Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([NH:33]O)=[NH:32])=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:33]=[C:31]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[N:32]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4cnc(N)nc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a white solid (60 mg, 27%). MS (ISP) 438.3 [(M+H)+]; mp 302° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 8.2 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (300.2 mg) and ethyl 4-aminophenylacetate hydrochloride (202.2 mg) were condensed in THF (5 ml) in the presence of triethylamine (422.4 μl) and pivaloyl chloride (153.9 μl), and then the resulting crude product was recrystallized from ethanol to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (35.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:28]3[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:17])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(Cc3ccncc3)CC2)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.269 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.124 g (1.08 mmol) of N-NEM and 0.0477 g (0.27 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.088 g (0.269 mmol) of TOTU. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0–17% MeOH in DCM.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:12]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)Oc1ccccc1O2

Procedure:
A mixture of 1-ethoxycarbonyl-4-piperidinone (17 g), pyrocatechol (13 g) and p-toluenesulfonic acid (2.5 g) in 250 ml of dry toluene was refluxed with continous removal of water. After 3 h the reaction mixture was concentrated in vacua, 2% NaOH (200 ml) was added followed by extraction with dichloromethane. After drying over magnesium sulfate and removal of solvent in vacuo, the remaining red oil was applied to a silica gel column (eluent: ethyl acetate/ heptane =1:1) giving 22 g of a slightly yellow oil, 1′-ethoxycarbonyl-spiro[1,3-benzodioxole-2,4′-piperidine].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30]S[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.CO.O[O:35][S:36]([O-:38])=O.[K+]>O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][S:36](=[O:38])(=[O:35])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCSCC3)cc1)nn2-c1c(F)cccc1F
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCS(=O)(=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
To a mixture of 7-chloro-1-(2,6-difluorophenyl)-3-(4-(thiomorpholin-4-yl)phenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (30 mg) obtained in Example 236 in a mixed solvent of methanol (3 mL) and water (0.15 mL) was added Oxone (registered trademark) (80 mg) at room temperature. The reaction mixture was stirred at 80° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with THF. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.7 mg).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.N1C=CC=NC=1>CC(C)=O>[CH:1]1([N:6]([C:22]2[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1cncnc1
Product: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Methyl 3-(cyclopentylamino)propanoate (838 mg, 0.005 mol) and K2CO3 (676 mg, 0.005 mol) were added to acetone (5 ml) and the resulting mixture cooled to 0° C. using an ice-bath before the addition of 2,4-dichloro-5-nitropyrimidine (1.044 g, 1.1 eq). The reaction mixture (RM) was then warmed to rt and stirring continued for an additional 16 h before the addition of a further 0.12 eq of the pyrimidine. Stirring was then continued for a further 3 h. The RM was then evaporated under reduced pressure and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried using MgSO4, filtered and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a brown oily residue (1.04 g, 65%); Rt=16 min (Vydac 1); ME+ve: 329.1.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
1.0 g (0.0033 mol) of L-alanyl-L-proline ethylamide hydrobromide was dissolved in 20 ml of dry pyridine and 0.63 g (0.0033 mol) of p-toluenesulphonyl chloride was added. The mixture was stirred at room temperature for 1 hour and the pyridine was then removed by evaporation. The oily residue was dissolved in chloroform and the solution was washed with water, dried over magnesium sulphate and evaporated to an oil. This oil was dissolved in water and freeze-dried to yield 0.40 g (33%) of N-(p-toluenesulphonyl)-L-alanyl-L-proline ethylamide; [α]D20 =-90.7° (c=0.94% in water).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[CH:20]=O)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[N:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CN4CCCC4)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 3-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and pyrrolidine provided the title compound. ESMS [M+H]+: 633.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]Br.CCOCC>O>[Br:12][C:5]1[N:4]=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ncccc1O
Reactant: BrBr
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1nc(Br)ccc1O
Yield: 70.7 %

Procedure:
To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300 mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200 mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
Solid K2CO3 (16.3 g, 0.12 mol, 1.2 equiv) was added to a solution of crude 14 (20.6 g, ˜0.10 mol, 1.0 equiv) in DMF (200 mL) followed by benzyl bromide (17.1 g, 11.9 mL, 0.10 mol, 1.0 equiv). The yellow suspension was heated at to 80° C.-90° C. for 4.5 hr. The mixture was cooled to room temperature and stirred for 48 hr. The mixture was poured into H2O (750 mL) and the aqueous mixture extracted with EtOAc (500 mL). The organic phase was diluted with heptanes (500 mL) and the solution washed with H2O (3×250 mL), brine (300 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving brown oil that crystallized. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded on a column of silica gel (250 g) packed in heptanes. The column was eluted with heptanes (1 L), 2.5% EtOAc/heptanes (2 L) and 5% EtOAc/heptanes (2 L). Product-containing fractions were concentrated under reduced pressure. The slightly oily solid was pumped on high vacuum for 0.5 hr, then triturated with cold heptanes (100 mL), filtered, washed with a small volume of heptanes and dried to give 17.8 g (62%) of 15 as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>S(=O)(=O)(O)O>[OH:1][CH:2]([CH3:7])[CH2:3][C:4]([O:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:5]
Reactant: CCCCCCCCCCO
Reactant: CC(O)CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)CC(C)O
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A 100 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 20.8 g (0.20 moles) 3-hydroxybutyric acid, 63.3 g (0.40 moles) decyl alcohol, and 0.1 g sulfuric acid (based on 0.5 g/mole 3-hydroxybutyric acid). The mixture was heated to 140° C. for 8 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 28.3 g (58% yield) of clear viscous colorless oil. According to GC the product is 89.4% pure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:38])([CH3:37])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@@:25]([O:28][C:29](=[O:31])[CH3:30])([CH2:26][CH3:27])[C:24](=[O:32])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=12.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[N:39]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:38])([CH3:37])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@@:25]([O:28][C:29](=[O:31])[CH3:30])([CH2:26][CH3:27])[C:24](=[O:32])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=12)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCN=[N+]=[N-]
Yield: 95.3 %

Procedure:
A solution of Compound 19 (1.96 g) and sodium azide (725 mg) in N,N-dimethylformamide (15 mL) was heated at 80° C. for 3 hours. The N,N-dimethylformamide was concentrated under reduced pressure and the residue was partitioned between chloroform (25 mL) and 1 N HCl (10 mL). The organic layer was separated, dried and concentrated to obtain the crude product and was purified by eluting on a silica gel column using 1-2% ethanol in dichloromethane to yield 95% of the required product (1.75 g).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=1)=O.C(OP([CH2:56][C:57]#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=2)=[CH:56][C:57]#[N:58])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3'-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3'nitrobenzophenone (1.44 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 3% hexane/methylene chloride) to afford 1.12 g (72%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120° C.; 1H NMR (CDCl3) δ 8.40-8.17 (m, 4 H), 7.90-7.55 (m, 4 H), 7.08-6.89 (m, 6 H), 5.84 (s, 1 H), 5.71 (s, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); 13CNMR (CDCl3) δ 160.2, 160.1, 151.7, 151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9, 129.7, 129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4, 117.3, 112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd for C17H14N2O4. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H, 4.64; N, 8.92.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(OCC)C>[C:20](=[O:21])([O:22][CH2:23][Cl:24])[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCCl
Reactant: OCCCOCc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(benzyloxy)propanol (synthesized by a procedure described in Wei et al., J. Org. Chem, 54, 5768-5774 (1989):15.1 g) and pyridine (7.18 g) in diethyl ether (150 ml), a solution of chloromethyl chloroformate (11.7 g) in diethyl ether (50 ml) was added dropwise under ice cooling over the period of 20 minutes. After stirring at room temperature for 15 hours, the resulting solid was removed off by filtration and washed with ethyl acetate (100 ml). The filtrate and the washings were combined, and washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml). After drying the solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 200 g, eluent: ethyl acetate-hexane=1:4) to obtain [3-(benzyloxy)propyl] chloromethyl carbonate (21.0 g) as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12.O1CCOCC1.[NH3:25]>C(O)(=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:25])=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12
Reactant: O=C(Cl)c1ccc2nc3ccccn3c(=O)c2c1
Reactant: N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride, prepared as in Example 12, were introduced into a mixture consisting of 200 ml of dioxane and 50 ml of concentrated ammonia, and the resulting mixture was stirred for 5 hours at room temperature. Thereafter, the reaction mixture was acidified with dilute acetic acid, and the crystals precipitated thereby were collected by suction filtration, yielding the compound of the formula ##STR22##
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Product: CNC(=O)Cn1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 355, 2-[2-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-imidazol-1-yl]-N-methyl-acetamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 405 MS: (ESI+)=497.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.93 (s, OH), 7.38 (d, J=0.8 Hz, 1H), 7.32 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.05 (d, J=0.8 Hz, 0H), 5.23 (s, 1H), 4.72 (s, 1H), 4.34 (t, J=5.0 Hz, 1H), 4.04 (s, 1H), 2.66 (t, J=4.4 Hz, 2H), 1.08 (s, 6H)
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:21](=[O:23])[CH3:22])([C@@:8]([C:18](=[O:20])[CH3:19])([C@:10]([C:15](=[O:17])[CH3:16])([C@H:12]([CH3:14])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>ClCCl>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@@:15]2([CH3:16])[O:17][C@@:4]([C:1](=[O:3])[CH3:2])([OH:5])[C@:6]([C:21](=[O:23])[CH3:22])([OH:7])[C@:8]([C:18](=[O:20])[CH3:19])([OH:9])[C@@:10]2([C:12](=[O:13])[CH3:14])[OH:11])=[CH:28][CH:27]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@H](C)O
Solvent: ClCCl
Product: COc1ccc([C@@]2(C)O[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]2(O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
1,2,3,4-Tetraacetyl-L-rhamnose (19.2 g, 57.8 mmol) and p-methoxyphenol (MPOH) (12.2 g, 98.3 mmol) were dissolved in 150 mL of dichloromethane and cooled to 0° C. BF3 OEt2 (23.0 g, 20.5 mL, 162.0 mmol) was added and the mixture stirred overnight while warming to room temperature. The reaction mixture was quenched by addition of saturated NaHCO3 solution, washed 2 times with water, dried over Na2SO4, concentrated and the residue was purified by column chromatography (3:1 hexane/EtOAc) yielding 18.3 g (80%) of 4-methoxyphenyl 1,2,3,4-tetraacetyl-α-L-rhamnose. 4-Methoxyphenyl 1,2,3,4-tetraacetyl-α-L-rhamnose (18.0 g, 45.4 mmol) was dissolved in 300 mL of methanol and 9 mL of 0.5 M NaOMe solution were added. The mixture was stirred for 12 h, the solvent was removed in vacuo. Column chromatography (4:1 dichloromethane/methanol) afforded 2.63 g (96%) as a colorless solid.
Reaction SMILES: Cl[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]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2ncnc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methylbenzophenone (279 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (97 mg, yield 92%).