Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:16]3[CH2:18][CH2:17]3)[CH:11]=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1>O1CCOCC1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:16]3[CH2:17][CH2:18]3)[CH2:11][NH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Reaction time: 16 h

Procedure:
Acetyl chloride (0.5 mL) is added to a solution of 7-amino-4-cyclopropyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.5 g), prepared in the Step above, in dioxane (20 mL) and stirring is carried out at ambient temperature for 16 hours. After removing the solvent by distillation under reduced pressure, the residue is taken up in water, and the precipitate, of 7-acetamido-4-cyclopropyl-4H-1,2,4-benzothiadiazine 1,1-dioxide, is collected by filtration, washed with water and dried. It is used directly in a subsequent step, according to the procedure described in Step D of Example 1, in order to obtain the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:3]3[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[CH:10][CH:9]=[C:8]4[C:4]=3/[C:5](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[O:18][CH3:19])/[C:6](=[O:11])[NH:7]4)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4[nH]ccc4c3)c21
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc4[nH]ccc4c3)c21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (Z)-5-amino-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (24 mg, 0.065 mmol) (from Step B above) in 2 mL tetrahydrofuran was added 2-thiopheneacetyl chloride (24 mg, 0.15 mmol) (Aldrich) and a saturated aqueous solution of sodium bicarbonate (0.15 mL). The reaction was stirred at room temperature for 14 hours at which time the reaction was diluted with water (10 mL), and the THF was evaporated in vacuo. The product was then extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting powder was recrystallized from EtOAc/Hex to give product as yellow crystals. (Yield 23 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetate (544 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetic acid (482 mg, yield 91%), which was then recrystallized from acetone-hexane. melting point: 153–154° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[I-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([S:18][C:19]2[NH:23][C:22]([CH2:24][O:25]CC3C=CC(OC)=CC=3)=[N:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C.CN(C)C=O>[ClH:1].[Cl:17][C:15]1[CH:14]=[C:13]([S:18][C:19]2[N:23]([CH2:2][C:3]3[S:4][CH:5]=[CH:6][CH:7]=3)[C:22]([CH2:24][OH:25])=[N:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11]([Cl:10])[CH:16]=1
Reactant: ClCc1cccs1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(CO)n(Cc2cccs2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
To dimethylformamide was added 67 mg of 2-(chloromethyl)thiophene and 152 mg of potassium iodide under ice-cooling, the mixture was allowed to warm up to room temperature and stirred for 20 minutes. Then, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b) was added, followed by addition of 126 mg of potassium carbonate. Then, the mixture was warmed up to 50° C., and allowed to react for 6 hours. After completion of the reaction, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, arid the solvent was distilled off under reduced pressure. To thus-obtained oil were added 5 ml of ethanol and 10 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 170 mg of Compound I-126 was obtained (yield 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[F:22][C@H:23]1[C@H:29](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:28][CH2:27][N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:25][CH2:24]1.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N>[F:22][C@H:23]1[C@@H:29]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:28][CH2:27][N:26]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:25][CH2:24]1
Reactant: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1ccn2c(-c3ccc4cccc(O[C@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)nnc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (300 mg, 1.09 mmol) was suspended in CH3CN (5 mL) at ambient temperature, and trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (454 mg, 1.09 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (263 μL, 1.30 mmol) were added. The dark solution was stirred at 40° C. overnight, then concentrated to a grey solid which was slurried in water for 10 minutes. The solid was filtered, washed and dried in vacuo to provide the desired product. MS ESI (+) m/z 492.3 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=O)[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[S:28])[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=S)c2sc(N3CCOCC3)nc2C1
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a stirred solution of Example 48 (0.266 g, 1 mmol) in THF (10 mL) at r.t. was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (0.808 g, 2 mmol). The reaction mixture was stirred for 2 h and then poured into saturated NaHCO3 solution (50 ml) and extracted with DCM (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation in vacuo to give the title compound (0.14 g, 50%) as a solid. δH (DMSO-d6) 3.72-3.60 (8H, m), 2.74 (2H, s), 2.61 (2H, s), 1.02 (6H, s). LCMS (ES+) 283.0 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Cl-].[Cl-].[Al+3].Cl.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Glutaryl chloride (28.2 g; 0.167 mole) was slowly added to a mixture of anhydrous aluminum trichloride (50 g; 0.375 mole) and 250 ml benzene. The mixture was stirred vigorously in an ice/water bath. After completion of the addition, the ice/water bath was removed and stirring was continued for two hours. The solution obtained was slowly poured into a mixture of 200 g crushed ice and 40 ml concentrated aqueous hydrochloric acid. The resulting product was recovered by extraction and crystallization to produce 1,5-diphenyl-1,5-pentanedione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([Cl:14])=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N:6][CH:7]=1
Reactant: [O-][n+]1cc(Br)cc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Product: Clc1c(Br)cnc2[nH]ccc12
Temperature: -20 °C
Yield: 48 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (19.18 g, 90 mmol) were suspended in 200 mL NMP and cooled to −20° C. Phosphorus oxychloride (41 mL, 450 mmol) was added dropwise over 30 min. The mixture was allowed to warm to 23° C. over 1 h after which it was cooled on an ice bath and quenched with water (800 mL). The solids were filtered and recrystallized from ethyl acetate and hexanes to give 5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (10 g, 48%). 1H NMR (500 MHz, DMSO-d6) δ 12.25 (bs, 1H), 8.4 (s, 1H), 7.65 (m, 1H), 6.52 (m, 1H). MS: m/z 230.8/232.8 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (2.5 g) obtained in Example 59 was suspended in dimethyl sulfoxide (120 ml), and potassium carbonate (2.2 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and t-butyl bromoacetate (1.4 ml) was added to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (900 ml), and the crystals precipitated were recovered by filtration. The crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (1.9 g, 68%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]([N:16]([CH2:31][CH3:32])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=1[CH3:30])=[O:21])[CH3:15]>>[CH2:31]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:26]([CH3:27])=[C:25]([CH:28]=[C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[NH:24][C:23]=1[CH3:30])=[O:21])[CH3:32]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(C(=O)O)ccc32)c1C
Yield: 92 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>C(OCC)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=3)=[O:4])[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-nitro-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 120-123° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CC[N:12](C(C)C)C(C)C>>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH2:12])=[O:9])[N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1c[nH]c(Cl)n1
Product: NC(=O)c1c[nH]c(Cl)n1

Procedure:
Scheme 2 illustrates the synthesis of compounds 9 and 10. Lithiation of compound 6 with n-BuLi followed by the addition of carbon dioxide affords 2-chloro-imidazole-4-carboxylic acid 7. Reaction of acid 7 with amine 2 in the presence of DMC and DIEA furnishes 2-chloro-imidazole-4-carboxamide 8, which undergoes Suzuki coupling reaction with arylboronic acid to give 2-aryl-imidazole-4-carboxamide 9. Reduction of amide 9 with Alane-N,N-dimethylethylamine complex gives compound 10. Alternatively, compound 10 is prepared from hydroxymethylimidazoles 12 via SOCl2 treatment and subsequent alkylation reaction with amine 2.
Reaction SMILES: C[Si](I)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20]C)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.CO>[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][OH:20])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Reaction time: 24 h
Yield: 47 %

Procedure:
Trimethylsilyl iodide (115 mL, 0.79 mol) was added to a solution of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (38.01 g, 0.158 mol) in acetonitrile (500 mL) and stirred for 24 hours. Methanol (300 mL) was added and the reaction stirred for 10 mins. 10% w/v Aqueous sodium thiosulfate pentahydrate (100 mL) was added to the mixture and stirred for 20 mins. The reaction mixture was neutralised with saturated aqueous sodium bicarbonate solution, the organic solvents removed in vacuo, and the product extracted into ethyl acetate (4×100 mL). The combined organic layers were dried (MgSO4), filtered and the solvents removed in vacuo. The crude material was crystallised from ethyl acetate to give the title compound (16.80 g).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]([C:28]2([C:31]3[CH:41]=[CH:40][C:34]4[O:35][C:36]([F:39])([F:38])[O:37][C:33]=4[CH:32]=3)[CH2:30][CH2:29]2)=[O:27])[CH:22]=[CH:21][C:20]=1[CH3:42]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[F:39][C:36]1([F:38])[O:35][C:34]2[CH:40]=[CH:41][C:31]([C:28]3([C:26]([NH:25][C:23]4[CH:22]=[CH:21][C:20]([CH3:42])=[C:19]([C:6]5[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=5)[N:24]=4)=[O:27])[CH2:30][CH2:29]3)=[CH:32][C:33]=2[O:37]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(C)c1
Temperature: 120 °C
Yield: 63.5 %

Procedure:
To a mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (68 mg, 0.30 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.24 mL) was added Pd(PPh3)4 (14 mg, 0.0030 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O before the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over MgSO4. After the removal solvent, the residue was purified by column chromatography (10-20% EtOAc-Hexane) to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (67 mg, 72%). 1H-NMR (400 MHz, CDCl3) δ 8.06 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.24 (td, J=10.0, 1.7 Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.61 (d, J=9.2 Hz, 1H), 3.60 (s, 3H), 2.33 (s, 3H), 1.77 (q, J=3.6 Hz, 2H), 1.19 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 440.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C1COCC1.CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1csc(Nc2cc(O)ccn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1csc(Nc2cc(Oc3ccccc3C#N)ccn2)n1
Temperature: 90 °C
Yield: 8.7 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-4-ol (0.100 g, 0.483 mmol), 2-fluorobenzonitrile (0.064 g, 0.531-mmol) and potassium carbonate (0.167 g, 1.21 mmol) were combined in DMSO and heated at 90° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified by MPLC, eluting with 3:1 hexane:ethyl acetate to afford the free base. The free base was dissolved in THF (3 mL) and 1M HCl in ether (6 mL) was added. The solution was diluted with ether (15 mL), triturated for 10 minutes, and filtered to afford 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzonitrile (0.013 g, 8.65% yield) as white solid. 1H NMR (CDCl3) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.60 (m, 1H), 7.32 (dt, 1H), 7.14 (d, 1H), 6.53 (dd, 1H), 6.42 (d, 1H), 6.33 (d, 1H), 2.23 (d, 3H); HPLC Rt=2.67 min; Mass spectrum (esi) m/z=309 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CN(C=O)C.C(=O)(O)[O-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1OCCOCCOCCOCCOC1.O>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([O:23][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCI
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g (5.8 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 30 ml of DMF, 2 drops of 15-crown-5 and 2 g (23.8 mmol) of sodium bicarbonate are introduced into a round-bottomed flask. 3.1 ml (20.8 mmol) of 1-iodohexane are added and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water and extracted with ethyl acetate and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 2 g (80%) of the expected hexyl ester are collected in the form of a pale red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=2)[C:5]([NH:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=2)[CH3:9])=[O:6])=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Reactant: O=C(Cl)C1CCC1
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (Step-1, single enantiomer) and cyclobutanecarbonyl chloride according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].C([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[C:33]([C:39](O)=[O:40])[CH:32]=[N:31]2)[CH2:26][C@H:25]1[CH3:42])=[O:23])C>>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][CH2:9][N:10]([CH2:11][C:12]([CH3:15])([CH3:13])[CH3:14])[C:39]([C:33]1[CH:32]=[N:31][N:30]([C@H:27]2[CH2:28][CH2:29][C@H:24]([C:22]([OH:23])=[O:21])[C@H:25]([CH3:42])[CH2:26]2)[C:34]=1[C:35]([F:38])([F:36])[F:37])=[O:40]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Reactant: COc1ncc(Cl)c(CCNCC(C)(C)C)c1Cl
Product: COc1ncc(Cl)c(CCN(CC(C)(C)C)C(=O)c2cnn([C@H]3CC[C@H](C(=O)O)[C@H](C)C3)c2C(F)(F)F)c1Cl

Procedure:
The title compound was prepared from N-(2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-1-amine and 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid by procedures similar to those described in example 872. MS (ESI) 593.2, 595.1 [M+H]+.
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[C:6]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[C:12]([Cl:25])[C:11]=1[CH3:26])(=[O:8])[CH3:7]>O.C(O)(=O)C.CC(C)=O>[C:6]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:1])[CH:19]=2)=[C:12]([Cl:25])[C:11]=1[CH3:26])(=[O:8])[CH3:7]
Reactant: [O-]Cl
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Cl)c2)c(Cl)c1C
Temperature: -15 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Calcium hypochlorite (14 mg) was dissolved in a mixture of water (2 mL) and glacial acetic acid (one drop). Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (35 mg) dissolved in acetone (2 mL) was added at −10° C. After stirring at −15° C. for 2 hours, the reaction mixture was concentrated and the residue partioned between sodium hydroxide (1 N) and ethyl acetate. After purification on column (silica gel, ethyl acetate/petrolium ether, 1:4), 17 mg (43%) of methyl[3,5-dichloro-4-(4-amino-3-chlorophenoxy)phenyl] acetate was obtained.