Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH2:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:15][CH2:14]1>>[CH2:17]([O:16][CH2:12][C@H:13]([OH:15])[CH2:14][O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: c1ccc(COC[C@H]2CO2)cc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC[C@@H](O)COCc1ccccc1

Procedure:
That is, (2S)-3-l-menthoxypropane-1,2-diol can be obtained by adding (1R, 2S, 5R)-5-methyl-2-(1-methylethyl)cyclohexyl alcohol (hereinafter, is referred to as "l-menthol") to (R)-(-)-benzyl glycidyl ether [the compound of formula (II)]in the presence of a Lewis acid catalyst to provide (2S)-1-benzyloxy-2-hydroxy-3-{(1R, 2S, 5R)-[5-methyl-2-(1-methylethyl)cyclohexyl]oxy}propane [the compound of formula (III)], and hydrogenolyzing the compound in the presence of a palladium-carbon catalyst to eliminate the benzyl group.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[CH2:8][OH:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/c1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a solution of ethyl trans-4-bromocinnamate (8 mL, 42.6 mmol) in anhydrous dichloromethane (150 mL) under N2 was added diisobutylaluminum hydride in dichloromethane (128 mL, 1M, 128 mmol) at −78° C. dropwise. After the addition, the mixture was allowed to warm from −78° C. to −30° C. over two hours. The mixture was then cooled back to −78° C. and aqueous 1 N HCl was added till acidic (pH=2). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to provide the title compound 1H NMR (300 MHz, CDCl3): 1.44 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:28][Cl:29].CCCCCC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[Cl:29][CH2:28][C:3](=[O:2])[C@@H:4]([N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: ClCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCl)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 99.7 %

Procedure:
N-(diphenylmethylene)-L-phenylalanine methyl ester (3.35 g) and bromochloromethane (0.83 ml) were added to dehydrated tetrahydrofuran (97 ml), and the mixture was cooled to −78° C. Then, a 1.53 M n-butyllithium hexane solution (8.3 ml) was added thereto. The mixture was stirred for 35 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to terminate the reaction. The resulting reaction solution was extracted twice with ethyl acetate at room temperature. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed, the ethyl acetate solution was concentrated to obtain desired (3S)-1-chloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone (3.52 g) in a yield of 99.7%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][OH:19])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 72.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S,2S)-1-(hydroxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.34 g, 4.48 mmol) (obtained as described in Reference Example 38(3)) in dimethylformamide (67 ml) were added t-butyldimethylsilyl chloride (810 mg, 5.37 mmol) and imidazole (527 mg, 5.37 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (5:1→3:1) as the eluant to afford 3-hydroxy-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.35 g, yield 97%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[H-].[Na+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([CH3:29])=[CH:24][N:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24]3[C:25]([CH3:29])=[CH:26][N:27]=[C:22]([Cl:21])[N:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)ncc3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (40.3 mg, 0.15 mmol, 1.2 equiv; intermediate A2) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h, 2,4-dichloro-5-methyl-pyrimidine (20.4 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 395.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:26][CH:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:32][C:29]1([CH3:33])[O:28][CH:27]([CH2:26][N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][O:30]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 73.0 mg), and the mixture was stirred at room temperature for 1 hr, (2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (523 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (122 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][O:21][CH3:22])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CC(C)=O>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:23])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][O:21][CH3:22])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1ccc2c(c1)OCC(C)(c1ccc(O)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc2c(c1)OCC(C)(c1ccc(OCc3ccccc3)cc1)C2=O
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of 3-(4-hydroxyphenyl)-7-methoxymethyloxy-3-methylchroman-4-one (3.55 g, 11.293 mmol) and potassium carbonate (9.35 g, 67.76 mmol) in acetone (130 ml) was added benzyl bromide (5.795 g, 33.879 mmol) at room temperature and stirred overnight. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:ethyl acetate=9:1 to 7:3) to give 4.59 g (yield: quant.) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])=[CH:8][CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])=[CH:8][CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)cc2)O1
Solvent: O
Solvent: CO
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
2.53 g (5 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 20 ml of methanol/water 1:1, about 100 mg of cation exchanger Amberlyst 15 is added and warmed for 1 hour to boiling temperature. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.74 g (3.75 mmol)=75% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1ccc(C#N)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 250 ml flask, 10 g of 4-methylbenzenecarbonitrile was dissolved in 30 ml of concentrated sulfuric acid and then cooled to 0° C. 7 ml of nitric acid mixed with 10 ml of concentrated sulfuric acid was slowly added thereto over one hour at −2° C. to 0° C. The reaction solution was poured into ice water and then stirred. The resulting precipitate was filtered, washed three times with water and then dried. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(1:3)]. The fractions containing the desired product were combined and then evaporated to obtain 11.2 g of the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19][CH3:20].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>C(#N)C>[O:40]=[C:39]1[NH:9][CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19][CH3:20])[C:21]2[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]=2[N:28]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=1
Reactant: CSc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (89 μL, 0.634 mmol) is added to a mixture of 4-{amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-methylsulfanyl-benzonitrile hydrochloride (INTERMEDIATE 5, 1.19 g, 2.54 mmol) and 1,1′-carbonyldiimidazole (480 mg, 2.96 mmol) in acetonitrile (4 mL) and the mixture is stirred at room temperature for 15 min. The reaction mixture is evaporated. Water is added, the precipitate is filtered and washed with water. The residue is dissolved in dichloromethane and evaporated. Yield: 1.02 g. ESI mass spectrum: [M+H]+=458; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]#[N:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]4[NH:30][N:29]=[N:28][N:20]=4)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:3]=1
Reactant: Cc1c(C#N)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 125 °C

Procedure:
To a stirred solution of 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carbonitrile (0.036 g, 0.093 mmol) in DMF (1.0 mL) was added sodium azide (0.012 g, 0.18 mmol) and ammonium chloride (0.01 g, 0.18 mmol) and the mixture heated at 125° C. for 1.5 hours. The solvent was concentrated in vacuo and the residue co-evaporated with toluene. The crude product was dissolved in 10% MeOH in DCM and the insoluble material removed by filtration. The residue was triturated from MeCN, the solid collected and dried under vacuum. The solid was purified by reverse phase preparative HPLC to give the product as beige solid after lyophilisation (0.021 g, 54%).
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][O:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:19])=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)C.CN.[CH2:24]([N:26](CC)CC)C>>[Cl:19][C:10]1[N:11]=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:7]2[O:6][CH2:5][C:4](=[O:21])[N:26]([CH3:24])[C:8]=2[N:9]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: CN
Product: CN1C(=O)COc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 140 °C
Yield: 37.5 %

Procedure:
A mixture of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (501 mg, 1.49 mmol), methylamine (1.0 mL, 2.0 mmol, 2 M in THF) and triethylamine (250 μL, 1.79 mmol) in IMS (10 mL) was heated at 140° C. for 35 minutes using microwave irradiation. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (SiO2, 0-20% ethyl acetate in cyclohexane) affording 2-Chloro-8-methyl-4-morpholin-4-yl-8H-pyrimido[5,4-b][1,4]oxazin-7-one (159 mg, 38%). LCMS: RT=2.93 min, [M+H]+=285/287.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2].[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=3)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-(5-bromothiophen-2-yl)-1-(2,6-dichlorophenyl)-1H-imidazole-4-carboxylic acid ethyl ester (335 mg, 0.75 mmol), 3-methanesulfonyl-phenylboronic acid (180 mg, 0.90 mmol), K2CO3 (0.32 g, 2.3 mmol), Cl2Pd(dppf)DCM (30 mg, 5 mol %) and H2O (0.4 mL) in DME (4 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 2 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 80:20) to give the title compound (313 mg, 80%) as a pale yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.82 (m, 2H), 7.64 (s, 1H), 7.51-7.62 (m, 4H), 7.24 (d, 1H), 6.72 (d, 1H), 438 (q, 2H), 3.05 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC([C:23]([NH2:25])=[O:24])=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54]([O:61][CH3:62])=[C:55](Br)[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54]([O:61][CH3:62])=[C:55]([C:23](=[O:24])[NH2:25])[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: NC(=O)c1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C(N)=O
Yield: 37 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-7-carboxylic acid amide, {1-[4-(6-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (115 mg, 0.20 mmol) was reacted to give the title compound (40 mg, 37%). LCMS (Method B): RT=4.58 min, [M+H]+=541.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH2:39])=[S:38])=[N:20]1.N>O1CCOCC1.O>[CH2:9]([O:8][C:6]([C:5]1[S:38][C:37]([NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2/[CH:29]=[CH:28]/[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)=[N:39][CH:4]=1)=[O:7])[CH3:10]
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: CCOC=CC(=O)OCC
Agent: N
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
Ethyl 3-ethoxyacrylate (0.22 mL, 1.5 mmol) was dissolved in dioxane (4.0 mL) and water (4.0 mL) and after cooling to −10° C., the solution was added with N-bromosuccinimide (0.29 g, 1.6 mmol), followed by stirring at room temperature for 1 hour. The mixture was added with Compound 161 (0.40 g, 1.4 mmol), followed by stirring at 80° C. for 1 hour. The reaction mixture was added with aqueous ammonia to stop the reaction. The precipitated crude product was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2) and triturated in ethyl acetate to obtain Compound 165 (45 mg, 8%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:19][C:18]=2[F:29])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:19][C:18]=2[F:29])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 99 %

Procedure:
The product of Example 12, 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide was hydrogenated in absolute ethanol in the presence of 5% Pd/C by the general procedure of Example 1, Step D. The resulting crude solid was purified by filtration through a plug of silica (MeOH as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methylbutyl)anilino]-N-(2-hydroxyethoxy)benzamide (99%) as a cream foam (hygroscopic). 1H NMR [400 MHz, (CD3)2SO] δ 10.09 (br s, 1 H), 7.60-7.55 (m, 1 H), 7.03-6.91 (m, 2 H), 6.86 (dd, J=8.2, 1.4 Hz, 1 H), 6.71 (ddd, J=8.6, 8.6, 5.8 Hz, 1 H), 4.22 (br s, 1 H), 3.79 (t, J=4.9 Hz, 2 H), 3.55 (t, J=4.9 Hz, 2 H), 2.60-2.49 (m, 2 H), 1.65-1.59 (m, 2 H), 1.13 (s, 6 H). HRMS (EI+) calcd for C20H23F3N2O4 412.1610 (M+), found 412.1617.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[CH:22]=3)[C:16]=1[CH2:40][OH:41])[CH2:8]2)(C)(C)C.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=C[C:48]=1[N:62]1CC2C(=CC=C(N(C)C)C=2)[C:63]1=O)(=O)C>>[CH3:48][N:62]([CH3:63])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[CH:22]=3)[C:16]=1[CH2:40][OH:41])[CH2:8]2
Reactant: CN1CCn2nc(Nc3cc(-c4cccc(N5Cc6cc(C(C)(C)C)ccc6C5=O)c4CO)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Product: CN1CCn2nc(Nc3cc(-c4cccc(N5Cc6cc(N(C)C)ccc6C5=O)c4CO)cn(C)c3=O)cc2C1
Yield: 24 %

Procedure:
Using the same general procedure as described for the preparation of 103 reaction of 123e (450 mg, 1.00 mmol) with 103l (260 mg, 0.800 mmol) followed by a hydrolysis gave a 24% yield (130 mg) of 123 as a white solid: mp 148-150° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.98 (d, 1H, J=2.0 Hz), 7.56 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=8.0 Hz), 7.39 (dd, 1H, J=8.0, 1.5 Hz), 7.33 (dd, 1H, J=8.0, 1.5 Hz), 7.24 (d, 1H, J=2.0 Hz), 6.88-6.85 (m, 2H), 5.88 (s, 1H), 4.89 (t, 1H, J=5.0 Hz), 4.85 (s, 2H), 4.31 (d, 2H, J=5.0 Hz), 3.91 (t, 2H, J=5.5 Hz), 3.59 (s, 3H), 3.48 (s, 2H), 3.04 (s, 6H), 2.77 (t, 2H, J=5.5 Hz), 2.34 (s, 3H); MS (ESI+) m/z 540.3 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:30][C:31]4[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=4)[C:4](=[O:29])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][O:26][N:25]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.257 mmol) and THF (2.5 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (42.4 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and a yellow precipitate formed. The precipitate was filtered then washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 25% yield (0.034 g, 0.0634 mmol).