Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH2:10]O)[C:5]#[N:6].P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:12]
Reactant: N#Cc1cc(F)c(CO)c(F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(F)c(CBr)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3,5-difluoro-4-(hydroxymethyl)benzonitrile (all material from above reaction) in DCM at 0° C. was added PBr3 (283 μL, 3 mmol). After stirring 1 h at 0° C., the reaction mixture was quenched with water and then extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated to yield 4-(bromomethyl)-3,5-difluorobenzonitrile (0.88 g, 63%, combined yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 1H), 4.51 (d, J=10.1, 1H); GC-MS (ES) m/z 231 (M).
Reaction SMILES: [BrH:1].Br.[NH2:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:7]=1[CH2:8][C:9](=[O:17])[NH:10]2>>[BrH:1].[NH2:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:7]=1[CH2:8][C:9](=[O:17])[NH:10]2
Reactant: COc1ccc(CCN)c2c1NC(=O)C2
Agent: Br
Product: NCCc1ccc(O)c2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A 10 ml portion of constant boiling hydrobromic acid (48%) was dissolved from stannous chloride directly into the reaction vessel. To this was added 0.533 g (1.76 mmole) of 4-(2-aminoethyl)-7-methoxy-2(3H)-indolone hydrobromide and the reaction was stirred at reflux under argon for 3 hours then allowed to cool to room temperature. After being stored at 0° overnight, the reaction mixture was filtered. The solid was washed with cold methanol to give 0.40 g (83%) of 4-(2-aminoethyl)-7-hydroxy-2(3H)-indolone hydrobromide as a straw-brown solid. This material began to decompose with darkening at 250°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([O:28][C:30](=[O:32])[CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(/C=C/C=C/c1ccccc1OCCCC(=O)OCC)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 60 mg of 4-[2-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenoxy]-butyric acid ethyl ester in 0.5 ml of pyridine is mixed with ice cooling and under argon atmosphere with 0.12 ml of acetic anhydride and stirred for 4 hours at room temperature. The reaction mixture is concentrated by evaporation and the residue is chromatographed on silica gel with n-hexane/ethyl acetate=95/5. 42 mg of 4-[2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenoxy]-butyric acid ethyl ester is obtained as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:23][C:24]1[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([C:27]5[CH:26]=[N:25][C:24]([Cl:23])=[CH:29][N:28]=5)[CH2:20][CH2:21]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Clc1cnc(Cl)cn1
Reactant: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
A flask was charged with (S)-3-(1H-indazol-5-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one (0.120 g, 0.400 mmol), 2,5-dichloropyrazine (0.0655 g, 0.439 mmol), DIEA (d 0.742) (0.0696 mL, 0.400 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using preparative TLC with 10% methanol in ethyl acetate to provide (S)-3-(1H-indazol-5-yloxy)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.0047 g, 0.0114 mmol, 2.85% yield). Mass spectrum (apci) m/z=413.2 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1C(=O)C1CC1
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a suspension of NaH (0.004 g, 0.18 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.05 g, 0.095 mmol), obtained in step (vi) of Example 1, at 0° C., and stirred for 15 min. Cyclopropanecarbonyl chloride (0.012 g, 0.11 mmol) was added to this at the same temperature and the reaction was stirred for 6 h. The aqueous layer was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-cyclopropanecarbonyl-1H-indole-2-carboxylic acid ethyl ester (0.04 g, yield: 71%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[N:34][C:27]=2[NH:26]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@@H:3]([CH2:2][NH:1][C:35]([C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)=[O:36])[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=C1COc2ccc(C(=O)O)nc2N1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(F)c(CCN3C[C@H](CNC(=O)c4ccc5c(n4)NC(=O)CO5)[C@H](O)C3)c2n1
Reaction time: 12 h
Yield: 36.4 %

Procedure:
To a solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (230 mg, 0.719 mmol) in DCM-DMF (6:1, 7 mL) at 25° C. were added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxylic acid (140 mg, 0.719 mmol), EDC (134 mg, 0.836 mmol) and HOBT (117 mg, 0.863 mmol). After 12 h, the solution was concentrated and purified by column chromatography (silica, 2-3% MeOH in DCM (1% NH OH)) yielding the title compound (130 mg, 36%) as a yellow foam: LC/MS (ES) m/e 497 (M+H); H NMR (CD OD, 400 Hz) δ 8.4 (s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H), 4.63 (AB quart., 2H), 4.20-4.24 (m, 1H), 3.9 (s, 3H), 3.55-3.59 (m, 1H), 3.40-3.43 (m, 1H), 3.23-3.28 (m, 2H), 3.16-3.19 (m, 1H), 2.91-2.94 (m, 1H), 2.7-2.82 (m, 2H), 2.49-2.52 (m, 2H), 2.37-2.42 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[N:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[CH:21]2)=[C:14]=[S:15]>C(O)C>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:14](=[S:15])[NH:13][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[CH:21]2
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Reactant: OCCC1Cc2ccccc2N1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3c4ccccc4CC3CCO)cccc2cn1
Reaction time: 24 h
Yield: 54 %

Procedure:
2-(2-Hydroxyethyl)indoline (43 g) and 5-isothiocyanato-3-methylisoquinoline (52 g) are dissolved in ethanol (800 cc). The solution, which is kept for 24 hours at a temperature of about 20° C., deposits a solid which is isolated by filtration, washed with ethanol (3×50 cc) and dried. (RS)-2-(2-Hydroxyethyl)-N-(3-methylisoquinol-5-yl)indoline-1-carbothioamide (51 g), a white solid, is obtained.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([CH2:17]CO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:1]([O:9][CH2:10][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OCCc1ccccc1
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 210 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
The reaction was set up as in Example 2 except that methyl benzoate (748.8 g, 5.50 mol) was used instead of benzoic acid and 671.9 g (5.50 mol) of 2-phenylethyl alcohol was used. After 4 h at 190° C., 230 g of distillate was collected and the reaction mixture was 51% product by GLC. The methanol was stripped from the distillate on a Buchi rotary evaporator and the residue was returned to the reaction flask. The batch was heated for 2 h at 200° C. and 2 h at 210° C., whereupon 170 g of distillate was collected and the reaction mixture was 80% product by GLC. The methanol was stripped from the distillate as before, and the residue was returned to the reaction flask. The batch was heated for 2 h at 210° C. and 2 h at 220° C., whereupon 40 g of distillate was collected and the reaction mixture was 94% product by GLC. The excess 2-phenylethyl alcohol (3.5% by GLC) and methyl benzoate (2.7% by GLC) were removed by vacuum distillation as usual and the product was treated with activated carbon as usual to afford 1000 g (81%) of 2-phenylethyl benzoate. The residual 2-phenylethyl alcohol was 0.30, the APHA color was 40, the acid number was 0.13 mg KOH/g, the saponification number was 245 mg KOH/g, and the residual tin was <10 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:9]=[C:4]3[CH2:3][CH:2]([CH3:1])[CH2:7][NH:6][C:5]3=[N:8][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Product: CC1CNc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2C1

Procedure:
The title compound was prepared from 5-methylpyridine-2,3-diamine and 1,2-bis(4-fluorophenyl)ethane-1,2-dione analogously to Intermediate E;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CNC
Product: CC(=O)c1ccc(N(C)C)cc1
Reaction time: 2 h

Procedure:
A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine is warmed in a pressure bottle at 90°-100° C. After two hours, a pale yellow oil is formed. The mixture is cooled, and the oil solidifies. The solid is collected and washed well with H2O to give 54.93 of p-dimethylaminoacetophenone, mp 101°-103° C., after heptane recrystallization. A 72 g sample of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene to reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene, and the filtrate and wash solution are evaporated to dryness in vacuo to afford 66 g of oil. This oil is chromatographed on SiO2 with 40% hexane/CH2Cl2 to give 38.9 g of 3.5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A 5.22 g sample of this oil is added portionwise to 2.75 g of SeO2 in 20 ml of dioxane and 0.7 ml of H2O at 55°-60° C. This mixture is heated at reflux temperature for 4.5 hours, cooled and filtered through siliceous earth. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15° C. and 2.77 g of t-butylamine is added dropwise to afford a tan precipitate. After stirring 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5° C. and 7 g of NaBH4 is added portionwise. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H2O at below 10° C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH2Cl2. The CH2Cl2 layer is washed with 100 ml of H2O, dried (MgSO4) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated carbon and concentrated to 15 ml. On cooling, crystals are obtained. The title product is collected as white crystals, mp 96°-99° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:29][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-phenyl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C20H23NO5 [M+H]+: 358.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: CCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 415 mg (2.16 mmol) of 1-bromononane in 30 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.60 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as light colorless oil: yield 502 mg (53%); silica gel TLC Rf 0.60 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ0.89 (t, 3H, J=7.2 Hz), 1.20-1.30 (m, 14H), 1.75 (m, 2H), 2.31 (s, 6H), 2.48 (s, 3H), 2.77 (dd, 2H, J=7.6, 7.6 Hz), 4.90 (s, 2H), 5.86 (s, 2H) and 7.40-7.44 (m, 5H); 13C NMR (CDCl3) δ 14.10, 14.33, 19.28, 22.67 27.74, 29.29, 29.29, 29.41, 29.51, 29.57, 31.62, 31.88, 75.72, 107.91, 128.01, 128.22, 128.72, 129.30, 129.30, 136.22, 147.35, 147.35, 152.59, 161.59 and 165.09; mass spectrum (APCI), m/z 434.3172 (M+H)+ (C28H40N30 requires 434.3171).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.[C:39](O)(=[O:42])[CH:40]=[CH2:41].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CO.C(Cl)(Cl)Cl>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:39](=[O:42])[CH:40]=[CH2:41])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:30][CH:29]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
3,N-(N,N-Dimethylaminopropyl)-1,N-ethylcarbodiimide hydrochloride (EDAC.HCl) (385 mg, 2.0 mmol) was added in one portion to a solution of 6-amino-4-(4-benzyloxyanilino)quinazoline (342 mg, 1.0 mmol), acrylic acid (144 mg, 2.0 mmol), and pyridine (163 mg, 2.06 mmol) in THF (10 mL) stirred under nitrogen at 0° C. After 4 hours at 0° C., tlc (10% MeOH/CHCl3) showed considerable SM, so the reaction mixture was stirred at 25° C. for 2 hours. The mixture was recooled to 0° C., and water (2 mL) was added dropwise. This solution was poured onto rapidly stirred ice-water (40 mL), the pH was raised to 7 with saturated Na2CO3 solution, and the very fine ppt was allowed to settle, collected by Buchner filtration, rinsed with water (2×10 mL), and dried in a vacuum oven at 65° C. for 4 hours. The pumpkin orange solid was refluxed and sonicated in CHCl3/acetone (1:1, 40 mL), containing silica gel (5 g). The volatiles were removed under reduced pressure and the residual solid was used as the origin of a silica gel flash chromatography column, eluting with 25% acetone/CHCl3. Removal of the solvent under reduced pressure gave N-(4-[4-benzyloxyanilino]quinazolin-6-yl)acrylamide (152 mg, 38%) as a bright yellow glass; mp 227-229° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19]1
Reactant: c1cc[nH]c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-n2cccc2)cc1
Temperature: 195 °C

Procedure:
To a solution of 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) (100 mg, 0.33 mmol) in DMF (5 mL) was added 1-H-pyrrole (0.66 mmol, 44 mg), K2CO3 (2.4 eq., 115 mg) and catalytic CuI (3 mg). The reaction tube was sealed, and heated in a microwave at 195° C. for 3 hours. The solution was extracted with ethyl acetate and washed with cold water. The product was purified twice by reverse phase HPLC (10 to 95% acetonitrile/water). The compound was re-dissolved in ethanol and evaporated to dryness. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (d, 6H)), 1.48 (s, 6H), 1.70 (m, 1H), 2.85 (t, 2H), 6.1 (d, 2H), 7.3 (m, 5H), 7.5 (d,2H). MS: M+H=285.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.Br[CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: C=C(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCOc1ccc(Br)cc1C(C)C
Temperature: 60 °C

Procedure:
4-Bromo-2-isopropylphenol (897 mg, 4.17 mmol) was dissolved in DMF (4.17 mL) and 4-bromo-2-methylbut-1-ene (1.24 g, 8.34 mmol) was added followed by K2CO3 (1.15 g, 8.34 mmol). The reaction mixture was heated to 60° C. overnight, cooled to room temperature, and diluted with Hexanes:EtOAc (1:1). Water was added and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with 0-15% EtOAc/Hexanes to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:6][CH:7]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[C:9]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:24][N:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A stirred mixture of 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (782.2 mg, 2.610 mmol, 1 eq) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.5 mL, 11 mmol, 4.3 eq) was heated at 100° C. for 18 hours. Excess 1,1-dimethoxy-N,N-dimethylmethanamine was removed under vacuum. The crude product was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptanes) to yield 740 mg (80%) of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione LCMS (ESI) m+H=355.2; 1H NMR (400 MHz, CDCl3) δ: 7.90 (d of d, 2H), 7.77 (d of d, 2H), 7.57 (s, 1H), 7.44 (d, 1H), 7.37 (overlapping d and s, 2H), 7.31 (t, 1H), 3.00 (s, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C@@:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)([OH:22])[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[CH3:19])[CH2:9]1)(OC(C)(C)C)=O.Cl>C(#N)C>[Cl:29][C:25]1[CH:24]=[C:23]([C@:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)([OH:22])[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[CH3:19])[CH:28]=[CH:27][CH:26]=1
Reactant: CC(F)(F)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: CC(F)(F)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
N-Boc-(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol (70 mg, 0.16 mmol) was dissolved in acetonitrile (16 mL) and 2M aq HCl (16 mL) and allowed to stir at rt overnight. The solvent was removed under high vacuum. The crude material was redissolved in CH2Cl2 and washed with satd NaHCO3 2×. The aqueous layer was extracted with CH2Cl2 3×. The combined organic layers were washed with brine and dried over sodium sulfate. After removing solvent under vacuum (S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol was isolated as an oil (28 mg) MS m/z 332 (M+H+).