Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]2=[O:22])[S:5][C:6]=1[C:7](O)=[O:8].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C)C=O>[CH2:53]([NH:60][C:7]([C:6]1[S:5][C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]2=[O:22])=[N:3][C:2]=1[CH3:1])=[O:8])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid (0.20 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.23 g, 1.67 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.15 g, 0.77 mmol), N,N-diisopropylethylamine (0.11 g, 0.83 mmol), and benzylamine (0.084 mL, 0.77 mmol). The reaction mixture was stirred at ambient temperature for 5 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (0.12 g, 47%): mp 235-237° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.8 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 7.87-7.77 (m, 2H), 7.52-7.49 (m, 3H), 7.34-7.18 (m, 5H), 7.08-7.00 (m, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.4, 153.7, 151.4, 150.6, 139.9, 135.9, 131.6, 130.9, 129.7, 128.8, 127.8, 127.5, 127.3, 124.5, 43.2, 17.6; MS (ES+) m/z 402.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)NC=C2C1CCN(C)CC=1.C[OH:36]>[Pt]>[CH:19]1([O:36][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:20][CH2:21][CH2:25][CH2:26][CH2:27]1
Reactant: CO
Reactant: CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: [Pt]
Product: CN1CCC(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
5-Chloro-3-(1-methyl-4-piperidinyl)indole: (0.89 g, 88%); from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4d, 1.0 g, 4 mmol) and 5% Pt/C (0.78 g, 0.2 mmol) in methanol under H2 ; mp 192-4° C.; HRMS-FAB+ for C14H17N2Cl calculated MH+: 249.11584, found: 249.11529.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13]>C(OCC)C.CN(C)C1C=CN=CC=1>[C:12]([O:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)c1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of 2-bromobenzoyl chloride 2.0 g, 9.11 mmol) in dry diethyl ether (40 mL) was added 2-methyl-2-propanol (0.96 mL, 10.02 mmol) followed by 4-(dimethylamino)pyridine (111 mg, 0.911 mmol) and the reaction mixture stirred at room temperature under nitrogen for 48 hours. The resulting white suspension was then partitioned between ethyl acetate (100 mL) and 1 M hydrochloric acid (100 mL). The organic phase was separated, washed with 1 M hydrochloric acid (100 mL), 2 M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using ethyl acetate/hexane as eluant gave the title compound (1.22 g, 52%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.O>[Br:13][C:9]1[C:8]([CH3:11])=[CH:7][C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butyl-5-methylphenol (24.6 g, 150 mmol) in CCl4 (100 mL) at 0° C. was added a solution of bromine (7.7 mL, 150 mmol) in CCl4 (100 mL) over a 4 hour period. The mixture was stirred at room temperature for 30 minutes and then diluted with H2O. The organic phase was separated, washed with saturated sodium bisulfite and brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.34 (s, 9 H), 2.24 (s, 3 H), 5.20 (s, 1 H), 6.54 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[I:25]CCI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[I:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Reactant: ICCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) in tetrahydrofuran (1 L), a solution of n-butyllithium in hexane (1.6 M; 130 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24 g) in tetrahydrofuran (50 mL) was added to the reaction mixture, and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([N:26]1[CH2:30][CH2:29][C@@H:28]([CH2:31][NH:32][CH3:33])[CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:30][CH2:29][C@H:28]([CH2:31][N:32]([CH3:33])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1)([CH3:25])[CH3:24]
Reactant: CNC[C@@H]1CCN(C(C)C)C1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(C)N1CC[C@H](CN(C)C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and (S)-1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine to give 222. MS: (ESI+)=452.2
Reaction SMILES: S1C=CC=C1[C@]1(O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]1N1[C:30](=O)[C:29]2=[CH:32]C=[CH:34][CH:35]=[C:28]2C1=O)O.N(CCCCCCO)=[N+]=[N-].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:11]([O:10][CH2:9][CH3:8])(=[O:13])[CH3:12].[CH3:34][CH2:35][CH2:28][CH:29]([CH3:32])[CH3:30]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2cccs2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [N-]=[N+]=NCCCCCCO
Solvent: CC#N
Product: CCCC(C)C
Product: CCOC(C)=O
Yield: 69 %

Procedure:
The crude product compound [3] (0.27-7.14 g, 0.54-14.2 mmol) and 6-azidohexanol (0.27-3.54 g, 1.08-14.1 mmol) are dissolved in dry acetonitrile, at 0° C., molecular sieves (0.2-5 g, 3 Å) and trimethylsilyl trifluoromethanesulfonate (0.02-1.56 g, 0.1-7 mmol) are added. After the reaction is complete, the mixture is filtered and washed with saturated sodium bicarbonate solution. Concentration results in the crude product, which is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.17-2.23 g, 0.35-4.58 mmol, about 69% yield). The product is then taken up in methanol/hydrazine hydrate (1:1) 1-30 ml) and heated at 80° C. until reaction is complete. After evaporation of the solvent, the crude product is taken up in dichloromethane/methanol (1:1) and stirred at 0° C. with acetic anhydride (3.5-45.8 mmol) until reaction is complete. After evaporation, the azide is reduced with hydrogen in the presence of catalytic amounts of palladium on carbon (10%) (0.01-1.5 g) in methanol (0.5-40 ml). The crude product resulting after evaporation is purified by gel chromatography on Biogel P2 (compound [4];0.08-1.02 g, 0.25-3.2 mmol, about 70% yield). FAB-MS: M+H+ =321. 1H-NMR [300 MHz, DMSO]: 7.68 (HNAc), 4.23 (GlcNAc-H-1), 3.78-3.6 (m), 3.49-3.23 (m), 3.08-3.02 (m) 2.58, 179 (GlcNCOCH3), 1.51-1.21 (O--(CH2)--N).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[Br:17]NC(=O)CCC(N)=O>CN(C)C=O.CCOC(C)=O>[Br:17][C:11]1[C:10]([O:14][CH3:15])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:16]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(ccc(OC)c2Br)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-butyl-5-methoxy-1-indanone (1.869 g, 8.56 mmol) in anhydrous dimethylformamide (8.6 mL) was treated with N-bromosuccinamide (1.676 g, 9.42 mmol). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 14 hours, and then heated in an oil bath at 50° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with water (4×50 mL) and brine (50 mL), dried over MgSO4, and evaporated under vacuum to a dark amber oil (2.468 g). The crude product was purified by column chromatography on EM silica gel 60 (230-400 mesh, 620 mL dry, packed under CH2Cl2), using CH2Cl2 as eluting solvent, to afford 4-bromo-2-butyl-5-methoxy-1-indanone (1.267 g, contains approx. 3% of the 6-bromo isomer) as a pale tan solid. Earlier fractions afforded the 6-bromo isomer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 90 °C
Yield: 38.7 %

Procedure:
A stirring mixture of 4-hydroxypyridin-2(1H)-one (1.2 g, 10 8 mmol, prepared according to the procedure described at Step A of Example 8), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (4.83 g, 17 3 mmol, prepared according to the procedure described at Step C of Example 1) and potassium carbonate (3.13 g, 22 7 mmol) in DMF (45 mL) was heated at 90° C. for 14 hrs and then cooled to room temperature. The resulting mixture was diluted with EtOAc and H2O and the aqueous layer was extracted further with EtOAc (5×). The combined extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residual was purified by flash chromatography on silica gel (0 to 10% MeOH/CH2Cl2) to yield 1.23 g (38.7%) of the product as a pinkish solid. MS (ESI) 295 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([CH:36]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:36]=[C:29]([CH:30]=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39])[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2)#[N:35]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Temperature: 75 °C
Yield: 85.7 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (50 mg, 0.183 mmol) and cesium carbonate (89 mg, 0.274 mmol) in DMF (2 mL) was added 5-(chloromethyl)-2-isopropoxybenzonitrile (46 mg, 0.22 mmol). The reaction was heated at 75° C. for 5 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (70 mg). LCMS m/z=447.4 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.40 (d, J=6.1 Hz, 6H), 1.51-1.61 (m, 1H), 1.98-2.08 (m, 1H), 2.08-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.82-3.92 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.61-4.68 (m, 1H), 5.00 (s, 2H), 6.17 (s, 1H), 6.85 (dd, J=8.8, 2.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:52](=[O:53])[N:31]2[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])=[C:33]([C@@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:52](=[O:53])[N:31]3[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])=[O:42])=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCOC(=O)C1=C([C@@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.108 g, 0.537 mmol) in DMF (2 ml) was cooled to -50° C. N,N-Diisopropylethylamine (0.103 ml, 0.59 mmol) followed by methanesulphonyl chloride (0.046 ml, 0.59 mmol) were added and the mixture was stirred at -50° C. for 30 min. A further quantity of N,N-diisopropylethylamine (0.086 ml, 0.493 mmol) was added and this mixture was added to a pre-cooled solution of pivaloyloxymethyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (0.185 g, 0.482 mmol) in DMF (2 ml) at 0° C. The resulting mixture was stirred at 0° C. for 40 min., then it was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, then triturated with ether to give the title compound (0.193 g, 71%) as a white solid. The spectral data was identical with that obtained for Example 8.
Reaction SMILES: [C:1]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH2:44])=[O:43])[CH:38]=[CH:39][CH:40]=1>C(OC)(C)(C)C>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]2[C:2]([C:1]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][N:8]3[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[O:6])=[C:3]([CH3:5])[N:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:45])([F:46])[F:33])[CH:36]=3)[C:42](=[O:43])[NH:44]2)=[CH:27][CH:26]=1)#[N:24]
Reactant: CC(=O)CC(=O)C1CCCCN1C(=O)OCc1ccccc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: COC(C)(C)C
Product: CC1=C(C(=O)C2CCCCN2C(=O)OCc2ccccc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
A stirred mixture of benzyl 2-acetoacetylpiperidine-1-carboxylate (Example 10A) (1.74 g, 5.74 mmol), 4-cyanobenzaldehyde (752 mg, 5.74 mmol), N-[3-(trifluoromethyl)phenyl]urea (976 mg, 4.78 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide anhydride (6.1 g, 9.5 mmol) in methyl tert.-butyl ether (44 ml) is refluxed overnight (16 h). The product is extracted with methyl tert.-butyl ether (300 ml), washed with aq. saturated sodium bicarbonate solution (200 ml), dried with anhydrous magnesium sulfate, filtered and concentrated. The residue is chromatographed with silica gel 60 using cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[C:12]([C:15]#[N:16])[C:13]#[N:14])SC)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CCO>[NH2:14][C:13]1[NH:19][N:18]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:15]#[N:16]
Reactant: NN
Reactant: CSC(Nc1ccc(Cl)cc1)=C(C#N)C#N
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2ccc(Cl)cc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-(((4-chlorophenyl)amino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((4-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Br:13][CH2:14][C:15]1C=CC(C#N)=[CH:17][CH:16]=1.CC(C[AlH]CC(C)C)C.Cl>CCOC(C)=O.CCCCCC.C1COCC1>[Br:13][CH2:14][C:15]1[CH:3]=[CH:2][C:1]([CH:5]=[O:4])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CBr)cc1
Reaction time: 1.5 h

Procedure:
To a THF-toluene (2.4 L-0.24 L) solution of α-bromo-p-tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature bellow 0° C. was added DIBAL in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying the title compound was obtained. (210 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22](=O)[CH2:23][C:24]([O:26]CC)=O)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:37]=[N:36][C:24](=[O:26])[CH:23]=2)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: NN
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(COCC2=CC(=O)N=N2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 38.7 %

Procedure:
A solution of ethyl 4-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.50 g) and hydrazine hydrate (0.50 g) in ethanol (20 ml) was kept at room temperature for 4 days and then evaporated. The residue was purified by chromatography on silica gel (1.0 g) using dichloromethane plus 0-5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ethyl acetate to give the title compound (0.18 g), m.p. 207° C. Found: C,57.11; H,5.15; N,9.19. C22H24ClN3O6 requires: C,57.20; H,5.24; N,9.10%.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].OO.[OH2:23].C(O)(=[O:26])C>>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:19])(=[O:26])=[O:23])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20]
Reactant: O
Reactant: CSc1ccc(-c2nn(C)c(=O)c3ccccc23)cc1
Reactant: CC(=O)O
Agent: OO
Product: Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c2ccccc2c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-methyl-4-(4-methylthiophenyl)-1-(2H)-phthalazinone (14.15 g, 0.05 mol) in acetic acid (330 mL) was added 30% H2O2 (22 mL). The mixture was heated to 35° C. overnight, additional 30% H2O2 (10 mL) was added and the mixture was stirred at 35° C. for 2 hours and finally one final portion of 30% H2O2 (10 mL) was added and the mixture was stirred for another 2 hours at 35° C. The reaction mixture was poured into water (1 L)/ice and the solid thus obtained was collected by filtration, washed with water, then ether, and then was dried to afford 14.6 g (93%) of 2-methyl-4-(4-methylsulfonylphenyl)-1-(2H)-phthalazinone as a pale yellow solid, m.p. 218°-220° C. when recrystallized from ethanol/chloroform (2×).
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][O:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][O:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1noc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
A mixture of 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 45) (40 mg, 1.118 mmol), triphenylphosphine (62 mg, 0.237 mmol) and water (4 μl) in THF was stirred at 60° C. for 5 hours. Excess amount of water (30 μl) was added to the mixture and stirred at 60° C. for another 10 hours. The volatile solvent was distilled out, the crude product was purified by ISCO (EtOAc: hexane=60%. 25 mg (68%) of 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isoxazolo[5,4-d]pyrimidin-4-one was obtained as colorless oil. m/z: 313 (MH+), 1H NMR (DMSO-d6): 0.55 (d, 3H), 0.95 (d, 3H), 2.02 (m, 1H), 2.15 (br, 2H), 2.55 (s, 3H), 3.59 (d, 1H), 5.38 (d, 1H), 5.65 (d, 1H), 7.25-7.42
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.CC(=O)OCC>ClCCl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCN2
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A round bottom flask containing trifluoroacetic acid (60 mL) was cooled to 0 C under nitrogen and triethylsilane (1.16 g, 1.6 mL, 9.96 mmol) was added followed by the dropwise addition of indole 1 (1.17 g, 3.32 mmol; prepared using a modification of the procedure reported by Macor, et al. J. Med. Chem. 1992, 35, 4503-4505) in 9 mL dry dichloromethane, added over 1 hour. Following complete addition, the solution was stirred for 10 min. Thin layer chromatography (2/1 Hex/EA) indicated no remaining 1. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO3 (2×), and brine. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on silica gel (2/1 hexane/ethyl acetate) afforded 2 as a yellow oil (0.79 g, 67%). 1H NMR (CDCl3, 300 MHz) δ7.34-7.31 (m, 5H) 6.99-6.85 (m, 1H)/6.34-6.27 (m, 2H), 5.12 (s, 2H), 4.13-3.71 (m, 2H), 3.58-3.16 (m, 5H), 2.05-1.87 (m, 4H), 1.73-1.57 (m, 2H) ppm.