Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[CH:25]1([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C(#CC1CCCCC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCC2CCCCC2)cc1O
Yield: 11 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclohexylethynyl)pyridazine (Intermediate 17) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions. The solid obtained was recrystallised from methyl tert-butyl ether and ethyl acetate to afford 6-(2-cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one as a cream solid (11% yield).
Reaction SMILES: C([O:8][C:9](=[O:59])[CH:10]([NH:23][C:24](=[O:58])[CH2:25][CH2:26][Si:27]([CH2:30][CH2:31][C:32]1[C:44]2[CH2:43][N:42]3[C:37](=[CH:38][C:39]4[C:49]([CH2:51][CH3:52])([OH:50])[C:48](=[O:53])[O:47][CH2:46][C:40]=4[C:41]3=[O:45])[C:36]=2[N:35]=[C:34]2[CH:54]=[CH:55][CH:56]=[CH:57][C:33]=12)([CH3:29])[CH3:28])[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1>C(COC)OC.C(O)C.[Pd]>[CH2:51]([C:49]1([OH:50])[C:39]2[CH:38]=[C:37]3[N:42]([C:41](=[O:45])[C:40]=2[CH2:46][O:47][C:48]1=[O:53])[CH2:43][C:44]1[C:32]([CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][C:24]([NH:23][CH:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:59])=[O:8])=[O:58])=[C:33]2[CH:57]=[CH:56][CH:55]=[CH:54][C:34]2=[N:35][C:36]3=1)[CH3:52]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)NC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: COCCOC
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC(=O)NC(CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound 49 (25 mg) in dimethoxyethane (1 ml) and ethanol (1 ml) was added 10% palladium on charcoal (10 mg). The mixture was stirred under hydrogen balloon pressure for 16 hours at room temperature. The resulted mixture was filtrated through Celite and the solvents were removed by rotary evaporation. The residue was purified by prepared TLC plate, eluting with methanol/dichloromethane (50/50), to afford Compound 50 as a yellow solid.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2cc(OCCCCl)ccc12
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2cc(OCCCN3CCOCC3)ccc12
Yield: 55 %

Procedure:
7-(3-Morpholin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 55% yield using the method described in example 87A, starting from 7-(3-Chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 143B) and morpholine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1.[Br:29][CH2:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:32][CH2:31][CH2:30][Br:29])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:14]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (10.10 g, 2.70 mmol) and 1,3-dibromopropane (2.18 g, 10.8 mmol) in acetone (75 mL) was added potassium carbonate (1.87 g, 13.5 mmol). The reaction mixture was heated to reflux for 3 hours and allowed to cool back down to room temperature. The mixture was partitioned between ethyl acetate and brine, and the layers were separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, washed with one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 8/92) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (1.11 g, 78%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 12.58 (s, 1H), 8.53 (d, 1H), 8.51 (s, 2H), 8.08 (s, 1H), 8.04 (d, 1H), 6.70 (dd, 1H), 4.24 (t, 2H), 3.96 (s, 3H), 3.62 (t, 2H), 2.37 (m, 2H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(OC)ccc2Oc2ccc(Cl)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(O)ccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a stirred suspension of 8-chloro-2-methoxydibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.00 g), prepared in the manner described above in Example 3, in methylene chloride (5 mL) at approximately 5° C. (ice water bath) under nitrogen was added dropwise boron tribromide (1.0 M in 6.7 mL of methylene chloride). The ice bath was removed and the reaction stirred at room temperature for 3 hours. The reaction was carefully quenched by the addition of 1 N HCl, and poured into ethyl acetate (100 mL). The solution was washed once with 1 N HCl (100 mL). The 100 mL of 1 N HCl wash was extracted with ethyl acetate (100 mL). The ethyl acetate solutions were combined and washed with 1 N HCl, Water and brine. Evaporation of the solution in vacuo resulted in a semi-solid residue. This was treated With 10 mL of ethanol (3A) and heated on a steam bath for several minutes to break up the solid. Upon cooling, the solidified product Was collected by filtration. Recrystallization from ethanol (3A) yielded 0.44 g (45%) pure product as a white solid. Melting Point: 200°-202° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>O1CCCC1>[F:11][C:12]([F:20])([F:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCCCBr
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)CCCCCc1cccs1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a solution of thiophene (4.2 g) in dry tetrahydrofuran (25 ml) at -15° C. under nitrogen, was added n-butyllithium (20 ml, 2.5M) dropwise and the solution stirred at -15° C. for 2 hours. The solution was then cooled to -78° C. and 6,6,6-trifluorohexylbromide (10.95 g) in dry tetrahydrofuran (20 ml) was added and solution stirred at -78° C. for 1 hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice, extracted with ether (2×75 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was distilled under reduced pressure to give a colourless oil, b.p. 66° C./20 mm.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCn2cncn2)c1OCCC(C)c1ccc(F)cc1
Yield: 72 %

Procedure:
Example 8a (85 mg, 0.17 mmol) was reacted with 1,2,4-triazole (2.5 eq.) and CsCO3 (1.94 eq.) as described under General Procedure L and the crude mixture was purified by flash chromatography (silica gel, Et2O) to afford the title compound as a pale yellow oil (58 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.95 (s, 1H), 7.17 (m, 2H), 7.01-6.95 (m, 2H), 4.39-4.36 (m, 4H), 3.83-3.78 (m, 5H), 2.91 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.94-1.89 (m, 2H), 1.27 (d, J=6.9 Hz, 3H). MS (ES+) m/z 476.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([O-])(O)=O.[Na+]>ClCCl>[C:9]([O:8][C:7]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)(N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A solution of 2-amino-2-methyl-1-propanol (921.2 mg, 10.33 mmol) in dichloromethane (5 ml) was cooled to 0° C. To the mixture was added a solution of di-t-butyl carbonate (Boc2O)(2.1045 g, 9.64 mmol) in dichloromethane (5 ml) dropwise for 30 minutes. After addition, the mixture was warmed to room temperature and stirred for 5 hours. The mixture was added to sat. NaHCO3 aqueous solution and extracted three times with ethyl acetate. The extract was dried over MgSO4 and concentrated to give the crude title compound (1.7204 g: 88%).
Reaction SMILES: CI.O1CCC[CH2:4]1.[CH3:8][CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1.[K]>O>[CH3:8][C:9]1([CH3:4])[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)OCC(C)C2=O
Agent: [K]
Solvent: CI
Solvent: O
Product: COc1ccc2c(c1)OCC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, 0.4 ml of methyl iodide was added to 10 ml solution tetrahydrofuran with 240 mg of 3-methyl-7-methoxychroman-4-one, 100 mg of potassium hydrogenate was added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=5/1) to obtain 145 mg of the above compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:15])=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[C:23](NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Br:15])[N:7]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:6][C@H:5]([CH3:22])[N:4]2[C:1](=[O:3])[CH3:2])(=[O:25])[CH3:24]
Reactant: CC(=O)N1c2cc(N)c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Product: CC(=O)Nc1cc2c(cc1Br)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-6-acetamido-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from isopropyl (S)-4-acetyl-6-amino-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[NH2:19]>>[CH3:24][O:23][C:21]1[CH:20]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([NH:2][CH3:1])[CH:4]=2)[CH:17]=[C:16]([O:15][CH3:14])[CH:22]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CNc1cc(C(=O)O)ccc1OC
Product: CNc1cc(C(=O)Nc2cc(OC)cc(OC)c2)ccc1OC
Yield: 50 %

Procedure:
Using 3-methylamino-4-methoxybenzoic acid and 3,5-dimethoxyaniline as materials, compound 40 is synthesized following a similar method as in Example 28. Yield: 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[CH:20]=O.C(O)(=O)C.Cl>CO>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28])[CH2:20][NH:15][C:13]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (200 mg, 819 μmol) in MeOH (3.5 ml) was added 3-chloro-4-(trifluoromethyl)benzaldehyde (94.0 mg, 451 μmol) followed by acetic acid (36.7 mg, 35.0 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (52.6 mg, 492 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml). The resulting suspension was filtered to collect the solid. Purification by flash chromatography (silica gel, 24 g, 2% to 4% MeOH in DCM) afforded a white solid as desired product (121.4 mg, 68% yield). MS +m/z: 436 (M+H)+
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:16])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Yield: 92.3 %

Procedure:
A mixture of the product from step 1 (3.9 g, 14.6 mmol) and 10% Pd—C (0.5 g, 50% wet) in ethyl acetate was hydrogenated under 50 psi hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was evaporated, providing 3.2 g of 4-(tert-butyldimethylsilyloxy)-3-methylaniline, in 93% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[C:13]2[N:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCNc2ncc(C(C)C)cn2)cc1Br
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ncc(C(C)C)cn2)cc1Br
Reaction time: 0.25 h

Procedure:
A solution of N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropylpyrimidin-2-amine (157 mg; 0.45 mmol) in dry THF was treated under nitrogen with KtBuO (75 mg; 0.67 mmol). After stirring for 15 minutes, 4-trifluoromethoxybenzyl bromide (171 mg; 0.67 mmol) was added and stirred for 30 minutes. The reaction was quenched by addition of an aqueous solution of NaHSO4 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropyl-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine as an oil in moderate yield, which was used in the next step without further purification
Reaction SMILES: [CH3:1][S:2]([C:4]([S:16][CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH3:1][S:2][C:4]([S:16][CH3:17])=[C:5]([Cl:27])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1
Reactant: CSC(=Cc1ccc(CC(C)C)cc1)S(C)=O
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSC(SC)=C(Cl)c1ccc(CC(C)C)cc1
Yield: 83.8 %

Procedure:
1-Methylsulfinyl-1-methylthio-2-(p-isobutylphenyl)ethylene (701 mg) was dissolved in 2 ml of chloroform, and 0.50 ml of triethylamine was added. With stirring under ice cooling, 5 ml of a chloroform solution of 380 mg of thionyl chloride was added over the course of 10 minutes. The mixture was further stirred for 30 minutes under ice cooling, and chloroform was added in an amount sufficient to adjust the total amount of the mixture to 30 ml. The mixture was then washed twice with 10 ml of water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a Florisil (chromatographic magnesium silicate) column using benzene as an eluent to afford 628 mg of 1,1-bis(methylthio)-2-chloro-2-(p-isobutylphenyl) ethylene as a colorless oil in a yield of 84%.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:28]2[CH2:30][CH2:29]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:31][NH:32][C:33](=N)[CH2:34][CH2:35][CH3:36]>>[CH:28]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:31][N:32]=[C:33]([CH2:34][CH2:35][CH3:36])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:29][CH2:30]1
Reactant: CCCC(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Product: CCCc1noc(N2CCC(N(C(=O)c3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-butyramidine following a procedure analogous to that described in Example 6. LC (method 10): tR=1.87 min; Mass spectrum (ESI+): m/z=511 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:19])[CH2:16][O:15][C:14]([CH2:17][CH3:18])=[N:13]1>II>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]([C:14]1[O:15][CH2:16][C:12]([CH3:19])([CH3:11])[N:13]=1)[CH3:18]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCC1=NC(C)(C)CO1
Agent: II
Product: CC(=Cc1ccc(Cl)cc1Cl)C1=NC(C)(C)CO1

Procedure:
2-[2-(2,4-dichlorophenyl)-1-methylethenyl]-4,4-dimethyl-2-oxazoline (P-2016) was prepared by reacting 2,4-dichlorobenzaldehyde with 4,4-dimethyl-2-ethyl-2-oxazoline in the presence of iodine catalyst.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]([F:21])([F:20])[O:9][C:10]1[CH:11]=[C:12]([NH:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][CH:2]([CH3:6])[C:3]([NH:19][CH2:18][CH2:17][NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:7])([F:20])[F:21])[CH:11]=1)=[O:4]
Reactant: NCCNc1cccc(OC(F)(F)F)c1
Reactant: CC(Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Cl)C(=O)NCCNc1cccc(OC(F)(F)F)c1
Yield: 92.2 %

Procedure:
A solution of 2-chloropropionic acid (103 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added dropwise at −30° C. to a solution of N1-(3-trifluoromethoxy-phenyl)-ethane-1,2-diamine (210 mg, 0.95 mmol) and N,N′-dicyclohexylcarbodiimide (226 mg, 1.10 mmol) in CH2Cl2 (20 mL), then after 1 h insoluble material was removed by filtration and the filtrate evaporated. Chromatography (SiO2; heptane/EtOAc 3:2) afforded the title compound (272 mg, 92%). Colorless oil, MS: 309.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][C:7]([CH3:14])=[N:6][C:5]=2[S:4][C:3]=1[C:15](=[O:17])[NH2:16].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[CH:8][C:9]=2[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])[S:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)c2c(N)c(C(N)=O)sc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCOCC2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid (see Example 10) (0.5 g, 2.0 mmol), morpholine (0.87 g, 10 mmol) and PyBop (0.88 g, 2.0 mmol) in DMF (10 mL) was stirred at room temperature overnight. It was diluted with water and extracted with methylene chloride (50 mL). Concentration of the organic phase the title compound as an orange solid (0.45 g, 70.3%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([F:31])[CH:25]=1>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[CH:25][C:26]=1[F:31])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccn2)cc1F
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline was reacted with 4-amino-3-fluorophenyl 2-pyridylmethyl ether to give 6-acetoxy-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline in 94% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CC(=O)O
Reactant: COCCOCCOc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COCCOCCOc1cccc(C=CC(=O)O)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde (9.18 g, 40.9 mmol) in pyridine (70 mL) under nitrogen was added malonic acid (8.69 g, 81.9 mmol) followed by piperidine (4.13 mL, 40.9 mmol). The reaction solution was stirred for 3 h at 85° C. and left stirring over night at room temperature. The reaction solution was concentrated to an oil and left on high vacuum over night to remove the remaining pyridine. To the oil was added ice (120 g) and under vigorous stirring, concentrated hydrochloric acid (13 mL) was added. The mixture was extracted with methylene chloride (3×65 mL) and the combined organic layer was washed with water (60 mL) and brine (60 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting oil was dried in high vacuum to give 10.8 g (99% yield) of the title compound. 1HNMR (300 MHz, DMSO-d6) δ 12.28 (br s, 1H), 7.56 (d, J=16 Hz, 1H), 7.28 (m, 3H), 6.99 (dd, J=8 Hz, J=2 Hz, 1H), 6.56 (d, J=16 Hz, 1H), 4.14 (t, J=5 Hz, 2H), 3.75 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.36 (t, J=5 Hz, 2H), 3.25 (s, 3H).