Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[F:35][C:36]([F:51])([S:47](F)(=[O:49])=[O:48])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][S:47]([C:36]([F:35])([F:51])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:42])([F:41])[F:40])(=[O:49])=[O:48])=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (100.0 mg, 0.2629 mmol) and triethylamine (55.0 L, 0.395 mmol) in acetonitrile (1 mL) was added 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonyl fluoride (60.0 L, 0.341 mmol). The mixture was stirred for 1 hour at room temperature then partitioned between water (25 mL) and ethyl acetate (25 mL). The organic was rinsed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (12 g) and ethyl acetate:hexane solvent gradient. The title compound was isolated as a pale yellow foam (0.128 g, 73%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.71-7.64 (m, 3H), 7.29-7.25 (m, 2H), 7.11 (s, 1H), 7.08 (t, J=7.0 Hz, 1H), 3.10 (s, 3H). MS=663 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-:27].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH2:25])=[O:27])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc2c(OCc3nnc4ccc(C(N)=O)cn34)ccnc2c1
Temperature: 50 °C
Yield: 95 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.5 mL). The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was slowly poured in to cold saturated aqueous sodium bicarbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was transferred with dichloromethane/methanol to a flask and dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.050 g, 95% yield) as a tan solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[C:30](Cl)=[O:31])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:37]([C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:35]=1[OH:36])[C:30]([O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:31])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 27.9 g of dibenzylhydroxylamine and 10.3 g of pyridine in 100 ml of methylene chloride is added a solution of 39.0 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 100 ml of methylene chloride. After stirring the mixture at room temperature for 24 hours, the reaction mixture is washed with 10% aqueous hydrochloric acid, water, brine and dried. Evaporation followed by crystallization of the residue from heptane affords the title compound as a white solid: mp 90°-92° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[Br:39][CH:40]([CH2:47][CH3:48])[CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44]>C(#N)C>[Br-:39].[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:14]2[C:13](=[O:30])[CH:12]([CH2:11][CH2:10][CH:9]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:48][CH2:47][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCC(Br)CC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of 3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 3 ml of absolute acetonitrile. 300 mg of KF•alumina (1.15 mol/100 g) and 375 mg of (3-bromopentyl)-trimethylammonium bromide are then added. The reaction mixture is stirred at room temperature overnight and then filtered. The mother liquor is concentrated using a rotary evaporator and the residue is purified using a 5 g SiO2 cartridge (dichloromethane/methanol 4:1). The product is obtained as an oil.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28][N:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1COCC(=O)N1
Product: CCCc1c(OCCCN2C(=O)COCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione was prepared as for Example 10 from morpholine-3,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:47][CH2:46][CH2:45][C:40]2([CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39]1)=O)(C)(C)C>>[CH2:44]1[C:40]2([CH2:45][CH2:46][CH2:47][NH:38][CH2:39]2)[CH2:41][CH2:42][N:43]1[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNC2)C1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC5(CCCNC5)C4)c3)nc12

Procedure:
1-{2-[3-(2,7-Diaza-spiro[4.5]dec-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=418.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]([NH:57][C:58](=[O:67])[C@H:59]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH3:60])[C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:40][CH:39]=1>C1COCC1>[CH2:3]([O:4][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]([NH:57][C:58](=[O:67])[C@H:59]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH3:60])[C@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])=[CH:42][CH:43]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CO
Reactant: C[C@H](C(=O)N[C@H](c1ccc(O)cc1)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 140 °C

Procedure:
A solution of 2-methyl-1-propanol (6.52 μL, 0.071 mmol), DEAD (11.19 μL, 0.071 mmol), and triphenylphosphine (18.53 mg, 0.071 mmol) in THF (520 μL) in a microwave vial was stirred at room temperature for 10 min. (R)-tert-Butyl 2-((R)-(4-hydroxyphenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (30 mg, 0.071 mmol) was added and the solution heated at 140° C. in a microwave (Biotage) for 20 min. The crude mixture was filtered through a plug of silica gel eluting with 50% EtOAc in hexanes. The filtrate was concentrated in vacuo and carried directly into the next reaction. LRMS (ESI) m/e 481.50 [(M+H)+, calcd for C29H41N2O4 481.31].
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][CH2:20][CH2:21][N:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([N:33]3[CH2:54][CH2:53][C:36]4([NH:40]/[C:39](=[N:41]/[C:42]([C:44]5[C:49]([NH2:50])=[N:48][C:47]([NH2:51])=[C:46]([Cl:52])[N:45]=5)=[O:43])/[NH:38][CH2:37]4)[CH2:35][CH2:34]3)=[O:32])[C:25]=2[CH:24]=[CH:23]1>CO>[OH:19][CH2:20][CH2:21][N:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([N:33]3[CH2:34][CH2:35][C:36]4([NH:40]/[C:39](=[N:41]/[C:42]([C:44]5[C:49]([NH2:50])=[N:48][C:47]([NH2:51])=[C:46]([Cl:52])[N:45]=5)=[O:43])/[NH:38][CH2:37]4)[CH2:53][CH2:54]3)=[O:32])[C:25]=2[CH:24]=[CH:23]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc5c4ccn5CCOC4CCCCO4)CC3)N2)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc5c4ccn5CCO)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
p-Toluenesulfonic acid monohydrate (1.6 mg, 0.0084 mmol) is added to a stirred solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carbonyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (Ex. 84) (50 mg, 0.084 mmol) in MeOH (3 ml) and the resulting solution is stirred at room temperature for 3 hrs, then heated at 50° C. for 16 hours. The solvent is removed in vacuo and the residue is dissolved in MeOH (3 ml) and loaded onto a 1 g PEAX cartridge which is eluted with MeOH (20 ml). The filtrate is concentrated in vacuo to afford the title compound; [M+H]+ 512/514
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])=[C:4]([CH:25]=[CH2:26])[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][C:27](=[O:29])[CH3:28])=[N:3][C:4]([CH:25]=[CH2:26])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(NC(C)=O)nc1C=C
Temperature: 60 °C

Procedure:
Under an argon atmosphere, to a solution of 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (100 mg, 292 μmol) in anhydrous pyridine (20 mL) were successively added 4-(dimethylamino)pyridine (DMAP) (3.0 mg, 25 μmol) and acetyl chloride (65.0 μL, 911 μmol) at room temperature. The mixture was heated at 60° C. and stirred for an hour. After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.O[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C@H:24]([C:25]([O:27][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:29][CH2:28]3)[CH2:21]2)=[CH:38][CH:39]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)CN1CCC2(CC1)C[C@@H](C(=O)O)N(Cc1ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Reactant: CN(C)C(=O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)[C@@H]1CC2(CCN(CC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To an N,N-dimethylformamide (1 mL) solution of the compound (80 mg) obtained in Example 32(5), 2-hydroxy-N,N-dimethylacetoamide (CAS Registry Number: 14658-93-6; 77 mg), diisopropylethylamine (39 μL) and N,N,N′,N′-tetramethyl-O-(7-azobenzotriazol-1-yl)uronium hexafluorophosphate (86 mg) were added. The reaction solution was stirred at room temperature for 16 hours. To this solution, an aqueous saturated sodium hydrogen carbonate solution was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (ethyl acetate:methanol=1:0→30:1→15:1) to obtain the title compound (68 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]CBr)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:20].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:20])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CCBr)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromethyl)-4(1H)-quinazolinone (from Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CN(Cc2ccccc2)c2ccccc21
Temperature: 80 °C
Yield: 74.5 %

Procedure:
[2-Oxo-3-(3-phenylpropionylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]acetic acid methyl ester (104a; 500 mg, 1.31 mmol), calcium carbonate (155 mg, 1.58 mmol), and benzyl bromide (170 μl, 1.44 mmol) were taken into 10 ml of dimethylformamide and heated to 80° C. for 8 hours. The mixture was diluted with 150 ml of ethyl acetate and washed 4 times with 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous, yellow oil that was purified by flash chromatography eluting with dichloromethane/ethyl acetate (8:2) to give 460 mg (75%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.34-7.05 (14 H. m), 6.32-6.28 (1H, d), 4.84-4.76 (1H, d), 4.76-4.70 (1H, m), 4.43-4.37 (1H, d), 4.26-4.18 (1H, d), 4.06-4.00 (1H, d), 3.79 (3H, s), 3.45-3.37 (1H, m), 3.02-2.95 (1H, m), 2.90-2.82 (2H, m), 2.5-2.34 ( 2H, m).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].CC[O-].[Na+].[F:12][C:13]([F:33])([F:32])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19]>C(O)C>[F:12][C:13]([F:32])([F:33])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]1[C:23](=[O:24])[NH:7][CH:5]=[N:6][C:18]1=[O:19]
Reactant: N=CN
Reactant: CCOC(=O)C(Cc1ccccc1C(F)(F)F)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1N=CNC(=O)C1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 g of formamidine acetate in 40 ml of absolute ethyl alcohol was treated with 1.2 g of sodium ethylate at room temperature, stirred at room temperature for 30 minutes and then treated dropwise at room temperature with a solution of 1.6 g of diethyl [o-(trifluoromethyl)benzyl]malonate in 8 ml of absolute ethyl alcohol. After stirring at 50° C. for 4 hours, the reaction mixture was worked-up and yielded 5-[o-(trifluoro-methyl)benzyl]-4,6(1H,5H)pyrimidinedione, melting point >290° C.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(Cl)cccc4Cl)cc3)c2cc1OC
Yield: 95.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2,6-dichlorophenyl isocyanate (125 mg) was added, and the admixture was refluxed with heat for 12 minutes. The separated crystals were filtered and then washed with toluene to obtain 81 mg of the title compound (yield: 96%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:30]1[NH:33][CH2:32][CH:31]1[OH:34].Cl>C(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:30][CH:31]([OH:34])[CH2:32]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (100 mg, 0.35 mmol) was dissolved in methylene chloride (2 ml), then diisopropylethylamine (237 μl, 1.39 mmol) and 3-hydroxy-1-azetidine hydrochloride (76 mg, 0.70 mmol) were added, followed by heating under reflux in a sealed tube under nitrogen atmosphere for 6 hours. After cooling, dilution with methylene chloride and washing with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resisting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (123 mg, quant) as a yellow white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH:14]([C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19](=[C:20]([CH3:30])[CH:21]=[C:22]2[CH:28]=O)[CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19](=[C:20]([CH3:30])[CH:21]=[C:22]2/[CH:28]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:28]/[C:22]3[C:23]4[C:19]([CH:18]=[C:17]([CH:14]([CH3:15])[CH3:16])[CH:26]=[CH:25][C:24]=4[CH3:27])=[C:20]([CH3:30])[CH:21]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)[CH:18]=1)([CH3:16])[CH3:15]
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: Cc1cc(C=O)c2c(C)ccc(C(C)C)cc1-2
Product: Cc1ccc2c(c1)O/C(=C\c1cc(C)c3cc(C(C)C)ccc(C)c1-3)C(=O)/C(=C/c1cc(C)c3cc(C(C)C)ccc(C)c1-3)O2

Procedure:
Calone is reacted with 5-isopropyl-3,8-dimethylazulene-1-carbaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(5-isopropyl-3,8-dimethylazulen-1-yl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10](Cl)=[N:11][OH:12])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.[CH2:25]([O:27][CH:28]=[CH:29][CH3:30])[CH3:26].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:29]([CH3:30])[CH:28]([O:27][CH2:25][CH3:26])[O:12][N:11]=3)=[C:7]([C:14]([NH:15][CH3:16])=[O:17])[C:6]=2[CH:18]=1
Reactant: CC=COCC
Reactant: CNC(=O)c1c(C(Cl)=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1ON=C(c2oc3cc(N(C)S(C)(=O)=O)c(Br)cc3c2C(=O)NC)C1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 5-bromo-N-hydroxy-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carbimidoyl chloride (400 mg, 0.91 mmol), 1-ethoxyprop-1-ene (392 mg, 4.56 mmol) and NaHCO3 (153 mg, 1.82 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. It was concentrated, diluted with water, extracted with EtOAc, the organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (PE:EA=2:1) to get product 5-bromo-2-(5-ethoxy-4-methyl-4,5-dihydroisoxazol-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (370 mg, yield: 83%). MS (M+H)+: 488/490.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Temperature: 45 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g of bis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I) iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine is added 0.36 g of (trimethylsilyl) acetylene. The resulting reaction mixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desired product as a white solid. CI MASS SPEC 299(MH+).