Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)CC)(=O)[CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Product: CCC1=Nc2c(OC)c(OC)cc3ncnc(c23)N1c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (120 mg, 0.32 mmol) (from Example 6, Step B, supra) in propionic anhydride (3 mL) (Aldrich) was heated at 170° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-2-ethyl-8,9-dimethoxy-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 50 mg, 38%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])=[CH:40][N:41]=1>>[CH:45]1([NH:44][C:42]([C:39]2[S:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[N:41][CH:40]=2)=[O:43])[CH2:47][CH2:46]1
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC3CC3)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.219 min, m/z=462.1; 1H NMR (CDCl3) 0.51 (m, 2H), 0.81 (m, 2H), 1.04 (s, 3H), 1.12 (s, 3H), 1.47 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40 (m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.09 (s, 1H), 6.94 (m, 2H), 7.21-7.39 (m, 5H), 7.61 (m, 2H), 8.01 (s, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH2:11])=[O:10].Br[CH2:13][C:14](=O)[CH2:15][CH3:16]>CC(C)=O>[CH2:15]([C:14]1[C:7]([CH2:8][C:9]([NH2:11])=[O:10])=[C:2]2[N:1]([CH:13]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH3:16]
Reactant: NC(=O)CCc1ccccn1
Reactant: CCC(=O)CBr
Solvent: CC(C)=O
Product: CCc1cn2ccccc2c1CC(N)=O
Reaction time: 6 h
Yield: 15.5 %

Procedure:
2-Pyridinepropaneamide (6.5 g, 43 mmol) was dissolved in warm acetone (500 mL). 1-Bromobutanone (10.0 g, 66 mmol) was added and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was cooled in a freezer and the acetone was decanted from a light brown solid (12 g). The solid was dissolved in hot ethanol (450 mL). Solid NaHCO3 (10 g) was added and the reaction mixture was heated under reflux with stirring for 6 h. The reaction mixture was filtered to remove NaBr and the filtrate was evaporated under reduced pressure to give a brown solid residue. The residue was extracted 4 times with boiling hexane (500 mL). Each time the solvent was decanted from the remaining solid and cooled in the freezer. A final extraction was with boiling heptane (500 mL). Collection of the cooled filtrates and drying of the collected solid gave 1.35 g of 2-(2-ethylindolizin-1-yl)acetamide. The 2-(2-ethylindolizin-1-yl)acetamide (440 mg ) in ethyl ether (90 mL) was treated with lithium aluminum hydride (360 mg) and heated under reflux in a nitrogen atmosphere overnight. After cooling to room temperature, an aqueous solution of Rochelle salt was cautiously added with stirring until a solution was observed. The phases were separated and the aqueous phase was extracted 3 times with ether. The combined organic layers were extracted with 0.1 N HCl, and the aqueous layer was made basic with 2.5 N NaOH. The aqueous phase was extracted with methylene chloride 3 times and the organic phase was evaporated under reduced pressure to give 410 mg of product as a yellow brown oil. The product (170 mg, 0.90 mmol) was dissolved in ethanol and treated with fumaric acid (52 mg, 0.45 mmol). The title compound was obtained as a golden brown solid, mp: 170-175° C. dec. MS [M+H]+ 189 m/z; microanalysis was consistent for C12H16N2+C4H4O4.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: CN1CCC[C@@H]1CO
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC[C@@H]1COc1cncc(C(F)(F)F)c1

Procedure:
(R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolved in 8 mL of DMF and stirred under N2, then 240 mg of NaH (80% dispersion in mineral oil) was added. The reaction mixture was stirred fifteen minutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) was added. The reaction mixture was stirred at 50° C. for 16 hours. The volatiles were removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2:1 ethyl acetate:hexane to give 336 mg of the title product. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H).
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>CCCCCC.CCOCC>[OH:15][C:11]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCC1
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2nccs2)CCC1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of n-BuLi (36 mL of a 2.5M solution in hexane, 90 mmol) in anhydrous ether (100 mL) at −78° C. was slowly added a solution of thiazole (6.35 g, 74.6 mmol) in anhydrous ether (60 mL). The resulting mixture was stirred for 1 h and then cyclobutanone (10.4 g, 148 mmol) in ether (20 mL) was added over 5 min. The mixture was stirred for 2 h at −78° C. and then sat. aq. NH4Cl was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided 2-[(1-Hydroxy)cyclobutyl]thiazole (5 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]1([CH3:17])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:15])[CH3:14])[CH:9](O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:6][CH:9]1[CH:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12][CH:7]([CH3:17])[CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1CC(C)CCC1C(C)C
Temperature: 150 °C

Procedure:
24 g of methacrylic acid, 31 g of menthol and 15 g of p-toluenesulfonic acid dissolved in 500 mL of toluene were heated under reflux at an oil temperature of 150° C. for 19 h. Subsequently, the reaction of the mixed solution was quenched by the addition of salt saturated sodium hydrocarbonate solution. The mixture was extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydroxide, salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydous. Finally, the resultant oily product was evaporated under reduced pressure to obtain menthyl methacrylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:12]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.5 %

Procedure:
To a solution of thiophene (9.5 mL, 0.12 mole) in 100 mL tetrahydrofuran at 0° C. was added 2M n-butyllithium (48 mL, 0.12 mole) dropwise. The solution was stirred 2.5 h and was then added via cannula to a stirred solution of anhydrous zinc chloride (26 g, 0.19 mole) in 100 mL of THF at room temperature. After 1 h this solution was transferred via cannula into a solution of bromobenzene (8.4 mL, 0.08 mole) and tetrakis-triphenylphosphine palladium (0.2 g) in 100 mL of THF. The solution was warmed to reflux overnight. The solution was cooled to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ether (3×50 mL). The ether extracts were washed with brine, dried (MgSO4), filtered and concentrated. The material was distilled (20 mm Hg) to yield 7.5 g (60%) of desired product, b.p.=150° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=4[F:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccc(F)c1F
Reaction time: 0.05 h
Yield: 13.7 %

Procedure:
To a stirred solution of 0.350 g of 2,3-difluorobenzoyl chloride in 5 ml of methylene chloride is added 0.346 ml of triethylamine. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours. The reaction mixture is filtered and the solid washed with methylene chloride. The solid is saved. The combined filtrate is washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give 100 mg of a solid. The two solids are combined and dried to afford 790 mg of the desired product as a solid, m.p. 252°-258° C.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][CH:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of (41) (270 mg, 0.663 mmol) in ethanol (20 mL) was stirred with 10% Pd on carbon (11 mg) in a 50 mL round-bottomed flask under an atmosphere of hydrogen gas (balloon). The reaction was judged complete in 30 min. (monitoring by TLC and LC/MS). The mixture was filtered through a pad of Celite, and the solvent removed in vacuo to afford the title compound (33) as a mixture of two diastereomers (177 mg, 84%). 1H—NMR (CDCl3, 400 MHz): δ 0.89 (m, 6H), 1.16 (m, 8H), 1.46 (d, 3H), 1.66 (m, 1H), 2.11-2.36 (m, 3H), 2.52 (m, 1H), 3.11 (m, 1H), 3.27 (m, 1H), 5.08 (t, 1H), 6.77 (m, 1H). MS (ESI) m/z 316.20 (M−H−).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Cl)nc1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 6-chloropyridin-3-ol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]=1[Cl:18].S(Cl)(Cl)=O.O.[OH-].[Na+].[CH2:26](O)[CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17][CH2:26][CH3:27])=[O:16])[C:3]=1[Cl:18]
Reactant: CCO
Reactant: Nc1nc(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)nc(N)c1Cl

Procedure:
To a solution of 6-amino-5-chloro-2-(4-chlorophenyl)-4-pyrimidinecarboxylic acid (i.e. the product of Example 4, Step C) (20.0 g, 70.4 mmol) in ethanol (70 mL) was added thionyl chloride (5.14 mL, 70.4 mmol) while maintaining the temperature below 15° C. using an ice bath. The reaction mixture was then heated at reflux overnight. Water was added. Then with external cooling aqueous sodium hydroxide (50%) was added to adjust the pH to 7. The resulting solid was isolated by filtration and dried to afford the title product, a compound of the present invention, as a light beige solid (20.1 g).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:18][C:19]1[C:24]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
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: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([OH:22])=O)[CH3:3].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:20]([NH2:25])=[O:22])[CH3:3]
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(-c3ccccc3)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A suspension of 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxylic acid (173 mg, 0.58 mmol) and 1,1'-carbonyldiimidazole (116 mg, 0.72 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 2 hours. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-5-phenyl-2-benzofurancarboxamide in 94% yield; mp=192°-130° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=1.[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:8][CH:7]=2)=[O:20])=[CH:35][C:36]=1[F:42])#[N:39]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 μmol, example 88) in MeCN (0.5 mL) was added 4-amino-2-fluorobenzonitrile (65 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (22 μL, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: C([Si]1(OC(C)=C)O[C@@H:7]([C:9]([O:12]C)([CH3:11])[CH3:10])[C@H:6]([C:14](C)(OC)C)O1)C=C.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:10][C@:9]([OH:12])([CH2:7][CH:6]=[CH2:14])[CH2:11][C@@H:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: C=CC[Si]1(OC(=C)C)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C=CC[C@](C)(O)C[C@H](O)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
Asymmetric tandem aldol-allylation reaction of benzaldehyde to give (1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol: To a solution of (4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane (0.75 mmol) in benzene (0.3 mL) was added benzaldehyde (0.50 mmol). The mixture was heated to 40° C. (oil bath) and stirred at that temperature for 48 hours. The solution was cooled and 1 M HCl (10 mL) was added followed by ethyl acetate (10 mL). The mixture was stirred for 20 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated. Analysis of the residue by HPLC and 1H NMR revealed a 5.5:1 mixture of diastereomers and an enantiomeric excess for the major product of 68%. The residue was purified by chromatography on silica gel to give (1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol in 70% yield and in 68% ee.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:12])=[CH:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:12])=[CH:4][C:3]=1[Br:13]
Reactant: BrBr
Reactant: COC(=O)c1nc(N)ccc1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(N)c(Br)cc1Br
Reaction time: 16 h

Procedure:
A solution of methyl 6-amino-3-bromopyridine-2-carboxylate (20.62 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623–4633) in chloroform (570 ml) was treated dropwise over 2 hours with bromine (4.62 ml) in chloroform (115 ml) and stirred 16 hours. The solution was washed with excess aqueous sodium bicarbonate, dried and evaporated. Crystallisation from EtOAc/hexane gave a solid (13.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[N:40]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:36])([CH3:37])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[N:40]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reactant: Cc1nccc(Cl)n1
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 4-chloro-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 1 tR=1.55, m/z=473 (M+1); 1H NMR (CDCl3) 8.96 (s, 1H), 7.98 (d, 2H), 7.84 (s, 1H), 7.29 (m, 2H), 7.10 (m, 4H), 5.72 (d, 1H), 3.05 (d, 1H), 2.97 (s, 3H), 2.91 (m, 1H), 2.51 (d, 1H), 1.61 (d, 3H), 1.38 (d, 3H), 1.27 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[CH:30][CH:31]=2)[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:33][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([N:24]5[CH:25]=[N:21][N:22]=[CH:23]5)[CH:27]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: NCc1cccc(-n2cnnc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3cccc(-n4cnnc4)c3)c2C1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (80 mg, 0.26 mmol) and (3-(4H-1,2,4-triazol-4-yl)phenyl)methanamine (120 mg, 0.40 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.6 mL, 4 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-50% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Yield: 100.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-6, step-1 using 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 500 mg, 2.39 mmol), 4-(trifluoromethyl)phenol (776 mg, 4.79 mmol) and K2CO3 (989 mg, 7.17 mmol) in CH3CN (5 mL) to afford 800 mg of the title product. MS (m/z): 335.09 (M+H)+.