Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[O:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (500 mg, 1.77 mmol) was dissolved in 10 ml of THF, to which solution was added 1,1′-carbonyldiimidazole (576 mg, 3.55 mmol), and stirred at room temperature for 1 hour. The THF was distilled off under reduced pressure and extracted three times with water and ethyl acetate. An obtained organic layer was distilled under reduced pressure and recrystallized from hexane/ethyl acetate (1/4) conditions to obtain imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired solid compound.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>ClCCl>[CH:12]([N:15]([CH:16]([CH3:18])[CH3:17])[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(C)NC(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)Cc1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4.21 g of 1-ethyl 3-(3-dimethylamino-propyl)-carbodiimide (EDAC) and 3.08 ml of diisopropylamine were added to a solution of 4.3 g of 4-bromo-benzeneacetic acid (BrPhCH2COOH) in 15 ml of dichloromethane and the mixture was stirred for 10 minutes at ambient temperature. After evaporation under reduced pressure, the crude product was chromatographed on silica, eluting with an ethyl acetate/cyclohexane mixture (2/8) to obtain 3.7 g of product in the form of an oil with a Rf=0.21 ethyl acetate/cyclohexane 2/8).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].CN(C)C=O.Br[CH2:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:10]=1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: Fc1cccnc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ncccc3F)c3ccccc3c2=O)cc1C

Procedure:
Compound 4ll was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-Dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 123.5 mg (0.65 mmol) of 2-bromomethyl-3-fluoro-pyridine. The crude product was purified by flash chromatography to yield 96 mg of 4ll as a colorless solid: LC-MSD, m/z for C24H19FN2O2, [M+H]+=387.5, [M+2H]+=388.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.192 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 5.56 (s, 2H), 7.17 (d, 1H), 7.31 (m, 1H), 7.38 (t, 1H), 7.46 (t, 1H), 7.56-7.70 (m, 4H), 8.35-8.42 (m, 2H), 8.42-8.47 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:10]([F:11])=[CH:9][C:7]([NH2:8])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2].[Cl:13]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([NH2:8])=[C:9]([Cl:13])[C:10]=1[F:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(N)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(N)c(Cl)c1F

Procedure:
In 10 mL of toluene, 0.5 g of 4-acetyl-2-chloro-5-fluoroaniline and 0.42 g of N-chlorosuccinimide are heated at reflux for several hours until the reaction is complete. The mixture is filtered and the filter cake is washed with H2O. The filtrate of the original reaction mixture is concentrated to afford a precipitate which is collected and washed with H2O. The solids are combined to afford the crude title compound, which is used further as is.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][Si:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:22])[CH3:21].CI>C1COCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH:23]([CH3:1])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 21.8 mL (0.156 mole) of diisopropylamine in 100 mL of THF at 0° was added 0.156 mole of butyl lithium/hexane. After 30 minutes at 0°, the solution was cooled to -78°, and 25 g (0.156 mole) of ethyl trimethylsilylacetate was added. After 30 minutes at -78°, 22.7 g (10 mL, 0.16 mole) of methyl iodide was added. After warming to room temperature, the mixture was filtered, and the filtrate was evaporated. The residue was treated with hexane and filtered under argon The hexane layer of the filtrate was concentrated and distilled in a small Vigreux column to give 12 g of ethyl 2-trimethylsilylpropionate, b.p. 61.4°/15 mm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cn1nnnc1SCCCC(=O)Cl

Procedure:
2.2 g of 4-(1-methyltetrazol-5-ylthio)-butyric acid are stirred in 20 ml of absolute benzene with 1.03 ml of thionyl chloride and 4 drops of DMF for 20 minutes at the reflux temperature. The solvent is then concentrated by evaporation under reduced pressure. After dissolving and concentrating by evaporation twice more in toluene, the pure title compound is obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:31])[CH:11]=[C:12]([CH2:29][OH:30])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[OH:33].[Na+].[Br-].[K+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+].S([O-])(O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:31])[CH:11]=[C:12]([C:29]([OH:33])=[O:30])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C1c2c(OCc3ccccc3)c(=O)cc(CO)n2CCN1Cc1ccc(Cl)c(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)([O-])O
Agent: [Br-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)c2n1CCN(Cc1ccc(Cl)c(Cl)c1)C2=O
Reaction time: 0.25 h

Procedure:
9-Benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (100 mg) obtained in Example 5, Step 6 was dissolved in acetone (1.6 ml) and saturated aqueous sodium hydrogen carbonate solution (1.0 ml) and potassium bromide (3 mg), 2,2,6,6-tetramethylpiperidine 1-oxyl and free radical (3 mg) were added, and 6% aqueous sodium hypochlorite solution (3.4 ml) was added dropwise under ice-cooling. After stirring for 15 min, the ice bath was removed and the mixture was stirred at room temperature for 4 hr. Furthermore, 6% aqueous sodium hypochlorite solution (0.1 ml) was added dropwise and the mixture was stirred for 1.5 hr. The obtained reaction mixture was poured into 5% aqueous potassium hydrogen sulfate solution and stirred for 30 min. The resulting crystals were collected by filtration to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carboxylic acid (94 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[O:25])=[CH:16][N:15]=1>CN(C=O)C>[CH:24]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[N:15][CH:16]=1)=[O:25]
Reactant: O=Cc1cnc(Cl)c2ccccc12
Reactant: NC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxybenzamide (0.96 g, 7.0 mmol) in DMF (15 mL) at rt was added sodium hydride (0.28 g, 7.0 mmol). After 1 h, 1-chloro-isoquinoline-4-carbaldehyde (WO01/53274, 1.34 g, 7.0 mmol) was added and the reaction heated at 120° C. for 16 h. The solvent was removed in vacuo and the residue washed with water (100 mL), ether (50 mL) and MeCN (50 mL) to give the title compound: RT=3.13 min; m/z (ES+)=292.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>>[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(Cc3nc4cccnc4s3)CC2)n1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(6-methyl-2-pyridinyl)piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR 1H NMR (300 MHz, DMSO-d6) δ 2.68 (m, 4H) 3.32 (s, 3H) 3.53 (m, 4H) 4.04 (s, 2H) 6.54 (m, 1H) 6.61 (d, J=8.48 Hz, 1H) 7.40 (m, 1H) 7.56 (dd, J=8.31, 4.58 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H); (ESI) m/z 326 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:8][N:9]([CH3:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of thiazole-2-carbaldehyde (Aldrich, 2.0 g, 17.7 mmol) in DCM (20 mL) was treated with dimethylamine (Aldrich, 40% in water, 3 mL) and molecular sieves (˜1.0 g) followed by NaBH(OAc)3 (4.2 g, 20 mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:32]([O:34][CH3:35])=[O:33].[Cl-].[NH4+]>C1COCC1.C(C1C=CC=CC=1)C.C1COCC1>[Cl:39][C:38]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[CH2:28][N:19]1[CH:20]=[CH:21][C:17]([NH:16][C:14]([C:13]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:12]=2[F:11])=[O:15])=[N:18]1
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reaction time: 0.33 h

Procedure:
1.0 M LiHMDS (5.00 ml, 5.00 mmol) in THF/ethylbenzene was added slowly to a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.12 g, 5 mmol) in THF (50 ml) under nitrogen at ambient temperature. The solution was stirred for 20 min and a solution of methyl 3-(bromomethyl)-4-chlorobenzoate (1.32 g, 5.0 mmol, synthesised according to WO2006079857) in THF (4 ml) was added in one portion. The solution was stirred for 2 h and left overnight. The solution was treated with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried (Na2SO4), filtered and solvent evaporated in vacuo. The residue was purified on a silica cartridge (50 g) eluted with 0-100% cyclohexane/EtOAc to give the title compound (1.95 g) as a white solid after evaporation from diethyl ether; LCMS: (System 4) MH+=406/408, tRET=2.69 min.
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][C@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(OCC)(=O)C.O.O1CCCC1>[CH3:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([N:35]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]2[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:4])=[CH:33][CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: C[C@@H](OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2CCCCC2C(=O)O[C@@H](C)C(=O)N2CCCC2)cc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 120.2 %

Procedure:
To (1R)-1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (1.2 g, 3.0 mmol), NaI (0.9 g, 6.0 mmol), triethylamine (0.9 g, 9.0 mmol) and tetrahydrofuran (6 mL) were added. To the solution, p-methoxyaniline (443 mg, 3.6 mmol) and tetrahydrofuran (6 mL) were added. The mixture was stirred at 40° C. for 20 hours. To the mixture, water and ethyl acetate were added for extraction. The obtained extract was dried with anhydrous magnesium sulfate, and the solvent was removed away under reduced pressure in order to obtain 1.3 g of oil. The oil was purified with silica gel column using ethyl acetate to obtain 793 mg of white solid (2.2 mmol, yield: 73%, The diastereo ratio calculated by NMR analysis was 92:8.).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].O>C1COCC1>[NH2:1][C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:2])[CH:18]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(F)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2M Ammonia (25.6 mL, 51.2 mmol) was added to Benzyl 2,4-difluoro-5-nitro-benzoate in 200 mL THF at 0° C. and the mixture stirred for 16 h at ambient temperature. Then 100 mL water were added, the preticipate was filtered off, washed with water and dried at 60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:10]2)=[C:5]([OH:22])[CH:4]=1.C([O-])(=O)C.[Tl+].[I:28]I.[Tl]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10]2)=[C:5]([OH:22])[C:4]=1[I:28]
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(OC)cc3o2)cc1
Reactant: II
Agent: CC(=O)[O-]
Agent: [Tl+]
Agent: [Tl]
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)c3c(O)c(I)c(OC)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 6 (2.98 g, 10.0 mmol) in 300 mL CH2Cl2 was added thallium(I) acetate (3.16 g, 10.2 mmol). With magnetic stirring, a solution of iodine (2.54 g, 10.0 mmol) in 200 mL CH2Cl2 was added dropwise over 1 h. During the addition, a fine suspension of thallium salts precipitated. The solution was stirred at room temperature overnight, then filtered through a bed of celite to remove the precipitated salts. The filtrate was extracted sequentially with 500 mL each of 5% NaHCO3, 10% Na2S2O4, and saturated brine, then dried over magnesium sulfate and filtered. Evaporation in vacuo provided an orange solid. Recrystallization from 300 mL CHCl3/EtOH (1:2) afforded fine yellow needles (3.10 g, 73.1%); mp 227-228° C. (lit.13 mp 205-207° C.); 1H NMR (CDCl3) δ 3.90 (s, 3 H), 4.00 (s, 3 H), 6.54 (s, 1 H), 6.64 (s, 1 H), 7.02 (d, 2 H, J=9.0 Hz), 7.85 (d, 2 H, J=9.0 Hz), 13.84 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 181.7, 164.4, 163.5, 162.9, 161.3, 158.3, 128.2, 123.3, 114.6, 104.4, 104.3, 90.5, 90.4, 56.8, 55.5; EI-MS m/z 424 (M+, 100). Anal. calcd for C17H13IO5: C, 48.14; H, 3.09. Found: C, 48.30; H, 3.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Br)ccc1Br
Temperature: 0 °C
Reaction time: 14 h

Procedure:
1,4-Dibromobenzene (25 g) was dissolved in concentrated sulfuric acid (30 ml). Thereto was added dropwise under ice cooling a mixed solution of concentrated sulfuric acid (30 ml)/nitric acid (8.9 ml). After 14 hours at room temperature, the reaction mixture was poured into ice water, was mixed with potassium carbonate and was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of potassium bicarbonate and an aqueous saturated solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated. The residue was subjected to purification using silica gel column chromatography (hexane) to obtain 1,4-dibromo-2-nitrobenzene (13.3 g) as light yellow crystals.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:15]O>>[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:15])=[O:10]
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(N)c1
Yield: 93 %

Procedure:
Thionyl chloride (43 g, 361.34 mmol, 5.00 equiv) was added dropwise with stirring at 0° C. to a solution of 3-aminobenzoic acid (10 g, 72.92 mmol, 1.00 equiv) in methanol (100 mL) and allowed to react, with stifling, overnight under reflux. The resulting mixture was concentrated under vacuum and quenched by the addition of 50 mL of water/ice. The resulting solids were collected via vacuum filtration and dried in an oven under reduced pressure, affording 10.3 g (93%) of methyl 3-aminobenzoate as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH2:30]=O>C(O)=O>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH3:30])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1C
Temperature: 85 °C

Procedure:
A mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (250 mg) (Prepared as described in Example 32), formic acid (5 ml) and formaldehyde (37% w/v in water) (2.5 ml) was heated to 85° C. for one hour. The reaction mixture was then evaporated under vacuum, azeotroped with toluene and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residues were then purified by flash chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (98/2-94/6). The fractions containing the desired product were combined and evaporated to give a colourless gum, which was triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.15 g); 1H NMR Spectrum: (DMSO d6) 1.55-1.83 (m, 3H); 1.95-2.10 (m, 1H); 2.20-2.35 (m, 1H); 2.45 (s, 3H); 2.68-2.85 (m, 1H); 2.93-3.10 (m, 1H); 3.92 (s, 3H); 1924.15 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (m, 1H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M+H)+ 417.
Reaction SMILES: [Li][CH2:2]CCC.[O:6]([C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH2:29][CH:30]=O)([CH2:23][CH2:24]2)[CH2:21][O:20]3)[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:27]([C:22]12[CH2:25][CH2:26][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:14]=3)([CH2:24][CH2:23]1)[O:20][CH2:21]2)[CH2:28][CH2:29][CH:30]=[CH2:2]
Reactant: O=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a 0° C. mixture of methyl triphenylphosphonium bromide (236 mg, 0.66 mmol) in THF (8 mL) was added dropwise n-BuLi (0.27 mL of a 2.5 M solution in hexane, 0.66 mmol). The reaction mixture was stirred at 0° C. for 30 min, and a solution of 4-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanal (116 mg, 0.33 mmol) in THF (2 mL) was added at 0° C. The reaction mixture was warmed to rt and stirred for 2 h, then was quenched with sat′d aq. NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2; gradient from 0 to 30% EtOAc:hexanes) to afford the title compound as a colorless oil (94 mg; 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 4H), 7.16-7.05 (m, 2H), 6.98 (dd, J=8.7, 1.0 Hz, 2H), 6.83 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.79 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.03-4.93 (m, 1H), 3.79 (s, 2H), 2.06-1.93 (m, 5H), 1.70-1.52 (m, 6H), 1.48-1.22 (m, 3H), 1.21-1.03 (m, 2H).