Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1)([CH3:20])[CH2:9][O:10][C@@:11]([C:17](=O)[NH2:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N.CO>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1)([CH3:20])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:14])([F:15])[F:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C(N)=O)C(F)(F)F)c1cccc(Br)n1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C#N)C(F)(F)F)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an at 0° C. per cooled solution of [(RS)-1-(6-bromo-pyridin-2-yl)-2-((R)-1-carbamoyl-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-carbamic acid tert-butyl ester (2.18 g, 4.64 mmol) and NEt3 (1.615 ml, 1.173 g, 11.59 mmol) in DCM (30 ml) was added dropwise TFAA (0.773 ml, 1.168 g, 5.56 mmol). After stirring for 5 min at 0° C., then for 1 h at rt the reaction mixture was diluted with sat. aq. Na2CO3 soln. and with DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated to leave a pale yellow oil which was stirred with 7N NH3/MeOH for 5 min. The mixture was evaporated to dryness and purified by flash chromatography (cyclohexane: EtOAc 0-3 min 100:0, 3-35 min 65:35) to yield the title compound as a clear oil.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:5]([CH2:22][CH3:23])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1[C:20]#[N:21])[CH3:4]>CS(C)=O>[CH2:22]([N:5]([CH2:3][CH3:4])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:18][CH3:19])[C:7]=1/[C:20](=[N:1]/[OH:2])/[NH2:21])[CH3:23]
Reactant: NO
Reactant: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Solvent: CS(C)=O
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1/C(N)=N/O
Temperature: 160 °C
Yield: 32.7 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.45 mL, 7.3 mmol) was added to 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (16 mg, 0.06 mmol) dissolved in DMSO (1 mL) in a microwave vial. The reaction was heated at 160° C. in the microwave for 30 min. Purification using preparative HPLC gave (Z)-5-(diethylamino)-3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-1H-pyrazole-4-carboximidamide (6.22 mg, 35%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 318.29 (M+H), 316.32 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.40 (m, 2H), 6.90 (m, 2H), 2.96 (q, 4H, J=7.2 Hz), 2.65 (q, 2H, J=7.4 Hz), 1.19 (t, 3H, J=7.4 Hz) and 0.95 (t, 6H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:39][N:20]1[CH:19]=[C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]2)[C:21]1=[O:38]
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: Cn1cc(Br)nc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)c1=O
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cn(C)c(=O)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.49711 mmol; 105 mg), tert-butyl N-[(3S)-1-(6-bromo-4-methyl-3-oxo-pyrazin-2-yl)-3-piperidyl]carbamate (0.6016 mmol; 233 mg), N,N′-Dimethylethylenediamine (0.049711 mmol; 4.382 mg; 0.00495 mL), copper iodide (0.49711 mmol; 95.629 mg), and potassium carbonate (0.99422 mmol; 138.79 mg) in 1,4-dioxane (10 ml) was purged with argon, then sealed and stirred at 100° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to % MeOH in DCM to afford tert-butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidyl]carbamate (181.4 mg, 70%).
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[CH3:18][Mg]Br.[NH4+].[OH-]>O1CCCC1.CCOCC>[CH3:18][CH:13]1[NH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH2:1][CH2:2][C:3]3=[CH:4][CH:5]=[CH:6][C:7]1=[C:8]23
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Reactant: C[Mg]Br
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1Nc2ccccc2N2CCc3cccc1c32

Procedure:
To a stirred solution of 2.00 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 40 ml of tetrahydrofuran, cooled under N2 to 0° C., is added dropwise 10 ml of a 2.5 molar solution of methyl magnesium bromide in ether. The reaction mixture is refluxed for 3 hours, cooled, and treated cautiously with saturated aqueous NH4OH solution. The mixture is partitioned between CH2Cl2 and water. The organic phase is separated, washed once with brine, dried over Na2SO4 and concentrated to a solid of 6-methyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 134°-136° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1.CN(C=O)C>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 124.3 %

Procedure:
To a 2 L 3-neck round bottom flask outfitted with an addition funnel and thermometer were added anhydrous THF (700 mL) and NaH (60 wt %, 3.90 g, 97.5 mmol). The suspension was cooled in an isopropanol/dry ice bath until the internal temperature was about −20° C. (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (20.0 g, 92.9 mmol) dissolved in anhydrous THF (300 mL) was added dropwise via the addition funnel maintaining the internal temperature between −20° C. to −15° C. Once the addition was complete, the reaction was stirred for 45 minutes at a temperature between 0° C. to 10° C. The reaction was then cooled to −70° C. and a solution of 2,6-dinitrobenzonitrile (19.9 g, 103 mmol) in anhydrous DMF (200 mL) was added dropwise via the addition funnel. The reaction was allowed to warm up gradually to room temperature overnight and THF was removed under reduced pressure. The remaining solution was cooled in an ice bath and treated with a cooled saturated NH4Cl solution (200 mL). The resulting mixture was diluted with EtOAc and successively washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (41.74 g) as an orange solid. MS 262 (MH+-Boc). This material was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[S:24][CH:25]=1.ClC1C=CC=CC=1C(N)=S.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[S:24][CH:25]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: ClCc1csc(-c2ccccc2Cl)n1
Agent: NC(=S)c1ccccc1Cl
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccccc3Cl)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-thiazole (prepared from 2-chloro-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(2-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: NC1N=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.[CH3:21][C@@H:22]1[N:27]([C:28]2[CH:29]=[N:30][C:31]([N+:34]([O-])=O)=[CH:32][CH:33]=2)[CH2:26][CH2:25][N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]1>>[C:40]([O:39][C:37]([N:24]1[CH2:25][CH2:26][N:27]([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[C@@H:22]([CH3:21])[CH2:23]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Yield: 93.1 %

Procedure:
Following the procedures as described for compound 101h, hydrogenation of 130a (5.8 g) afforded 130b as a brown solid (4.9 g, 96%). LCMS: [M+H]+ 293
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:5][CH2:6]1)(=[O:26])[CH3:25]
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A mixed solution of 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (free base, 0.30 g, 0.96 mmol) and acetic anhydride (0.11 ml, 1.16 mmol) in ethyl acetate (25 ml) was heated at 55-60° C. with stirring for 1 hour. The solvent was then distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to provide the title compound (0.185 g) as colorless powders melting at 160-161° C.
Reaction SMILES: ClC1C(Cl)=C(OCC(OC(C)(C)C)=O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1.[Cl:28][C:29]1[C:41]([Cl:42])=[C:40]([O:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[CH:39]=[C:38]2[C:30]=1[C:31]1[C:36]([CH2:52][CH2:53][CH3:54])([CH2:37]2)[CH2:35][CH2:34][C:33](=[O:55])[CH:32]=1>>[Cl:28][C:29]1[C:41]([Cl:42])=[C:40]([O:43][CH2:44][C:45]([OH:47])=[O:46])[CH:39]=[C:38]2[C:30]=1[C:31]1[C:36]([CH2:52][CH2:53][CH3:54])([CH2:37]2)[CH2:35][CH2:34][C:33](=[O:55])[CH:32]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C)c(Cl)c1Cl)C2
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Carrying out a reaction as described in Example 53, Step B, except that the tert.-butyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate is replaced by an equimolar amount of tert.-butyl [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate, thereby is obtained [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)C)cc2)cc1

Procedure:
The colourless solid, (E)-ethyl 3-(4′-isopropyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 4-isopropylphenyl boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[Na].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl) pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ehtoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([O:21]C)=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)O
Yield: 48 %

Procedure:
N-[2-(S)-N(1-(R)-Methoxycarbonylethyl)amino-4,4-dimethylpentanoyl]-L-alanine N-butylamide (65 mg) in methanol (30 ml) was treated with IN-sodium hydroxide (3 ml) at 20° for 6 h. Excess acetic acid was then added and the solvent evaporated in vacuo. The residue was chromatographed on reverse phase silica (RF 18) in a gradient of 20%-80% methanol in water. Elution in 70% methanol in water afforded the title compound (30 mg) as a freeze-dried powder, m.p. 137°-138°; (Found: [m+1]+ =344.2548. C17H34N3O4 requires [m+1]+ =344.2549); δ(D2O) 0.9 (3H,t,J=6 Hz,CH2CH3); 0.94 (9H,s,C(CH3)3); 1.2-1.8 (6H,m,(CH2)2 and CH2); 1.4 (3H,d,J=8 Hz,CH3); 1.52 (3H,d,J=7 Hz,CH 3); 3.18 (2H,t,J=6 Hz,NHCH2); 3.66 (1H,q,J=5 Hz,CHCO); 3.88 (1H,d,J=10 Hz,CHCH2) and 4.38 (1H,q,J=5 Hz,CHCH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl(3-hydroxyphenyl)carbamate (3.02 g, 14.4 mmol) and potassium carbonate (2.99 g, 21.7 mmol) in N,N-dimethylformamide (35 mL) was added 2-chloro-5-nitropyridine (2.52 g, 15.9 mmol), and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 50 mL). The organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl{3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate as a yellow solid. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].P(S)(OCC)(OCC)=[S:14]>O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[S:14]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCOP(=S)(S)OCC
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of methyl 4-cyanobenzoate (5.0 g, 31.0 mmol) and O,O-diethyl hydrogen dithiophosphate (10.41 g, 62 mmol) in water (100 mL) was stirred at 80° C. for 16 h under N2. The mixture was cooled to 20° C. and filtered. The precipitate was washed with water (50 mL) and dried under vacuum to give crude methyl 4-(aminocarbothioyl)benzoate (5.93 g, 98%) as a yellow powder: mp (water) 181-184° C.; 1H NMR δ 10.04 (br s, 1H, NH2), 9.65 (br s, 1H, NH2), 7.83-8.00 (m, 4H, H-2, H-3, H-5, H-6), 3.88 (s, 3H, OCH3); MS m/z 196.5 (MH+, 100%). A mixture of the crude benzoate (5.72 g, 29.2 mmol) and dichloroacetone (3.72 g, 29.3 mmol) in anhydrous DMF (50 mL) was stirred at 80° C. under N2 for 16 h. The mixture was cooled to 20° C. and poured into ice/water (400 mL) and stirred for 30 min. The precipitate was filtered, washed with water (30 mL) and dried. The residue was purified by column chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give benzoate 51 (5.40 g, 69%) as a white powder: mp (EtOAc/pet. ether) 110-111° C.; 1H NMR (CDCl3) δ 8.11 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-2, H-6), 8.02 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-3, H-5), 7.38 (s, 1H, H-5′), 4.76 (s, 2H, CH2Cl), 3.95 (s, 3H, OCH3); MS m/z 268.6 (MH+, 100%). Anal. calcd for C12H10ClNO2S: C, 53.83; H, 3.76; N, 5.23. Found: C, 53.77; H, 3.72; N, 5.03%.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 72 h
Yield: 89.2 %

Procedure:
Toluene (0.7 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.35 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-chlorophenyl boronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (43 mg, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:24]=S>CO>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]1[O:14][C:3]2[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cc1cccc(Cl)c1N=C=S
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3c(C)cccc3Cl)oc2c1F
Reaction time: 120 h
Yield: 90.8 %

Procedure:
Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol) was dissolved in methanol (30 ml). To the resulting solution was added 2-chloro-6-methylphenyl isothiocyanate (841 mg, 4.58 mmol) at room temperature. After the resulting mixture was stirred for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 23 hours. After cooling, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1) eluate fractions, methyl (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.45 g, 95%) was obtained as a red amorphous substance.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][N:3]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: COC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (90 mg, 0.35 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with acetic ether (15 mL×3). The combined organic phase was dried by sodium sulfate, then filtered. The filtrate was concentrated in vacuum to give 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid (60 mg, 70%). LRMS (M+H)− m/z: cald. 243.09. found 243.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][CH:29]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH:29]([CH3:28])[CH2:33][C:32]=3[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.42 g, 100%).