Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)[CH:33]=[O:34].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][C:30]=4[CH3:29])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: Cc1cc(C=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.2 g, 0.45 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.138 g, 0.56 mmol) and Pd(PPh3)4 (0.052 g, 0.045 mmol) in 1,4-dioxane (6 mL) was purged with argon for 10 min. 2 M Na2CO3 solution (0.14 g, 1.35 mmol) was then added to it and mixture purged with argon again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and the extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@@H:12]1[O:13]C(=O)C>N.CO>[C@@H:11]1([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.6 %

Procedure:
Compound 3(200 mg,0.5 mmol) was dissolved in saturated NH3/MeOH (5 mL) and stirred at room temperature for two hours. The solvent was evaporated in vacuo to obtain crude 4 (170 mg) which was used for the subsequent reaction without any further purification: UV (Me(OH)λmax 263.0 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](I)[C:7]([CH2:11][F:12])=[CH:6][C:5]=1[NH2:13].[CH:15]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1)([CH3:17])[CH3:16]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH:15]([CH3:17])[CH3:16])[N:19]=[CH:20][CH:21]=2)[C:7]([CH2:11][F:12])=[CH:6][C:5]=1[NH2:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Reactant: COC(=O)c1cc(I)c(CF)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(CF)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
To a solution of 2-amino-4-fluoromethyl-5-iodo-benzoic acid methyl ester (650 mg, 2.10 mmol) in dioxane (30 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (1.01 g, 1.2 equiv) and Pd(dppf)2Cl2 (172 mg, 0.1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. 0.1 equiv of catalyst was added and the mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 35:75)) to provide a light yellow solid (243 mg, 40%) (ES-MS: m/z 292.3 [M+H]+, rt 5.31 min).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([CH2:43][NH2:44])[OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:44][CH2:43][CH2:41][OH:42])=[O:40])=[CH:34]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: NCCO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCCO)c3)ccc2n1CC1CCOCC1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (47 uL, 35 mg, 0.27 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (60 mg, 0.14 mmol) (see following step B for preparation), ethanolamine (17 mg, 0.27 mmol) and HATU (103 mg, 0.27 mmol) in DMF (5 mL). The crude product was purified by MPLC using EtOAc/MeOH (9:1) on silica gel to give 48 mg (72%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.42-1.58 (m, 4H), 1.61 (s, 9 H), 2.23-2.36 (m, 1 H), 3.25-3.34 (m, 2 H), 3.38 (t, J=5.76 Hz, 2 H), 3.61 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.44 (d, J=7.42 Hz, 2 H), 6.67 (dd, J=3.32, 1.76 Hz, 1H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.82-7.85 (m, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.98 (d, dd, J=8.7, 1.5 Hz, 1 H), 8.28 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=489.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].Cl.[CH3:15][N:16](C)[NH2:17]>C(O)C>[CH3:15][N:16]1[C:2]2[C:3](=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[C:11]([CH3:12])=[N:17]1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)N
Agent: Cl
Solvent: CCO
Product: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Yield: 627.7 %

Procedure:
To a solution of 1-(2-chloro-5-nitrophenyl)ethanone (500 mg, 2.5 mmol) in anhydrous ethanol (15 mL) was added 1,1-dimethylhydrazine hydrochloride (3.38 g, 35.0 mmol) under nitrogen protection. The mixture was heated at reflux for 10 h and evaporated under reduced pressure to afford crude 307a (3.0 g), which was used in the next step without further purification. MS-ESI: [M+H] 192.2
Reaction SMILES: [NH:1]1[C:5]([NH:6][CH:7]=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17]C)=O)=[N:4][N:3]=[N:2]1.[OH-].[NH4+]>CO>[NH:1]1[C:5]([N:6]2[C:15](=[O:17])[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:8]=[CH:7]2)=[N:4][N:3]=[N:2]1
Reactant: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccccc2ncn1-c1nnn[nH]1
Reaction time: 1 h

Procedure:
A slurry of 3 g of N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine in 10 ml of methanol was stirred at room temperature. A solution of 0.8 ml of 14.8M ammonium hydroxide in 5 ml of methanol was added to the mixture which was stirred for 1 hour. The white solid which formed was separated by filtration, washed with aqueous 2-propanol and vacuum oven dried to give the ammonium salt of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:25])[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][N:11]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-((benzyloxycarbonyl)(methyl)amino)piperidine-1-carboxylate (0.3 g, 0.682 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (2.5 ml) was added at 0° C. and stirring was carried out for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=[O:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1.[NH4+].[Cl-].CCCCCC.C(OCC)(=O)C>O.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][OH:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cccc(NO)c1)c1nc(Cl)ncc1F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-nitrophenyl)carbamate (0.78 g) in mixture of ccetone (3 ml) and water (2 ml) was added NH4Cl (0.22 g) and the reaction mixture was heated to 60° C. Zn dust (289 mg) was added to the reaction mixture at 60° C. portion wise. The reaction mixture was stirred for 45 minute at 60° C. and monitored on TLC using hexane:ethyl acetate (3:7) as mobile phase. After completion of the reaction, the reaction mixture was poured in water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure to give crude product. Crude material was purified by using column chromatography. Desired product eluted with 5% ethyl acetate in hexane to give, after concentration, 0.409 g of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(hydroxyamino)phenyl)carbamate. M+1=354.8. 1H NMR: DMSO-d6 (400 MHz): 1.400 (s, 9H), 6.612 (d, 1H, J=7.6), 6.688 (s, 1H), 6.774 (d, 1H, J=8.4), 7.170-7.210 (t, 1H, J=8), 8.434 (d, 2H, J=6.4), 8.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccs1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Clc1c(CCCNCc2cccs2)ccc2ccccc12
Yield: 70 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and thiophen-2-carbaldehyde in 70% yield as a slightly red oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1Cl.Cl[C:24]([O:26][CH3:27])=[O:25].C(Cl)(=O)C1C=CC=CC=1>>[C:16]([N:13]1[CH2:14][CH2:15][C@H:12]1[CH2:11][O:10][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][NH:1][C:24]([O:26][CH3:27])=[O:25])[CH:4]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Solvent: O=C(Cl)c1ccccc1
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Yield: 94 %

Procedure:
Following the general procedure of Example 92c, substituting 5-aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 205b for 5-aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine and methyl chloroformate for benzoyl chloride therein, the title compound (0.23 g, 94%) was prepared: 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.41 (m, 2H), 3.72 (s, 3H), 3.87 (t, J=7.5 Hz, 2H), 4.15 (dd, J=2.5, 10.0 Hz, 1H), 4.33-4.39 (m, 3H), 4.55 (m, 1H), 7.10 (s, 1H), 8.17 (s, 1H), 8.27 (d, J=1.5 Hz, 1H); MS (CI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([NH2:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)[N:12]=3)[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2c(N)n[nH]c2c1
Reactant: O=C(CBr)c1cccc(O)c1
Product: COc1ccc2c(c1)[nH]n1cc(-c3cccc(O)c3)nc21

Procedure:
Compound 3-(7-methoxy-5H-imidazo[1,2-b]indazol-2-yl)phenol (W298) was prepared using the general procedure for cyclization between 6-methoxy-1H-indazol-3-amine (80 mg, 0.5 mmol) and 2-bromo-1-(3-hydroxyphenyl)ethanone (107 mg, 0.55 mmol), as a white solid (40 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 9.84 (brs, 1 H), 8.63 (s, 1 H), 7.85 (d, J=9.2 Hz, 1 H), 7.36 (t, J=8.0 Hz, 1 H), 7.31-7.29 (m, 1 H), 7.24 (t, J=2.0 Hz, 1 H), 7.13 (d, J=2.0 Hz, 1 H), 6.99 (dd, J=9.2, 2.0 Hz, 1 H), 6.88 (m, 1 H), 3.90 (s, 3 H); MS (ESI) m/z 280 (M+H+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].[C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Br)=[CH:13][CH:12]=1)#[N:10]>C1COCC1>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:16][C:15]([C:14]1[CH:19]=[CH:20][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: FC(F)(F)CS
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)CSCC(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 2,2,2-trifluoroethanethiol (1.5 mL, 17.2 mmol) in anhydrous THF (28 mL) at 0° C. under nitrogen, add sodium hydride (629 mg, 15.7 mmol) and stir for 15 min. Then, add 4-cyanophenacyl bromide (3.2 g, 14.3 mmol) and stir at ambient temperature overnight. Quench with water and extract with EtOAc. Dry the combined organics extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (3.1 mg, 84%).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C(#[N:30])C>>[CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:30])[C:7]=2[N:6]=[CH:5]1
Reactant: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Reactant: CC#N
Product: CCCOc1ccc(-c2cccc3nc(N)c4ncn(CC(C)C)c4c23)cc1
Reaction time: 36 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol). The amination reaction was stirred for 36 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide an oil, which was stirred with acetonitrile to provide a solid. The solid was isolated by filtration and recrystallized from acetonitrile to provide 165 mg of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as light tan needles, mp 181–182° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH:12]1[S:13][CH:14]=[C:15]2[C:21]=1[C:20](=O)[NH:19][C:18]1[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=1[NH:16]2.[OH-].[Na+]>O>[CH:12]1[S:13][CH:14]=[C:15]2[C:21]=1[CH2:20][NH:19][C:18]1[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=1[NH:16]2
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCc1cscc1N2

Procedure:
A reaction mixture comprising 3.8 g. of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran, 5 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one [U.S. Pat. No. 3,953,430 (Example 25)] and 125 ml. of dry tetrahydrofuran is heated, with stirring under reflux for 18 hours. The reaction mixture is cooled and 4 ml. of water is carefully added dropwise with stirring and ice bath cooling. Following this, 4 ml. of 15% sodium hydroxide and 12 ml. of water are added. The mixture is filtered and the precipitate is washed thoroughly with tetrahydrofuran and ether. The combined organic phases are dried over sodium sulfate filtered and the filtrate is concentrated to dryness. The dark brownish-green crystals are triturated in hexane, filtered, washed with hexane and dried. The product is heated to boiling in 50 ml. of chloroform, filtered and the filtrate is combined with 50 ml. of hexane and cooled in a chill room. The crystals are recovered by filtration, washed with hexane and dried. Recrystallization from chloroform-hexane is repeated. A 200 mg. portion of these crystals is recrystallized by dissolving in 10 ml. of chloroform with warming, treating with activated charcoal, filtering through diatomaceous earth and adding 20 ml. of hexane to the filtrate. These crystals are collected, washed with hexane, and dried giving the desired final product, mp. 167°-169° C.
Reaction SMILES: [C@H:1]12[CH2:20][C@H:4]([N:5]([C:7]([C:9]3[CH:10]=[N:11][N:12]4[C:17](I)=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=34)=[O:8])[CH2:6]1)[CH2:3][O:2]2.CC1(C)C(C)(C)OB([C:29]2[O:33][C:32]([Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Cl-].[NH4+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:15]1[CH:16]=[C:17]([C:29]2[O:33][C:32]([Si:34]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:35]([CH3:36])[CH3:37])=[N:31][CH:30]=2)[N:12]2[N:11]=[CH:10][C:9]([C:7]([N:5]3[CH2:6][C@@H:1]4[CH2:20][C@H:4]3[CH2:3][O:2]4)=[O:8])=[C:13]2[CH:14]=1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: Cc1cc(I)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: Cc1cc(-c2cnc([Si](C(C)C)(C(C)C)C(C)C)o2)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(7-iodo-5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone (300 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (330 mg), tetrakis(triphenylphosphine)palladium(0) (90 mg) and 3N aqueous potassium carbonate solution (0.522 mL) in DME (3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give (5-methyl-7-(2-(triisopropylsilyl)-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone. The obtained (5-methyl-7-(2-(triisopropylsilyl)-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone was dissolved in THF (3 mL), and 1N hydrochloric acid was added thereto. The reaction mixture was stirred at room temperature for 30 min, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (83 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH:32]=[CH2:33].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH2:20][C:21](=[O:22])[O:23][CH3:24])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of dimethyl 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (1.00 g), benzyl acrylate (1.021 g), palladium acetate (II) (0.047 g), tris(2-methylphenyl)phosphine (0.128 g), triethylamine (0.878 mL), and DMA (7.5 mL) was stirred at 130 C for 2 hours under microwave irradiation under an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.770 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15](Br)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][NH:35][CH3:36]>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([N:35]([CH3:36])[CH3:34])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Br)CS[C@H]12
Reactant: CNC
Product: CN(C)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
p-Nitrobenzyl 7-phenylacetamido-3-bromo-3-cephem-4-carboxylate is reacted with dimethylamine by following the reaction conditions of Example 4 to provide p-nitrobenzyl 7-phenylacetamido-3-dimethylamino-3-cephem-4-carboxylate.
Reaction SMILES: C([O:3][C:4](/[C:6](/[CH3:30])=[CH:7]/[C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[C:4](/[C:6](/[CH3:30])=[CH:7]/[C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(=C\c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1)C(=O)O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1.00 g (0.0023 mol) of (E)-2-(2-ethoxycarbonylpropenyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a mixture comprising 5 ml of tetrahydrofuran and 20 ml of ethanol, followed by the addition of 20 ml of a 1N aqueous solution of sodium hydroxide. The obtained mixture was stirred at room temperature for several hours, neutralized with 20 ml of 1N hydrochloric acid and concentrated under a reduced pressure. The crystal thus formed was recovered by filtration, washed with water and air-dried to give 0.85 g of the title compound.