Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>CC(C)=O>[Br:9][CH2:10][CH2:11][CH2:12][C:13]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:14]
Reactant: O=C(Cl)CCCBr
Reactant: Nc1ccc(O)cc1
Solvent: CC(C)=O
Product: O=C(CCCBr)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A mixture of 30.9 g (0.28 mol) of p-aminophenol in about 300 mL of acetone was stirred in an ice bath and a solution of 25 g (0.14 mol) of 4-bromobutyryl chloride in about 50 mL of acetone was dripped in over 20 minutes. The reaction was stirred cold for another 1/2 hour and then at room temperature for two hours. It was then ice cooled and the mixture filtered. The precipitate was washed with about 200 mL of cold acetone. The filtrate was evaporated and the residue slurried in about 200 mL of 1N HCl, whereupon a precipitate formed. The mixture was ice cooled, filtered, and the precipitate was washed with additional 1N HCl followed by water. The precipitate was dissolved in about 100 mL of ethanol at room temperature, diluted with about 160 mL of water, ice cooled and filtered. The precipitate was washed with a mixture of water and ethanol and then with hexane to yield 18.1 g (52%) of 4-bromo-N-(4-hydroxyphenyl)butanamide, mp 142.5°-144.5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20]N)=O>>[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]1[NH:20][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: NNC(=O)c1sccc1Cl
Agent: Cl
Product: Cc1ccc(-c2n[nH]c(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellow solid (0.054 g, 17%). 1H NMR (CD3OD): 7.80 (d, J=7.8 Hz, 2H), 7.52 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 6.97 (d, J=5.10 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](=O)([O-:35])[O:15][C:16]1C(C)=C(C2C=CC(C3CCCCC3)=CC=2)C=CN=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O.C1COCC1>[CH:37]1([C:43]2[CH:44]=[CH:45][C:46]([N:1]([C:14]([O:15][CH3:16])=[O:35])[C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:47][CH:48]=2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: Cc1c(-c2ccc(C3CCCCC3)cc2)ccnc1OC(=O)[O-]
Reactant: Cc1c(-c2ccc(C3CCCCC3)cc2)ccn(C(=O)[O-])c1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(c1ccc(C2CCCCC2)cc1)[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 96 %

Procedure:
To a stirred mixture of D-threonine (0.119 g, 1.0 mmol) and NaHCO3 (0.125 g, 1.49 mmol) in H2O (3.0 mL), the crude mixture containing (4-cyclohexylphenyl)-methyl-2-pyridyl carbonate and (4-cyclohexylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.464 g, 1.49 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.32 g, 96%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 353 [M−NH4]+; (ESI) m/z: 334 [M−H]−. 1H NMR (DMSO-d6): δ 1.08 (d, J=6.4 Hz, 3H), 1.07-1.55 (m, 6H), 1.63-1.86 (m, 5H), 3.94 (dq, J=3.6, 9.0 Hz, 1H), 4.07 (dd, J=3.6, 6.4 Hz, 1H), 5.00 (s, 2H), 6.88 (d, J=9.0 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.27 (d, J=7.95 Hz, 2H), 12.54 (s, 1H).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.N1C=CC=CC=1.[CH3:22][N:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]1>C(#N)C>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[N:7]=[C:6]([NH:5][C:2]([NH:3][S:28]([C:27]2[N:23]([CH3:22])[N:24]=[CH:25][C:26]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:30])=[O:29])=[O:1])[N:11]=1
Reactant: N#C[O-]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 45 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
7.27 g of anhydrous sodium cyanate, 15.78 g of 2-amino-4,6-dimethoxypyrimidine, 8.04 g of pyridine and 40 g of dry acetonitrile were mixed together and the mixture was warmed to 45° C. under nitrogen atmosphere. To this mixture was added 28.46 g of 1-methyl-4-ethoxycarbonylpyrazole-5-sulfonylchloride over 2 hours and the reaction mixture was stirred for further 2 hours while maintaining the temperature of 45° C. After the completion of the reaction was identified by liquid chromatography, the reaction product was extracted with 200 g of dichloromethane and 40 g of 5% aqueous sulfuric acid solution. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The organic solvent was removed from the product to obtain 41.30 g (Yield 98%) of the title compound as a solid state.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[CH3:25]>C1COCC1.O>[F:14][C:15]1[C:16]([CH3:25])=[C:17]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
Potassium tert-butoxide (2.59 g, 23.1 mmol) was added to a solution of 2-aminopyridine (1.14 g, 12.1 mmol) in THF (30 mL) at 0° C. and the reaction mixture stirred at 0° C. for 20 min. 1,3-Difluoro-2-methyl-4-nitrobenzene (2 g, 11.6 mmol) was added as a solution in THF (10 mL) and the reaction mixture stirred at 0° C. for 30 min. The reaction mixture was diluted with water and the product extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a yellow solid (2 g, 70%). 1H NMR 400 MHz δ (CDCl3): 8.53 (1H, br s), 8.19 (1H, ddd, J=5.1, 1.9, 0.8 Hz), 8.02 (1H, dd, J=9.2, 5.7 Hz), 7.57 (1H, ddd, J=8.2, 7.3, 1.9 Hz), 6.94 (1H, dd, J=9.1, 8.2 Hz), 6.86 (1H, ddd, J=7.3, 5.1, 1.0 Hz), 6.69 (1H, dt, J=8.3, 0.9 Hz), 2.06 (3H, d, J=2.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[CH3:19]N(C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:19])=[O:13]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 83.1 %

Procedure:
To a solution of 2-[(2,6-dichlorophenyl) amino]benzoic acid (25 g, 89 mmol) [J. S. Kaltenbronn et al, Arzneim-Forsch/Drug Res. 33(1),4a, 621-627 (1983)] and dimethylformamide (6.8 g, 93 mmol) in dry tetrahydrofuran (500 ml) is added oxalyl chloride (17 ml, 196 mmol) dropwise with stirring under an atmosphere of dry nitrogen at 0° C. The ice bath is removed and the reaction mixture is stirred without cooling for 15 minutes. The reaction mixture is poured into methanol (1500 ml). The solvent is evaporated and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried (MgSO4) and evaporated. Recrystallization of the residue from methanol provides pure 2-[(2,6-dichlorophenyl) amino]benzoic acid, methyl ester (21.9 g, 83%); mp 100°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Na+].S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.26 mmol) of ethyl 4-(2-(tert-butoxycarbonylamino)ethyl)benzoate in 40 mL of dry THF under a nitrogen atmosphere was added dropwise, 4.7 mL (4.7 mmol) of NaHMDS (1.0 M in THF) at 0° C. After stirring for 10 min, 0.50 mL (5.3 mmol) of dimethyl sulfate was added and the reaction was warmed to 22° C. and stirred for about 16 h. The reaction was quenched by adding 25 mL of saturated NaHCO3 and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were dried (Na2SO4) and evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 10% ethyl acetate/hexane to give ethyl 4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate as a colorless oil.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:33])[NH:31][CH3:32]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:31][CH3:32])=[O:33])=[C:24]([F:23])[CH:25]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Product: CNC(=O)c1ccc(-c2cc3nc(CCc4cc(OC)cc(OC)c4)cnc3[nH]2)cc1F

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 3-fluoro-4-(methylcarbamoyl)phenylboronic acid (from Combi-Blocks). LCMS calculated for C24H24FN4O3 (M+H)+: m/z=435.2. Found 435.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20](=[O:27])[C:21](=[CH:25][CH:26]=3)[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4]1.C1(N=C=NC2CCCCC2)CCCCC1.OCCN(CCO)S(C1C=CC(C2NC(=O)C(=CC=2)C(O[N:63]2[C:67](=[O:68])[CH2:66][CH2:65][C:64]2=[O:69])=O)=CC=1)(=O)=O>CN(C)C=O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[NH:19][C:20](=[O:27])[C:21](=[CH:25][CH:26]=3)[C:22]([O:24][N:63]3[C:67](=[O:68])[CH2:66][CH2:65][C:64]3=[O:69])=[O:23])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:4]1
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)cc2)[nH]c1=O
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)cc2)[nH]c1=O

Procedure:
From 5.0 g. of 6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 130 ml. of dimethylformamide, and 2.89 g. of N,N'-dicyclohexylcarbodiimide in 10 ml. of dimethylformamide, following the procedure of (a) above, there is obtained 6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 201°-204° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCn1c2ccccc2c2ccccc21
Temperature: 95 °C
Reaction time: 0.42 h
Yield: 95 %

Procedure:
Carbazole (23.66 g, 0.16 mol), potassium hydroxide (14.45 g. 0.226 mol), water (30 g) and line (100 g) were added into a 500 ml four neck flask equipped with Dean-stark apparatus, and refluxed. Water (about 30 g) was separated, and the reaction mixture was cooled to 90 to 100° C. Hexyl bromide (33 g, 0.2 mol) was added dropwise thereto over about 25 minutes, and then reflux was carried out for 1 hour. 9-hexylcarbazole was obtained in a 95% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
2-cyanophenyl boronic acid (0.102 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.071 g in 79% yield.
Reaction SMILES: [H][H].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.[CH3:16][O:17][CH2:18][C:19](OC)=[O:20].O>C(O)C>[F:3][C:4]([F:14])([F:15])[C:5]1[CH:6]=[C:7]([CH:11]([C:19](=[O:20])[CH2:18][O:17][CH3:16])[C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Reactant: COCC(=O)OC
Solvent: O
Solvent: CCO
Product: COCC(=O)C(C#N)c1cccc(C(F)(F)F)c1
Yield: 88.5 %

Procedure:
In this example 5.6 grams of metallic sodium was added to 120 ml of anhydrous ethanol at room temperature under a nitrogen atmosphere resulting in the evolution of hydrogen. After evolution of hydrogen was completed a mixture containing 30 g of (3-trifluoromethylphenyl)-acetonitrile and 18.5 g of methyl methoxyacetate in anhydrous ethanol was added and the resulting mixture refluxed for 3 to 4 hours. The mixture was then added to 300 ml of water and extracted three times with petroleum ether. The remaining aqueous phase was acidified with aqueous 10% hydrochloric acid to about pH 1 and extracted three times with ethyl ether. The ethyl ether extracts were combined, washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated by evaporation. The concentrate was evaporated under high vacuum affording an oil which was triturated with ethyl ether. This mixture was then filtered to remove solids and the filtrate evaporated under vacuum affording 36.9 g of the title compound as a brown solid.
Reaction SMILES: [CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)=[O:2].[CH2:27]([Mg]Br)[CH3:28].Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)[CH2:27][CH3:28]
Reactant: CC[Mg]Br
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 79 %

Procedure:
A solution of 0.2 g (0.56 mmol) of (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 1 in 15 mL of tetrahydrofuran (THF) was cooled to −78° C. and reacted with ethyl magnesium bromide (0.22 mL, 1.2 eq) at −78° C. for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7 with 1N-HCl at 0° C. and concentrated in a vacuum. The residue was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The concentrate was purified using silica gel chromatography to afford (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.17 g, yield 79%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(O)c(O)c1
Yield: 53 %

Procedure:
To the solution of 3,4-dihydroxybenzoic acid (1.13 g) in benzene (50 ml) were added benzyl alcohol (3.8 ml) and p-toluenesulfonic acid (139 mg), and the mixture was heated at reflux in the presence of Molecular Sieves 4A for 2 days. Further amount of benzyl alcohol (1.5 ml) was added. The mixture was then heated at reflux overnight. After cooling by standing, saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation, the residue was dissolved in ethyl acetate and extracted with 1N sodium hydroxide. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the solvent was removed by distillation. The residue was purified by column chromatography on silica gel with an eluent system of chloroform:methanol=30:1 to give 953 mg of benzyl 3,4-dihydroxybenzoate (yield, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:18]1[CH2:17][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])([C:10]([O:12][CH3:13])=[O:11])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 82.0 mmol) and N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (19.5 g, 82.0 mmol) in DCM (400 mL) was added dropwise TFA (0.32 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give methyl 1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine-3-carboxylate (21.7 g, 79%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1.C(N(C(C)C)C(C)C)C>>[ClH:18].[ClH:18].[CH3:25][C:21]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][NH:2][CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Cc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC3(CCNC3)CC2)ccn1
Product: Cl
Temperature: 90 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
Synthesis of this amine was carried out in analogy to Amine AMN-33 employing tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1 eq.) and 4-chloro-2-methylpyridine (5 eq.) as starting materials. In step 1 the number of equivalents of N-ethyl-diisopropylamine was adjusted to 5 and the reaction mixture was stirred at 90° C. for 48 h. Step 1—yield: 87%; Step 2—yield: >99%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH2:15].[H-].[Na+].Br[CH2:19][C:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=2)[N:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=1>CN(C=O)C>[Cl:31][C:25]1[CH:24]=[C:23]2[C:28]([C:29](=[O:30])[C:20]([CH2:19][NH:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][N:22]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1
Reactant: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Reactant: COc1cc2ncnc(N)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
In a 25 mL round-bottomed flask, 6,7-dimethoxyquinazolin-4-amine (69.3 mg, 0.338 mmol) was combined with DMF (2.0 mL) to give a colorless solution. Sodium hydride (60% suspension in oil) (23.0 mg, 0.575 mmol) was added in three portions. The reaction mixture was stirred at room temperature for 15 min. After this time, the reaction mixture was a yellow solution. A DMF solution of the crude 3-bromomethyl-7-chloro-1-phenyl-1H-quinolin-4-one was next added dropwise via a syringe. The reaction mixture was stirred at 50° C. for 3 hr. After this time, TLC is quite messy, but LC/MS gives a strong peak for the desired product (approx 44%). The reaction mixture was cooled to room temperature, then was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, then concentrated to furnish a brown oil. This crude product was dissolved in methylene chloride, then this solution was concentrated over silica gel. The silica gel-supported crude product was loaded onto a 80 gram SiliCycle column. Flash chromatography (2.5% methanol-methylene chloride ramped to 6% methanol-methylene chloride) afforded 7-chloro-3-[(6,7-dimethoxy-quinazolin-4-ylamino)-methyl]-1-phenyl-1H-quinolin-4-one. MS calcd. for C26H21ClN4O3 [(M+H)+] 472.9, obsd. 473.0.