Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl[C:12]1[N:13]=[CH:14][CH:15]=[C:16]2[C:20]([CH3:21])=[C:19]([CH2:22][CH3:23])[NH:18][C:17]=12>>[CH2:22]([C:19]1[NH:18][C:17]2=[C:12]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[CH3:21])[CH3:23]
Reactant: CCc1[nH]c2c(Cl)nccc2c1C
Reactant: c1ccc2c(c1)CCNC2
Product: CCc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
1,2,3,4-Tetrahydroisoquinoline (1 ml) was added to 7-chloro-2-ethyl-3-methyl-1H-pyrrolo[2,3-c]pyridine (850 mg, 4.37 mmol) prepared in Preparation 28. The reaction mixture was stirred overnight at 140° C., cooled to room temperature, and then purified with silica gel column chromatography to give 660 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][CH2:5][N:4]2C(OC(C)(C)C)=O)[CH2:2]1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[CH2:2]1[C:3]2([CH2:7][CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCCC12CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CNC2(C1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-azaspiro[2.4]heptane-4-carboxylate (Compound 11-1) (0.75 g, 3.80 mmol) and TFA (3 mL) were added in DCM (10 mL) and the mixture was stirred at room temperature for 1 hour and concentrated to give Compound 11-2 (800 mg, 99.6%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CO.C(OCC)C>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)Cc1ccccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CCCCOc1ccccc1CC(=O)OC
Yield: 65.3 %

Procedure:
16.6 g of methyl 2-hydroxyphenyl acetate are dissolved in 100 ml of methanol. 15 g of potassium carbonate and 18 g of n-butyl bromide are added. After 24 hours of refluxing followed by filtration, the solution is concentrated under reduced pressure. The oil obtained is taken up in diethyl ether and washed with NaHCO3 and H2O. Drying over sodium sulfate and removal of the solvent leaves 14.5 g (65%) of a yellow oil which can be purified by distillation.
Reaction SMILES: [C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([OH:27])[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([O:27][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CCN(O)CC1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CCN(OCc2ccccc2)CC1

Procedure:
The general procedure of Example 1 is repeated using 1-hydroxypiperidin-4-yl stearate, poassium carbonate and benzyl bromide in ethanol solvent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][C:13]#[N:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([OH:21])[CH3:20].Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][C:13](=[NH:14])[O:21][CH2:19][CH3:20])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)COc1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 194.6 %

Procedure:
A solution of 15 g (0.0578 mol) of 4-(4-chlorophenoxy)-phenoxy-acetonitrile prepared as indicated in Example 29a) and of 3.7 ml (0.0637 mol) of anhydrous ethanol in 75 ml of anhydrous diethyl ether is kept at about -5° C. and a stream of dry hydrogen chloride gas is passed into it for 2 hours. Thereafter the reaction mixture is left for 4 hours at about 2° C. and 19.25 g of a white powder are isolated by filtration.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:3]1=2.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:24]([CH:25]([CH3:27])[CH3:26])=[O:28])[CH:13]=[CH:14][C:3]1=2
Reactant: Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Yield: 46.1 %

Procedure:
5,5-Dioxo-2-aminodibenzothiophene (J Med Chem, (1994), 37 (13), 2085-9; 231 mg, 1.0 mmol) was suspended in a solution of DCM (10 ml) and triethylamine (111 mg, 1.1 mmol). iso-Butyrylchloride (106.5 mg, 1.0 mmol) was added dropwise and the resultant mixture was stirred for 16 hours at ambient temperature. The mixture was evaporated in vacuo and the residue was purified by chromatography (Bond Elut column) eluting with 0-2.5% methanol in DCM to give the product as a colourless solid (139 mg). NMR: 10.38 (brs, 1H), 8.37 (s, 1H), 7.85-8.00 (m, 3H), 7.80 (d, 1H), 7.74 (d, 1H), 7.63 (t, 1H), 2.66 (m, 1H), 1.13 (d, 6H); m/z 302.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][CH:13]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86 μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][C:6](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[C:5]1=[O:9]
Reactant: CC1(C)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
10% strength sodium hydroxide solution (100 cc) is added to a mixture of 2,2-dimethylcyclopentanone (10 g) and 4-chlorobenzaldehyde (13.8 g) in ethanol (100 cc) at 0° C. After 10 minutes, the thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-5-(4-chlorobenzylidene)-1-cyclopentanone (12.5 g), m.p. 120° C., is obtained.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[CH:4].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]#[C:4][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2
Reactant: C#CC(N)(CC)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(N)(C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)CC

Procedure:
Using Method C above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-4-[3-amino-3-ethyl-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 45 mg, 95%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]#[N:16])[O:11][N:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH:18]S(O)(=O)=O>>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]([NH2:16])=[O:18])[O:11][N:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2noc(CC#N)n2)cc1
Reactant: O=S(=O)(O)O
Product: Cc1ccc(C(=O)c2noc(CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 23 g of [3-(4-toluoyl)-1,2,4-oxadiazol-5-yl]acetonitrile and 200 ml of 98% H2SO4 was stirred at room temperature overnight. The resulting solution was added slowly to 3000 ml of ice water with mechanical stirring to precipitate a solid. The collected solid was washed with excess water and 600 ml of cold isopropanol, and dried in vacuo to give 21 g (86%) of a solid, m.p. 169°-171°.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCC(O)CCCC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C#CCC(CCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[C:20]([CH:23]=1)[C:21]#[N:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:3]=2)[CH2:9][C@H:10]1[CH3:13]
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Product: C[C@@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](/[CH:11]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cccc(Cl)c12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])/C=C/c1c[nH]c2cccc(Cl)c12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-chloroindole-3-carbaldehyde (314 mg, 1.75 mmol) and ammonium acetate (404 mg, 5.25 mmol) in nitromethane (6 mL) was stirred at 100° C. for 20 min. The reaction mixture was cooled, diluted with water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silicagel column chromatography (50-100% EtOAc/heptane) to give compound B19-1 (224 mg, 58%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOC(=O)c1cccc(CBr)c1OCC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(C(=O)OCC)c2OCC)ccc(C(C)=O)c1O

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with 3-(bromomethyl)-2-ethoxybenzoic acid ethyl ester according to the procedure of Example 69 and the product was purified by HPLC to give 3--[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester, the title compound, m.p. 59°-62° in 90% yield.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].[CH2:15]([CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH3:16]>CO>[CH2:15]([C:17]1[C:18](=[O:19])[NH:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][C:23]=1[OH:24])[CH3:16]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(O)nc(-c2ccccc2)[nH]c1=O
Yield: 50.9 %

Procedure:
A mixture of 45.19 g (0.29 mol) of benzamidine hydrochloride hydrate, 127.42 g (0.59 mol) of 25% sodium methoxide in methanol, 55 mL (0.29 mol) of diethyl ethylmalonate and 175 mL of methanol was heated at reflux for 25 h. The mixture was rotovapped to remove the bulk of the methanol. The residue was diluted with 300 mL of water and the pH was adjusted to 7 with concentrated hydrochloric acid. The solid precipitate was collected by filtration and dried under vacuum at 50° C. to afford 31.89 g (51%) of crude 5-ethyl-6-hydroxy-2-phenyl-4(3H)-pyrimidinone as a pale yellow solid. 1H-NMR (d6 -DMSO)δ1.05(3H, t), 2.39(2H,q), 7.5(3H,m), 8.1(2H,m).
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH2:10][NH3+:11])[CH2:8][NH3+:9]>>[CH2:3]1[CH2:4][N:11]2[C:1](=[N:9][CH2:8][CH2:7][CH2:10]2)[CH2:2]1
Reactant: [NH3+]CCC[NH3+]
Reactant: O=C1CCCO1
Product: C1CN=C2CCCN2C1
Yield: 47.2 %

Procedure:
Using a method similar to Example 1, 25.4 mol of butyrolactone were reacted with 35 mol of 1,3-DAP (molar ratio=1.38). After a reaction time of 32 hours, the temperature of the liquid in the flask was 220° C. and 73% of the theoretically possible amount of water had been distilled off. Distillation gave 12 mol of DBN having a purity of more than 99.1%. The total yield of DBN, including the amount still present in the distillation residues, was 83.3%.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][C:12]1[C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=[CH:14][N:13]=1>C1(C)C=CC=CC=1.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>[F:11][C:12]1[C:17]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: CSc1nc(C)nc(I)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nc(C)nc(-c2nccnc2F)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
A mixture of 2-iodo-4-methyl-6-(methylthio)-1,3,5-triazine (100 mg, 0.374 mmol), 2-fluoro-3-(tributylstannyl)pyrazine (145 mg, 0.374 mmol) and tetrakis(triphenylphosphine)palladium(0) (43.3 mg, 0.037 mmol) in toluene (2 mL) was stirred at 110° C. for 18 h. The mixture was cooled down to room temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 2-(3-fluoropyrazin-2-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (42 mg, 0.177 mmol, 47.3% yield). 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H); 8.42 (s, 1H); 2.73 (s, 3H); 2.65 (s, 3H). m/z (ESI, +ve ion) 238.0 (M+H)+.
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=[CH:38][C:35]=1[CH:36]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([O:42][CH3:43])[C:34]=3[O:33][CH3:32])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])([O:20][CH2:21][CH3:22])=[O:23])[CH3:19]
Reactant: CCOP(OCC)OCC
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Product: CCOP(=O)(Cc1c(C)oc2c([N+](=O)[O-])cccc12)OCC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (226 mg) and triethyl phosphite (0.52 ml) was stirred at 100° C. for 6 hours. The reaction mixture was cooled and concentrated in vacuo and to the residue was added toluene. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from diisopropyl ether to give 3-(diethoxyphosphorylmethyl)-2-methyl-7-nitrobenzo[b]furan (93 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29]C)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10−5 mol) in dichloroethane (3 mL) is treated with 1M BBr3 in dichloromethane (222 μL, 2.21.10−4 mol). The mixture 1s heated at 80° C. for 4 hours before 1M BBr3 in DCM (222 μL, 2.21.10−4 mol) is added. The reaction mixture is heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr3. The solvent is evaporated in vacuo and this operation repeated 3 times. 1M HCl (2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].C1N2CCN(CC2)C1.C(N=C=O)CCC>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:1]=[O:2])(=[O:16])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: CSCc1ccccc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: CCCCN=C=O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CSCc1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (2.5 ml, 35 mmol) was added portionwise into a nitrogen-purged mixture containing 6.8 g (31 mmol) of o-methylthiomethylbenzenesulfonamide, 0.1 g of DABCO, and 3.8 g (38 mmol) of n-butyl isocyanate in 60 ml of dry xylene, while the temperature was maintained at 130°-135° C. between additions. Stirring was continued for 1 hour at 130°-135° C. The mixture was cooled to room temperature and the solid was filtered off under nitrogen. The filtrate was concentrated to yield 9.0 g (theo 7.6 g) of oil: IR cm-1 2240 (N=C=O), no NH at ca 3300. The oil was taken up in 90 ml of dry methylene chloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH2:17])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[C:29]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:18]=[CH:19][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]cc3N)nc2c1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1c[nH]nc1-c1nc2cc(C(=O)O)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester [200 mg, Example 233(k)] in tetrahydrofuran (5 ml) was added diisopropylethylamine (545 μl) and isobutyryl chloride (327 μl) dropwise and the reaction stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M potassium hydroxide in tetrahydrofuran/methanol (1:3, v/v) (5 ml) and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was taken up in 1M sodium hydroxide in water/methanol (5 ml) and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water and the layers separated. The aqueous layer was acidified to pH 3-4 with 5% citric acid solution, extracted with ethyl acetate and the organic layer washed with brine. The organic layer was then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (140 mg) as a white solid. LC-MS (METHOD C): RT=2.87 minutes, 313.33 (M+H)+.