Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[C:17](O)(=[O:21])[C:18]([CH3:20])=[CH2:19].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:17](=[O:21])[CH:18]([CH3:20])[CH2:19][C:5]=2[C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)C(=O)O
Reactant: Cc1sccc1-c1cccc2ccccc12
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1sc2c(c1-c1cccc3ccccc13)CC(C)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
A mixture of 5 g of 2-methyl-3-naphthalen-1-ylthiophene (0.022 mol) and 2.1 ml of methacrylic acid (0.025 mol) was added within 15 minutes at 80° C. to 125 ml of Eaton's reagent. After a further 5 minutes, the reaction mixture was poured into ice-water and the precipitated product was dissolved by adding 300 ml of dichloromethane. The organic phase was removed, washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removing the solvent, 5 g of product (2) were obtained which, according to GC analysis, was present as a single isomer in 99% purity.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Ni].C(O)C.O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)c1cn(-c2ccccc2)c2ccccc12
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cn(-c2ccccc2)c2ccccc12
Yield: 67 %

Procedure:
A mixture of 10 g (34.1 mmol) of ethyl 1-phenylindole-3-glyoxylate and about 25 g of Raney nickel in 350 ml of ethanol and 150 ml of water was heated at reflux for 6 hours. The suspension was filtered through glass fiber filter paper and the solid was washed with four 50 ml portions of ethyl acetate while taking care not to allow the solid to dry. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. There were obtained 6.38 g of ethyl 1-phenylindole-3-acetate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21]Cl)=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][NH:10][CH3:11].N1C=CC=CC=1.O.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CN1CCCC1=O>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][CH2:21][N:10]([CH3:11])[CH2:9][CH2:8][O:7][C:6]=2[CH:12]=1
Reactant: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCCl
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 9.9 g of 2-[5-chloro-2-[(2-chloroethyl)phenoxy]phenoxy]-N-methyl-ethylamine dissolved in 500 ml of N-methyl-2-pyrrolidone was slowly added to a mixture of 1 1 of N-methyl-2-pyrrolidone and 500 ml of pyridine at 85° C. and stirred overnight at this temperature. Water was added, the mixture was extracted with diethyl ether and the ether layer was washed with water and dried over sodium sulphate. The organic solution was evaporated to dryness and the residue was crystallized from dichloromethane-diethyl ether after addition of 1 eq of maleic acid to obtain 2.3 g (28%) of 3-chloro-7,8,9,10-tetrahydro-8-methyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine (Z)-2-butenedioate (1:1). Mp 145-157° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:35])=[O:29]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(C)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(C)cccc2Cl)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
N-[(2,6-Dichlorophenyl)carbonyl]-4-[[(2-chloro-6-methylphenyl)carbonyl]amino]-L-phenylalanine methyl ester was prepared from 4-[[(2-chloro-6-methylphenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2,6-dichlorobenzoic acid using the general procedure described in example 3.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1B(O)O.O>C(Cl)Cl.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.CCO.COCCOC>[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2[nH]cnc12
Reactant: Cc1ccncc1B(O)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: ClCCl
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccncc1-c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
A vial was charged with tetrakis(triphenylphosphine)palladium(0) (0.129 g, 0.112 mmol), 4-bromo-1H-benzo[d]imidazole (0.200 g, 1.015 mmol), sodium carbonate (0.430 g, 4.06 mmol), and 4-methylpyridin-3-ylboronic acid (0.146 g, 1.066 mmol). The mixture was stirred at room temperature for 10 min under N2, then water (1.894 mL), DME (3.79 mL), and EtOH (1.894 mL) were added sequentially. The resultant mixture was stirred under N2 for 15 min, then heated at 90° C. overnight. After 21.5 h, the reaction mixture was allowed to cool to room temperature, then quenched with water and diluted with EtOAc. The layers were separated and the aqueous phase extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 and chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 1-20% MeOH in CH2Cl2 over 30 min, tr=20 min) gave the title compound (132 mg, 0.631 mmol, 62.1% yield) as a white foam. ESI MS (M+H)+=210.0. HPLC Peak tr=14.20 minutes. Purity >99%. HPLC conditions: Xbridge Phenyl column, 4.6×150 mm. 30 min gradient (10-100% B), 2 mL/min, 23° C. @ 220 nm, Solvent A: 10 mM NH4HCO3 pH 9.5 in H2O:MeOH (95:5), Solvent B: 10 mM NH4HCO3 pH 9.5 in H2O:MeOH (5:95).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(Cl)Cl>[C:24]1([C:23]2[O:21][C:20]([C:18]3[CH:17]=[N:16][C:12]4[O:13][CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[C:11]=4[CH:19]=3)=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Reactant: NNC(=O)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCOc2ncc(-c3nnc(-c4ccccc4)o3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.8 %

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (40 mg, 0.118 mmol; Example 1 Step 1) in DCM (1.5 mL) was added benzohydrazide (32.2 mg, 0.236 mmol) and DIPEA (50 μL, 0.286 mmol). The reaction was stirred at room temperature for 16 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and was extracted with DCM (3×2 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was dissolved in DMF (3 mL) and treated with Burgess reagent (28.1 mg, 0.118 mmol). The reaction mixture was heated to 180° C. by heating under microwave irradiation for 5 minutes. The mixture was concentrated in vacuo. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 10-90% EtOAc. The resulting tan solid was triturated with water (2×10 mL) to provide 7-(5-phenyl-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (4.6 mg, 10.39 μmol, 8.80% yield) as a white solid. LCMS (+ESI) m/z=421.0 [M+H]+; 1H-NMR (CDCl3) δ 8.90 (d, 1H), 8.84 (d, 1H), 8.17 (m, 2H), 7.74 (m, 2H), 7.65 (tt, 1H), 7.59-7.51 (m, 5H), 4.02 (m, 2H), 3.95 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].CC(C)=O>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a mixed solution of 100 g of 3-bromo-para-anisaldehyde in MeOH (700 ml) and THF (100 ml), on ice, was added 7.50 g of NaBH4. After the solution was warmed to room temperature and stirred for two hours, acetone was added. The reaction solution was concentrated under reduced pressure, water and EtOAc were added to the residue, and liquid separation was performed. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1; v/v) to obtain 99.8 g of the title compound (colorless solid).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([S:21][C:22]2[C:23](=[O:24])[O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:26]=2[OH:27])[CH:18]=[CH:19][CH:20]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1cccc(Cl)c1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc(Cl)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-chlorophenyl)thio]propanedioic acid (1.53 g, 5.07 mmol). m.p. 181°-182° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.88 (s, 1H), 7.13 (dt, 2H), 7.19 (dt, 1H), 7.29 (t, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][CH:39]=1)[CH2:8][O:9][C:10]1[CH:36]=[CH:35][CH:34]=[CH:33][C:11]=1[CH2:12][C:13]1[C:14]([O:21][C@@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]2[OH:24])=[N:15][NH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])(=O)C.C[O-].[Na+]>CO>[C@@H:22]1([O:21][C:14]2[C:13]([CH2:12][C:11]3[CH:33]=[CH:34][CH:35]=[CH:36][C:10]=3[O:9][CH2:8][C:7]3[CH:37]=[CH:38][CH:39]=[C:5]([OH:4])[CH:6]=3)=[C:17]([CH:18]([CH3:20])[CH3:19])[NH:16][N:15]=2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]
Reactant: CC(=O)Oc1cccc(COc2ccccc2Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (150 mg) in N,N-dimethylformamide (1 mL) were added 3-bromomethylphenyl acetate (131 mg) and potassium carbonate (105 mg), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1˜5/1) to give 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (12 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 5 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (8 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[CH:11]3)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc2c(ccc(=O)n2C)c1
Yield: 28 %

Procedure:
A mixture of 5.4 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 5.5 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml of benzene was heated under reflux for 48 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed with a 10% sodium hydroxide solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue and the crystals were combined and purified by using a column chromatograph. The resulting crystals were recrystallized from methanol to give 1.5 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2-dihydroquinolin-2-one, melting at 248°-251° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[Li+].[BH4-]>C1COCC1.CO.[OH-].[Na+]>[Cl:32][C:31]1[C:26]([CH:14]2[CH2:15][CH2:16][CH2:17][CH:18]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:13]2[CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2Cl)CCCC1c1ncccc1Cl
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(CN2C(c3ncccc3Cl)CCCC2c2ncccc2Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
To a cold (0° C.) solution of 5-cyano-2-(3,3″-dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (391 mg, 0.813 mmol) in THF (4 mL) and MeOH (4 mL) was added LiBH4 (88 mg, 4.1 mmol), and the mixture was warmed to room temperature and stirred for 3.5 h. The mixture was diluted with 1.0 N NaOH (20 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide 4-(3,3″-Dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-hydroxymethyl-benzonitrile (367 mg) without any further purification. To a solution of the crude material (160 mg) in MeOH (4.5 mL) was added H2O (2.5 mL) and NaBO3.4H2O (108 mg, 0.707 mmol). The resultant mixture was heated to 50° C. for 5 h and stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5 then 85:10:5) to afford COMPOUND 52 (54 mg, 32% over 2 steps) as a white solid. 1H NMR (CDCl3) δ 1.63-1.79 (m, 3H), 1.93-2.06 (m, 1H), 2.11-2.30 (m, 2H), 2.33-2.47 (m, 2H), 3.63 (s, 2H), 4.59 (d, 2H, J=9.92 Hz), 4.41 (s, 2H), 4.99 (br s, 1H), 5.67 (br s, 1H), 6.15 (br s, 1H), 6.85-6.96 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=1.8 Hz), 7.38 (d, 1H, J=1.5 Hz), 7.48 (dd, 2H, J=7.8, 1.5 Hz), 8.30 (dd, 2H, J=4.5, 1.2 Hz); 13C NMR (CDCl3) δ 24.98, 31.59, 57.28, 62.72, 66.56, 123.45, 126.39, 128.11, 129.90, 131.55, 131.70, 137.47, 140.08, 142.64, 147.77, 158.55, 169.17; ES-MS m/z 473 (M+1+H). Anal. Calcd. for C24H24N4Cl2O2.0.5H2O: C, 60.01; H, 5.25; N, 11.66. Found: C, 60.00; H, 5.15; N, 11.49.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([O:42]C)=O)[C:28]([C:44]([F:47])([F:46])[F:45])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].O[N:49]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CO.O.CC(C)=O.CN(C=O)C>[C:4]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:49])=[O:42])[C:28]([C:44]([F:45])([F:47])[F:46])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)([CH3:5])([CH3:7])[CH3:6]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide mono hydrate (43.0 mg, 1.03 mmol) was added to a suspension of methyl 2-(2-(2-(2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I78) (211 mg, 0.344 mmol) in THF (10 mL), MeOH (1.0 mL) and water (1.5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The organics were removed in vacuo then 2 M aqueous NaOH solution (100 mL) was added. The resulting solution was extracted with EtOAc (2×100 mL), then the combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to yield a white solid. The solid was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To this solution were added 1-hydroxybenzotriazole (72 mg, 0.53 mmol), EDCl (101 g, 0.529 mmol) and N,N-diisopropylethylamine (246 μL, 1.41 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (203 mg, 2.12 mmol) was added in one portion and the reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo and the residue was taken up in EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with water (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was dissolved in a small amount of acetone and precipitated with petroleum benzine 40-60° C. to yield the title compound (I79) (138 mg, 65%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 4H), 6.96-6.81 (m, 4H), 3.58 (d, J=12.7 Hz, 2H), 3.50 (s, 2H), 3.15-2.93 (m, J=15.2, 6.3 Hz, 4H), 2.67 (t, J=12.0 Hz, 2H), 1.79 (d, J=11.4 Hz, 2H), 1.55-1.42 (m, 2H), 1.39 (s, 9H). LCMS Method C: rt 5.30 min; m/z 599 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29](Br)=[CH:28][C:27]=2[F:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C>[F:32][C:30]1[CH:31]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:27]([F:34])=[CH:28][C:29]=1[N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Br
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)c(F)cc1OCc1ccccc1
Temperature: 140 °C

Procedure:
In two microwave vials were placed 4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,5-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL), L-Proline (43 mg, 0.373 mmoL) and DMF (5 mL) and the mixture was degassed by sonication under a flow of argon. To each vial was added CuI (71 mg, 0.373 mmoL) and the solutions were heated to 140° C. in the microwave reactor. After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added and heated for an additional hour. The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The combined crude materials were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D22), (258 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:12][O:11][CH2:10][CH2:9][CH:8]([NH:13][C:14]1[C:23]2[C:18](=[C:19]([C:24]([NH2:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:56](=[O:57])[C:55]2[CH:59]=[CH:60][C:52]([O:51][C:50]([F:49])([F:61])[F:62])=[CH:53][CH:54]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A mixture of 4-{[1-(3-aminophenyl)-3-methoxypropyl]amino}quinazoline-8-carboxamide (50.00 mg; 0.14 mmol; 1.00 eq.), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (30 mg; 0.16 mmol; 1.10 eq.) and 1H-1,2,3-benzotriazol-1-ol (22 mg; 0.16 mmol; 1.10 eq.) in dry DMF (1 mL) were added 4-(trifluoromethoxy)benzoic acid (33 mg; 0.16 mmol; 1.10 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.08 ml; 0.43 mmol; 3.00 eq.). The mixture was stirred overnight. After concentration, the crude was purified by reverse phase HPLC to obtain 26 mg of the title product in 34% yield. LCMS [540 (M+1)]. 1H NMR (400 MHz, DMSO-D6): 2.1875 (m, 1H), 2.3432 (m, 1H), 3.2379 (s, 3H), 3.3835 (m, 1H), 3.4522 (m, 1H), 5.7150 (m, 1H), 7.0524 (m, 2H), 7.2017 (m, 1H), 7.3317 (m, 1H), 7.6285 (m, 1H), 7.9371 (m, 6H), 8.0791 (m, 1H), 8.5544 (m, 1H), 8.6647 (s, 1H), 8.8136 (s, 1H), 10.3786 (s, 1H).