Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.C[Si]([C:16]#[CH:17])(C)C>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[C:16]([C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)#[CH:17]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34][C:35]([CH3:38])(C)C)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])C1C=CC=CC=1.Br.C(=O)(O)[O-:41].[Na+]>C(O)(=O)C>[C:35]([O:34][CH2:33][CH2:32][NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])(=[O:41])[CH3:38]
Reactant: O=C([O-])O
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N(CCOC(C)(C)C)Cc3ccccc3)ccc21
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Reaction time: 72 h

Procedure:
200 mg (0.4 mM) of 1-benzyl-1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea are heated on a steam-bath for 10 minutes in 3 ml of a 33% solution of hydrogen bromide in glacial acetic acid and then left to stand at room temperature for 3 days. The mixture is neutralised with sodium bicarbonate and extracted several times with methylene chloride. The methylene chloride extracts are combined, dried over sodium sulphate, filtered and concentrated. The residue is purified in a pressure column (0.2-0.4 atmospheres of nitrogen) on 15 g of silica gel (particle size 0.04-0.06 mm) using ethyl acetate as the eluting agent and crystallised from ethyl acetate/ether, there being obtained 2-[3-[5-(o-fluorophenyl)-2,3-dihydro -1-methyl-2-oxo-1H-1,4-benzodiazepin-7yl]ureido]ethyl acetate which melts at 196°-198° C.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH2:10](Br)[CH2:11][Br:12].[OH-].[Na+]>>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:10][CH2:11][Br:12]
Reactant: COc1ccccc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1OCCBr
Reaction time: 0.5 h

Procedure:
0.2 mole(22.4 ml) of guaiacol and 0.4 mole (34.6 ml) of ethylene dibromide are heated to 100° C. while stirring vigorously, and within 30 minutes, 125 ml of 1.6 N sodium hydroxide solution is added to continue the stirring and the pH value is adjusted to 7. Upon cooling, the mixed solution's organic layer is extracted with chloroform and rinsed with 2N sodium hydroxide before rising again with saturated sodium chloride solution and magnesium sulfate. Upon reduction, the solution is filled into the silicone tube for separation. Using the ratio of hexane: ethyl acetate=9:1 as the diluent, white crystallized product, 2-(2-methoxyphenoxy ethylbromide, is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[N-:9]=[N+:10]=[N-:11].[Na+]>>[N:9]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])=[N+:10]=[N-:11]
Reactant: COCCOCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COCCOCCN=[N+]=[N-]
Yield: 76.5 %

Procedure:
1-Azido-2-(2-methoxy-ethoxy)-ethane (607 mg) was prepared by following General Procedure U starting from 1-bromo-2-(2-methoxy-ethoxy)-ethane (1.0 g) and sodium azide (1.07 g). The crude product was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:35])=[C:21]([CH:34]=1)[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)CC)C>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[C:21]4[CH:34]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=4[CH3:35])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)CNc1cccnc1N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Nc3ncccc32)cn1

Procedure:
As described for Example 1, 6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepine (2 mmol) is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride (2.1 mmol) in the presence of triethylamine (4 mmol) in dichloromethane to give the product as a solid, m.p. 102° C.-104° C.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:7][N:8]=1>C(O)(C)C>[CH3:20][C:17]1([CH3:21])[O:16][C@@H:15]2[CH2:14][CH2:13][C@@H:12]([C:9]3[N:5]4[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]4=[N:11][CH:10]=3)[C@@H:19]2[O:18]1
Reactant: N
Reactant: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(Cl)nccn23)O1
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(N)nccn23)O1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Liquid ammonia (50 mL) was added to 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (2-9) (1.5 g, 5.1 mmol, 1 equiv) in isopropanol (50 mL). The resulting solution was placed in a high pressure vessel and heated to 100° C. After 16 hours, no more starting material was present, the amber solution was concentrated to afford desired 3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (2-10) as a tan solid that was carried to the next step without further purification. 1H NMR (500 MHz, CDCl2): δ 7.50 (d, J=4.7 Hz, 1H); 7.36 (t, J=4.6 Hz, 1H); 7.23 (s, 1H); 5.60 (s, 2H); 4.78 (s, 1H); 4.64 (d, J=5.7 Hz, 1H); 3.44 (d, J=6.9 Hz, 1H); 2.43-2.33 (m, 1H); 2.04-1.93 (m, 3H); 1.55 (s, 3H); 1.34 (s, 3H). LRMS m/z (M+H) 275.0 found, 275.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)/[C:23]1=[O:40])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:40])=[O:21])[CH3:18]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (20 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in example 6b (0.3 g, 0.83 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.45 g, 100%).
Reaction SMILES: [NH2:1]CC1C=CC(C2C=CC=CC=2C#N)=CC=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1>>[NH2:1][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1

Procedure:
The title compound is prepared similarly to 4-aminomethyl-2'-cyanobiphenyl except 4-bromomethyl-2't-butoxycarbonylbiphenyl is used in place of 4-aminomethyl-2'-cyanobiphenyl.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:6]=[CH:5]2.C([Li])CCC.[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])#[N:27]>O1CCCC1>[OH:31][CH:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[N:6]=[CH:5]2)[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]#[N:27]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Reactant: N#Cc1ccccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A solution of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole (1.8 g, 4.6 mmol) in tetrahydrofuran (9.2 mL) was cooled to −78° C., and n-butyllithium was added (1.6M in hexanes, 3.4 mL, 5.5 mmol). After 15 min., 2-cyanobenzaldehyde (0.78 g, 6.0 mmol) in 2.0 mL tetrahydrofuran was added quickly and the solution was allowed to warm to room temperature. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.17 g (9%) of 2-(hydroxy{1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}methyl)benzonitrile. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.23 (m, 1H), 7.09 (m, 1H), 6.50 (s, 1H), 1.77 (m, 3H), 1.06 (m, 18H); MS (EI) for C24H31N3OSi: 250 (M−SiiPr3).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12]2)C1C=CC=CC=1>[Pd].Cl.CO>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(N2CC3CCC(C2)N3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Clc1ccc(N2CC3CCC(C2)N3)cc1
Reaction time: 4 h
Yield: 198.8 %

Procedure:
8-Benzyl-3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane (8.5 g, 27.17 mmol) and 10% palladium on carbon (8.5 g) were combined in 1N hydrochloric acid/methanol (600 ml). The mixture was hydrogenated at atmospheric pressure for 4 hours under hydrogen gas. The reaction was filtered through Celite and the filtrate was concentrated to yield 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (7.0 g, 100%) as an off-white solid. A portion recrystallized from water yielded white crystalline flakes which had the following properties: M.p. 270-275° C.; 1H NMR (CDCl3) δ: 9.70 (brd s, 2H), 7.22 (d, J=9.1 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.06 (brd s, 2H), 3.55 (d, J=11.6 Hz, 2H), 3.12 (d, J=12 Hz, 2H), 2.01-1.79 (m, 4H); IR (KBr): 3969, 3913, 3862, 3739, 3670, 3194, 3094, 2990, 2972, 2947, 2867, 2778, 2748, 2696, 2657, 2609, 2574, 2537, 2500, 2431, 2396, 2384, 2252, 2133, 2092, 2078, 2033, 1991, 1951, 1922, 1903, 1873, 1799, 1750, 1688, 1600, 1570, 1500, 1460, 1421, 1383, 1367, 1344, 1323, 1269, 1252, 1220, 1207, 1165, 1155, 1120, 1099, 1079, 1059, 1012, 1001, 978, 937, 922, 904, 872, 828, 817, 808, 783, 749, 700, 651, 632, 534, 520, 468, 415, 403, (cm−1); Elemental Analysis, Calculated for C12H16CIN2: C, 55.61; H, 6.23; N, 10.81; Found: C, 55.35, H, 6.21, N, 10.79.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl.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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
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: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred mixture of (4-methylphenyl)boronic acid (0.818 g, 0.00602 mol) and 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3556 g, 0.00500 mol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol), and the mixture was heated at reflux under nitrogen for 12 hours and allowed to cool. The mixture was diluted with toluene and dichloromethane (10 mL/10 mL), and filtered through a pad of Celite. The Celite was washed with additional toluene and dichloromethane. Filtrate and washings were combined and washed with 2.0 M aqueous sodium carbonate, brine, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved in chloroform and purified by column chromatography on silica gel (144 g, 230-400 mesh), eluting with hexanes-acetone (6:1, 17×125 mL) to give 0.98 g of 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 121-122° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=3)[N:10]=2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH:26][C@H:27]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28](O)=[O:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:28](=[O:29])[C@H:27]([OH:26])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3c(O)cccc3F)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.5 %

Procedure:
3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.74 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0° C. (internal temperature). Under an N2 atmosphere, (R)-2-hydroxy-4,4-dimethylpentanoic acid (118.4 mg, 0.81 mmol) was added followed by triethylamine (0.207 mL, 1.48 mmol). To this stirring solution was added HATU (337 mg, 0.888 mmol). After the complete addition of HATU, the mixture was allowed to warm to 10° C. After 45 min the reaction was complete, and it was quenched with an equal portion of ice water. A yellow precipitate formed which was collected by vacuum filtration, dissolved in CH2Cl2, and the CH2Cl2 solution was desiccated with Na2SO4, filtered, and concentrated to a viscous yellow-orange oil. The crude material was purified via silica gel chromatography using 70% CH2Cl2/hexanes (1:1) and 30% EtOAc to afford (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one as a yellow solid (171 mg, 50%). LC/MS: m/z 467.1 (M+H)+ at 2.63 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.43 (dd, J=8.6, 1.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.87 (d, J=7.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.01-3.75 (m, 8H), 2.52 (s, 3H), 1.55 (dd, J=14.3, 3.0 Hz, 1H), 1.40 (dd, J=14.3, 8.8 Hz, 1H), 0.96 (s, 9H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:8][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=2)=[O:27])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2.33 g (11.8 mmol) of 3,5-dinitrobenzylalcohol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 6.9 g of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])#[N:2].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)=[N:6][C:5]=1[CH3:13])#[N:2]
Reactant: BrCCc1ccccc1
Reactant: Cc1[nH]c2ncccc2c1CC#N
Solvent: CC#N
Product: Cc1nc2n(CCc3ccccc3)cccc-2c1CC#N
Yield: 25.3 %

Procedure:
A solution of 130 mg (0.76 mmol) of 3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine and 150 mg (0.81 mmol) of 2-bromoethyl-benzene in 2 ml of acetonitrile was refluxed for 40 h. The solvent was evaporated and the crude product was chromatographed on silica gel with ethyl acetate: methanol: water 100:12:4. Recrystallization from a small amount of ether: petroleumether 1:1 gave 53 mg (25%) of 3-cyanomethyl-2-methyl-7-(2-phenylethyl)pyrrolo[2,3-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=O)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][N:38]5[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: O[C@@H]1CCNC1
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@@H](O)C2)C1

Procedure:
The title compound was prepared by the method of Preparation 62 using (R)-1-(4-fluorophenyl)-6-[6-morpholin-4-yl-pyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde and (R)-pyrrolidin-3-ol. LCMS (Method F): 595 (M+H)+, Retention time 3.2 minutes.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20](O)=[O:21].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:17]([O:16][CH3:15])[CH:18]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (1.6 g, 8.0 mmol) in ClCH2CH2Cl (50 mL), 3-methoxy-4-nitrobenzoic acid (1.8 g, 9.3 mmol) and P2O5 (4 g) as a light yellow solid (1.2 g, 3.2 mmol, 40%). 1H NMR (CDCl3) 7.84 (d, J=8.2, 1H), 7.54 (d, J=1.4, 1H), 7.32 (dd, J=8.2, 1.4, 1H), 6.85 (s, 2H), 6.07 (s, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][CH:16]=1>CN(C=O)C>[N+:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:11][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1)([O-:27])=[O:26]
Reactant: CC(C)(O)c1ccnc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 8.7 %

Procedure:
To a stirred solution of 2-(2-aminopyridin-4-yl)propan-2-ol (40) (1.55 g, 10.0 mmol) in DMF (30 mL), under nitrogen at 0° C., was added sodium hydride (60% wt, 0.61 g, 15.0 mmol) and the resulting mixture was stirred at 0° C. for 5 min. A solution of 1-fluoro-4-nitronaphthalene (14) (1.95 g, 10 mmol) in DMF (30 mL) was added dropwise and the resulting dark-red mixture was stirred at 0° C. for a further 5 min and then at RT for 2 hr. The reaction mixture was quenched by the addition of saturated aq NH4Cl solution (10 mL). Water (150 mL) and EtOAc (150 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 80 g, 0-60% EtOAc in isohexane, gradient elution) to afford the title compound (41) (282 mg, 8%) as a red oil: m/z 324 (M+H)+ (ES+).