Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][S:31]([CH3:33])=[O:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[N:21][OH:22])[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH:34](=O)[CH3:35].C([OH:39])C>O>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][S:31]([CH3:33])(=[O:39])=[O:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:34]([CH3:35])[O:22][N:21]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CCO
Reactant: CS(=O)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=NO)c2cc1C1CC1)S(C)(=O)=O
Reactant: CC=O
Solvent: O
Product: CC1NC(c2c(-c3ccc(F)cc3)oc3cc(N(CCS(C)(=O)=O)S(C)(=O)=O)c(C4CC4)cc23)=NO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of Example 12C (sulfone/sulfoxide mixture, 0.105 g) in ethanol (2 mL) and water (2 mL) was treated with acetaldehyde (1.92 mL, 34 mmol), and the reaction mixture was stirred at room temperature for 3 days. Additional acetaldehyde (1 mL) was added and stirring was continued at room temperature for 3 more days. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (3×25 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel flash chromatography eluting with a gradient of 1:10 ethyl acetate/hexane to 1:2 ethyl acetate/hexane, then 2:1 ethyl acetate/hexane containing 2% methanol, followed by 2% methanol/dichloromethane, afforded the title compound (0.0115 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.58 (dd, J=5.80, 2.90 Hz, 1H), 0.89 (dd, J=9.61, 4.27 Hz, 1H), 0.98-1.14 (m, 2H), 1.38 (t, J=5.42 Hz, 3H), 2.28-2.35 (m, 1H), 3.03 (s, 3H), 3.23 (s, 3H), 3.99-4.20 (m, 2H), 5.73-5.81 (m, 1H), 7.27-7.33 (m, 2H), 7.38-7.47 (m, 2H), 7.92 (s, 1H), 8.02 (dd, J=8.24, 5.49 Hz, 2H); MS (ESI+) m/z 536 (M+H)+; (ESI−) m/z 534 (M−H)−.
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[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[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[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 70 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (118 mg, 0.21 mmol, 69%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.50-7.41 (m, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.23 (m, 2H), 6.87 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 6H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]([O:12]C)=[O:11])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.O.CO>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[N:7]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (120 mg, 0.48 mmol) was dissolved in THF (1 mL). To this solution was added lithium hydroxide monohydrate (70 mg) in water (1 mL) and MeOH (0.1 mL). The resulting solution was stirred at room temperature overnight. Upon completion of the reaction, the product was purified by reverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (110 mg, 99%) as an oil. MS (m/z): 235.3 [M+H]+; HPLC retention time 3.03 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.CNC.C(O)C.Br[CH2:20][C:21]([NH:23][C:24]1[S:25][C:26]([C:34]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])=[C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:22]>C1COCC1.C(OCC)C>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]1[N:28]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][N:10]2[CH2:11][CH2:12][N:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[S:25][C:26]=1[C:34]([CH:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)=[O:35]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(C2CCOCC2)CC1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Yield: 54 %

Procedure:
In a manner similar to that in Example 533, by using 1-(tetrahydropyran-4-yl)piperazine (154 mg, 9.00 mmol) in place of the solution of dimethylamine in THF, followed by reslurrying with a mixed solvent of ethanol and diethyl ether, the entitled Compound 571 (79.8 mg, 54%) was obtained from Compound 531; (120 mg, 0.300 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.CO.[OH-].[K+]>O>[F:1][C:2]([F:15])([F:16])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(NCC(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NCC(F)(F)F)cc1
Yield: 84.7 %

Procedure:
step d—To a solution of 124 (0.349 g, 1.497 mmol), MeOH (3 mL), H2O (1 mL) was added KOH (0.420 g, 7.48 mmol) and the resulting solution was heated at reflux for 1 h. The MeOH was evaporated and the residue diluted with H2O (15 mL) and acidified to pH of 2 with 6N HCl. The white precipitate was filtered, washed with H2O and air dried to afford 0.278 g (85%) of 126.
Reaction SMILES: [NH2:1][OH:2].CC[O-].[Na+].[Cl:7][C:8]1[C:20]([CH3:21])=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:22]([OH:24])=O)[C:17]=3[NH:18]2)=[CH:10][CH:9]=1>C(O)C>[Cl:7][C:8]1[C:20]([CH3:21])=[C:19]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:22]([NH:1][OH:2])=[O:24])[C:17]=3[NH:18]2)=[CH:10][CH:9]=1
Reactant: NO
Reactant: Cc1c(Cl)ccc2c1[nH]c1c(C(=O)O)cccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cl)ccc2c1[nH]c1c(C(=O)NO)cccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
Under cooling, a solution of 200 mg. of hydroxylamine in 15 ml. of ethanol is combined with 10 ml. of a sodium ethylate solution containing 1% sodium, as well as, in incremental portions, with 1.0 g. of the ethyl ester of 7-chloro-8-methylcarbazole-1-carboxylic acid. The mixture is stirred for one hour at 0° C. and for another 12 hours at room temperature and is then concentrated under vacuum. The residue is taken up in water, acidified to pH 1 with hydrochloric acid, extracted with ethyl acetate, and the extract is washed and concentrated. The residue is recrystallized from ethanol - water, thus obtaining in a 20% yield, 7-chloro-8-methylcarbazole-1-carbohydroxamic acid, m.p. 200° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2].S(Cl)([Cl:32])=O>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:32])(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-Acetoxy-5-sulfophenylazo)acetoacetanilide (20 g) was added to thionyl chloride (100 ml). After the addition of dimethylformamide (4 ml), solution was complete, then followed by precipitation of the product. It was filtered off and dried in the vacuum oven at 40° C. Yield: 16.7 g, m.p. 225 to 226° C.
Reaction SMILES: [NH3:1].[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:16][CH2:17][O:18][CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]=[C:14]=[S:15]>C(O)C>[CH3:19][O:18][CH2:17][CH2:16][N:6]([CH2:5][CH2:4][O:3][CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:1])=[S:15]
Reactant: N
Reactant: COCCN(CCOC)c1ccccc1N=C=S
Solvent: CCO
Product: COCCN(CCOC)c1ccccc1NC(N)=S
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 10° C. The mixture was stirred at 0° C. for 8 hours and then stirred without cooling for 16 hours. The solvent was then removed by evaporation and the residue purified by chromatography on a silica column eluted with a 1:4 mixture of ethyl acetate and hexane and then a 1:1 mixture of ethyl acetate and hexane to give 1-{2-[bis(2-methoxyethyl)amino]phenyl}thiourea (m.p. 118°-119° C.).
Reaction SMILES: C([Cl:4])(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:15]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:14][C:13]=1[C:25]#[N:26]>C(O)C>[ClH:4].[CH2:21]([C:15]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[C:25]([NH2:26])[C:13]=2[N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)Cl
Reactant: CCCCc1nc(C#N)c(-c2ccccc2N)n1CC(C)C
Solvent: CCO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Product: Cl
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Under a nitrogen atmosphere, a solution of acetyl chloride (412 mg, 5.25 mmol) in anhydrous ethanol (17.5 mL) was stirred for 15 minutes. 5-(2-Aminophenyl)-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile (1.04 g, 3.50 mmol) was added, and the reaction was heated at reflux under nitrogen for 21.5 hours, allowed to cool to room temperature overnight, and further cooled on an ice bath. A solid was present and was isolated by filtration, washed with diethyl ether, and air-dried to provide 1.04 g (89%) of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]([CH3:41])[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]([CH3:41])[CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: CC1CC(N)c2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CC(C)c3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-3-methyl-indane
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH:17]([N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH3:22])([CH3:19])[CH3:18].C[O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CC(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:20]2[CH2:21][CH2:22][CH2:25][C@H:23]2[CH2:24][C:28]([OH:34])=[O:27])[N:3]=1.[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:17]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:28]([OH:27])=[O:34])([CH3:19])[CH3:18])[N:3]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1cc2nc(C(C)(C)N3CCC[C@H]3C(=O)O)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCC[C@H]3CC(=O)O)nc(N)c2cc1OC

Procedure:
A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (92.8 mg, 0.387 mmol), diisopropylethyl amine (50 mg, 0.387), and (S)-proline methyl ester (50.0 mg, 0.387 mol) in 2-propanol (1 mL) was heated at 90° C. (24 h). The solvent was removed in vacuo and the residue subjected to preparative HPLC Water Delta Prep 4000 (C18, isocratic 50% CH3CN [0.1% TFA]-50% H2O [0.1% TFA]) to afford (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-2-carboxymethyl pyrrolidine and (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-2-carboxyisopropyl pyrrolidine. For (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-2-carboxymethyl pyrrolidine:
Reaction SMILES: [Cu]C#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1.O>C1COCC1>[CH3:5][C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][N:12]=1)([CH3:7])[CH3:6]
Reactant: Brc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(OCc2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
To a stirred solution of copper (I) cyanide (18.31 g) in dry THF (400 ml) was added, at −78 C., tertbutylmagnesium chloride (1M in THF, 409 ml). The reaction mixture was stirred at this temperature for 15 min before slowly adding a solution of 2-bromo-5-[(phenylmethyl)oxy]pyridine (13.5 g) in THF. This was stirred for 2 h at −78 C. before warming to 25-30 C. and stirring for a further 20 h. The reaction mixture was poured into water and extracted with ethyl acetate. This was concentrated in vacuo and purified through silica, eluting with 0-2% ethyl acetate in hexane. Appropriate fractions were combined and concentrated in vacuo to yield the title compound, 6.3 g
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15]>O1CCCC1>[C:4]([CH:5]([CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)c1ccccc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1Oc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A mixture of sodium hydride (60% oil dispersion, 0.157 g, 3.92 mmol) and tetrahydrofuran (6.1 mL) was cooled to 0° C., treated dropwise with ethyl 3-oxobutanoate (0.413 mL, 3.27 mmol) and stirred at 0° C. for 30 minutes. A solution of 2-bromo-1-(2-phenoxyphenyl)ethanone (1.05 g, 3.6 mmol) in tetrahydrofuran (2 mL) was added dropwise and stirring was continued for 5.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution and washed with saturated aqueous sodium chloride. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-20% ethyl acetate in hexanes) to give 1.1 g (100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.I[CH3:11]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(O)c(Br)c1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(C)cc1Br
Temperature: 55 °C
Reaction time: 3 h

Procedure:
3-Bromo-2-hydroxy-5-methylpyridine (5.012 g, 26.7 mmol), silver carbonate (9.58 g, 34.7 mmol), and iodomethane (5 mL, 80.0 mmol) were combined in CHCl3 (75 mL) and stirred at 55° C. for 3 hours. The mixture was cooled and filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-bromo-2-methoxy-5-methyl-pyridine.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Nc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a solution of 4-hydroxydiphenylamine (200 mg, 1.08 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (80 mg, 2 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (387 mg, 1.09 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (289 mg, 73%).
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
Diethylamine (55 mmol, 5.69 mL) and t-Butanol (55 mmol, 5.26 mL) are added to a stirred solution of Zinc Chloride (74 mmol, 10 g) in anhydrous toluene (100 mL). After two hours of stirring at room temperature, Zinc Chloride is completely dissolved. 1-(4-Fluorophenyl)-ethanone (40 mmol, 4.90 mL) is added, followed by the addition of bromoacetophenone (37 mmol, 7.4 g). The reaction is allowed to stir at room temperature for 3 days. A 5% aqueous solution of sulfuric acid (75 mL) is added and the organic phase is separated from the aqueous phase. The aqueous phase is extracted with Ethyl Acetate (50 mL) and the two organic phases are combined. The organic phase is dried with Sodium Sulfate, filtered and concentrated to give 1-(4-fluoro-phenyl)-4-phenyl-butane-1,4-dione (5.2 g) confirmed by LCMS, as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(c1ccc(Br)cc1F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluoro-benzoic acid and pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[C:30]([CH:39]=O)[CH:29]=1)[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[C:30]([CH2:39][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)[CH:29]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1-c1ccccc1
Yield: 95 %

Procedure:
Compound 96 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH2:10])=[N:6][C:7]=1[O:8][CH3:9].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)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>[CH3:9][O:8][C:7]1[N:6]=[C:5]([NH2:10])[C:4]([N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[CH3:14]
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1nc(N)c([N+](=O)[O-])cc1I
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(N)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 5-iodo-6-methoxy-3-nitro-2-pyridineamine (1.03 g, 3.49 mmol), trimethylboroxin (456 mg, 3.63 mmol), cesium carbonate (3.56 g, 10.9 mmol), tetrakis(triphenylphosphine)palladium(0) (412 mg, 0.357 mmol) and N,N-dimethylformamide (10 ml) was stirred at 90° C. under nitrogen atmosphere. After 2 hours and 30 minutes, trimethylboroxin (500 μl, 3.58 mmol) was added, and the reaction mixture was further stirred under the same conditions for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and water. Insoluble substance was filtered off, the organic layer of the filtrate was washed 3 times with a saturation ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (silica gel: 40 g, eluting solvent: heptane, heptane/ethyl acetate=90/10) to yield the title compound (350 mg, 1.91 mmol, 54.8%) as a yellow solid.