Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 82.0 g (0.31 mol) of 1-benzyl-3-(R)-hydroxymethyl-4-(S)-phenyl pyrrolidine (from Step C) and 46.5 g (0.36 mol) of N,N-diisopropylethylamine in 1 L of CH2Cl2 was treated with 54.2 g (0.36 mol) of t-butyldimethylsilyl chloride and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 750 mL of sat'd NaHCO3 and the layers were separated. The organic layer was combined with 150 g of silica gel and aged for 45 min. The mixture was filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH2:15]=[CH:16][CH2:17][C:18](=[N:22][OH:23])[C:19](=O)[CH3:20]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:19]([CH3:20])[C:18](=[N:22][OH:23])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CCC(=NO)C(C)=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCOCC
Product: C=CCC(=NO)C(C)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
2,6-Dichloro-4-trifluoromethylphenylhydrazine (6.6 g) and 1-hexene-4,5-dione 4-oxime (3.4 g) were stirred in diethyl ether (200 ml) for 18 hours. The solvent was removed under reduced pressure to give 1-hexene-4,5-dione 5-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 4-oxime, m.p. 86°-88°.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]1[C:9]#[N:10].C[OH:12]>>[ClH:1].[CH3:2][N:3]1[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[CH:9]=[N:10][OH:12]
Reactant: CO
Reactant: CN1CC=CCC1C#N
Agent: Cl
Product: CN1CC=CC=C1C=NO

Procedure:
To 200 ml. of cooled, but freshly boiled methanol, 17.0 g. (0.084 mol) of the hydrochloride form of the precursor compound (1-methyl-2-cyano-1,2,3,6-tetrahydropyridine hydrochloride) obtained earlier was added. The suspension was mixed under nitrogen for 11/2 hours. During that time, a solution was formed and a new product was precipitated. The product was filtered, washed with ether, and dried in vacuo to yield 11.7 g. (80%) of the objective compound (1-methyl-1,6-dihydropyridine-2-aldoxime hydrochloride), mp 179° C (decomp). The NMR spectrum was consistent with the structure of the compound obtained. The analysis of the compound by I.R. (KBr pellet) showed strong and medium bands at 1655, 1700. U.V. analysis in 0.1 N HCl-251 nm (ε=13,300); pH of 8 - 308 nm; 0.1N NaOH-260 nm (ε=7640) and 340 nm (ε=5440).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:7][N:6]1[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1NCCCNC(=O)OC(C)(C)C
Yield: 85 %

Procedure:
Following Example 58, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 3-aminopropylcarbamate gave tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a pale yellow gum (1.27 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 6.75 (s br, 1H), 4.67 (s br, 1H), 3.84 (s, 3H), 3.54 (q, J=6.6 Hz, 2H), 3.27 (q, J=6.6 Hz, 2H), 1.90-1.79 (m, 2H), 1.44 (s, 9H)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH2:27])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH:27][C:29](=[O:31])[CH3:30])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2ccc(-c3cc(Oc4cccc5sc(N)nc45)ncn3)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc5c(c4)OC(C)(C)C5)ncn3)cccc2s1
Temperature: 85 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-[6-(2,2-dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 133(b)), (0.50 g, 1.3 mmol) was added toluene (7 mL) and acetic anhydride (0.40 mL, 3.8 mmol, Aldrich). The reaction mixture was heated at 85° C. for 2 h. The toluene was removed in vacuum and the resulting orange solid was re-dissolved in dichloromethane (125 mL), washed with water (150 mL), dried over Na2SO4 and concentrated in vacuum. The resulting orange solid was suspended in dichloromethane (100 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 224-225° C. MS (ESI, pos. ion.) m/z: 433 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:28]4[CH2:31][CH:30]([CH2:32][C:33]5[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=6)[NH:35][CH:34]=5)[CH2:29]4)[O:12][C:8]3=2)[N:3]=1
Reactant: Cc1ccc2[nH]cc(CC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Product: Cc1ccc2[nH]cc(CC3CN(CC4COc5ccc6nc(C)ccc6c5O4)C3)c2c1

Procedure:
This compound was prepared as described for Example 10, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4 g, 0.9 mmol), 3-azetidin-3-ylmethyl-5-methyl-1H-indole (0.19 g, 0.9 mmol), to afford 0.15 g of the (S)-enantiomer of the title compound as a light brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid, m.p. 150° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:18]1([OH:28])[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[CH2:20][O:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:25]2[CH:24]=[CH:23][C:22]3[B:18]([OH:28])[O:19][CH2:20][C:21]=3[CH:26]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile (1.12 g, 4.12 mmol, 1.00 equiv) in DMSO (50 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (650 mg, 4.33 mmol, 1.05 equiv) and Cs2CO3 (1.60 g, 4.92 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 40° C., then quenched by the addition of 100 mL of ice water. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of water and 1×50 mL of brine, then dried over Na2SO4 and concentrated under vacuum. This resulted in 1.3 g (80%) of 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile as a white solid. LC-MS (ES, m/z): 387 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.28 (1H, s), 8.60 (1H, s), 7.81 (1H, d, J=7.8 Hz), 7.33 (1H, s), 7.25 (1H, d, J=7.8 Hz), 5.02 (2H, s), 4.00 (2H, t), 2.35 (2H, t), 2.05 (3H, s), 1.8-1.6 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(O)(=O)C>C(O)C>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.63 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.23 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.394 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19](Cl)[N:18]=[C:17]([O:22][CH3:23])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:33][CH2:34][CH2:35][OH:36]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:33][CH2:34][CH2:35][OH:36])[N:18]=[C:17]([O:22][CH3:23])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
To a stirred solution of 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 3.0 mmol, 1.0 equiv) in acetonitrile (45 mL) was added N-ethyl diisopropylamine (1.56 mL, 1.18 g, 9.0 mmol, 3.0 equiv) at rt, followed by 2-amino-ethanol (0.36 mL, 0.37 g, 6.0 mmol, 2.0 equiv). The reaction mixture was heated to 50° C. for 3.5 h, then poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, then dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 1.00 g (90%) of the title compound as colorless foam. MS (ISP): 369.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:12][CH3:13])[C:5](=[CH:9][C:10]=1[CH3:11])[C:6]([OH:8])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[OH:8][C:6]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=2)[N:12]([CH3:13])[C:14](=[O:16])[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(C)c(C)cc1C(=O)O
Solvent: CC(=O)O
Product: Cc1cc2c(O)cc(=O)n(C)c2cc1C

Procedure:
To a solution of 4,5-dimethyl-N-methyl anthranilic acid (30.0g.; 0.168 mole; m.p. 190°- 191°C) in glacial acetic acid (75 ml.) was added acetic anhydride (75 ml.) and the mixture was refluxed for 4 hrs. After cooling the dark solution was poured onto crushed ice, made alkaline (pH 9), and filtered. On bringing the filtrate to pH5 with concentrated hydrochloric acid the title product separated as a white solid, m,p. (EtOH) 300°- 305°C (Found: C, 70.12; H, 6.30; N, 7.12; C12H13NO2 requires; C, 70.92; H, 6.45; N, 6.89%).
Reaction SMILES: [CH2:1]([CH:5]1[N:9]=[CH:8][C:7](Cl)([CH2:10][C:11]([O:13]C)=[O:12])[N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].C(C1N=CC([Cl:39])(CC(O)=O)N1CC1C=CC([N+]([O-])=O)=CC=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([Cl:39])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1N=CC(Cl)(CC(=O)OC)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC1N=CC(Cl)(CC(=O)O)N1Cc1ccc([N+](=O)[O-])cc1
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-butyl-5-chloro-1-(4-nitrobenzyl)-imidazole-5-acetate was also prepared by the procedure described in Example 2 Part B from 2-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid. NMR (200 MHz, CDCl3) δ 8.23 (d, 2H, J=10 Hz); 7.20 (d, 2H, J=10 Hz); 5.21 (s, 2H); 3.75 (s, 3H); 3.67 (s, 2H); 2.58 (t of t, 2H, J=7 Hz); 1.32 (q of t, 2H, J=7 Hz); 0.86 (t, 3H, J=7 Hz). Mass Calcd. for C17H20ClN3O4 ; 365.1142. Found 365.1132.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11]C)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:15][CH2:14][CH:13]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=2)=[CH:3]1)[CH2:17][CH3:18]
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COC)n1cc(-c2ccc(CC#N)cc2)c2c(=O)[nH]ccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (50.0 mg) obtained in Step A-2 of Example 17 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (33.8 mg), tetrakis(triphenylphosphine)palladium(0) (15.9 mg) and potassium carbonate (38.3 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (20.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].C(O)(=O)C.[OH-].[Na+]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])=[C:2]([F:1])[CH:14]=1
Reactant: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCOC2=O)c(F)c1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained in Step B (10.37 mmoles) in ethanol (25 ml) there are added 122 microlitres of acetic acid. The solution is heated at reflux and stirred for 10 minutes. Powdered iron (2.08 g) and 75 mg of FeCl3.6H2O are added. After stirring for 2 hours at reflux, the mixture is brought to ambient temperature and then concentrated to dryness. 50 ml of water are added to the residue obtained, and the pH is made alkaline using sodium hydroxide. The solution is extracted 4 times with AcOEt. The organic phases are combined and washed with saturated aqueous NaCl solution and then dried with MgSO4. After filtration, the organic phase is evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@:6]1([CH3:28])[CH2:22][O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:5]1[CH2:4][CH2:3]2.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[CH3:30][C:29]([O:21][C@@H:16]1[CH2:17][O:18][C:19](/[C:15]/1=[CH:14]/[CH2:13][C@H:12]1[C@:2]2([CH3:1])[CH2:3][CH2:4][C@H:5]3[O:25][C:24]([CH3:27])([CH3:26])[O:23][CH2:22][C@@:6]3([CH3:28])[C@H:7]2[CH2:8][CH2:9][C:10]1=[CH2:11])=[O:20])=[O:31]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Solvent: O
Product: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
3,19-Isopropylidene andrographolide (15 g) obtained in step 1 was refluxed in distilled acetic anhydride (110 ml) for 45 min. After confirming the complete formation of the product (by TLC analysis), the contents were cooled to room temperature, diluted with water (500 ml) and extracted with dichloromethane (3×200 ml). The organic layer was separated and dried over Na2SO4 and concentrated to get a brown oily material. The crude material was purified by flash column chromatography (silica gel 230-400 mesh; 250 g, eluting system light petrol: ethyl acetate=85:15) to obtain pure 14-acetyl-3,19-isopropylidene andrographolide (13 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[CH2:20][CH:19]([C:34]([O:36]C)=[O:35])[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:22][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=3)[CH2:20][CH:19]([C:34]([OH:36])=[O:35])[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
785 mg (1.48 mmol) of the compound from Example 113A and 1.66 g (14.8 mmol) of potassium tert-butoxide were reacted according to the General Method 9A. Yield: 740 mg (97% of theory).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[S:17]
Reactant: NCCNCc1cc[nH]n1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1cc[nH]n1

Procedure:
Treating N-(3-pyrazolylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: NCCN1CCOCC1
Product: O=C(C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1)NCCN1CCOCC1
Yield: 60 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 and 4-(2-aminoethyl)morpholine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (80 mg, Yield 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:30](OCC)(=[O:32])C>CO.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:32][CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 7-methyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), 30% sodium methoxide-methanol (0.5 mL), and CuBr (0.005 g, 0.04 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-methyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.80 (s, 3H), 3.91 (s, 3H), 4.26 (s, 2H), 4.83 (s, 2H), 6.82 (d, 2H), 7.26 (d, 2H), 7.42 (d, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][N:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][N:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(-n2ccncc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccncc3=O)cc2F)C1)c1ccc(Cl)s1

Procedure:
71.2 Using general method H, 5-chloro-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide. White solid. MS 476.0 ([M+H]+)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].CC(C1C=C(C(C)C)C(S([N:42]=[N+:43]=[N-:44])(=O)=O)=C(C(C)C)C=1)C>O1CCCC1.C1(C)C=CC=CC=1>[N:42]([C@@H:15]([C:16]([CH3:17])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:24])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:25])=[N+:43]=[N-:44]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CC(C)(CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of (4S)-4-benzyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one (1.0 g, 3.0 mmol, from Reference Example 26) in anhydrous tetrahydrofuran (16 mL) is cooled to −78° C. in a dry-ice/acetone bath while stirring under a nitrogen atmosphere. Potassium hexamethylsilazide (0.5 M solution in toluene, 6.6 mL, 3.3 mmol) is added dropwise to the solution via syringe. After stirring for 1 hour at −78° C., trisyl azide (1.2 g, 3.8 mmol) in tetrahydrofuran (8 mL) is added dropwise. The reaction mixture is stirred for 2-3 minutes at −78° C. and then quenched by the addition of glacial acetic acid (0.8 mL). Stirring is continued for 1 hour at 40° C. The reaction mixture is diluted with brine and diethyl ether. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford a white/yellow solid. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford a clear, straw colored oil (1.1 g, 79%). TOF MS (ES+): (M+H)=379.2