Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:11]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[NH:31][C:32]2[CH:38]=[C:37]([C:39]([NH:41][NH2:42])=[O:40])[CH:36]=[CH:35][C:33]=2[N:34]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[NH:31][C:32]2[CH:38]=[C:37]([C:39]3[O:40][C:11]([NH:9][C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)=[N:42][N:41]=3)[CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: COc1ncccc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1nnc(-c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)o1
Reaction time: 72 h

Procedure:
Combine 2-methoxy-3-amino-pyridine (75 mg, 0.606 mmol) and di-imidazol-1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir for 7.5 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Stir for 3 days. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by reverse phase HPLC (35-50% ACN/H2O+5 mM NH4OH) to afford the title compound as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.98 (s, 3H) 7.07 (dd, J=7.77, 4.99 Hz, 1H) 7.62-7.68 (m, 1H) 7.72 (d, J=1.89 Hz, 1H) 7.70 (s, 1H) 7.74-7.92 (m, 3H) 8.00-8.23 (m, 1H) 8.42 (dd, J=7.83, 1.64 Hz, 1H) 10.12 (br. s., 1H) 13.30 (br. s., 1H); MS m/z=452.9 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:31](=[O:33])[CH3:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (54 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (102 mg, 45%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.94 (d, 2H), 4.97 (s, 1H), 4.05 (t, 2H), 3.80 (m, 2H), 3.59 (m, 2H), 3.46 (d, 2H), 2.66 (t, 2H), 2.57 (m, 4H), 2.03 (m, 4H), 1.80 (m, 8H).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>O1CCOCC1>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)=[O:23]
Reactant: NC1c2ccccc2CSc2ccccc21
Reactant: O=C(Cl)CCCCCl
Solvent: C1COCCO1
Product: O=C(CCCCCl)NC1c2ccccc2CSc2ccccc21
Yield: 93.4 %

Procedure:
A mixture of 8.8 g of 11-amino-6,11-dihydrodibenzo[b,e]thiepin, 6.0 g of 5-chlorovaleryl chloride and 100 ml of dioxane is heated with stirring under reflux for 15 hours. The solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol to give 12.5 g of the title compound, m.p. 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:36][CH3:37])=[C:18]([CH:25]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:19]([CH3:24])=[C:20]([C:22]#[N:23])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[ClH:38].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:36][CH3:37])=[C:18]([CH:25]4[CH2:28][NH:27][CH2:26]4)[C:19]([CH3:24])=[C:20]([CH:21]=3)[C:22]#[N:23])[CH3:15])[N:9]=[C:10]([CH:11]([F:12])[F:13])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.20 g, 0.39 mmol) in methylene chloride (5 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (0.60 mL, 2.4 mmol). The resulting mixture was stirred at room temp for 3.5 h. The solvents were evaporated and the residue dried in vacuo to give 0.23 g of the product as the HCl salt. LCMS calculated for C20H22F2N7O (M+H)+: m/z=414.2; Found: 414.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[I-:15].[Na+].CNCCNC>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1ccc(I)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 0.45 g (1.7 mmol) 2-(4-bromo-phenyl)-2-methyl-propionic acid methyl ester (WO2008/002671) in 1.5 mL 1,4-dioxane are added 34 mg (0.18 mmol) copper(I) iodide, 0.53 g (3.5 mmol) sodium iodide and 0.04 mL (0.35 mmol) N,N′-dimethylethylendiamine under inert gas atmosphere. The mixture is stirred at 110° C. for 12 h. After cooling, the mixture is diluted with EtOAc and washed with 5% ammonia and water. The organic layer is dried over sodium sulphate. The solvent is evaporated to yield the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[CH2:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 3-Ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (95 mg, 0.35 mmol), lithium hydroxide monohydrate (120 mg, 2.77 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 67.8 mg (74%). MS m/e 329.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:25][CH2:26][C:27]([OH:29])=[O:28])[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(F)cc1)NCC(=O)O
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a 25 ml flask was added ethyl 2-((S)-3-(4-fluorophenyl)-1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylamino)acetate 103.1.C (331 mg, 0.78 mmole), lithium hydroxide monohydrate (65.3 mg, 1.56 mmole), 1 ml of water and 6 ml of tetrahydrofuran. After 3 hours, 0.78 ml of 2N-hydrogen chloride solution was added to neutralize. The solvent was removed by rotary evaporation. The crude product was purified by silica gel chromatography to give 103.2 (268 mg, 87% yield) as colorless amorphous. LCMS ESI (pos.) m/e: 398 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J=5.5 Hz, 2H), 7.72 (d, J=6.3 Hz, 2H), 7.33 (dd, J=8.4, 5.7 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 6.81 (s, 1H), 3.66 (s, 3H), 3.58 (t, J=6.8 Hz, 1H), 3.21 (d, J=16.9 Hz, 1H), 3.11 (d, J=17.2 Hz, 1H), 3.02 (dd, J=13.6, 5.9 Hz, 1H), 2.89 (dd, J=13.6, 7.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][CH:20]([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][CH:20]([CH3:25])[CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:23]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)CC(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 3-methyl-butyryl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl [5-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)pyridin-3-yl]carbamate (1.50 g, 3.53 mmol) in methanol (30 mL) was added 10% palladium on carbon (150 mg, 0.141 mmol), and the mixture was hydrogenated under 25 psi of H2 for 2 hours with shaking. The solution was filtered through a pad of celite, and filtrate was concentrated. The residue was purified by flash column chromatography to give the desired product (1.40 g, 92%). LCMS calculated for C23H33N4O4(M+H)+: m/z=429.1.
Reaction SMILES: [CH3:1][C:2]1[C:8](=O)[C:7]([CH3:11])([CH3:10])[CH2:6][C:4](=O)[CH:3]=1.S([O-])([O-])(=O)=O.[NH4+:17].[NH4+:18].N.[H][H]>C(O)C.[Ni]>[NH2:17][CH:8]1[CH:2]([CH3:1])[CH2:3][CH:4]([NH2:18])[CH2:6][C:7]1([CH3:11])[CH3:10]
Reactant: [H][H]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: [NH4+]
Agent: [Ni]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC1CC(N)CC(C)(C)C1N
Temperature: 180 °C
Reaction time: 20 h

Procedure:
A mixture of 152 g of 4-oxoisophorone (formula IIa), 150 g of ammonium sulfate, 50 g of Raney Ni and 1 liter of ammonia was charged with 80 bar hydrogen in a 3 liter autoclave at room temperature and then stirred at 180° C. for 20 h. When the uptake of hydrogen was complete, the reaction mixture was let down, taken up in ethanol, filtered and subjected to fractional distillation. 130 g of the diamine of formula Ia having a boiling point of 62 to 65° C. under 0.1 mbar were obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([NH:41][NH2:42])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)(=[O:21])=[O:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=547.2 (M+H)+
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16]OS(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=O.C([O-])(O)=O.[Na+]>CC#N>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:28]4[NH:27][CH:31]=[CH:30][N:29]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)n1ccnc1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(COS(C)(=O)=O)nc(=O)c1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ncc[nH]3)nc(=O)c1-2
Temperature: 0 °C
Yield: 29.8 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyloxy methyl)pyrazolo[3,4-d]pyrimidin-4-one (1.8 g, 15.3 mmol), 1-(methylcarbonyl)imidazole (640 mg, 5.8 mmol) and CH3CN (36 mL) was heated at reflux for 6 hours. The solvent was stripped, ice water and saturated NaHCO3 were added and the mixture was extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The product was combined with that from a similar experimental run and the mixture was recrystallized from ethyl acetate. The product was then treated with 2N HCl, extracted with ethyl acetate and the aqueous layer was neutralized with NaHCO3, extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The residue was recrystallized from ethyl acetate to afford 0.54 g of 1-cyclopentyl-3-ethyl-6-(1-imidazolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 252-253° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1[S:16][C:17]1[S:18][C:19]([NH2:22])=[N:20][N:21]=1)[C@H:11]([NH:23][C:24](=[O:57])[C:25]([C:31]1[N:32]=[C:33]([NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:34][C:35]=1[Cl:36])=[N:26][O:27][CH2:28][CH2:29][F:30])[C:10]2=[O:58])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:37][C:33]1[S:34][C:35]([Cl:36])=[C:31]([C:25](=[N:26][O:27][CH2:28][CH2:29][F:30])[C:24]([NH:23][C@@H:11]2[C:10](=[O:58])[N:9]3[CH:12]2[S:13][CH2:14][C:15]([S:16][C:17]2[S:18][C:19]([NH2:22])=[N:20][N:21]=2)=[C:8]3[C:6]([OH:7])=[O:5])=[O:57])[N:32]=1
Reactant: CC(C)(C)OC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NOCCF)c4nc(N)sc4Cl)C3SC2)s1

Procedure:
To a solution of (7R)-7-[2-[5-chloro-2-(tritylamino)-thiazol-4-yl]-2-(2-fluoro-ethoxyimino)-acetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid t-butyl ester (8 mg, 0.009 mmol) in dichloromethane (0.16 mL) was added triethylsilane (0.04 mL), followed by trifluoroacetic acid (0.16 mL). After 3 hr at room temperature the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (3 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH3:35][C:36]([CH3:40])([CH3:39])[CH:37]=[O:38]>C1COCC1.CCCCCCC>[OH:38][CH:37]([C:36]([CH3:40])([CH3:39])[CH3:35])[CH2:17][C:8]1[C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(O)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.23 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 10 mL anhydrous THF at −78° C. under nitrogen was added 0.93 mL 2 M LDA in heptane, THF, and ethylbenzene. After 15 minutes, 0.160 g trimethylacetaldehyde was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 30 minutes, evaporate the reaction mixture under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 75˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, J=9.2 Hz, 1H), 7.12 (dd, J=2.7 & 9.1 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 3.89 (s, 3H), 3.48˜3.52 (br m, 1H), 3.40 (br d, J=7.0 Hz, 1OH), 3.10˜3.16 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H). LC-MS: 4.23 min. (m/Z=245.2, 315.2, 355.2=M+Na, 259.1). A faster-eluting isomeric side-product was also isolated during purification: 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one. 1H NMR (CDCl3, 500 MHz) 7.34 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.5 & 9.0 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 4.53 (s, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.84 (s, 3H), 1.32 (s, 9H), 1.06 (s, 9H). LC-MS: 3.77 min. (m/Z=355.2=M+Na, 315.2). The structures of the isomers were further confirmed by COSY and NOESY spectroscopy.
Reaction SMILES: [O:1]=O.[C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]>C(O)(=O)C>[C:3]([C:6]12[CH2:15][C:10]3([OH:1])[CH2:11][CH:12]([CH2:14][C:8]([N+:16]([O-:18])=[O:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]
Reactant: O=O
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(O)(C1)CC([N+](=O)[O-])(C3)C2
Yield: 80 %

Procedure:
In an atmosphere of oxygen, the mixture of 10 mmole of 1-carboxy-3-nitroadamantane, 1 mmole of NHPI, 0.05 mmole of V(AA) 3 and 25 mL of acetic acid was allowed to react for 4 hours at 85° C. The reaction products were analyzed by gas-mass spectroscopy, and as a result, 1-carboxy-3-nitro-5-adamantanol was formed in a 80% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(O[C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:50][C:47]1[CH:46]=[CH:45][C:44]([CH:41]2[CH2:40][CH2:39][N:38]([CH3:36])[CH2:43][CH2:42]2)=[CH:49][CH:48]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 70.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (44 mg) was obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12].[K].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:14]([NH:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)n(N)c(=O)c1C#N
Agent: [K]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)n(NC(=O)c2ccccc2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
To a solution of 10.16 g (50 mmol) of potassium 1-amino-5-cyano-2-hydroxy-4-methyl-6-pyridone in 50 ml of water was added a solution of 7.03 g (50 mmol) of benzoyl chloride in 50 ml of methylene chloride. The mixture was stirred rapidly for 1 hr, and then filtered. The solid was washed with isopropanol and air dried. The yield of product was 3.90 g (29.0%); mp: 256° C. dec. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C14H11N3O3: C, 62.5; H, 4.1; N, 15.6. Found: C, 62.23; H, 4.31; N, 15.85.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylcyanoacetate (1.14 g, 10.0 mmol, 2 eq) in 1 mL DMF was added at 0° C. to a suspension of sodium hydride (0.4 g, 60% in mineral oil, 5.02 mmol) in 3 mL DMF under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes before the dropwise addition of 4-fluoro-3-nitro-benzoic acid methyl ester (1.05 g, 22.7 mmol) in 5 mL DMF. After stirring for 2 hours at room temperature, 2 M HCl (20 mL) and ethyl acetate (20 mL) were added to the red solution. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated to give the title compound as an orange oil, which was used without further purification (1.47 g, 5.03 mmol). 1H NMR (CDCl3) δ 8.83 (1H, d, J=1.5), 8.38 (1H, dd, J=8.0, 1.8), 7.89 (1H, d, J=8.1), 5.74 (1H, s), 4.30 (2H, q, J=7.1), 4.00 (3H, s), 1.32 (3H, t, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: N#Cc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 3-bromomethyl-benzonitrile using the conditions described in Example 10C to provide 3-(4-chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.