Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:36](O)([C:38](F)(F)F)=O.C([O-])(O)=O.[Na+].C(Cl)(=O)CC>C(Cl)Cl.CCOC(C)=O>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:38])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH2Cl2 (100 mL), was added TFA (41.8 mL) and the mixture stirred at rt for 1 h. Concentrated in vacuo and partitioned between 2M NaOH(aq) (300 mL) and CH2Cl2 (200 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (2×200 mL). The organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown foam. The foam was dissolved in CH2Cl2 (50 mL) and was added simultaneously portionwise with sat.NaHCO3(aq) (50 mL) to a vigourously stirring solution of propionyl chloride (2.63 g, 28.5 mmol) in CH2Cl2 (50 mL) at rt. The resulting biphasic mixture was stirred at rt for 1 h. Further propionyl chloride (0.566 g, 6.12 mmol) was added and continued stirring vigorously for 20 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (100 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give a brown gum. The gum was stirred in EtOAc (100 mL) and the resulting solid filtered (9.4 g). The mother liquors were concentrated in vacuo and purified by column chromatography through a Biotage® amino silica gel eluting with EtOAc/MeOH, 100/0 to 90/10 to give a yellow foam which was then stirred in EtOAc (20 mL) and the resulting solid filtered (870 mg). Both batches of solids were combined and stirred in refluxing EtOAc (50 mL) for 1 h. Filtered to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (9.42 g, 76% yield). 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.05 (m, 3H) 1.87-2.32 (m, 4H) 2.77-2.86 (m, 2H) 3.25-3.88 (m, 6H) 3.93 (s, 3H) 3.98 (s, 2H) 4.55-4.80 (m, 1H) 6.70-6.80 (m, 1H, N—H) 7.86-7.92 (m, 1H) 8.27-8.33 (m, 1H) 8.33-8.37 (m, 1H) LCMS: [M+H]+=451.0, Rt(6)=1.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)=[O:4].[Br:16][CH2:17][C:18](Br)=[O:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18](=[O:19])[CH2:17][Br:16])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Yield: 63.6 %

Procedure:
4-Methoxycarbonylamino-2-nitroaniline (30 g) was dissolved in toluene (300 ml) and the solution treated with bromoacetyl bromide (28.7 g). The mixture was refluxed for 3 hours and toluene (300 ml) was added. The hot mixture was filtered and the filtrate allowed to cool to give N-(4-methoxycarbonylamino-2-nitrophenyl)-2-bromoacetamide (30 g), m.p. 160°-162° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]3[CH2:11][CH:6]([CH2:7][CH2:8]3)[C:5]=2[C:4]([CH2:12][O:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.C(Cl)Cl.O.NN>C(O)C>[NH2:14][O:13][CH2:12][C:4]1[C:5]2[CH:6]3[CH2:11][CH:9]([CH2:8][CH2:7]3)[C:10]=2[N:2]([CH3:1])[N:3]=1
Reactant: Cn1nc(CON2C(=O)c3ccccc3C2=O)c2c1C1CCC2C1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cn1nc(CON)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a mixture of 2-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methoxy]-1H-isoindole-1,3(2H)-dione 148 (1.80 g, 5.57 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.32 mL, 5.57 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 149 (0.68 g, 64%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([CH:14]=[O:15])[S:13][C:8]=2[CH:7]=1)=[O:5])C.[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[CH:14]([C:12]1[S:13][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][C:9]=2[CH:11]=1)=[O:15]
Reactant: CCOC(=O)c1cc2sc(C=O)cc2[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: O=Cc1cc2[nH]c(C(=O)O)cc2s1

Procedure:
2-Formyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see, for example, Gale, W. W. et al., J. Org. Chem., 29: 2160-2165 (1964)) was hydrolyzed according to Procedure F (50° C. overnight; acidified aqueous phase extracted with ethyl acetate; combined organic phases dried over MgSO4, concentrated).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C4C=CC=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.N>C1COCC1.CO>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:41][C:39]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=2)=[O:40])=[CH:11][CH:10]=3)[N:16]=1
Reactant: COc1cnc(C(N)=O)cn1
Reactant: O=C(NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCOC(N)=N2)c2cc(Br)cnc2O3)cn1
Reaction time: 5 h

Procedure:
The title compound was synthesized analogous to step 1 (Method D) described in example 34, but using (S)—N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide (88 mg, 0.153 mmol, Intermediate 24B) and 5-methoxypyrazine-2-carboxamide (28.1 mg, 0.183 mmol). The residue from step 1 was dissolved in THF (1 mL) and treated with ammonia (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) at 50° C. After 12 hours another portion of ammonia, (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) was added and the reaction mixture was allowed to stir for additional 5 hours The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 10 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-methoxypyrazine-2-10 carboxamide were obtained as an off-white solid. MS m/z=497.1 [M]+. Calculated for C21H17BrN6O4: 497.30. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1H) 1.94-2.04 (m, 1H) 4.08 (s, 3H) 4.11-4.18 (m, 1H) 4.20-4.30 (m, 1H) 7.31 (d, J=9.21 Hz, 1H) 7.69-7.77 (m, 2H) 7.94 (d, J=2.34 Hz, 1H) 8.18 (d, J=1.32 Hz, 1H) 8.32 (d, J=2.48 Hz, 1H) 9.04 (d, J=1.32 Hz, 1H) 9.55 (s, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:18][NH2:19])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].CCN(CC)CC.Cl>C1COCC1.CN(C=O)C>[O:26]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:16]4[O:17][C:27](=[O:28])[NH:19][N:18]=4)[CH:20]=[CH:21][CH:22]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2cccc(Oc3ccc4c(c3)S(=O)(=O)N=C3CCCN34)c2)o1

Procedure:
A suspension of 150 mg (0.40 mmol) of the product obtained in Step B, 85 mg (0.52 mmol) of 1,1′-carbonyldiimidazole and 95 μl (0.68 mmol) of Et3N in a mixture of THF (3.7 ml) and DMF (3.7 ml) is refluxed for 3 hours. The mixture is allowed to return to ambient temperature and is acidified with 1N HCl. A white precipitate forms, which is filtered off to yield the title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN1C(=O)N(C)CCC1.O>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:7]=[C:6]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)[N:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1cc(C)cc(-c2cc(-c3cc(C)cc(C)c3)ncn2)c1
Reaction time: 1 h

Procedure:
In a recovery flask equipped with a reflux pipe were put 5.97 g of 4,6-dichloropyrimidine, 12.04 g of 3,5-dimethylphenylboronic acid, 8.48 g of sodium carbonate, 0.34 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (abbreviation: DMPU), and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, in the flask were further put 2.58 g of 3,5-dimethylphenylboronic acid, 1.78 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of DMPU, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (49 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 8.45 (s, 1H), 7.50 (br, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.21 (m, 3H), 7.13 (d, J=7.8 Hz, 1H), 6.87 (br, 2H), 4.31 (q, J=7.0 Hz, 2H), 3.69 (br, 4H), 2.96 (t, J=7.4 Hz, 2H), 2.91 (t, J=7.4 Hz, 2H), 2.67 (br, 2H), 2.46 (br, 6H), 2.17 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[N:15][CH:16]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1>[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]56[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]5)[O:25][CH2:24]6)=[CH:19][CH:18]=4)=[N:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)CO2
Temperature: 25 °C
Reaction time: 7 h
Yield: 41 %

Procedure:
To a mixture of methyl 2-(4-(4-(5-(5-cyclobutyl-1,3,4-oxadiazol-2-ylamino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (38 mg, 0.08 mmol) and THF (1 ml) was added NaOH (0.24 ml, 0.24 mmol). The mixture was stirred at room temperature for 7 hour. The resulting content was concentrated and purified on prep-HPLC to afford the title compound as white solid after drying (15 mg, 41% yield). HR/MS (M+H)+ found 461.2188. calc. 461.2184. RT: 5.63 (Condition Z). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.13 (m, 10H) 2.27-2.40 (m, 6H) 3.69 (quind, J=8.43, 8.43, 8.43, 8.43, 0.88 Hz, 1H) 3.91 (s, 2H) 7.41 (d, J=8.59 Hz, 2H) 7.90-8.01 (m, 3H) 8.10 (dd, J=8.59, 2.78 Hz, 1H) 8.75 (d, J=3.03 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: ClCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCCCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
4-Cyano-3-hydroxybenzoic acid methyl ester, Example 34 Step 3 (300 mg, 1.7 mmol) was dissolved in DMF (85 ml) and treated with phenylbutylchloride (287 mg, 1.7 mmol). Cs2CO3 (610 mg, 1.87 mmol) was then added and the reaction mixture stirred at room temp. for 18 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:24]1([NH:30][N:31]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=NNc2ccccc2)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
One gram of 3,5-di-t-butyl-4-hydroxybenzophenone and 880 mg of phenylhydrazine were refluxed under heating in 30 ml of benzene in the presence of 20 mg of p-toluenesulfonic acid for 3.5 hours. The reaction mixture was poured into water and extracted with benzene. The extract was chromatographed on a silica gel column, and recrystallized from diethyl ether/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone phenylhydrazone as colorless needles.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH:16]([CH3:18])[CH3:17])[O:10]C1(C)C)=O)(C)(C)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH2:32])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[NH2:8][C@H:12]([C:13]1[NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:26][C:27]=2[N:32]=1)[C@H:11]([OH:10])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Product: CC(C)[C@@H](O)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 60) and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[C:53]1([N:59]=[C:60]=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:60]([NH:59][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:61])[CH2:48][CH2:47]1
Reactant: Clc1cnc2nc1Nc1ccc(OCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCC(COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z=556.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[NH2:36].CCCCCC>CCOC(C)=O>[CH3:25][O:26][C:27](=[O:37])[C:28]1[C:33]([Cl:34])=[CH:32][C:31]([Cl:35])=[CH:30][C:29]=1[NH:36][C:16](=[O:18])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Br:20])[CH:11]=1)[CH3:19]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2)c(Br)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 70.6 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-benzyloxy-3-bromo-phenyl)-propionic acid (1.0 g, 3.00 mmol), SOCl2 (1.10 mL, 14.9 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.50 g, 2.40 mmol). After normal workup, the pure objective compound (0.91 g, 71%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.53 (s, 3H, CH3), 3.62 (q, J=7.1 Hz, 1H, CH), 3.79 (s, 3H, CO2CH3), 5.16 (s, 2H, CH2Ph), 6.94 (d, J=8.4 Hz, 1H, ArH), 7.15 (d, J=2.30 Hz, 1H, ArH), 7.20 (dd, J=8.6, 2.0 Hz, 1H, ArH), 7.31-7.48 (m, 5H, ArH), 7.54 (d, J=2.4 Hz, 1H, ArH), 8.41 (d, J=2.0 Hz, 1H, ArH), 9.15 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid (669, 2.0 g, 0.0076 mol) in methanol (20.0 mL) was added sulfuric acid (0.90 mL, 0.017 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified with silica gel column chromatograph eluting with 20% ethyl acetate in hexane to give a white solid (670, 1.27 g, 62%). MS (ESI) [M−H+]−=274.1.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[C:9]([O:10][CH3:11])=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:11][O:10][C:9]1[C:4]([C:3]([OH:16])=[O:2])=[CH:5][N:6]=[CH:7][C:8]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cncc(C(=O)OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cncc(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 5.3 g (23.5 mmol) of methyl-4-methoxy-5-methoxycarbonyl-nicotinate in 150 ml of methanol and 50 ml of water is added a solution of 0.94 g (23.5 mmol) of sodium hydroxide in 10 ml of water. The resulting mixture is stirred at room temperature overnight. The methanol is removed under vacuum, the aqueous solution is made slightly acidic and extracted with ethyl acetate. The combined organic phases are dried and filtered through silica. The filtrate is evaporated to near dryness and diluted with diisopropyl ether. A precipitate is obtained, filtered off and dried. There is obtained 2.83 g (57% yield) of a white solid (M+1=212).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[C:36]2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=C[C:35]=2OC1>C(O)CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:36][OH:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: OCCO
Product: COc1ccccc1C(OCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-hydroxyethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and ethane-1,2-diol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]I>>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1Br
Reactant: CI
Product: COC(=O)C=Cc1ccccc1Br

Procedure:
Esterification of 2-bromocinnamic acid (10.0 g) with methyl iodide (9.4 g) as described in Example 1 gave the title compound as an oil which was purified by chromatography on silica eluting with chloroform in quantitative yield. υmax (film) 1725, 1640, 1470, 1440 cm-1, δ(CDCl3) 3.79 (3H, s, CH3), 6.30 (1H, d, J 16 Hz, C=CHCO2), 7.19 (2H, complex m), 7.50 (2H, complex m), 7.97 (1H, d, J 16 Hz, ArCH=C).
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11]2)CCC.[BrH:24].C(O)(=O)C>>[Br:24][CH2:17][CH:16]([C:10]1[C:9]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:8]=2[C:7]2[C:6](=[O:5])[NH:15][CH:14]=[CH:13][C:12]=2[N:11]=1)[CH3:18]
Reactant: Br
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Solvent: CC(=O)O
Product: CC(CBr)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12

Procedure:
A solution of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (26 mg, 0.063 mmol) in HBr/acetic acid (33% wt) (1.0 ml) was stirred for 18 hr at room temperature. The reaction mixture was concentrated to a crude solid that was taken up into acetonitrile (5 mL) and concentrated again in an attempt to drive off more acetic acid. The resulting solid was triturated with EtOAc (1 mL), then collected by vacuum filtration to afford 6-(2-bromo-1-methylethyl)-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one (HBr salt). LRMS (ESI) calc'd for (C15H12BrFN2O) [M+H]+, 335.0; found 335.0.