Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39]([C@H:41]4[CH2:45][CH2:44][CH2:43][N:42]4[C:46]([O:48][CH2:49][CH:50]4[C:62]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:56]5[C:51]4=[CH:52][CH:53]=[CH:54][CH:55]=5)=[O:47])=[O:40])=[CH:34][CH:33]=3)[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:39]([C@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46]([O:48][CH2:49][CH:50]3[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:56]=4[C:57]4[C:62]3=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:47])=[O:40])=[CH:36][CH:37]=2)[CH2:22][C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)=[N:14][C:15]=3[CH:21]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(CN(Cc2ccc3[nH]c([C@@H]4CCCN4)nc3c2)c2ccc(F)cc2)cc1)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 27.5 %

Procedure:
The product from Example 99E (0.38 g, 0.455 mmol) was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (3 mL) at ambient temperature for 3 hours, then concentrated to dryness, taken up in ethyl acetate and washed with sodium bicarbonate solution. The organic was dried over sodium sulfate, filtered, and concentrated to give 0.092 g (28%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:19][O-:20].[Na+].O>CO>[Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCN(C(=O)C(C)(C)C)c1nc(OC)ccc1Br
Yield: 89.3 %

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethyl-N-2-propen-1-ylpropanamide (12.388 g, 37.370 mmol) in methanol (100 ml) at rt under argon was treated with sodium methoxide solution (25% w/v in methanol, 17.76 g, 82.212 mmol) and then heated at reflux for 42 h. The reaction was then cooled, treated with water (500 ml), and extracted with diethyl ether (3×200 ml). The organic extracts were dried (MgSO4), and evaporated to give the product (10.918 g, 89%).
Reaction SMILES: [SH2:1].[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19]#[N:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:2]([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:19](=[S:1])[NH2:20])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)=[O:6])[CH3:3]
Reactant: S
Reactant: CCOC(=O)c1cn(CC)c2cc(C#N)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC)c2cc(C(N)=S)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
Hydrogen sulfide was passed through a solution of 1.50 g (5.2 mmol) 7-cyano-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 25 ml pyridine and 1 ml triethylamine for five hours. After stirring overnight in a closed flask, the precipitated solid was filtered, washed with pyridine and ether, and dried to afford 1.28 g of yellowish solid of the title compound, mp 198°-199° C. (dec).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[C:48]3[N:49]([CH2:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:50](=[O:61])[N:51]([CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]#[N:60])[C:47]=3[C:46](Br)=[CH:45][N:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN1CCCC1=O.[Cu]Cl.COC(C)(C)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[C:48]3[N:49]([CH2:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:50](=[O:61])[N:51]([CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[C:59]#[N:60])[C:47]=3[C:46]([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH2:10])=[CH:45][N:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Reactant: NC(=O)c1ccccc1O
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3C(N)=O)c3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Temperature: 130 °C
Yield: 17.1 %

Procedure:
Salicylamide (0.056 g), cesium carbonate (0.130 g), 2,2,6,6-tetramethyl-3,5-heptanedione (0.005 mL), and copper(I) chloride (0.010 g) were added to a solution of 4-[3-benzyl-7-bromo-1-(2-cyanobenzyl)-2-oxo-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-car boxylic acid t-butyl ester (0.123 g) in 1-methyl-2-pyrolidone (2 mL). This was then heated at 130° C. for 22 hours under a nitrogen atmosphere. The reaction solution was cooled, t-butyl methyl ether was added, and this was filtered through celite. The celite was washed with ethyl acetate (25 mL), and the organic layers were combined, and then washed sequentially with 2 N hydrochloric acid (10 mL), 0.5 N hydrochloric acid (10 mL), 1 N aqueous sodium hydroxide solution (10 mL), and saturated aqueous sodium chloride solution (10 mL). This was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.023 g).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].C(N(CC)C(=O)OCN1CC(CCC)CC1=O)C.[Cl:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>C(#N)C>[Cl:30][C:31]1[N:35]([CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2c(Cl)nc3ccccc32)C1
Yield: 49.2 %

Procedure:
A solution of 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (0.472 g, 1 eq, 3 mmol), (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (38.5 mg, 5 mol %, 0.15 mmol) and 2-chloro-1H-benzimidazole x163 (1.2 eq, 3.3 mmol, 0.504 g) in acetonitrile (3 ml) is irradiated in a microwave apparatus (CEM discover) during 0.75 h (100 w). After cooling, evaporation of the solvent under reduce pressure and purification by preparative chromatography on reverse phase, 1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propyl-pyrrolidin-2-one 300 is isolated as a clear oil (0.42 g).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Temperature: 60 °C
Yield: 84.9 %

Procedure:
To a suspension of 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (22.01 g, 71.38 mmol) in EtOH/H2O (200 mL/50 mL) was added iron powder (79.73 g, 1428 mmol) and NH4Cl (3.818 g, 71.38 mmol). The reaction mixture was heated to reflux for three hours, cooled to 60° C. and filtered through a pad of Celite. The pad of Celite was washed with 20:1 EtOH/Et3N (800 mL) and 1:1 MeOH/DCM (600 mL). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4) and concentrated under reduced pressure to give the product (16.87 g).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 18.7 %

Procedure:
Using the general method of Example 146 Part B, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.50 g, 8.9 mmol) was reacted with phenyl isocyanate (1.78 mL, 16.4 mmol) to provide 0.67 g of N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[N+:16]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C>[Pd]>[NH2:16][C:9]1[CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=[CH:13][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1NC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(CO)ccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To (4-cyclohexylamino-3-nitro-phenyl)methanol (1.46 g, 0.0058 mol) in ethanol (35 mL, 0.6 mol) was added 5% Pd/C (0.20 g, 0.00009 mol). The mixture was flushed with hydrogen then stirred for 2 hr at room temperature under 1 atm of hydrogen. The reaction mixture was concentrated and the residue purified by flash chromatography with a gradient from 40 to 100 percent ethyl acetate in hexanes to provide 1.010 g the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=2)[C:35]#[N:36])O1.C([O-])([O-])=O.[Na+].[Na+].O>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.COCCOC>[C:35]([C:34]1[CH:37]=[C:30]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:31]=[N:32][CH:33]=1)#[N:36]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
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: COCCOC
Product: N#Cc1cncc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)c1

Procedure:
3-bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL) and the cartridge was washed with MeOH (10 mL). The combined filtrates were evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound. LC-MS (Condition 5) tR=1.24 min, m/z=384.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:34]([Mg]Br)[CH3:35]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([CH:20]([OH:21])[CH2:34][CH3:35])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2cc(C=O)cs2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CC[Mg]Br
Product: CCC(O)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner similar to that of Example 9(a), by reaction of 33 g (65 mmol) of 5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]thiophene-3-carbaldehyde with 44 mL (130 mmol) of ethylmagnesium bromide, the product is obtained in the form of a yellow oil (m=28.4 g; Y=88%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]2[C@@H:19]([CH3:20])[CH2:18][O:17][CH2:16][C:15]2=O)=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:19]2[CH3:20])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)COC[C@@H]2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOC[C@@H]2C)cc1
Temperature: 0 °C

Procedure:
Into a 5000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a suspension of lithium aluminum hydride (60.04 g, 1.58 mol) in THF (2000 mL), followed by the dropwise addition of a solution of (S)-4-(4-methoxybenzyl)-5-methylmorpholin-3-one (186 g, 790.48 mmol) in THF (300 mL). The resulting solution was heated to reflux for 1 hour. The reaction mixture was cooled to 0° C., quenched by adding 500 mL of ethyl acetate and then 500 mL of water, the resulting solution was extracted three times with 2000 mL of ethyl acetate. The combined organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica, 1:30 ethyl acetate/petroleum ether) to afford the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[SH:27]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3cc(Cl)c(Cl)cc3Cl)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 2,4,5-trichlorothiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Cl)[CH3:12].C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH2:11][CH3:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (880 mg, 5.03 mmol) in THF (10 mL) was added EtMgCl/THF (2.0 M, 3 mL, 6.0 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred at rt overnight. The mixture was quenched with sat. aq. NH4Cl (5 mL) at 0° C., then diluted with Et2O (50 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=80:20) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.00 (t, J=7.4 Hz, 3H), 1.95-2.11 (m, 2H), 2.82 (d, J=10.4 Hz, 1H, —OH), 5.34 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1)=[O:9]
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and m-toluidine (69.8 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was dissolved in 20 ml of CH2Cl2 and the organic phase was washed with 2M hydrochloric acid (5 ml), water (5×2 ml), dried over sodium sulphate and evaporated in vacuo to give yellow solid. The crude product was further purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 120 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[C:20]2[C:21]([OH:29])=[C:22]([CH2:26][CH2:27][CH3:28])[CH:23]=[C:24]([Cl:25])[C:19]=2[O:18][CH:17]=1>C(Cl)CCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[O:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([CH2:26][CH2:27][CH3:28])=[C:21]([O:29][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[C:20]=3[C:16]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(Br)cc3)c(C)c2c1OC(=O)c1ccc(Br)cc1
Reaction time: 0.17 h

Procedure:
A solution of p-bromobenzoyl chloride (1.1 gm; 5.0 mmoles) in ethylene dichloride (5 mL) was added slowly to a cooled suspension of aluminium chloride (3.3 gm; 25 mmoles) in ethylene dichloride (75 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.95 gm; 4.2 mmoles) in dichloroethylene (20 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethyleneacetate in hexane to yield 260 mg gm of 2-(p-bromobenzoyl-3-methyl-4-(p-bromobenzoyloxy)-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH3:10][N:11]([CH2:54][CH:55]=O)[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1.[BH3-]C#N.[Na+].C(O)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:55][CH2:54][N:11]([CH3:10])[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: COCCNCCOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCN(CCOC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using bis(2-methoxyethyl)amine in place of L-proline-tert-butyl ester. Into a 25-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (1 mL), bis(2-methoxyethyl)amine (25 mg, 0.19 mmol, 1.20 equiv), NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv), acetic acid (1.0 mg, 0.02 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 47.9 mg product was obtained. This resulted in 47.9 mg (40%) of (S)—N1-(2-(bis(2-methoxyethyl)amino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 747 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.24 (s, 1H), 9.50 (s, 1H), 9.20 (d, J=9 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.24-8.32 (m, 2H), 7.99 (d, J=6 Hz, 2H), 7.86 (d, J=6 Hz, 1H), 7.60-7.69 (m, 3H), 7.30 (s, 1H), 7.10-7.24 (m, 4H), 5.25 (t, J=6.9 Hz, 1H), 3.80 (d, J=33 Hz, 5H), 3.63 (s, 6H), 3.33 (s, 12H), 2.97 (s, 4H), 2.74 (s, 2H), 1.96-2.00 (m, 2H), 1.73-1.88 (m, 6H), 1.60 (d, J=6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:26]3[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3nc(N)nc(N)c3n2)ccc1O
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (378 mg, 1.93 mmole), K2CO3 (1075 mg, 7.78 mmole) and 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (599 mg, 2.32 mmole) in 1,4-dioxane (29 ml) and water (6 ml) was purged with a nitrogen stream for 30 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmole) was added and purging with N2 was continued for 15 minutes. The reaction mixture was then heated at reflux under a N2 atmosphere for 2 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and brine and the organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel flash chromatography with 10% methanol and 1% Et3N in CH2Cl2 as mobile phase, afforded the pure title compound (375 mg, yield 69%) which was characterized by its mass spectrum as follows: MS (m/z): 284 ([M+H]+, 100).