Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].O.CS(C)=O.C([CH:12]1[CH2:17][C:16]([C:32]#[N:33])([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:15][CH2:14][C:13]1=[O:34])(OC)=O>C(O)(C)C>[C:32]([C:16]1([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:19]=2)[CH2:17][CH2:12][C:13](=[O:34])[CH2:14][CH2:15]1)#[N:33]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 155 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water (315 mL) was added the dimethyl sulfoxide (4.2 L) solution of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-one (323 g, 0.87 mol) and the resulting suspension was heated to 155° C. for 1.75 h. The reaction was cooled to 40° C., was quenched into 8 L of iced water (2° C.) and was extracted with ethyl acetate (3.5 L). The aqueous layer was isolated and re-extracted with 2.5 L of ethyl acetate. The combined organic extract (6 L) was washed two times with deionized water (2×1 L) and once with brine (1 L). The organic layer was isolated and concentrated in vacuo to afford a residue. This residue was dissolved in refluxing isopropanol (500 mL), was cooled to 0° C. and held at this temperature for 1 hour. The crystals were isolated by filtration, were washed with 250 mL of isopropanol (0° C.), and were dried in a vacuum oven (45° C. at 20 inches) to produce 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one. m.p. 111-112° C.; Anal. (C19H23NO3) calcd: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:14][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cccccc-2n1
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc2cccccc-2n1
Temperature: 70 °C

Procedure:
With reference to the method disclosed in Chemical and Pharmaceutical Bulletin, vol. 16, No. 7, pages 1300 to 1307 (1968), 10 g of 2-hydroxycycloheptimidazole, 150 g of phosphorus oxychloride and 12 g of N,N-diethylaniline were stirred with heating to the inner temperature of 70° C. for 6 hours and 30 minutes. After the reaction, phosphorus oxychloride was distilled away under reduced pressure and 500 ml of ice water was added to the residue. Then, a sodium bicarbonate solution was added thereto to neutral pH, and extracted with chloroform (250 ml×2). The chloroform layer was dried over anhydrous sodium sulfate, solvent was distilled away, and the residue was purified by silica gel column chromatography using ethyl acetate as a developing solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[O:12]C>Br.CC(O)=O.C1(C)C=CC=CC=1>[F:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:12]
Reactant: COc1c(F)ccc([N+](=O)[O-])c1F
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(O)c1F

Procedure:
A solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (0.50 g, 2.644 mmol) in 33% HBr in AcOH (4 mL) was heated at 100° C. for 1 h using microwave irradiation. The cooled reaction mixture was diluted with toluene and concentrated in vacuo. The resulting residue was partitioned between aqueous NaHCO3 and EtOAc. The aqueous phase was acidified with 1M HCl and extracted twice with DCM. The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a buff solid (0.29 g, 63%). 1H NMR (CDCl3, 300 MHz): 7.70 (1H, ddd, J=9.5, 7.8, 5.4 Hz), 7.06 (1H, ddd, J=9.4, 9.0, 2.2 Hz), 5.61 (1H, bs)
Reaction SMILES: C(OC([N:8]1[C:17]2[CH:16]=[C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][C:12]=2[CH:11]2[CH2:23][CH2:24][CH2:25][C:10]2([F:26])[C:9]1=[O:27])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O.C(OCC)(=O)C>[F:26][C:10]12[CH2:25][CH2:24][CH2:23][CH:11]1[C:12]1[CH:13]=[CH:14][C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:17]=1[NH:8][C:9]2=[O:27]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(F)CCCC2c2ccc(-c3ccco3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1Nc2cc(-c3ccco3)ccc2C2CCCC12F
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 1.44 g (3.9 mmol) of 5-tert-butoxycarbonyl-3a-fluoro-7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]-quinolin-4-one in 20 ml of dichloromethane is mixed with 8 ml of trifluoroacetic acid at room temperature. After 2 hours, the batch is diluted with water and ethyl acetate. The organic phase is separated, washed with water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 0.53 g of product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=N)=[CH:5][CH:4]=1.Cl.C1C[O:34]CC1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=[O:34])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: CSc1ccc(C(=N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: Cl
Product: CSc1ccc(C(=O)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-(Methylthio)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanimine (1.00 g, 2.37 mmol, prepared using AF from Preparation #AE.1 with (4-(methylthio)phenyl)magnesium bromide) was dissolved in THF (25 mL) then 6 N HCl (1.18 mL, 7.10 mmol) was added. The mixture was stirred rt for about 1 h then concentrated under reduced pressure. Saturated aqueous NaHCO3 (40 mL) and water (10 mL) were added then the mixture was extracted with DCM (50 mL and 15 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give (4-(methylthio)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanone (0.754 g, 75%): LC/MS (Table 2, Method b) Rt=2.77 min; MS m/z 424 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].C[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Triethyleneglycol monomethyl ether (50 g, 304.5 mmol) was taken in tert-butyl acrylate (35.1 g, 274 mmol) and the mixture was stirred for 10 minutes. Sodium methoxide (1.97 g, 36.5 mmol) was added and stirred at ambient temperature for 8-10 hours. The reaction completion was checked by thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate (200 mL) and the organic layer was washed with water, saturated brine solution and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain tert-butyl 2,5,8,11-tetraoxatetradecan-14-oate (67 g, 75.3%).
Reaction SMILES: C(OC([N:8]([CH:26]1[CH2:28][CH2:27]1)[CH:9]([C:11]1[CH:16]=[C:15]([CH:17]=[CH2:18])[N:14]=[C:13](/[CH:19]=[CH:20]/[NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:12]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH:26]1([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([CH:17]=[CH2:18])[N:14]=[C:13](/[CH:19]=[CH:20]/[NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:12]=2)[CH3:10])[CH2:28][CH2:27]1
Reactant: C=Cc1cc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc(/C=C/NC(=O)OC)n1
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(C(C)NC2CC2)cc(/C=C/NC(=O)OC)n1

Procedure:
Methyl [(E)-2-(4-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-6-vinylpyridin-2-yl)vinyl]carbamate and trifluoroacetic acid were treated in the similar manner to Reference Example 113(8) to give methyl ((E)-2-{4-[1-(cyclopropylamino)ethyl]-6-vinylpyridin-2-yl}vinyl)carbamate [Ex(297-5)] as a pale yellow oil.
Reaction SMILES: OC[CH2:3][C:4]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6]C(OC(C)(C)C)=O.Br.[OH-].[Na+]>C(O)(=O)C>[O:18]1[C:17]2=[CH:16][CH:15]=[CH:14][C:5]([NH2:6])=[C:4]2[CH2:3][CH2:19]1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1CCO
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cccc2c1CCO2
Temperature: 25 °C
Yield: 97.8 %

Procedure:
2-(2′-Hydroxyethyl)-3-methoxy-N-tert-butoxycarbonyl-aniline (158 g, 0.59 mol) was added portionwise to a stirred solution of hydrogen bromide in acetic acid (30%, 1.7 L) at room temperature. The reaction was then heated to reflux for 4 h. The reaction mixture was cooled to room temperature, basified to pH 14 with aqueous sodium hydroxide solution (6 N) and extracted with dichloromethane (3×2 L). The organic extracts were combined, dried (magnesium sulphate) and evaporated to give the title compound as an orange oil (78 g, 92%); NMR (400 MHz, CDCl3) δH 2.99 (2H, t, J 8.5 Hz), 3.55 (2H, br s), 4.57 (2H, t, J 8.5 Hz), 6.19 (1H, d, J 7.5 Hz), 6.25 (2H, d, J 7.5 Hz), 6.92 (1H, t, J 8.0 Hz); IR νmax (Nujol)/cm−1 2853, 2610, 1544, 1462, 1262, 1234, 986 and 761.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:26]3[CH:27]=[N:28][C:23]([C:22]([F:32])([F:21])[F:31])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(C(F)(F)F)nc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2218 mmol), 6-Trifluoromethyl-pyridine-3-carbaldehyde (42.7 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 5.98 mg (5%) of the title compound. (300 MHz, DMSO-d6) 9.45 (s, 1H), 8.69 (d, J=9 Hz, 1H), 8.09 (m, 2H), 7.76 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.37 (m, 1H), 5.24 (t, J=17 Hz, 8 Hz, 1H), 2.89 (s, 1H), 2.79 (s, 1H), 2.66 (d, J=9 Hz, 1H), 2.63 (d, J=9 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=493 (M+H), HPLC: 2.66 min. (G Method)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[C:14]([O-:16])=[O:15]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([C:13](=[O:17])[C:14]([OH:16])=[O:15])=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccncc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
15.0 g. (0.095 mol) of 4-bromopyridine in 7 ml. of dry tetrahydrofuran (THF) was added dropwise at -70° C. to a solution of butyl lithium (1.6 M, 60.9 ml., 0.098 mol) dissolved in 120 ml. of dried THF over a ten minute period. The resulting very deep purple mixture was stirred at -70° C. for 30 minutes and then transferred by nylon tubing under positive nitrogen pressure into a stirred 0° C. solution of ethyl oxalate (55.2 g., 0.38 moles) in 90 ml. of dry THF. The solution was stirred at 0° C. for 45 minutes and then quenched by addition of 65 ml. glacial acetic acid. This was warmed to room temperature and poured into 500 ml. of water adjusted to pH 7.0 with saturated sodium bicarbonate and extracted with 3×200 ml. ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate filtered and concentrated to a brown oil. This oil was flash chromatographed on silica gel eluted with 1:2 ethyl acetate hexane. A viscous yellow oil was obtained; 5.8 g (34%), m/e 179, spectral data consistent with structure of title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[N:7][N:6]=[CH:5]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]([F:35])([F:34])[F:23])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(Nc2nncc3cc(Br)ccc23)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(Nc2nncc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine (6-bromo-phthalazin-1-yl)-(4-tert-butyl-phenyl)-amine (60 mg, 0.19 mmol), 2-(trifluoromethyl)phenyl-boronic acid (50 mg, 0.26 mmol) in 1,2-dimethoxyethane (10 mL) and bubble nitrogen into the mixture for 10 minutes. Add tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) and 2M Na2CO3 (1 mL) and heat at 80 C. for 48 hours. Let the mixture cool to room temperature, dilute with water (10 mL), and extract twice with EtOAc (10 mL each). Dry (Na2SO4), evaporate, and purify on a preparative silica gel plate (2000 micron) eluting with 75% hexane-EtOAc to provide (4-tert-butyl-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazin-1-yl]-amine as a straw colored solid. Mass Spec. 421.2.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:25])([F:24])C(OCC)=O)[CH:13]=2)=[CH:8][CH:7]=1)C.O>CO.[Li+].[OH-].CN(C=O)C.Cl>[F:25][CH:18]([F:24])[C:14]1[CH:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:26])=[O:3])=[CH:11][CH:10]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(C(F)(F)C(=O)OCC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Ethyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)pyridin-2-yl)-2,2-difluoroacetate 203-4 (476 mg, 1.3 mmol) was dissolved in 5 mL MeOH and 2 mL 2N LiOH. The reaction mixture was stirred at 55° C. for 12 hrs. After cooling to room temperature, the mixture was redissolved in 5 mL DMF and 1.5 mL concentrated HCl. The solution was stirred at 130° C. for 3 hrs. After cooling to room temperature, the solution was poured into 5 ml water and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5. MS m/z 264.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:18]([O:22][C:23]([N:25]([CH2:43][CH:44]=O)[CH2:26][C@H:27]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:44][CH2:43][N:25]([CH2:26][C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N(CC=O)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: COC(=O)c1cccc(-c2cccc(N)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c1
Yield: 66.6 %

Procedure:
To a stirred solution of 3′-amino-[1,1′-biphenyl]-3-carboxylic acid methyl ester (3.0 g) and (R)-[(tert-butoxycarbonyl)-[2-(tertbutyidimethylsilanyloxy)-2-(3-chlorophenyl)ethyl]amino}acetaldehyde (8.2 g) in anhydrous dichloromethane (65 mL) was added acetic acid (8 drops). After stirring for twenty-five minutes, sodium triacetoxyborohydride (5.6 g) was added and the reaction stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate and more dichloromethane was added. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to yield a white foam. The residue was purified by silica gel chromatography and eluted with 9:1 hexane:ethyl acetate to provide the title compound as a white foam (5.62 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1.Cl>CN(C=O)C>[CH3:27][C:19]1[CH:18]=[C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
Indole 5-carboxylic acid (0.5 g, 3.1 mmol) was added to a suspension of sodium hydride (0.27 g, 6.8 mmol, 60% oil dispersion) (washed with hexanes) in DMF (20 mL) cooled to 0° C. The reaction was allowed to stir for 1 h and the 4-chloromethyl-2-methyl-quinoline (0.72 g, 3.8 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was neutralized with 1 N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic acid (0.68 g, 69%) as a brown residue, MS (M+H)+=317.
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[OH:47])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].[CH3:48][O:49][C:50](=[O:55])[CH2:51][CH2:52][CH:53]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[CH3:48][O:49][C:50](=[O:55])[CH2:51][CH2:52][CH2:53][NH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[OH:47])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40]
Reactant: COC(=O)CCC=O
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](N)c2ccccc2O)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCCN[C@@H](Cn1c(=O)c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300 MHz, CDCl3) δ 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>C(O)(C)C>[Cl:12][C:8]1[CH:7]=[CH:6][C:5]([OH:13])=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)=[CH:26][CH:25]=1)=[N:3]2
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Oc1ccc(Cl)c2cnc(Cl)nc12
Solvent: CC(C)O
Product: Oc1ccc(Cl)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc12
Temperature: 90 °C

Procedure:
To a solution of isolated 2,5-dichloroquinazolin-8-ol (1 eq) in isopropanol was added 4-morpholinoaniline (1 eq) and the mixture was heated to 90° C. for 1 h. The SNAR went to completion by LC/MS and on concentration yielded 5-chloro-2-(4-morpholinophenylamino) quinazolin-8-ol in quantitative yield. ES/MS m/z 357 (MH+).
Reaction SMILES: C(OC([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:22]([F:35])=[C:21]([NH2:36])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:37])=O)C=C.C(N(CC)CC)C.C(O)=O.O>O1CCCC1.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>[NH2:36][C:21]1[C:17]2[C:18](=[O:20])[CH:19]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([F:37])[CH:10]=3)[O:15][C:16]=2[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28](=[O:34])[N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[C:22]=1[F:35]
Reactant: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)N(CC)CC)c(F)c3o2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56.2 %

Procedure:
223 mg (0.429 mmol) of the above 2-(4-allyloxycarbonylamino-3-fluorophenyl)-5-amino-7-diethylcarbamoyloxymethyl-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 20 mL of tetrahydrofuran, 0.29 mL of formic acid-triethylamine and 50 mg (0.043 mmol) of tetrakis(triphenylphosphine)palladium were added and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) and recrystallized from ethyl acetate/n-hexane, to give 105 mg of Compound 156 (yield: 56%).