and 2:1 dioxane-water (189 mL) was stirred for 6 hours at ambient temperature. The mixture was quenched with sodium sulfite, diluted with water and extracted 3× with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo affording 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup (4.6 g).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[C:15]([CH3:38])([CH3:37])[CH:16]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][CH:16]([CH:29]=[CH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:15]([CH3:37])([CH3:38])[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([OH:40])=[O:5])[CH2:13][CH2:12]2)=[O:39])=[O:28])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(C=Cc2ccccc2)NC(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(C=Cc1ccccc1)NC(=O)c1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
N-4-Amidinobenzoyl-β-styryl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (30 mg, 0.055 mmol) was dissolved in a mixed solution of TFA (10 ml) and water (0.5 ml). The resulting solution was stirred at room temperature for 3 hours. After the TFA was distilled off at room temperature, the residue was purified by the same method as in Example 2-(6-4) to yield N-(N-4-amidinobenzoyl-β-styryl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (7.2 mg, 26.7%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[N:9]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C1NOCC(=S)N1
Reactant: C1COCCN1
Product: O=C1N=C(N2CCOCC2)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
To a solution of 0.5 g (0.0037 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of dry freshly distilled dioxane is added 0.34 g (0.0039 mole) of morpholine. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.5 g (74 percent) of 5-(4-morpholinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: Cl.[OH:2][C:3]1([C:7]([OH:9])=[O:8])[CH2:6][NH:5][CH2:4]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[OH-].[Na+].O>[CH2:10]([O:17][C:18]([N:5]1[CH2:6][C:3]([OH:2])([C:7]([OH:9])=[O:8])[CH2:4]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1(O)CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(O)(C(=O)O)C1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 2.5 g (16.3 mmoles) of 3-hydroxyazetidine-3-carboxylic acid (prepared in Example 6) dissolved in a solution of 2.04 g of sodium hydroxide in 54 ml of water is added 3.34 g (1.2 equivalents) of benzyloxycarbonyl chloride under stirring at room temperature, and the mixture is stirred overnight and then mixed with 10% aqueous sodium hydroxide solution. The resulting alkali solution is washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized from n-pentane and then recrystallized from ether-n-pentane to yield 3.137 g of 1-benzyloxycarbonyl-3-hydroxyazetidine-3-carboxylic acid as needles, mp. 134°-136° C., in 76% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: CC(C)S(=O)(=O)Cl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)C(C)C)cc3)cc2C1=O

Procedure:
The compound of example 95 was prepared analogous to compound of example 77 by reaction of compound of example 6 with isopropyl sulfonyl chloride. The compound of example 95 was used directly without isolation for the preparation of compound of example 96.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:38]=[CH:39][C:34]([F:33])=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ncc(F)cn2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.03 g (57%). 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 2H), 8.04-7.93 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (s, 1H), 4.07 (s, 3H), 3.00-2.92 (m, 3H), 2.37 (s, 3H), 1.80-1.72 (m, 2H), 1.54-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ−113.44, 146.33 LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12]>C(O)C>[CH3:4][O:5][C:6]1[CH:14]=[C:10]2[C:9]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:2][NH:3][C:11]2=[O:12])=[CH:8][CH:7]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1
Yield: 89.7 %

Procedure:
18.5 mL (380 mmol) of hydrazine hydrate are added to a solution of 21.6 g (75 mmol) of 5-methoxy-2-(4-methoxybenzoyl)benzoic acid in 150 mL of ethanol and the mixture is refluxed for 2 hours. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40° C. 19 g of a white solid are obtained (90% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[CH2:21](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][CH3:21])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of compound 76 (122 mg, 0.30 mmol) in 4 mL of 1,2-dichloroethane was added triethylamine (84 μL, 0.60 mmol), aqueous formaldehyde (37%, 24 μL, 0.30 mmol) and sodium triacetoxyborohydride (254 mg, 1.20 mmol). The reaction mixture was allowed to stir overnight at room temperature. The reaction was quenched by adding sat'd aqueous NaHCO3 and stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate and sat'd aqueous NaHCO3, the organic layer was washed with brine, collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography using dichloromethane/methanol/NH4OH (ratio: 92/7/1) to afford compound 23a (38.1%, 35 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:35][C:2]([CH3:1])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of ethyl (2E)-3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylpyrimidin-4-yl)acrylate (180 mg) in THF (2.0 ml) and ethyl acetate (2.0 mL) was added 10% palladium-activated carbon (18 mg), and the mixture was stirred for 2 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (180 mg) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9](F)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[C:15]([O-])([O-])=[O:16].[K+].[K+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]([O:16][CH3:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(F)c(C#N)cc1Cl
Agent: [K+]
Solvent: CO
Product: COc1cc(C(=O)O)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 2-chloro-4-cyano-5-fluorobenzoate (840 mg; 3.93 mmol; 1 eq.) and K2CO3 (2 717.55 mg; 19.66 mmol; 5 eq.) in MeOH (16.80 mL) was stirred at RT for 24 hours. The reaction mixture was concentrated and the residue was taken up in water. The aqueous layer was washed with EtOAc then the aqueous phase was acidified with HCl cc and extracted with EtOAc. The combined organic phases were washed with water, brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid used without further (0.63 g, 75%). 1H NMR (DMSO-d6, 300 MHz) δ 14.05 (br s, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 3.96 (s, 3H). HPLC (Method A) Rt 3.11 min (Purity 88.5%).