Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:14].N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=S1CCC2(CC1)OCCO2
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydrideand 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2 X with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[NH:38][CH2:37][CH2:36][N:25]2[C:26](=[O:35])[C:27]2[N:28]([CH:30]=[C:31]([C:33]#[N:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1.O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[N:38]([C:13]([C:12]4[C:8]([CH3:7])=[N:9][O:10][CH:11]=4)=[O:15])[CH2:37][CH2:36][N:25]2[C:26](=[O:35])[C:27]2[N:28]([CH:30]=[C:31]([C:33]#[N:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1
Reactant: Cc1nocc1C(=O)O
Reactant: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To generate the acid chloride, oxalyl chloride (100 μL, 1.18 mmol) and DMF (1 drop) were added to 3-methyl-1,2-oxazole-4-carboxylic acid (100 mg, 0.84 mmol) in CH2Cl2 (2 mL) at 0° C. The suspension was allowed to stir 15 min at 0° C. followed by 1 hour at room temperature. The resulting solution was concentrated in vacuo (without heating) to give an oil that was dissolved in CH2Cl2 and concentrated in vacuo. To a chilled (0° C.) suspension of the acid chloride (generated as above, 0.84 mmol) in pyridine (0.5 mL) was added a cloudy mixture of 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (50 mg, 0.16 mmol) in pyridine (0.5 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give a crude residue that was purified by flash chromatography (Biotage SP4 12 g cartridge, 0 to 5% MeOH in EtOAc) and reverse phase chromatography (5-50s-55-100% acetonitrile-water, water contained 0.1% formic acid). The compound 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (89) was isolated as a white solid (2.2 mg, yield 3%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]([CH2:18][N:19]([CH3:31])[C:20]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:21])([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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.O>[C:32]([C:34]1[CH:39]=[C:38]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([CH2:18][N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH:37]=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(CC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(CC1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a flask containing 1-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.094 g, 0.164 mmol) was added Pd(PPh3)4 (0.02 g, 0.017 mmol, 10 mol %), 3-cyanophenylboronic acid (0.037 g, 0.25 mmol, 1.5 eq.) and Na2CO3 (0.212 g, 2 mmol). The mixture was suspended in toluene (3 mL), EtOH (1.5 mL) and H2O (1 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give a brown solid which was purified by HPLC to give the title compound 1-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-yl methyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.053 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.92 (d, 1H), 7.79-7.66 (m, 4H), 7.57 (d, 2H), 7.41 (s, 2H), 7.33 (br.s, 1H), 7.06 (s, 1H), 3.76 (m, 2H), 3.63 (s, 1H), 3.60 (s, 2H), 3.08 (s, 3H), 2.87 (br.m, 2H), 2.69 (m, 5H), 1.14 (br.m, 1H), 0.84 (d, 2H), 0.44 (d, 2H)
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][N:17]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16]1
Reactant: CC1CNCC(C)C1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CC(C)CC(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), 3,5-dimethylpiperidine (0.20 ml, 1.48 mmol), and DIPEA (0.26 ml, 1.48 mmol) were dissolved in acetonitrile (12 ml) and stirred at room temperature for 16 hours. Acetonitrile was evaporated and the crude was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain ethyl 2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetate (203 mg, 59.7% yield) as colourless oil.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].O>C(OCC)C.CS(C)=O>[CH3:25][O:24][C:14]([C:15]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][NH:11][CH:10]=1)=[O:23]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Reaction time: 1 h
Yield: 31.2 %

Procedure:
A solution of 4-toluenesulphonylmethyl isocyanide (4.9 g, 25.2 mmol) and methyl trans-cinnamate (4.0 g, 24.7 mmol) in diethyl ether (40 ml) and dimethyl sulphoxide (20 ml) was added drop-wise over 30 minutes to a stirred suspension of sodium hydride (60% dispersion, 1.25 g, 31.3 mmol) in diethyl ether (100 ml) under nitrogen. After 20 minutes a further portion of dimethyl sulphoxide (25 ml) was added to the reaction vessel. The mixture was stirred for 1 hour then water (200 ml) was cautiously added. The product was extracted into dichloromethane (1×400 ml and 1×250 ml) then the combined dichloromethane layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica gel eluting with a gradient of heptane:ethyl acetate:dichloromethane 2:1:0→1:1:1. Appropriate fractions were combined and the solvents removed in vacuo to leave 4-phenyl-1H-pyrrole-3-carboxylic acid methyl ester as a white solid (1.55 g, 31%). TLC (single spot, Rf=0.25, heptane:ethyl acetate 2:1), HPLC-MS (main UV peak with Rt=7.849 mins, 202.1 [M+H]+, 425.1 [2M+Na]+).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(-c3cccnc3)c2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2ccnc(-c3cccnc3)c2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.09 mL, 0.79 mmol) was dropwise added to a solution of the methoxy compound (30.5 mg, 0.08 mmol) prepared in Example 24 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (35 mg, 79%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([C:23](O)=[O:24])[C:16]=3[N:15]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:62][S:63]([C:66]1[CH:73]=[CH:72][C:69]([CH2:70][NH2:71])=[CH:68][CH:67]=1)(=[O:65])=[O:64]>CN(C=O)C.[Cl-].[Na+].O>[CH3:62][S:63]([C:66]1[CH:73]=[CH:72][C:69]([CH2:70][NH:71][C:23]([C:22]2[C:16]3[NH:15][C:14]([NH:13][C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[N:18][C:17]=3[CH:19]=[CH:20][C:21]=2[O:26][CH3:27])=[O:24])=[CH:68][CH:67]=1)(=[O:64])=[O:65]
Reactant: COc1ccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1C(=O)O
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1C(=O)NCc1ccc(S(C)(=O)=O)cc1
Yield: 47.2 %

Procedure:
33 mg (0.1 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-5-methoxy-1H-benzoimidazole-4-carboxylic acid and 100 mg (0.25 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.4 mL of DIEA was treated with 32 mg (0.15 mmol) of 4-methanesulfonyl-benzylamine hydrochloride as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 25 mg (47%) of isoquinoline-3-carboxylic acid [7-(4-methanesulfonyl-benzylcarbamoyl)-6-methoxy-1H-benzoimidazol-2-yl]-amide. LCMS: 530 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.Cl.Cl[C:18]1[CH:19]=[C:20]([CH2:24][NH:25][OH:26])[CH:21]=[CH:22][CH:23]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:25]([O-:26])[CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccnc1)c1ccc(F)cc1
Reactant: ONCc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: [O-][N+](Cc1ccccc1)=C(Cn1ccnc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
A suspension of 2.00 g (0.0098 mol) of 1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethanone (1, R1 =4-F), 1.30 g (0.011 mol) of N-(phenylmethyl)hydroxylamine (2, R2 =H), 0.82 g (0.010 mol) of sodium acetate, and 0.60 ml (0.010 mol) of acetic acid in 25 ml of ethanol is heated to reflux under a nitrogen atmosphere and stirred for 24 hours. Upon cooling to ambient temperature, the suspension is poured into 50 ml of water, neutralized with sodium bicarbonate and extracted with chloroform (2×50 ml). The combined organic extract is dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash-chromatographed on neutral silica gel using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.63 g (54%) of 1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)-N-(phenylmethyl)ethanimine N-oxide (3, R1 =4-F, R2 =H) as a light yellow oil. This oil (0.0053 mol) is dissolved in 50 ml of toluene, 1.5 ml (0.013 mol) of styrene (4, R3 =C6H5) is added, and the solution is refluxed under a nitrogen atmosphere for 28 hours, cooled to ambient temperature and concentrated in vacuo. The resulting cis- and trans-diastereomeric mixture of compound 5 (R1 =4-F, R2 =H, R3 =C6H5) is flash-chromatographed on neutral silica gel using a 98.2 by volume mixture of chloroform and methanol as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg, 1.01 mmol) in DMF (5 mL) was added cesium carbonate (494 mg, 1.515 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (215 mg, 1.515 mmol) was added. The reaction solution was stirred for 2 h and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine. LCMS-ESI+: calc'd for C7H6BrN3: 211.98 (M+H+); Found: 212.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C1C=CC=CC=1)(C)(C)C.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 92 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 7.536 g (48 mmol) of bromobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.009 g (0.04 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.065 g (0.12 mmol) of di-tert-butylphenylphosphonium tetraphenylborate obtained in Example B-9 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 125° C. for 4 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 9.028 g of triphenylamine (yield: 92 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]>O1CCOCC1.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]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:4]=[C:6]([CH3:14])[CH3:7])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccccc2C1
Yield: 311.4 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.89 mmol) and 2,2-dimethyethylenelboronic acid (133 mg, 1.34 mmol) in dioxane (15 mL) is added PdCl2(dppf) ([1,1′-bis(diphenylphosphine)ferrocene]-dichloropalladium(II), 73 mg, 8.9% mmol) and 2M aqueous solution of CsCO3 (1.34 mL, 2.67 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 2 h. After concentration in vacuo, the residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (134) as a pale yellow solid (523 mg, 78%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CNCC(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylisobutylamine (287 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 3.90 (s, 3H), 3.44 (s, 2H), 2.38 (s, 3H), 2.14 (s, 3H), 2.10 (d, J=8 Hz, 2H), 1.81 (m, 1H), 0.90 (d, J=7 Hz, 6H).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.BrC(C)=C.COCN[C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][N:33]=[C:32]2[NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)=[C:42]([Cl:55])[CH:41]=1)=[O:28].Cl>O1CCCC1>[Cl:55][C:42]1[CH:41]=[C:40]([NH:39][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:27](=[O:28])[C:2]#[C:1][CH3:3])[CH:30]=3)[N:35]=[CH:34][N:33]=2)[CH:45]=[CH:44][C:43]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=1
Reactant: CC(C)NC(C)C
Reactant: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: C=C(C)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4.22 ml of N,N-diisopropylamine in tetrahydrofuran (25 ml) cooled to −78° C. was added dropwise 18.8 ml of 1.6 mol/L n-BuLi hexane solution. After completion of addition, a temperature was elevated to 0° C., and the mixture was stirred at 0° C. for 20 minutes, and cooled again to −78° C. 1.33 ml of 2-bromo-1-propene in tetrahydrofuran (25 ml) was added, and the mixture was stirred at −78° C. for 2 hours. To the mixture was added dropwise a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methoxy methyl amide (XI-1, 2.33 g) in tetrahydrofuran (50 ml) and, after completion of addition, a temperature was elevated to 0° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the filtrate was concentrated, and the resulting crystalline residue was washed with methylene chloride to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 1.71 g) as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2B(O)O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([S:31]([NH:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2[C:25]2[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][C@@H:35]([CH3:40])[C:36]([F:38])([F:37])[F:39])=[CH:29][N:30]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)nc1)C(F)(F)F
Reactant: COC(=O)c1c(B(O)O)n(C2CCCC2)c2cc(C)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 1-cyclopentyl-5-fluoro-3-(methoxycarbonyl)-6-methyl-1H-indol-2-ylboronic acid (2.2 mmol), (S)-6-chloro-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.53 g, 1.83 mmol), PdCl2dppf (0.15 g, 0.183 mmol), aq. K2CO3 (2.0 M, 3.6 mL, 7.2 mmol) in acetonitrile (10 mL) was stirred at room temperature over the weekend. The mixture was treated with ethyl acetate and washed with water and brine and then concentrated. The residue was purified by flash chromatography with 0-15% ethyl acetate in CH2Cl2 to provide (S)-methyl 1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylate (0.52 g, 54%). MS m/z 528.2 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.21 (1H, d, J=1.8 Hz), 8.25 (1H, dd, J=8.2 Hz, J=2.2 Hz), 7.87 (1H, d, J=10.6 Hz), 7.73 (1H, d, J=8.2 Hz), 7.27 (1H, d, J=5.2 Hz), 5.09 (1H, d, J=9.6 Hz), 4.39-4.31 (1H, m), 4.17-4.10 (1H, m), 3.70 (3H, s), 2.44 (3H, d, J=1.8 Hz), 2.41-2.36 (2H, m), 2.20-1.96 (4H, m), 1.67-1.63 (2H, m), 1.45 (3H, d, J=7.0 Hz).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:15]([O-:18])(=[O:17])C.[Na+]>>[CH3:7][O:6][C:5]1[CH:4]=[C:3]2[C:12](=[CH:11][C:8]=1[O:9][CH3:10])[C:15](=[O:17])[O:18][C:2]2=[CH:1][C:3]1[CH:12]=[CH:11][CH:8]=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(=Cc1ccccc1)OC2=O

Procedure:
In a 25 ml flask were charged 4.0 g of m-hemipinic anhydride, 4.54 g of homoveratric acid, and sodium acetate, and the flask was buried in a sand bath at 235° to 240° C. to allow the mixture to react for 6 hours. The reaction mixture was purified by silica gel column chromatography (dichloromethane) to yield the title compound as a colorless amorphous compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(N1CCCC1C(O)=O)=O)(C)(C)[CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([B:24]4[O:25][C:26]([CH3:32])([CH3:31])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH:10]2[CH2:11][CH:12]1[CH2:33][CH2:34]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1

Procedure:
3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was prepared following the procedure for 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, substituting 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C26H36BN3O4: 465.28 (M+); Found: 466.21 (M+H+).