Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[CH2:27][CH2:28][OH:29])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[CH2:27][CH2:28][O:29][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Tert-butyl-dimethyl-silyl chloride (3.62 g, 24.02 mmol) and imidazole (3.27 g, 48.03 mmol) were added to a solution of the compound of step 2 (4.609 g, 20.01 mmol) in 75 ml of DCM and the resulting solution was stirred at room temperature for 3 h. The mixture was washed with 50 ml of water and then 50 ml of brine. The aqueous phase was extracted once with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6.90 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:14][OH:15]>>[F:1][C:2]([F:12])([F:11])[S:3][CH2:4][C:5](=[N:14][OH:15])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: NO
Reactant: CC(C)(C)C(=O)CSC(F)(F)F
Agent: Cl
Product: CC(C)(C)C(CSC(F)(F)F)=NO

Procedure:
Using the method of example 2, 1-trifluoromethylthio-3,3-dimethyl-2-butanone was reacted with hydroxylamine hydrochloride to provide the desired oxime, m.p. 94.5° to 96°C.
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[N:5]=[C:6]([CH3:25])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][C:13]=2[Cl:24])[C:8]=1[CH:9]=[O:10].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27].O>O1CCOCC1.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>[Cl:24][C:13]1[CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[C:8]([CH:9]=[O:10])=[C:4]([CH:26]=[CH2:27])[N:5]=[C:6]1[CH3:25]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Br)c2C=O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1nc(C)n(Cc2ccc(OCCCCC)cc2Cl)c1C=O
Yield: 87.7 %

Procedure:
Lithium chloride (180 mg) was suspended in 1,4-dioxane (10 ml), and 4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (707 mg), vinyltributyltin (617 mg) and tetrakis(triphenylphosphine)palladium(0) (102 mg) were added. The mixture was refluxed under heating for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane/ethyl acetate=5/1. The objective fraction was concentrated under reduced pressure to give 1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethenyl-2-methyl-1H-imidazole-5-carbaldehyde(538 mg) as a pale-yellow gum.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:5]([N+:24]([O-])=O)[CH:4]=1)#[N:2].O.NN>C(O)C.[Ni]>[NH2:24][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]([CH3:9])=[CH:7][C:6]=1[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C#N
Temperature: 45 °C
Yield: 85 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[(4-cyano-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate (D91) (3 mmol) in ethanol (30 mL) was treated with Raney Nickel and hydrazine hydrate (30 mmol, 1.5 g, 10 eq) under argon at room temperature. The mixture was then heated at 45° C. for 1 h. The catalyst was then filtered off and washed with ethanol and methanol. The filtrate was concentrated under reduced pressure to give the title compound as a solid (2.55 mmol, 840 mg, 85% yield). M+H 331.3, 275.2, 231.2 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31]>CCO.C(N(CC)CC)C>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: O=C(NCCCCc1ccc(O)c2ccccc12)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCCc1ccc(OCC(O)CO)c2ccccc12)OCc1ccccc1
Yield: 84.4 %

Procedure:
A solution of benzyl 4-(4-hydroxynaphthalen-1-yl)butylcarbamate (20, 287 mg, 0.82 mmole), oxiran-2-ylmethanol (21, 0.07 mL, 1.00 mmole) and triethylamine (0.01 mL, 0.05 mmole) in absolute EtOH (9.28 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford butylcarbamate 22 (293 mg, 83%) as a light yellow thick oil: 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.52-7.45 (m, 2H), 7.37 7.28 (m, 5H), 7.18 (d, J=7.7 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.09 (br s, 2H), 4.71 (br s, 1H), 4.29-4.20 (m, 3H), 3.98-3.81 (m, 2H), 3.23 (q, J=6.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.65 (d, J=4.5 Hz, 1H), 2.06 (t, J=5.8 Hz, 1H), 1.83-1.53 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1cccc(C(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([N:18]1[CH2:21][CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1)C1C=CC=CC=1.FC1C=CC([N+:37]([O-:39])=[O:38])=CC=1>CO.N1C=CC=CC=1.[Pd]>[N+:37]([C:16]1[CH:17]=[CH:12][C:5]([N:18]2[CH2:19][CH:20]([OH:22])[CH2:21]2)=[CH:14][CH:15]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
Ammonium formate (15.1 g, 246 mmol) was added to a solution of 1-benzhydryl-3-(tert-butyl-dimethyl-silanyloxy)-azetidine (which was obtained in Example 395) (8.7 g, 24.6 mmol) and 10%Pd/C (1 g) in methanol (100 mL). The reaction was stirred for 3 hours at room temperature. The solution was passed through celite and concentrated to afford a crude solid. The crude solid was taken up in pyridine (75 mL) and the salts were removed by filtration. 4-Fluoronitrobenzene (2.9 mL, 27.1 mmol) was added to the above solution and the reaction was stirred at reflux overnight. Pyridine was removed by vacuum distillation and the resultant crude was treated with water (100 mL), followed by extraction with ethyl acetate (3×25 mL). The organic layers were combined, dried (Na2SO4), filtered, and passed through a plug of silica. The solvent was evaporated and triturated with hexanes to give 3.91 g of the desired product as red solid; 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 1H), 3.89(m, 2H), 4.31 (m, 2H), 4.87 (m, 1H), 6.31 (d, 2H, J=7.14), 8.09 (d, 2H, J=7.14 Hz); MS (ES) m/z: 194.8 (MH+); Anal. Calcd. for C9H10N2O3: C, 55.67; H, 5.19; N, 14.43. Found: C, 55.67; H, 5.05; N, 14.59.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]2[NH:29][C:28]1=[O:36]>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:4]3[CH:3]=[C:2]([N:27]4[CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]5[NH:29][C:28]4=[O:36])[CH:7]=[CH:6][CH:5]=3)[CH2:11][CH2:12]2)[N:21]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: O=C1NC2CCCCC2N1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NC6CCCCC65)c4)CC3)cccc2n1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}2-methylquinoline and octahydro-2H-benzimidazol-2-one.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:9]=[C:10]([O:14]C(=O)C)[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.P(Br)(Br)([Br:23])=O.C([O-])([O-])=O.[K+].[K+].Cl>CC#N.O>[Br:23][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Reactant: O=P(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred mixture of acetic acid 3-(4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-phenyl ester, 27, (1.72 g, 6.0 mmol) in MeCN (25 mL) under a nitrogen atmosphere was added POBr3 (8.6 g, 30 mmol) and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was quenched by pouring onto iced water (200 mL) and the aqueous layer was neutralized by addition of solid NaHCO3. The precipitate formed was collected by filtration and dried. The resulting tan solid (1.6 g) was dissolved in THF/MeOH (1:1 v/v, 20 mL). K2CO3 (1.76 g, 12.8 mmol) was added and the mixture stirred at rt for 3.5 h. The reaction mixture was diluted with H2O (20 mL), acidified to pH 3-4 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), concentrated and purified by flash chromatography (70:30 hexanes/EtOAc as eluent) to afford the title compound, IVa, as a colourless solid (0.76 g; 41%).
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (393 mg, 1.14 mmol) in 20 mL of 1,2-dichloroethane was placed in a pressure vessel and heated to 70° C. The rapidly stirred solution was then treated with 5 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (239 mg, 1.25 mmol), the reaction vessel was capped, and heating was continued for 2 h. The reaction mixture was then cooled to ambient temperature and treated with 50 mL of CH2Cl2. The reaction mixture was washed with H2O, 1% Na2CO3 solution (3×), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated. Chromatography (SiO2, 5% MeOH/CHCl3) followed by crystallization from propyl acetate/hexanes gave N-benzyl-2-butyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (237 mg) as light-yellow crystals. mp 159.3–160.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.54 (m, 1H), 7.42–7.31 (m, 6H), 5.44 (s, 2H), 5.26 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 2.71 (t, J=8.4 Hz, 2H), 1.74 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 346 (M+H)+; Anal. Calcd for C21H23N5: C, 73.02; H, 6.71; N, 20.27. Found: C, 72.75; H, 6.55; N, 20.46.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:44])[N:41]([CH3:43])[NH:42][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CCOC(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of acetylalanylalanylproline (2 mmole) and N-methylmorpholine (2 mmole) in dry tetrahydrofuran (20 ml) at -20° to -25° C. is added isobutyl chloroformate (2 mmole). After 5 minutes a solution of 2-azaalanine ethyl ester (2 mmole) in tetrahydrofuran (3 ml) is added dropwise and the reaction mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 4 hours. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography on silica gel (50 gm) and elution with 10% methanol in chloroform gives pure acetylalanylalanylprolyl-2-azaalanine ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 5 h
Yield: 28.9 %

Procedure:
(3S)-3-(dimethylamino)pyrrolidine (161 μl, 1.27 mmol) and triethylamine (177 μl, 1.27 mmol) were added to a dimethyl sulfoxide (9 ml) solution of tert-butyl N-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-β-alaninate (I-278) (335 mg, 0.847 mmol), followed by stirring in an oil bath at 150° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1, v/v) to obtain the entitled compound (120 mg, 29%) as a brown oily substance.
Reaction SMILES: BrBr.[C:3]([NH:7][NH:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([N:7]=[N:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:5])([CH3:4])[CH3:6]
Reactant: CC1CC(C)(C)CC(C#N)(NNC(C)(C)C)C1
Agent: BrBr
Product: CC1CC(C)(C)CC(C#N)(N=NC(C)(C)C)C1

Procedure:
1-tert.-butylazo-1-cyano-3,3,5-trimethylcyclohexane was prepared by bromine oxidation of the above 1-tert.-butylhydrazo-1-cyano-3,3,5-trimethylcyclohexane in the same way that 4-tert.-butylhydrazo-4-cyano-2,6-dimethylheptane was oxidized in Example VII C. The yield of liquid product was 8.2 g. (63%) and the infra-red spectrum was consistent with the structure of the proposed compound.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([NH:25][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:26]=1
Reactant: Cc1ccc(F)cc1N
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1C
Reaction time: 96 h

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.18 mL, 36.0 mmol), pyridine (3.88 mL, 47.9 mmol) and 5-fluoro-2-methylaniline (3.00 g, 23.97 mmol). Heating continued for 4 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(5-fluoro-2-methylphenylamino)-2-methyl-3-oxopropanoate as a tan solid. Mass Spectrum (ESI) m/e=254.2, (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30].CCN(C(C)C)C(C)C>C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Cl)c([N+](=O)[O-])c4)cc3)sc2c1
Yield: 96.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.50 g, 1.95 mmol), 4-chloro-3-nitrobenzoyl chloride (0.43 g, 1.95 mmol) and Hunig's base (0.28 g, 2.15 mmol) in dry THF (20 ml) to give the title compound (0.83 g, 97%) as a yellow solid after work-up.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]2.[OH:28]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]2)=[O:28]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc4ccccc4n3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc4ccccc4n3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(2- quinolyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[CH:7]=[CH:8]/[C:9]2[N:17]=[C:16]3[N:11]([C:12]([CH3:19])=[N:13][CH:14]=[C:15]3[CH3:18])[N:10]=2)[N:4]([CH3:20])[N:3]=1.[F:21][C:22]([F:29])([F:28])[C@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:19][C:12]1[N:11]2[N:10]=[C:9](/[CH:8]=[CH:7]/[C:5]3[N:4]([CH3:20])[N:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH2:27][C@@H:23]4[C:22]([F:29])([F:28])[F:21])[N:6]=3)[N:17]=[C:16]2[C:15]([CH3:18])=[CH:14][N:13]=1
Reactant: FC(F)(F)[C@H]1CCCN1
Reactant: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCC[C@@H]4C(F)(F)F)nn3C)nc12
Yield: 14.5 %

Procedure:
Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (100 mg, 299 μmol, Eq: 1.00) instead of 2-[(E)-2-(5-Bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and (R)-2-(trifluoromethyl)-pyrrolidine (83.3 mg, 598 μmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (17 mg, 14.5%) as a light yellow solid. MS: m/z=393.4 (M+H+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:10]2=3)[CH:2]=1.CO.[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:10]2=3)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2

Procedure:
Compound 9a, 3.9 g, obtained in Example 1 was heated to reflux for an hour in a solvent mixture of 200 ml of methanol, 50 ml of water and 10 ml of 10N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and 4N hydrochloric acid aqueous solution was added to the residue to adjust pH to 7. After concentrating under reduced pressure, the residue was subjected to high porous polymer (HP-10; manufactured by Mitsubishi Chemical Industry Co., Ltd.) column chromatography (eluting solvent; methanol) to give 2.5 g of the crude product. The crude product was recrystallized from water to give 2.0 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].CN(C=O)C.[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O>[CH3:22][O:23][C:24](=[O:46])[C@@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=4[C:10]=3[CH3:16])=[O:15])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27]
Reactant: CCOc1cccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 115 mg (0.46 mmol) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid in 2 mL of oxalyl chloride was refluxed for 4 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 201 mg (0.56 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were then removed under vacuum. Column chromatography with silica gel gave 237 mg (93% yield) of (S)-2-{4′-[(4-ethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off white solid.