Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29]>>[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Product: COCCOc1cc2ncnc(Oc3ccc(CC(=O)O)cc3F)c2cc1OCCOC
Yield: 41 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] below Table III in Example 8 that is concerned with the preparation of starting materials, 4-chloro-6,7-di-(2-methoxyethoxy) quinazoline was reacted with 2-(3-fluoro-4-hydroxyphenyl)acetic acid to give 2-{3-fluoro-4-[6,7-di-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}acetic acid in 41% yield; Mass Spectrum: M+H+ 447.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)=[O:27])=[N:24][CH:25]=1>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)=[O:27])=[N:24][CH:25]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)cn1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Yield: 240 %

Procedure:
In a similar fashion (Route 20, GP I; except using DMF instead of DMSO as solvent), 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.20 mmol) and 5-chloro-N-(cyclopropylmethyl)pyridine-2-carboxamide (84 mg, 0.40 mmol) gave the title compound as colourless oil (25 mg, 0.48 mmol, 0.047 mmol, 23%) after purification by preparative HPLC.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=C(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:31][C@H:32]2[O:34][CH2:33]2)=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Yield: 83 %

Procedure:
To an 8 ml dimethylformamide suspension of 60 mg of sodium hydride was added, under ice cooling, 300 mg of 4-(tert-butoxycarbonylamino)phenol. The resultant mixture was stirred at room temperature for 1 hour. Under ice cooling, 372 mg of (S)-glycidyl 3-nitrobenzenesulfonate was gradually added, then the resultant mixture was stirred at room temperature for 2 hours. The reaction was quenched with a 5 ml of saturated aqueous ammonium chloride solution, then the product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column.chromatography (hexane:ethyl acetate=3:1) to give the above-referenced compound (9) in an amount of 315 mg (yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Br.C(O)(=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:22]5[CH2:15][CH2:14][NH:13][CH2:12][CH2:8]5)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=NCCc4ccc(N5CCNCC5)cc43)CCC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-ylamine (400 mg, 0.75 mmol) was dissolved in HBr/acetic acid (10 ml, 33%) and stirred for 3 h at 70° C. Another 10 ml of the HBr/acetic acid solution was added and the mixture was stirred for another 8 h at 70° C. The solvent was diluted with 1 N sodium hydroxid solution and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulphate. The residue was purified by flash column chromatography on silica with dichloromethane/methanol 98:2→95:5. The product was obtained as a brown oil (100 mg, 0.26 mmol, 35%) that was sufficiently pure for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:7]=1.[C:16](O)(=O)[C@H:17]([CH3:19])[OH:18].N>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][C:11]([F:12])([F:14])[F:13])[C:16]([C@@H:17]([OH:18])[CH3:19])=[N:15][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)ccc1NCCC(F)(F)F
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Agent: N
Product: C[C@H](O)c1nc2cc(Cl)ccc2n1CCC(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
A mixture of 4-chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (478 mg, 2.0 mmol) and L-lactic acid (180 mg, 2.0 mmol) in 6 N aqueous HCl (4 mL) was heated with stirring at 100° C. in a sealed tube for 18 hours. After the reaction was complete, the mixture was poured into aqueous ammonia (10 mL) and then extracted by EtOAc (25 mL×3). The organic layers were combined and then concentrated in vacuo. The residue was purified by flash column chromatography to afford (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol as yellow oil (320 mg, yield 63.0%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Br.OO.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Yield: 63.6 %

Procedure:
2.6 g (0.0095 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 10 ml of chloroform at room temperature and 1.07 ml of a 48% strength aqueous solution of HBr are added. 4.24 ml (0.041 mol) of a 30% strength solution of H2O2 are slowly added dropwise at about 45° C. with vigorous stirring and the mixture is stirred for a further 24 hours. The reaction mixture is added to 200 ml of water, the phases are separated, the aqueous phase is extracted several times with chloroform and the combined organic phases are washed with 5% strength sodium bicarbonate solution and with water. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Distillation of the crude product in a kugelrohr (25 torr, 100°-200° C. bath temperature) yields 1.65 g (60% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine, which, according to GC, is 98.3% pure.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]3[CH2:22][NH:21]3)=[CH:19][C:14]=2[O:13][CH2:12]1>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[C:2]([N:21]1[CH2:22][CH:20]1[C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)=[CH:1][C:7]([O:9][CH3:10])=[O:8]
Reactant: c1cc2c(cc1C1CN1)OCO2
Reactant: COC(=O)C#CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C=C(C(=O)OC)N1CC1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.1 %

Procedure:
Dimethyl acetylene dicarboxylate (75 μL, 0.61 mmol, 1.0 equiv) was added via syringe to a stirred solution of aziridine 15 (100 mg, 0.61 mmol, 1.0 equiv) in tetrahydrofuran (1.0 mL) at 25° C. The resulting bright yellow solution was stirred at 25° C. for 2 d. The reaction mixture was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (1% triethylamine and 24% ethyl acetate in benzene) to afford 26 (110 mg, 57% yield, 3:1 E:Z mixture) as a yellow film. E-26: Rf=0.31 (1% triethylamine and 24% ethyl acetate in benzene); 1H NMR (500 MHz, C6D6) δ 6.64 (m, 1H, ArH), 6.52-6.54 (m, 2H, ArH), 5.30 (s, 1H, vinyl H), 5.22-5.25 (m, 2H, OCH2O), 3.52 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 2.84 (dd, 1H, J=6, 3.5 Hz, ArCHN), 1.84 (d, 1H, J=6 Hz, CH2N), 1.71 (d, 1H, J=3.5 Hz, CH2N).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CNCCCl
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CCNC)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:25]1[CH:26]=[C:22]([I:21])[N:23]=[CH:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trityl chloride (3.8 g, 13.6 mmol) was added to a cooled (0° C.) solution of 4-iodoimidazole (2.25 g, 11.6 mmol) and triethylamine (2 ml, 14.3 mmol) in methylene chloride (25 ml). After stirring for 30 min the reaction mixture was warmed to room temperature and stirred ther for 2 h. The reaction mixture was washed well with water and saturated NaHCO3 then dried (Na2SO4). Concentration gave the product as a white solid. 1H NMR (CDCl3) d 6.92 (s, 1 H), 7.08-7.20 (m, 6 H), 7.28-7.40 (m, 10 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O.CN1C(=O)CCC1>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[CH:15]=[C:14]([NH:35][C:34]4[CH:36]=[CH:37][C:31]([CH3:30])=[CH:32][CH:33]=4)[N:13]=[CH:12][C:11]=3[CH:10]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Yield: 33.1 %

Procedure:
tert-Butyl-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-6-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (17) (44 mg 0.105 mmole) and 4-methylaniline (13 mg 0.12 mmole) were placed in a microwave vial and potassium phosphate (53 mg 0.25 mmole), XantPhos (10.5 mg 0.022 mmol) and Pd2(dba)3 (10.1 mg 0.011 mmol) were added. NMP containing water (3%) (1.2 mL) was then added and the vial sealed under argon. It was microwaved at 80° C. for 1.5 hrs. The reaction was added to water (10 mL) and extracted with ethyl acetate (3×6 mL). The combined organics were washed with water (3×5 mL) and with brine, dried and evaporated. The residue was applied to three 1 mm 20×20 cm silica prep tlc plates, which were twice eluted with 1:2 ethyl acetate:cyclohexane. The product band was recovered using acetone to give the product (17 mg). 1H-NMR (CDCl3, 500 MHz): δ 1.51 (s, 9H), 1.70 (s, 9H), 2.36 (s, 3H), 6.58 (m, 1H), 6.68 (br s, 1H, NH), 7.18 (d, J=8.20 Hz, 1H), 7.25 (d, J=8.51 Hz, 2H), 7.54 (m, 1H), 7.83 (d, J=0.63 Hz, 1H), 8.23 (s, 1H), 8.44 (m, 1H). ESI-HRMS Found 490.2452, calculated for C27H32N5O4 [M+H]+: 490.2449.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:13][CH2:14][CH:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH2:16]1)[CH:10]1[O:12][CH2:11]1>C(O)C>[CH2:1]([NH:8][CH2:11][CH:10]([OH:12])[CH2:9][O:13][CH2:14][CH:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(COCC2CO2)O1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC1(C)OCC(COCC(O)CNCc2ccccc2)O1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 500-ml three-necked flask equipped with a dropping funnel, thermometer and reflux condenser was charged with 174 ml (1.59 mol) of benzylamine and48.0 ml of ethanol. While heating and stirring the mixture at 80° C.in a nitrogen atmosphere, 20.3 g (0.11 mol) of 2,3-(dimethylmethylenedioxy)propyl glycidyl ether were added dropwise over2 hours. After completion of the addition, the heating and stirring were continued for an additional 1 hour under the same conditions. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by flash chromatography on silica gel, thereby obtaining 20.4 g (yield: 64%) of the title compound (3a) as a pale yellow oil.
Reaction SMILES: [Br-:1].[Br-].[CH2:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH:4]=[CH2:5].[O-]CC.[Na+]>C(O)C>[O:12]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:3][CH:4]1[CH2:5][Br:1]
Reactant: C=CCc1ccccc1O
Reactant: [Br-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: BrCC1Cc2ccccc2O1
Yield: 79.7 %

Procedure:
A solution of bromine (90 g) in carbon disulphide (100 ml) was added dropwise to a well stirred solution of O-acetyl-2-allylphenol (100 g) in carbon disulphide (300 ml) at -10° C. over 1 hour. The solution was evaporated to dryness in vacuo, to afford O-acetyl-2-allylphenol dibromide which was immediately dissolved in dry ethanol (300 ml) containing 10 ml of a saturated ethanolic-hydrogen chloride solution. The solution was heated under gentle reflux for 2 hours, and then evaporated to dryness in vacuo. The residue was triturated with n-pentane, and the solid 2-allylphenol dibromide (135 g) was collected and washed twice with portions of n-pentane. The product is pure enough for further reaction. 2-Allylphenol dibromide (135 g) in dry ethanol (300 ml) was treated with a solution of sodium ethoxide (38 g) in ethanol (100 ml) with cooling and stirring, keeping the temperature of the reaction between 30° and 35° C. After addition, the reaction was stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue was partioned between n-pentane and water. The n-pentane fraction was washed with 2% sodium hydroxide solution, water, and dried (Na2SO4). Evaporation to dryness in vacuo afforded crude (2,3-dihydro-2-benzofuranyl)-methyl bromide (90 g), which distilled at 110°-118° C./0.5 mm to afford product (78 g) of slightly higher purity.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:38]=[CH:39][CH:40]=1)[CH:26]=[CH:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=1>CCCCCC.C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:38]=[CH:39][CH:40]=1)[CH:26]=[CH:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[O:33])=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of diisobutyl aluminum hydride (0.01 mol) in hexane is added dropwise to a solution of methyl 4-(3-(2-quinolinylmethyloxy)styryl)benzoate (0.01 mol) in 100 ml of THF at 0° C. The reaction mixture is stirred at 0° C. for 40 minutes and then quenched with methanol and Rochelle salt. Extraction with ethyl acetate and purified by column chromatrography gives 4-(3-(2-quinolinylmethoxy)styryl)-benzaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[ClH:21]>CN1CCCC1=O.O>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:21])[C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: Cl
Reactant: O=C(O)c1ccc2c(c1)CCc1c(Br)cccc1C2=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc2c(c1)CCc1c(Cl)cccc1C2=O

Procedure:
0.81 G. of 2-carboxy-9-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene and 0.32 g. of cuprous chloride were refluxed for 8 hours in 10 ml of N-methylpyrrolidinone. The solution was cooled and added to a solution of 4.4 g. of ferric chloride hexahydrate in 6 ml of water and 3 ml of concentrated hydrochloric acid. The mixture was heated to 90° for 1 hour, then was poured into water and filtered. The residue was recrystallized from aqueous dimethylformamide to afford 2-carboxy-9-chloro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene, m.p. 258.5°-260°.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12]>C1COCC1>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]([OH:8])[CH3:1])[C:5]=1[OH:12]
Reactant: [Li]C
Reactant: O=Cc1cccc(F)c1O
Solvent: C1CCOC1
Product: CC(O)c1cccc(F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Methyl lithium (25.5 mL, 35.7 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 3-fluorosalicylaldehyde (2 g, 14.3 mmol) dissolved in THF (50 mL). The reaction mixture was stirred for 3 hours and then warmed up to room temperature. After 3 hours the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 20% EtOAc in hexanes) to give the title compound as a clear oil (2.2 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.58 (d, J=6.6 Hz, 3H), 2.68 (s, 1H), 5.13 (m, 1H), 6.78 (td, J=7.8, 4.8 Hz, 1H), 6.87 (d, J=7.6, 1H), 6.99 (m, 1H), 7.33 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.[CH3:11][O:12][C:13](=[O:30])[C:14]1[C:15](=[C:20]([NH:24]CCCCC)[CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17].C([O-])(O)=O.[Na+]>>[CH3:11][O:12][C:13](=[O:30])[C:14]1[C:15](=[C:20]([NH:24][CH2:1][C:3]2[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cccc(NCc2ccc(C(=O)O)o2)c1C(=O)OC

Procedure:
5-Formyl-furan-2-carboxylic acid (1 g, 7.14 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester except the combined aqueous NaHCO3 extracts were washed with methylene chloride (1×70 ml) and the pH adjusted to 2–3 by dropwise addition of concentrated HCl. The mixture was then extracted with ethyl acetate (3×75 ml). The combined ethyl acetate extracts were washed with brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give 0.90 g product as an off-white solid: 1H NMR (CDCl3) δ 7.42–7.36 (m, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.03–6.97 (m, 2H), 6.90 (dd, J=1.0 Hz and 7.3 Hz, 1H), 6.48 (d, J=3.5 Hz, 1H), 4.60 (d, J=5.2 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: COc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: COc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-methoxybromobenzene. MS (ESI): mass calcd. for C17H14FN3O, 295.11; m/z found, 296.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.85 (m, 1H), 7.45-7.29 (m, 4H), 7.14-7.00 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O.O.O.O.O.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:2]
Reactant: O=CO
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
To 671 ml of formic acid, 226 ml of acetic acid and 226 ml of toluene was added 1437 ml of acetic anhydride. After 910 g of L-aspartic acid and 12.8 g of magnesium acetate tetrahydrate were added to the thus prepared solution, the mixture was kept at a temperature of 45° C. and reacted for 3.5 hours with stirring. To the resulting slurry was added 3970 ml of toluene. After ice-cooling for an hour with stirring, the mixture was filtered, while performing suction, to give 917 g of crystalline N-formyl-L-aspartic anhydride.
Reaction SMILES: [BH4-].[Na+].[I-].[CH2:4]([N+:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:18][CH3:19])[CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5]>CO>[CH2:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:18][CH3:19])[CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)[CH3:5]
Reactant: CC[N+]1=Cc2c(cc(OC)cc2OC)CC1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCc2cc(OC)cc(OC)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
Sodium borohydride (260 mg, 6.86 mmol) was added to a cooled (0° C.) solution of 2-ethyl-6,8-dimethoxy-3,4-dihydroisoquinolinium iodide (1.19 g, 3.43 mmol) in methanol (15 mL). On complete addition the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was evaporated in vacuo and the resultant residue was partitioned between diethyl ether and water. The organic phase was dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (741 mg, 98%). 1H NMR (CDCl3, 300 MHz): 6.27 (d, J=2.3 Hz, 1H), 6.24 (d, J=2.3 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.51-3.47 (m, 2H), 2.89-2.83 (m, 2H), 2.71-2.64 (m, 2H), 2.60 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=1.62 min, M+H+=222.