Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN1CC2C(C1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
To a solution of 3-hexyl-6-phenyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 27, 40 mg, 0.15 mmol) in anhydrous tetrahydrofaran (2 ml) at room temperature under nitrogen, was added dropwise a solution of lithium aluminium hydride 1.0 M in tetrahydrofuran (0.3 ml, 0.3 mmol), then the mixture was heated to 60□ C. for 4 hours, cooled and stirred at room temperature for 64 hours. Water (30 ml) was carefully added, then the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (30 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1.5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (14 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CC[C@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1

Procedure:
Prepared according to the method described in Example 1d) from (3RS,4S)-4-(4-bromophenoxy)-1-pyridin-3-yl-hex-1-yn-3-ol (3.42 g, Example 87c)) and 5% rhodium on carbon (0.5 g) in ethyl acetate (100 ml). After work up crude material was purified by flash column chromatography over silica eluting with ethyl acetate to give a mixture of diastereomers. The mixture was separated by normal-phase HPLC eluting with 2% propan-2-ol in dichloromethane to give the sub-title compound as the second eluting, major diastereomer (2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH3:32])[C:26]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:26]1[C:27]([CH2:31][CH3:32])=[N:28][CH:29]=[CH:30][C:25]=1[NH:24][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCc1nccc(N)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1nccc(NC(=O)Cc2ccc(O)cc2)c1Cl
Temperature: 5 °C
Yield: 48.2 %

Procedure:
0.76 g (5.0 mmol) of 4-hydroxyphenyl acetic acid was dissolved in 20 ml of 1,4-dioxane, and the solution was stirred at 5° C. Then, 0.97 g (6.0 mmol) of 1,1'-carbonyldiimidazole was added thereto, and the mixture was stirred for one hour at 5° C. Then, 0.76 g (5.0 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was refluxed under heating for 20 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) and then recrystallized from ethanol to obtain 0.7 g of the desired product as a white powder (melting point: 158° to 161° C.).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([CH2:20][CH2:21][C:22](O)=O)[CH2:19]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH:19]2[CH2:14][CH2:20][CH2:21][CH2:22]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: O=C(O)CCCCC1CCCCC1
Product: O=C(CCCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanepentanoic acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:21])[CH3:20]>>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1c(N)cccc1Br
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Br)c1C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetyl chloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to off-white solids. Trituration with hexanes afforded title compound as white solids (4.4 g, 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([F:11])[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1
Reactant: [C-]#N
Reactant: COc1cc(F)cc(CCl)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc(CC#N)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
To a solution of 1-(chloromethyl)-3-fluoro-5-methoxybenzene (2.9 g, 17 mmol) in DMSO (20 mL), a solution of KCN (2.2 g, 34 mmol) and KI (5.6 g, 34 mmol) in H2O (10 mL) was added. The mixture was stirred at 45° C. for 6 h, poured into H2O (20 mL), and extracted with DCM (3×30 mL). The organic phase was washed with brine (2×10 mL), dried over Na2SO4, and concentrated to give 2.62 g of 2-(3-fluoro-5-methoxyphenyl)acetonitrile. 1H NMR (CDCl3): δ 6.62-6.68 (m, 2H), 6.56-6.60 (m, 1H), 3.80 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Cc1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(-c2cc(Cl)c3ccc(C)cc3n2)cc1

Procedure:
The title compound, m. p. 110-111 ° C., MS: m/e=267 (M+), was prepared from 4-chloro-7-methyl-quinoline and 4-bromotoluene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[O:11][C:10](=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:9][C:10](=[O:19])[O:11]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2cccc(F)c2)c2ccc(CBr)cc2o1
Reaction time: 8 h

Procedure:
To a solution of 4-(3-fluorophenyl)-7-methyl-2H-chromen-2-one (1.25 g, 4.9 mmol) in carbontetrachloride (30 mL), N-bromosuccinimide (963 mg, 5.41 mmol) and benzoylperoxide (60 mg, 0.25 mmol) were added. The reaction was then stirred overnight at reflux. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified on a short column of silica gel (eluting with CH2Cl2). The filtrate was concentrated and the solid obtained was swished in a mixture of CH2Cl2/hexanes. The title product was collected by filtration. 1H NMR (400 MHz, acetone-d6): 7.72-7.6 (m, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.45-7.3 (m, 4H), 6.4 (s, 1H), 4.78 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[S:26][C:27]([CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[C:28]([CH3:30])[CH:29]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:37])[C:15]=1[NH2:38]>C(Cl)Cl.C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]([NH:38][C:15]1[C:16]([CH3:37])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[S:26][C:27]([CH2:31][N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[C:28]([CH3:30])[CH:29]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[Cl:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(N)c(Cl)c3)no2)cc1C
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(NC(=O)COCc4ccccc4)c(Cl)c3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
A solution of benzyloxyacetyl chloride (142 mg, 767 μmol) in DCM (2 mL) is added to a solution of 2-chloro-4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenylamine (30 mg, 77 μmol) in DCM (2 mL). The mixture is stirred at rt for 15 h. The mixture is diluted with diethyl ether and washed with 1 N aq. HCl. The organic extract is washed with 33% aq. KOH solution, dried over MgSO4, filtered and concentrated. The crude product is purified by reverse phase MPLC to give 2-benzyloxy-N-{2-chloro-4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-acetamide (12 mg) as a pale yellow oil; LC-MS: tR=0.68 min; [M+1]+=529.18. The material is dissolved in THF:ethanol 1:1 (5 mL) and Pd/C (10 mg, 10% Pd) is added. The mixture is stirred at rt for 15 h under 5 bar of H2. The catalyst is removed by filtration and the filtrate is concentrated. The crude product is purified on prep. TLC plates with DCM containing 4% of methanol to give the title compound (4 mg) as a white solid; LC-MS: tR=0.50 min; [M+1]+=448.98; 1H NMR (CD3OD): δ 1.13 (t, J=7.0 Hz, 6H), 2.29 (s, 3H), 2.39 (s, 3H), 2.66 (q, J=6.8 Hz, 4H), 3.80 (s, 2H), 4.24 (s, 2H), 7.75 (s, 1H), 8.00 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([O:15]C)=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([OH:15])=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C(=O)O)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of the ester prepared in Example 1 (14.0 g, 58.9 mmol) in 140 mL MeOH, was added a solution of KOH (6.4 g, 113.8 mmol) in 5 mL water. The reaction mixture was stirred at 60° C. (pot temperature) for 2 hours. TLC showed 70% conversion. A solution of KOH (3.0 g, 53.6 mmol) in 100 mL water was then slowly added to the pot. After 1 hour, the reaction was completed. After cooling to room temperature, the solvents were removed at a reduced pressure. The residue was dissolved in 500 mL water, and then washed with EtOAc. The aqueous layer was cooled in an ice-water bath, and then acidified with conc. HCl to pH<3.0. The product was extracted into 300 mL CH2Cl2, washed with water (2×100 mL), then dried over Na2SO4. After Na2SO4 was filtered off, the CH2Cl2 solution was stirred with 3.0 g of charcoal for 2 hours. The charcoal was removed by filtration through a pad of Celite®. The title product (12.5 g, 95%) was obtained as a light brown solid after solvent removal and vacuum drying. 1H NMR (DMSO-d6) δ12.20(b, 1H), 7.30(d, 1H), 7.06(d, 1H), 6.82(dd, 1H), 6.22(s, 1H), 3.75(s, 3H), 3.45(t, 1H), 3.30(s, 2H), 1.90(m, 1H), 1.78(m, 1H), 0.90(t, 3H).
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[N:11]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccccc1
Reactant: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)n1c(=O)c2c(C)cc(Cl)nc2n1Cc1ccccc1

Procedure:
In analogy to example 2, 50 mg (0.16 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridin-2-carboxylic acid hexylamide were reacted with 33 mg (0.19 mmol) of bromomethylbenzene in DMF with triethylamine. Yield: 20 mg (31%), M+H+: 401.16.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[NH2:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:7]([C:9]4[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 69 %

Procedure:
To a sealed vial is added 2-[3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]propan-2-ol (60 mg, 0.13 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aqueous Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Ar at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-7% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (42 mg, 68%). LCMS (ESMS): m/z 469.50 (M++1)
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:62]=[N+:63]=[N-:64])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[N:62]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[C:2]([CH3:16])([CH3:15])[CH3:1])=[N+:63]=[N-:64]
Reactant: CCCSc1ccc(C(O)C(C)(C)C)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCSc1ccc(C(N=[N+]=[N-])C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
To a stirred solution of 2,2-dimethyl-1-[4-(propylthio)phenyl)propan-1-ol (466 mg, 1.95 mmol) in THF (10 ml) were added triphenylphosphine (666 mg, 2.54 mmol), diethyl azodicarboxylate (0.40 ml, 2.54 mmol), and finally diphenylphosphoryl azide (0.55 ml, 2.54 mmol). The mixture was stirred at room temperature over for 3 days. Water (1 ml) was added and the mixture was evaporated. The residue was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic phase was separated, washed with brine (30 ml), dried over MgSO4, filtered and evaporated to give an oil. The crude product was chromatographed on silica eluting with 4% EtOAc in hexanes to give the title product as a pale yellow oil (284 mg). 1H NMR δ (CDCl3) 7.29-7.27 (2H, m), 7.17-7.15 (2H, m), 4.23 (1H, s), 2.92 (2H, t, J=7.3 Hz), 1.73-1.67 (2H, m), 1.04 (3H, t, J=7.4 Hz), 0.90 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:9])[CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN(C)c1cc(C)ncn1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1cc(C)ncn1
Yield: 56 %

Procedure:
4-Chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added to a solution of 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) and the mixture heated at reflux for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (75 mg, 39%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.46 and 2.47(2s, 3H); 3.35 and 3.42(2s, 3H); 3.97 and 3.98 (2s, 3H); 4.2(br s, 1H); 4.3(br s, 1H); 4.5(br s, 2H); 7.05 and 7.3(2s, 1H); 7.4 and 7.5(m, 2H); 7.62(t, 1H); 7.7(d, 1H); 8.25(br s, 1H); 8.8 and 8.9(2s, 2H) MS-ESI: 469 [MH]+
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17][NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.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>[CH3:13][O:12][C:10]1[CH:11]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:19](=[O:20])[NH:18][CH3:17])=[CH:22][CH:23]=2)[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 40 °C

Procedure:
Under nitrogen, the mixture of methyl 2-chloro-4-methoxy-5-nitrobenzoate (292 mg, 1.19 mmol), 4-(methylcarbamoyl)phenylboronic acid (319 mg, 1.79 mmol), dichlorobis(triphenylphosphine)palladium (II) (41 mg, 0.06 mmol) and sodium carbonate (378 mg, 3.57 mmol) in THF (8 mL) and water (2 mL) is heated at 40° C. overnight. The reaction mixture is cooled to room temperature and then partitioned between EtOAc and brine. The organic extracts are dried (Na2SO4), concentrated in vacuo, and purified by silica gel chromatography (EtOAc/Hexanes:1/3) to afford Methyl 5-methoxy-4′-(methylcarbamoyl)-4-nitrobiphenyl-2-carboxylate; ESMS m/z 345.1 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[C:12]([SiH2:16][O:17][C:18]([CH3:27])([CH3:26])[CH:19]1[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][O:20]1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([SiH2:16][O:17][C:18]([CH3:27])([CH3:26])[CH:19]1[CH2:24][C:23]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([OH:25])[CH2:22][CH2:21][O:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)CCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)C1CC(O)(C#C[Si](C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A cold (−78 ° C.), stirred solution of (trimethylsilyl)acetylene (1.01 g, 10.3 mmol) in anhydrous THF (25 mL) was treated with nBuLi (4.12 mL in hexane, 10.3 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one (1.48 g, 6.06 mmol) in anhydrous THF (25 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 1.75 g (84%) of yellow oil: 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.16 (s, 9H), 0.89 (s, 9H), 1.43 (m, 1H), 1.78 (td, 1H), 1.83 (d, 1H), 1.94 (d, 1H), 3.52-3.70 (m, 4H), 4.00 (m 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19]>C1COCC1>[F:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[C:6]([I:8])[C:7]=1[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Cc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(I)c(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A −78° C. solution of 2-fluoro-4-iodo-1-methylbenzene (25 g, 105.9 mmol) in THF (200 mL) was treated dropwise with LDA (2M solution in THF, 58.5 mL, 116 mmol), stirred at −78° C. for 1 hour, treated with excess powdered dry ice, stirred at −78° C. for 30 minutes, and warmed to room temperature gradually over about 18 hours. The mixture was concentrated and the residue was partitioned between 4N NaOH and diethyl ether. The aqueous phase was adjusted to pH 2 with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 19.4 g (66% yield) of the desired product. MS (ESI(+)) m/e 279 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].Cl>N1C=CC=CC=1>[CH2:30]([O:32][N:33]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)[CH3:2])[CH3:31]
Reactant: CCON
Reactant: CC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a mixture of 0.41 g of 5-acetyl-2-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)pyridine and 10 ml of pyridine was added 0.17 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 89%) of 5-(1-(N-ethoxyimino)ethyl)-2-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)pyridine, nD24.5 1.5701.