Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1.CC#N.O>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][N:41]([C:24]([NH:23][C:19]3[CH:18]=[C:17]([O:16][C:13]4[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[O:30])=[CH:11][CH:12]=4)[CH:22]=[CH:21][N:20]=3)=[O:29])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)C(C)(C)C)nc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of Example C2 (0.120 g, 0.29 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.053 g, 0.290 mmol) and N-methylpyrrolidine (0.012 g, 0.15 mmol) in dioxane (5 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM/Et3N) to afford a light yellow oil, which was dissolved in MeCN/H2O, frozen and lypholized overnight to afford 4-(4-methylpiperazin-1-yl)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide as a white solid (63 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.22 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.12-8.05 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 4.13-4.02 (m, 2H), 3.38-3.31 (m, 1H), 2.77-2.64 (m, 2H), 2.52-2.26 (m, 8H), 2.16 (s, 3H), 1.75-1.62 (m, 2H), 1.31-1.23 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 539.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1.Cl>[OH-].[Na+].C1COCC1.CO>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)/C=C/c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)propanoate (from Example 66) in 1 N NaOH, THF and methanol (1:5:2, 0.1 N) was heated at 60° C. for 3 hours. After cooling to room temperature the reaction mixture was neutralized with 1 N HCl to pH 7, and was concentrated to give a crude residue which was purified by chromatography (silica gel, 0-20% methanol in dichloromethane) to afford (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate as a white solid. 1H NMR: (methanol-d4): δ 8.73 (d, 1H), 8.54 (d, 1H), 8.20 (d, 1H), 7.45 (s, 1H), 7.37 (d, 1H), 7.00-6.97 (m, 2H), 6.92 (d, 1H), 3.19 (t, 2H), 3.04 (t, 2H), 2.81 (t, 2H), 2.53 (t, 2H), 2.50 (s, 3H), 2.25 (s, 3H). LRMS [M+H]=400.2
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[O:37][CH3:38])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccccc23)CC1
Yield: 47.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=102-104° C., as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[S:32]([Cl:48])([C:35]1[C:47]2[CH:46]=[CH:45][CH:44]=[C:40]([N:41]([CH3:43])[CH3:42])[C:39]=2[CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[ClH:48].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([C:35]3[C:47]4[C:39](=[C:40]([N:41]([CH3:43])[CH3:42])[CH:44]=[CH:45][CH:46]=4)[CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(N4CCCNCC4)cc3NS(=O)(=O)c3ccccc3)cccc12
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and dansylchloride (73 mg, 0.27 mmol) to give 51 mg AS purple solid. M+1 580.3 Calcd 580.20. 1HNMR δ 8.86 (d, 1H), 8.62 (d, 1H), 8.08-7.46 (m, 9H), 6.64 (d, 1H), 6.32 (dd, 1H), 6.14 (d, 1H), 3.53 (app t, 2H), 3.45 (s, 6H), 3.16-3.06 (m, 4H), 2.03-1.95 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: CN(Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccc(Br)cc1
Reaction time: 20 h
Yield: 56.7 %

Procedure:
N-benzyl-N-phenyl-N-methylamine (4.41 g, 0.0224 mol) was dissolved in anhydrous dichloromethane (150 mL) and 2,4,4,6-tetrabromocyclohexadiene-1-one (9.16 g, 0.0224 mol) was added in 10 equal portions over a 30 min. period. Stirring was continued at ambient temperature for 20 hours. The organic phase was successively washed with 0.5N solution of sodium hydroxide in water (100 mL), 1N solution of sodium hydroxide in water (100 mL), water (120 mL) and brine (120 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:99) as mobile phase to yield N-benzyl-N-(4-bromophenyl)-N-methylamine (3.52 g, 0.0127 mol) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.O.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.C(#N)C>[S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)([OH:43])(=[O:42])=[O:41].[O:17]=[C:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[O:6][C:5](=[O:7])[CH2:4][CH:3]([N:2]([CH3:9])[CH3:1])[CH3:8]
Reactant: CC(CC(=O)O)N(C)C
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC(CC(=O)ON1C(=O)CCC1=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.55 g (50 mMol) 3-dimethylamino-butyric acid 20 was added to 5.75 g (50 mMol) N-hydroxysuccinimide and 11.05 g (55 mMol) dicyclohexyl carbodiimide in 100 ml CH2Cl2. The reaction mixture was stirred for 16 h at RT. The obtained urea was filtrated and the solution was evaporated. The residue, dissolved in 10 ml acetonitrile, was added under stirring to a solution of 9.51 g (50 mMol) 4-toluenesulfonic acid monohydrate in acetonitrile (30 ml). The solvent was evaporated under vacuum and the product was recrystallized from acetonitrile or acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][C:17]([CH3:25])([CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)[OH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([C:17]([OH:18])([CH3:25])[CH3:16])[CH2:20]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: CC(C)(O)C1CCCNC1
Product: CC(C)(O)C1CCCN(C(=O)c2cnoc2-c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and dimethyl-3-piperidylmethanol (10.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.7 mg). Calcd for C18H21ClN2O3: 348.1241, found 348.1236.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a12) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>[OH-].[K+]>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1ccc(OC(C)(C)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(Oc1ccc(N)cc1)C(=O)O
Yield: 61.5 %

Procedure:
1.18 g (0.005 mol) of the 2-(4-acetaminophenoxy)-2-methyl propionic acid is boiled in 10% KOH (60 ml) for 1/2 hour. The solution is then cooled and acidified with acetic acid to yield 0.6 g (62% yield) of 2-(4-aminophenoxy)-2-methyl propionic acid as a yellowish white powder, mp 214°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1.ClC1C=C(Cl)C=CC=1C1[C:33]([C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42]C2C=CC([N+]([O-])=O)=CN=2)[N:29]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[C:33]([C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42][C:12]2[N:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)[N:29]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3F)n2)nc1

Procedure:
6-[(2-{[4-(2-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 2-fluorbenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(C(=O)c2ccnc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.40 g (1.8 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.18 g (0.60 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH2:16][O:17][CH2:18][CH2:19][C:13]=2[N:12]=1.[CH3:20]CN=C=NCCCN(C)C.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH3:20][C:44]1[CH:45]=[C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]4[NH:15][C:14]5[CH2:16][O:17][CH2:18][CH2:19][C:13]=5[N:12]=4)[CH:4]=3)[CH2:33][CH2:34]2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc2c([nH]1)COCC2
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C2CCN(C(=O)c3ccc(C)c(-c4nc5c([nH]4)COCC5)c3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A mixture of 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 1.11, 60 mg, 0.22 mmol, 1.00 equiv, 95%), EDCI (88.4 mg, 0.46 mmol, 2.00 equiv), DMAP (85.12 mg, 0.70 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52 mg, 0.23 mmol, 1.00 equiv) in DMF was stirred at room temperature. After 3 h, the reaction mixture was diluted with 40 mL of DCM and washed with 2×10 mL of NH4Cl (aq.sat.) followed by 2×10 mL of brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product (˜100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, WATER WITH 0.05% TFA and CH3CN (15.0% CH3CN up to 42.0% in 12 min, up to 100.0% in 1 min); Detector, uv 254/220 nm. The fractions containing pure compound were combined and lyophilized to yield 32.9 mg (34%) of the title compound as a white solid. m/z (ES+) 427 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.73-7.65 (m, 4H), 7.61 (d, J=5.7 Hz, 1H), 7.50 (d, J=6.0 Hz, 2H), 4.89-4.78 (1H partially obscured by water peak), 4.81 (s, 2H), 4.10 (t, J=4.1 Hz, 2H), 3.94-3.81 (m, 1H), −3.35 (1H partially obscured by methanol solvent peak), 3.08-1.95 (m, 2H), 2.92 (t, J=4.1 Hz, 2H), 2.52 (s, 3H), 2.08-1.92 (m, 1H), 1.92-1.65 (m, 3H). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.30 (s, 1H) 7.50 (m, 2H), 4.89 (d, J=13.0 Hz, 1H), 4.81 (s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.30 (t, J=13.0 Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s, 3H), 2.06 (d, J=13.7 Hz, 1H), 1.86 (d, J=12.9 Hz, 1H), 1.76 (q, J=12.8 Hz, 1H), 1.57 (q, J=11.7 Hz, 1H).
Reaction SMILES: C([NH:11][C@:12]([CH3:25])([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)(OCC1C=CC=CC=1)=O.[CH2:26](N(CC)CC)C.[Cl:33]C[CH2:35][C:36]([CH3:41])([CH3:40])[C:37]([O-:39])=[O:38].CN(C)C=O>O>[ClH:33].[OH:21][C:16]1[CH:15]=[C:14]([CH2:13][C@@:12]([CH3:25])([C:22]([O:24][CH2:26][O:39][C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[O:23])[NH2:11])[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: CCN(CC)CC
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(CCCl)C(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@](C)(N)Cc1ccc(O)c(O)c1
Product: Cl

Procedure:
A solution of 4.2 g. (0.012 mole) of racemic N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalanine, 1.3 g. (0.013 mole) of triethylamine and 1.26 g. (0.013 mole) of chloromethylpivalate in 20 ml. dimethylformamide is stirred at 90° C. for 20 hours and then poured into 200 ml. water. The product is extracted into 100 ml. of ethyl acetate and washed with 25 ml. of a saturated sodium bicarbonate solution and 25 ml. of water. After drying over anhydrous magnesium sulfate and filtering, the filtrate is concentrated under reduced pressure to give the N-carbobenzyloxy derivative of the desired ester. This material is dissolved in 100 ml. of absolute ethanol containing 10 ml. of a 9.6 N ethanolic-anhydrous hydrogen chloride solution and hydrogenated with 3 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 35 p.s.i. for 24 hours. After removing catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in 25 ml. of water, made basic with a saturated sodium carbonate solution to pH 8 and the insoluble product extracted with 100 ml. of ethyl acetate. After drying over anhydrous magnesium sulfate and filtering, 5 ml. of 9.6 N ethanolic anhydrous hydrogen chloride solution is added and the solution concentrated under reduced pressure to give 1.5 g. (22.6%) of the hydrochloride of the racemic pivaloyloxymethyl 3-(3,4-dihydroxyphenyl)-2-methylalaninate, homogeneous upon thin layer chromatography [fluorescent silica gel plate developd with a 5-2-3 (by volume) mixture of n-butanol-acetic acid-water] Rf=0.86.
Reaction SMILES: [OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[CH3:21][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[C:4]([CH3:21])=[C:3]1[CH3:11]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=CC(=O)CC1(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=C(C)C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 1a (27.8 g, 0.1 mole) in anhydrous tetrahydrofuran (THF, 600 ml) was cooled to 0° C. with an ice bath under an atmosphere of nitrogen. Lithium hexamethyl disilazane (1.0 M solution in THF, 150 ml) was added dropwise via a syringe over about 30 minutes. The resulting solution was stirred at 0° C. for 30 minutes and the ice bath was removed. A solution of methyl iodide (8.09 ml, 18.4 g, 0.13 mole) in anhydrous THF (20 ml) was added via a syringe over 20 minutes. The resulting solution was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (200 ml) and water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organic solution was dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column eluted with ethyl acetate and hexane. The title compound was obtained as a white solid (17.1 g). 1HNMR (CDCl3): δ7.84 (d, 1H), 6.16 (d, 1H), 5.75 (s, 1H), 3.70 (s, 3H), 2.44 (d, 1H), 2.34 (d, 1H), 2.00 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H). MS (ESI—): m/e=291.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(NC(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline (0.2 g, 0.7 mmol), cyclohexanemethylamirie (0.5 ml, 3.5 mmol) and DMSO (3 ml) is heated at 110° C. for 6 hours. The reaction mixture is poured into water (50 ml), extracted with CH2Cl2 (4×25 ml), and the organic layers are combined and evaporated. The residue is slurried in ether, and a yellow solid is collected by filtration and recrystallized from ethanol/ethyl acetate to afford 200 mg of 1-ethyl-6-acetamido-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 277°-278° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:11])([F:12])[F:10])=[CH:4][N+:3]=1[O-:18]
Reactant: Cc1cc(C(F)(F)F)cnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
A mixture of 2,3-dimethyl-5-trifluoromethyl-pyridine (0.700 g, 4.00 mmol), 3-chloroperoxybenzoic acid (77%, 2.8 g, 12 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 20 h. After that period of time saturated aqueous NaHCO3 (5 mL), and the mixture was extracted with CH2Cl2 (5×20 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed, and the residue was purified on silica gel column (EtOAc), affording 2,3-dimethyl-5-trifluoromethyl-pyridine 1-oxide as a pale yellow solid (0.620 g, 81%).