Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([CH2:11][NH:12]C(=O)OC(C)(C)C)=[C:6]([CH3:20])[CH:5]=2)[CH2:3][CH2:2]1.CCOC(C)=O.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:12][CH2:11][C:7]1[C:8](=[O:10])[NH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[CH3:20]
Reactant: Cc1cc(C2CC2)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C2CC2)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl [(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 min., followed by addition of 4M HCl in dioxane (5.03 mL, 20.12 mmol), and the contents were stirred at room temperature overnight. The volatiles were then removed in vacuo to afford a solid. The solid was triturated with ether, filtered, and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected as 0.22 g (100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (m, 2 H), 0.95-1.03 (m, 2 H), 1.83 (tt, J=8.46, 5.05 Hz, 1 H), 2.16-2.22 (m, 3 H), 3.75 (q, J=5.47 Hz, 2 H), 5.79 (s, 1 H), 8.02 (br. s., 3 H), 11.92 (br. s., 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[N:21]=[CH:20]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[N:21]=[CH:20]2)[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)OC(C)(C)C)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(F)ccc1Oc1ccc2c(cnn2C)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Intermediate (26t) (50 mg, 0.135 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (60%, 8.1 mg, 0.20 mmol) and methyl iodide (42 μL, 95.5 mg, 0.67 mmol) were added to the solution at 0° C. and then the mixture was allowed to warm to room temperature. After 1 hour of stirring, the mixture was poured into saturated NH4Cl solution and extracted 3 times with 30 mL of ether. The combined organic layer was washed with 5 mL of water twice and brine one, dried over MgSO4 and evaporated under reduced pressure. The pale yellow residue was purified on silica gel with EtOAc/hexane (1:2) to obtain compound (27t) as a colorless oil (52 mg, quantitative). 1HNMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.35 (s, 0.4H), 7.33 (s, 0.6H), 7.11 (s, 0.6H), 7.08 (s, 1.4H), 6.98 (d, J=8.6 Hz, 1H), 6.92-6.81 (m, 1), 6.81-6.73 (m, 1H), 4.49 (s, 0.8H), 4.45 (s, 1.2H), 4.04 (s, 3H), 2.89 (s, 1.8H), 2.85 (s, 1.2H), 1.45 (s, 3.6H), 1.41 (s, 5.4H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]([CH:15]=O)=[CH:13][C:12]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)(C)(C)C.CC1C2N(N=C(COC3C=CC=CC=3)C=2)CCN=1>>[O:18]([CH2:17][C:12]1[CH:13]=[C:14]2[CH:15]=[N:7][CH2:8][CH2:9][N:10]2[N:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCn1nc(COc2ccccc2)cc1C=O
Agent: CC1=NCCn2nc(COc3ccccc3)cc21
Product: C1=NCCn2nc(COc3ccccc3)cc21

Procedure:
The compound was prepared from [2-(5-formyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester using the method described in the preceding example 24 (4-methyl-2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([O:9][C:10]2[C:15]([CH2:16][N:17]([CH3:28])[CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:29])[N:13]=[C:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[C:37](=O)[CH2:38][CH3:39])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1>N1C=CC=CC=1>[CH:4]1([O:9][C:10]2[C:15]([CH2:16][N:17]([CH3:28])[CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:29])[N:13]=[C:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=3[C:37](=[N:2][OH:3])[CH2:38][CH3:39])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCC(=O)c1c(F)cccc1-c1cc(OC2CCCC2)c(CN(C)C2CCCc3ccccc32)c(C)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=NO)c1c(F)cccc1-c1cc(OC2CCCC2)c(CN(C)C2CCCc3ccccc32)c(C)n1
Temperature: 70 °C

Procedure:
Hydroxylamine hydrochloride (47 mg, 0.7 mmol) is added to a solution of 1-[2-(4-cylopentyloxy-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridin-2-yl)-6-fluoro-pheny]-propan-1-one (151 mg, 0.3 mmol) in pyridine at room temperature. The mixture is heated to 70° C. for 16 hours. Solvent is removed in vacuo and the crude product is purified by PTLC eluting with 2% MeOH in DCM to give the title product.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(=CC)C.Cl([O-])=[O:20].[Na+].Cl([O-])=O.P([O-])([O-])([O-])=O>O.CC(O)C.O1CCOCC1>[Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]([OH:20])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: Cn1c(Br)c(C=O)c2ccccc21
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cn1c(Br)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a vigorously stirred solution of 2.38 g (10 mmol) of 2-bromo-1-methylindole-3-carboxaldehyde [XXVI: R1 =H, R3 =CH3, X=Br], 10 mL of 2-methyl-2-butene, and 40 mL of p-dioxane at 25° C. was added dropwise over ca. 15 minutes a solution of 5 g (55 mmol) of sodium chlorite and 5 g (36 mmol) of NaH2PO4.H2O in 25 mL of water. The solution was maintained at 25° C. After 3.5 hours, the mixture was treated with an additional 2.5 g each of the chlorite and phosphate. After a total reaction time of 24 hours, the mixture was extracted 3 times with dichloromethane, then the aqueous phase was acidified to pH 2 with aqueous HCl, and extracted once more. The combined organic extracts were washed with water, dried, and evaporated to leave a solid residue that was boiled in 2 -propanol. After cooling, the solids were collected by filtration, washed with a little 2-propanol, and dried to leave 2.21 g (87%) of 2-bromo-1-methylindole-3-carboxylic acid [XXVII: R1 =H, R3 =CH3, X=Br] as a beige solid; mp ca. 198° C. (dec), in 2 crops.
Reaction SMILES: CO[C:3]([N:5]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]1=[O:11])=O.NC[CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17]>C(=O)([O-])O.[Na+]>[O:10]=[C:9]1[CH:8]=[CH:7][C:6](=[O:11])[N:5]1[CH2:3][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CC(C)(CCN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CCN1C(=O)C=CC1=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 1.39 g (8.95 mmol) of N-methoxycarbonylmaleimide in 44 ml of saturated sodium hydrogencarbonate solution were added, at 0° C., 1.5 g (8.95 mmol) of 4-amino-2,2-dimethylbutyric acid, and the mixture was stirred for 40 min. Subsequently, the cooling bath was removed and the reaction mixture was stirred for a further 1 h. While cooling with ice, the reaction mixture was then adjusted to pH 3 by adding sulphuric acid, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. 1.17 g (79% purity, 49% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:11])[NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (1.068 g, 5.71 mmol) and 4-amino-1-Boc-piperidine (1.0 g, 5 mmol) was dissolved in CH2Cl2 (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (1) (1.7 g, 4.39 mmol, 88%). 1H NMR (d6-DMSO, 300 Mhz): ∂ 8.77 (s, 1H), 7.55 (s, 4H), 6.26 (d, J=10 Hz, 1H), 3.80 (d, J=Hz, 2H), 3.64 (m, 1H), 2.88 (br, 2H), 1.78 (d, J=5 Hz, 2H), 1.38 (s, 9H), 1.23 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:25][CH:26]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)c1ccc(NC(c2cc3ccccc3s2)C2CCCCC2)cc1
Reactant: CCOC(=O)CCNC
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cc3ccccc3s2)C2CCCCC2)cc1

Procedure:
Using 4-{[1-benzothiophen-2-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above and ethyl 3-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4), the title object compound (277 mg, 90%) was obtained as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[CH:11][CH:10]=1.O>C1COCC1>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH3:25])[CH3:7])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(NCc2ccccc2N)cc1
Yield: 58.2 %

Procedure:
To a suspension of lithium aluminium hydride (0.61 g) in THF (30 ml) was added dropwise under ice-cooling a solution of N-(4-dimethylaminophenyl)-2-aminobenzamide (2.0 g) in THF (20 ml) and the mixture was heated finder reflux. To this mixture was added dropwise small portions of water, the insolubles were filtered, and the solvent was distilled off. Purification of the residue by a silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallization from ethyl acetate/hexane afforded N-(2-aminobenzyl)-N',N'-dimethyl-1,4-phenylenediamine (1.1 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc2cc(C(C)O)c(Cl)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a suspension of 2-chloro-8-methylquinoline-3-carboxaldehyde (10 g, 48.6 mmol) in dry THF (100 mL) under nitrogen cooled to −78° C. was added dropwise over 1 h methylmagnesium bromide (40 mL, 121.6 mmol, 3.0M solution in Et2O). The reaction was allowed to warm to r.t. and stirred for a further 1 h before being poured slowly into NH4Cl solution (100 mL). The mixture was extracted with EtOAc (2×200 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as an off-white solid (8.0 g, 74%). δH (CDCl3) 8.33 (s, 1H), 7.68 (d, J 8.0 Hz, 1H), 7.55 (d, J 7.2 Hz, 1H), 7.44 (t, J 7.6 Hz, 1H), 5.34-5.40 (m, 1H), 2.77 (s, 3H), 1.61 (d, J 6.4 Hz, 3H). LCMS (ES+) 222, 224 (M+H)+, RT 3.01 minutes (Method 5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCO
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: CC(=O)n1ccc(=O)c(O)c1C
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with 1-amino-5-hydroxypentane under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one as white crystals, m.p. 136°-138° C.; δmax (nujol) 1625, 3350 cm-1 : δ(d6DMSO) 1.3 (m, 6H), 2.40 (s, 3H), 3.25 (t, 2H), 4.20 (t, 2H), 7.20 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]2[CH2:40][CH2:41][CH2:42][CH:36]2[CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][N:37]3[CH2:40][CH2:41][CH2:42][CH:36]3[CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCN2CCCC2C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN4CCCC4C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 2-((2-bromophenyl)sulfonyl)octahydropyrrolo[1,2-a]pyrazine. MS (ESI): mass calcd. for C23H24FN5O2S, 453.16; m/z found, 454.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J=1.4, 1H), 8.24 (d, J=1.4, 1H), 8.17-8.13 (m, 1H), 7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.48-7.45 (m, 1H), 7.36-7.30 (m, 2H), 3.89-3.35 (m, 4H), 3.26-2.53 (m, 6H), 2.18-1.97 (m, 3H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](=O)[CH2:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13]1>C(#N)C>[CH2:3]([N:10]1[C:22]([C:20]2[CH:19]=[CH:18][C:17]3[O:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:21]=2)=[CH:23][C:24]([C:25]([F:28])([F:26])[F:27])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc2c(c1)CCCO2
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: FC(F)(F)c1cc(-c2ccc3c(c2)CCCO3)n(Cc2ccccc2)n1
Yield: 39.7 %

Procedure:
A solution of benzylhydrazine dihydrochloride (394 mg, 2.03 mmol) and 1-(3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,4-trifluorobutane-1,3-dione (49b) (500 mg, 1.84 mmol) in acetonitrile (80 mL) was refluxed for 16 hours. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate (5 mL). The organic layer was successively washed with water (10 mL) and brine (10 mL) before being dried over sodium sulfate and concentrated in vacuo. The oil was purified by preparative TLC (cyclohexane/ethyl acetate 100/0 to 90/10) to provide the desired pyrazole (49c) (260 mg, 0.73 mmol, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)([O-:3])=[O:2].[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a solution of 1-(2-nitro-4-bromophenyl)indoline (15 g, 0.047 moles) in dimethylformamide (150 ml) at -10° C. was added dropwise a solution of N-bromosuccinimide (9.4 g, 0.054 mole) in dimethylformamide (50 ml) over 10 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. The solution was added slowly to water (1 1) with vigorous stirring. The solid was filtered, dried, and dissolved in dichloromethane (300 ml). The solution was added to boiling methanol (1 1). The precipitate was collected by filtration to give 12.7 g (68%) of product, mp 150°-152° C.
Reaction SMILES: [C:1]([C:3]1[N:13]=[CH:12][C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)#[N:2].C([Sn]([N:27]=[N+:28]=[N-:29])(CCCC)CCCC)CCC>COCCOCCOC>[NH:27]1[C:1]([C:3]2[N:13]=[CH:12][C:6]3[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=3[CH:4]=2)=[N:2][N:29]=[N:28]1
Reactant: N#Cc1cc2c(=O)[nH]cnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: COCCOCCOC
Product: O=c1[nH]cnc2cnc(-c3nnn[nH]3)cc12
Yield: 440.9 %

Procedure:
6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3 g) in diglyme (2 ml) was treated with tributyl tin azide (0.49 g) at reflux under N2 for 15 hours. The cooled mixture was partitioned between ethyl acetate and water and the aqueous phase extracted further with ethyl acetate. The aqueous phase was concentrated in vacuo, the residue taken up in methanol and inorganics removed by filtration. Subsequent concentration gave the title compound (1.4 g) as a beige solid; δH [2H6]DMSO 8.96 (1H,s), 8.50 (1H,s), 8.27 (1H,s); m/z (M+1+) 216.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (30.00 mL) was cooled to −10° C. with an ice/salt bath. To this, 1,2,3,4-tetrahydro-quinoline (10.60 g, 75.60 mmol) and a solution of nitric acid (99.5%, 4.80 g, 75.60 mmol) in sulfuric acid (15.00 mL) were added simultaneously within 1 hour, so that the temperature of the reaction mixture does not exceed 10° C. The mixture was stirred then for 2.5 hours at −5° C., then poured over ice and treated with sodium carbonate (0.10 kg) until pH 8-9 was reached. The solid was filtered, washing with water, then dissolved in dichloromethane. The organic phase was washed with water, dried over magnesium sulphate and evaporated. 7-Nitro-1,2,3,4-tetrahydro-quinoline was obtained as a viscous brown oil, 13.70 g (85%), 84% purity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:5][C:6](=[O:23])[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:29].[H][H]>CO.[Pd]>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:5][C:6](=[O:23])[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(C)C

Procedure:
A solution of 1.95 g. of Nα -benzyloxycarbonyl-D-leucyl-L-leucine methyl ester in 50 ml. of absolute methanol containing 2.08 ml. of 2.38N hydrogen chloride in methanol is treated with 250 mg. of 10% palladium on carbon and is shaken in a hydrogen atmosphere until thin layer chromatography of solution samples indicate completion of the reaction. The catalyst is removed by filtration and the filtrate taken to dryness. The product is used without further purification.
Reaction SMILES: [CH:1]1(/[C:4](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5]\[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[CH:5]=[C:4](\[CH:1]2[CH2:3][CH2:2]2)/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)C2CC2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
As in Example 115, (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid (2.7 g) and 4-nitrophenol (1.844 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.3 g) and the mixture was stirred at room temperature overnight. After the usual work up, the ester was crystallized from 2-propanol to yield 2.8 g of (E,E)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 111°-112.5° C.
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.[C:21]([O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([NH:32][C:33](=[O:35])[CH3:34])=[CH:27][C:26]=1[CH3:36])(=[O:23])[CH3:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[C:21]([O:24][C:25]1[CH:30]=[C:29]2[C:28](=[CH:27][C:26]=1[CH3:36])[N:32]([C:33](=[O:35])[CH3:34])[N:13]=[CH:31]2)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1cc(C)c(OC(C)=O)cc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1cc2cnn(C(C)=O)c2cc1C
Reaction time: 9 h
Yield: 45.6 %

Procedure:
Acetic anhydride (0.96 ml, 10.2 mmol), tetrabutylammonium bromide (55 mg, 0.169 mmol), potassium acetate (665 mg, 6.78 mmol) and isoamyl nitrite (0.592 ml, 4.41 mmol) were added to a solution of 4-(acetylamino)-2,5-dimethylphenyl acetate (750 mg, 3.39 mmol) in ethyl acetate (7.5 ml) at room temperature, and the resulting mixture was refluxed. After 9 hours, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 1-acetyl-6-methyl-1H-indazol-5-yl acetate (359 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([CH3:30])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)cc1C
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)c(C)c3)cccc2c1N
Yield: 74.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (125 mg, 0.40 mmol) and (4-methoxy-3-methylphenyl)boronic acid (133 mg, 0.80 mmol) were reacted to afford the title compound (105 mg, 75% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.59 (bs, 1H), 7.76-7.82 (m, 2H), 7.67-7.72 (m, 1H), 7.53 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (m, 1H), 6.96 (d, J=8.2, 1H), 3.89 (s, 3H), 3.46 (apparent q, J=6.7 Hz, 2H), 2.30 (s, 3H), 1.67(apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=351 (M+H) HPLC 1.88 min.