Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)=[O:8].N1CCCCC1CC(C1C=CC2C=CC3C(C=2C=1)=CC=CC=3)=O.C(O)(=O)/C=C\C(O)=O.C(OC(C1C=CC2SC3C=CC=CC=3C=2C=1)CC1CCCCN1)(=O)CO>>[CH:10]1[C:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][C:9]=1[CH:7]([OH:8])[CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][NH:1]1
Reactant: O=C(CC1CCCN1)c1ccc2c(c1)Cc1ccccc1-2
Agent: O=C(CC1CCCCN1)c1ccc2ccc3ccccc3c2c1
Agent: O=C(CO)OC(CC1CCCCN1)c1ccc2sc3ccccc3c2c1
Agent: O=C(O)/C=C\C(=O)O
Product: OC(CC1CCCN1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Following essentially the same procedure but substituting 2-fluorenyl 2-pyrrolidinylmethyl ketone for the 3-phenanthryl 2-piperidylmethyl ketone and further substituting maleic acid for the glycolic acid, results in the preparation of α-(2-fluorenyl)-2-pyrrolidineethanol as the maleate salt having a M.P. of 147-9°C. (dec.)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]\[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[CH:2].I[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>CN(C)C=O.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])/[C:6]/3=[CH:13]\[C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2ccc(C#Cc3ccc([N+](=O)[O-])cc3)cc2/C1=C/c1ccc[nH]1
Temperature: 70 °C

Procedure:
A solution of (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) and 1-iodo-4-nitrobenzene (175 mg, 0.70 mmol) (Aldrich) in N,N-dimethylformamide (3 mL) (Fisher Scientific) and triethylamine (3 mL) was degassed by bubbling argon through the solution for 15 minutes. Copper(I) iodide (13 mg, 0.068 mmol) (Aldrich) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) were added, and the reaction mixture was heated at 70° C. for 13 hours. Water (15 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane to give (Z)-1,3-dihydro-5-(4-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 111 mg, 49%).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[Na]>C(#N)C.C(OCC)(=O)C>[N:16]1([CH:2]([CH3:15])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]=2)=[O:4])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cn1
Agent: [Na]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccc(C(F)(F)F)cn1)n1cncn1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-bromopropionyl)-5-trifluoromethylpyridine (5.8 g.) in acetonitrile (65 ml.) was added sodium 1,2,4- triazole (2.0 g.) and the solution was stirred for 90 minutes. The acetonitrile was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure to give a yellow gum. Chromatography on silica, using petroleum ether (bp (60°-80°):ethyl acetate 60/40 v/v as eluent, gave 2-[2-(1,2,4-triazol-1-yl)propionyl]-5-trifluoromethylpyridine as a pale yellow oil. Nmr in deuteriochloroform: δ1.88 (3H,d); 6.62 (1H,q); 7.9 (1H,s); 8.14 (2H,m); 8.36 (1H,s); 8.94 (1H,d).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 87.4 %

Procedure:
The title compound (114 mg) was prepared as in Example 177, Steps C and D, using 208 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 211 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C15H18FN3, 259.15; found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.43-3.38 (m, 2H), 3.33-3.28 (m, 2H), 3.18-3.12 (m, 2H), 2.80-2.75 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2C=O)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].COP([C:27](=[N+]=[N-])[C:28](=O)C)(=O)OC.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:11][C:12]([C:27]#[CH:28])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: O=Cc1ccccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (1.82 g, 6.0 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (2.3 g, 12.1 mmol) in methanol (30 mL), was added potassium carbonate (4.18 g, 30.3 mmol), and stirred for 1 h at rt. The reaction mixture was concentrated and the residue was purified by FC (PE/EtOAc 20:1) to afford the title compound as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])#[N:4].II>C1COCC1>[OH:9][CH2:8][C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[CH2:5][C:3]#[N:4]
Reactant: N#CCc1ccccc1C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium borohydride (454 mg, 12.0 mmol) in THF (20 mL) was slowly added a solution of 2-cyanomethylbenzoic acid (1.61 g, 10.0 mmol) in THF (20 mL), then a solution of iodine (1.30 g, 5.0 mmol) in THF (20 mL) was slowly added at rt. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with 3 N HCl (10 mL), then extracted with Et2O (3×20 mL). The combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=80:20→60:40) to give the title compound as a yellow oil. 1H NMR (CD3OD): δ=3.98 (s, 2H), 4.27 (s, 2H), 7.33 (m, 2H), 7.41 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH:15][C:16](=[O:23])[C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19]O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:15]4[CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[C:16]4=[O:23])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:24]([NH2:26])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)C1=O
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide (Intermediate 58-1, 89 mg, 0.213 mmol), diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) in THF (1 mL) was stirred at rt for 1 h. More diethyl azodicarboxylate (0.051 mL, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol) were added, and these additions repeated again after 1 h more. The mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide), then by preparative HPLC. The appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide 4-bromo-7-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide as a yellow solid (44 mg, 52%). 1H NMR (400 MHz, methanol-d4) δ 8.66 (1 H, d, J=8.58 Hz), 7.94 (1 H, d, J=1.54 Hz), 7.73 (1 H, d, J=8.36 Hz), 7.55 (1 H, dd, J=8.80, 1.98 Hz), 7.39 (1 H, d, J=8.14 Hz), 3.97 (2 H, t, J=6.93 Hz), 2.11 (2 H, t, J=6.93 Hz), 1.28 (6 H, s). Mass spectrum m/z 400, 402 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:8][CH2:9][OH:10])[CH2:7][O:6][CH2:5]1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[CH3:18][S:19]([O:1][CH2:2][CH2:3][C:4]1([CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:7][O:6][CH2:5]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(CCO)COC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of 2-[3-(2-Hydroxy-ethyl)-oxetan-3-yl]-ethanol (123) (1.3 g, 8.9 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (2.7 g, 26.7 mmol) and methanesulfonyl chloride (2.0 g, 17.8 mmol). The solution was allowed to warm to RT and stirred for 15 min. The reaction mixture was diluted with water (80 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to give the product (124) (2.0 g, 6.6 mmol, yield: 74%). ESI-MS (M+1): 303 calc. for C9H18O7S2 302.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29]([OH:31])=O)[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:39])([CH3:38])[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29](=[O:31])[NH:37][CH2:36][CH2:35][C:34]([CH3:39])([CH3:38])[CH3:33])[CH:28]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(C)CC1
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(C(=O)NCCC(C)(C)C)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a mixture of (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (50 mg, 0.112 mmol) and 3,3-dimethylbutan-1-amine (22.66 mg, 0.224 mmol) in DMF (2 mL) was added DIEA (0.098 mL, 0.560 mmol), HATU (85 mg, 0.224 mmol) and DMAP (2.74 mg, 0.022 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ethyl acetate (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.336 mL, 0.336 mmol) in MeOH (2.000 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(2-((3,3-dimethylbutyl)carbamoyl)-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (41.6 mg, 0.079 mmol, 70.4% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.13 (t, J=5.6 Hz, 1H), 6.77 (s, 1H), 5.46 (s, 1H), 3.37-3.28 (m, 6H), 1.92 (s, 3H), 1.67-1.55 (m, 2H), 1.54-1.40 (m, 4H), 1.14 (s, 9H), 1.08 (br. s., 6H), 0.96 (s, 9H). LCMS (M+H)=502.5.
Reaction SMILES: [CH2:1]([CH:3]([CH3:31])[C:4]([NH:6][C:7]1[C:8]2[S:15][C:14]3[CH:16]=[C:17]([NH:20]C(OCC4C=CC=CC=4)=O)[CH:18]=[CH:19][C:13]=3[C:9]=2[N:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2]>Br.C(O)(=O)C.CCOCC>[CH2:1]([CH:3]([CH3:31])[C:4]([NH:6][C:7]1[C:8]2[S:15][C:14]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:13]=3[C:9]=2[N:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCC(C)C(=O)Nc1nn(C)c2c1sc1cc(NC(=O)OCc3ccccc3)ccc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(C)C(=O)Nc1nn(C)c2c1sc1cc(N)ccc12
Temperature: 25 °C

Procedure:
A suspension of this crude amide in 200 ml of 48% hydrobromic acid in acetic acid was stirred at room temperature for several hours until it was all dissolved. The reaction mixture was then diluted with ether and the solid precipitate that formed was collected by filtration. The solid was distributed between methylene chloride and 10% sodium bicarbonate solution and the organic layer was separated and dried over potassium carbonate. The residue obtained after removal of the solvent in vacuo was chromatographed on silica gel, using toluene/ethyl acetate as solvents, to yield a crystalline product. Recrystallization of this product from nitromethane gave 2-ethyl-N-(6-amino-1-methyl-1H-(1)benzothieno[3,2-c]-pyrazol-3-yl)propanamide, m.p. 196°-197° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:16][CH2:15][C@:14]([CH3:21])([C:17]([O:19][CH3:20])=[O:18])[C:13]1([CH3:23])[CH3:22])=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][C@@H:12]1[CH2:16][CH2:15][C@:14]([CH3:21])([C:17]([O:19][CH3:20])=[O:18])[C:13]1([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@]1(C)CC[C@@H](NC(=O)OCc2ccccc2)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@]1(C)CC[C@@H](N)C1(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
To a flask, charged with 10% palladium on carbon (90 mg, 0.845 mmol), under a steady nitrogen flow was added ethanol (5 ml), followed by addition of a solution of (1S,3R)-methyl 3-(benzyloxycarbonylamino)-1,2,2-trimethylcyclopentanecarboxylate (900 mg, 2.82 mmol) in ethanol (11.300 ml). The flask was evacuated and flushed with hydrogen and then filled with one atmosphere of hydrogen. The reaction was stirred at room temperature for 14 hrs. The flask was evacuated and backfilled with nitrogen. The suspension was filtered through a pad of Celite. The Celite cake was washed with ethanol (3×, 20 ml). The ethanol wash was concentrated under reduced pressure to yield the title compound (478 mg, 2.58 mmol, 92% yield) as a colorless oil. LC/MS found [M+H]+=186.3. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.68 (s, 3H), 3.10 (t, J=9.1 Hz, 1H), 2.57-2.47 (m, 1H), 2.11-2.02 (m, 1H), 1.46-1.35 (m, 2H), 1.19-1.17 (m, 3H), 1.07-1.03 (m, 3H), 0.72 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][S:29][CH3:30])[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.COC(=O)[C@H](CCSC)N(C(=O)C1C=CC(N)=CC=1)C(OC(C)(C)C)=O>C(Cl)Cl.CCN(CC)CC>[CH3:22][O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][S:29][CH3:30])[NH:26][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(C)cc(-c2cc([N+](=O)[O-])ccc2C(=O)O)c1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1cc(C)cc(C)c1
Yield: 56.8 %

Procedure:
4-nitro-2-(3,5-dimethylphenyl)benzoic acid (0.15 g, 0.55 mmol), methionine methyl ester hydrochloride salt (0.11 g, 0.55 mmol), EDCI (0.11 g, 0.55 mmol), HOBT (0.07 g, 0.55 mmol) and Et3N (0.08 ml) in dry CH2Cl2 (2.2 ml) were reacted and worked up according to the procedure for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. After recrystallization from ethyl acetate and hexanes, 0.13 g (58.4%) of pure product was isolated. mp 122-124° C.; 1H NMR (CDCl3) 1.2-1.84 (1H, m), 1.85-1.97 (1H, m), 2.01 (3H, s), 2.05 (3H, t, J=7.7 Hz), 2.38 (6H, s), 3.70 (3H, s), 4.67-4.74 (1H, m), 6.03 (1H, d, J=7.9 Hz), 7.05 (2H, s), 7.09 (1H, s), 7.84-7.87 (1H, m), 7.84-7.87 (1H, m), 8.23-8.26 (2H, m); 13C NMR (CDCl3), 15.20, 21.26, 29.22, 31.15, 51.79, 52.57, 122.07, 25.11, 126.27, 130.03, 130.53, 137.77, 138.82, 140.29, 141.56, 148.41, 167.14, 171.53.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1

Procedure:
A mixute of 12.9 g of 6-chloro-2[(4-methoxyphenyl)amino]-3-nitrobenzoic acid, 25 ml of chlorobenzene and 50 ml of phosphorus oxychloride was stirred and heated to reflux temperature over a period of one hour, and held under reflux for 4.5 hours. The mixture was cooled, filtered, and the filtrate concentrated to a viscous dark residue by evaporation under reduced pressure. The evaporation residue, and the precipitate collected previously were dissolved in 130 ml of acetic acid and cautiously treated with 15 ml of water, while stirring. The dark red title compound is collected, washed with water, and dried to 11.5 g (95%), mp 262-264 degrees.
Reaction SMILES: [NH2:1][C:2]1([CH2:19][OH:20])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2.CC(C)([O-])C.[Li+].Br[CH2:28][C:29]#[N:30]>C1COCC1>[NH2:1][C:2]1([CH2:19][O:20][CH2:28][C:29]#[N:30])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2
Reactant: NC1(CO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Reaction time: 16 h
Yield: 78 %

Procedure:
A 3-neck RBF was charged with (5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (20.7 g, 57.6 mmol) and THF (10 mL). The flask was equipped with two addition funnels which were charged with lithium tert-butoxide solution (1.0M in THF; 98 mL, 98 mmol) and a solution of bromoacetonitrile (6.82 mL, 98 mmol) in THF (10 mL), respectively. The two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours. Upon complete addition, the addition funnels were recharged with lithium tert-butoxide solution, 1.0 M in THF (98 mL, 98 mmol) and a solution of bromoacetonitrile (6.82 mL, 98 mmol) in THF (10 mL), respectively. The two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and stirred for 16 hours. The reaction was diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure, and the resulting black solid was triturated with ether and filtered to afford a brown precipitate. The filtrate was further concentrated and purified by chromatography (50-100% EtOAc/hexanes). The solids obtained through trituration and purification by chromatography were combined to afford 2-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)acetonitrile (17.9 g, 44.9 mmol).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)C=C.[CH3:25][C:26]1C=CC=C[C:31]=1C>>[CH2:31]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:9][CH:10]=[N:11]2)[CH:26]=[CH2:25]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1cc2c(Nc3ccc(Cl)cc3)ncnc2cc1OC
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.50 g, 1.46 mmol) (from Example 16, Step C, supra) in o-xylene (50 mL) was heated at 150° C. for 7 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solvent was evaporated and the residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.4 g, 80%).
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19](OC)=[CH:18][CH:17]=[CH:16][C:15]=2[O:22]C)CCCCC1.[C:30]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.IC1C2OC3C=CC=CC=3C=2C=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:16]1[C:15]2[O:22][C:10]3[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=3[C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Ic1cccc2c1oc1ccccc12
Product: c1ccc(-c2ccccc2Nc2cccc3c2oc2ccccc23)cc1
Yield: 837.7 %

Procedure:
Toluene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 g, 4.2 mmol), and Pd2(dba)3 (1.0 g, 1.1 mmol). The mixture was bubbled with nitrogen for 15 min, then [1,1′-biphenyl]-2-amine (3.4 g, 20.0 mmol), 4-iododibenzo[b,d]furan (10.3 g, 35.0 mmol), and sodium tert-butoxide (6.7 g, 70.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 24 h. After cooling, the reaction mixture was filtered through a silica pad and washed with DCM. The solvent was removed in vacuo and the residue was purified by flash chromatography using 25% DCM/hexane (containing 0.75% triethylamine) to yield N-([1,1′-biphenyl]-2-yl)dibenzo[b,d]furan-4-amine (11.8 g, 98% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH:15]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(N(C(C)C)C(C)C)C.[CH3:39][C@@:40]1([CH2:47][S:48](Cl)(=[O:50])=[O:49])[C:44](=[O:45])[NH:43][C:42](=[O:46])[NH:41]1>CCO.CN(C=O)C>[CH3:39][C@:40]1([CH2:47][S:48]([N:13]2[CH2:14][CH:15]=[C:10]([C:9]#[C:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=3)[CH2:11][CH2:12]2)(=[O:50])=[O:49])[NH:41][C:42](=[O:46])[NH:43][C:44]1=[O:45]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: Cc1ncc(C#CC2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(C#CC2=CCN(S(=O)(=O)C[C@@]3(C)NC(=O)NC3=O)CC2)cn1
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
tert-Butyl 4-[(2-methylpyrimidin-5-yl)ethynyl]-3,6-dihydropyridine-1(2H)-carboxylate was treated with TFA in EtOH and after completion of the reaction the solvent was evaporated and the mixture was freeze dried. The residue was taken up in DMF (1.5 mL) and the mixture was cooled to 4° C. N-Ethyldiisopropylamine (2.2 eq.) was added and the mixture was stirred for 20 minutes before adding [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (Example 1f) (1.1 eq.) in DMF (1 mL). The mixture was stirred for 10 min at 4° C. and then stirred for 2 h at room temperature before the solvent was evaporated. The product was purified by preparative HPLC to give the title compound (0.022 g, 30%).