Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C:4]([N:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:31])([CH2:10][CH2:11][CH2:12][CH2:13][B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:21])([CH3:22])[O:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OCC)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Ethyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.64 g, 1.50 mmol) was dissolved in THF (5 mL) and cooled to 0° C. NaHMDS (1 M solution in THF, 2.5 mL, 2.5 mmol) was added dropwise and the reaction was stirred for 20 min. Methyl iodide (0.47 mL, 7.5 mmol) was added and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution (5 mL), diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2-25% ethyl acetate in heptane to afford the desired product (0.518 g, 79%). Rf 0.53 (30% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 5.78-5.62 (m, 1H), 5.15-5.03 (m, 2H), 4.12 (q, J=9.0 Hz, 2H), 2.90 (s, 3H), 2.89-2.81 (m, 1H), 2.58-2.51 (m, 1H), 1.94-1.83 (m, 1H), 1.76-1.66 (m, 1H), 1.54-1.08 (m, 29H), 0.77 (t, J=8.0 Hz, 2H). ESI MS found for C23H42B1N1O6 m/z [440.2 (M+1)].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][C:16](=[N:31][OH:32])[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(NC3CCC(=O)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ncc2c(NC3CCC(=NO)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-{[1-Ethyl-5-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}cyclohexanone (0.025 gm, 0.063 mmol) (example 17), hydroxylamine hydrochloride (0.008 gm, 0.126 mmol) and potassium carbonate (0.043 gm, 0.315 mmol) were taken in acetonitrile and the reaction mixture was stirred at room temperature for about 6 h. Excess of solvent was removed under reduced pressure and solid separated was washed with hexane and dried in vacuum.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]2)[CH:7]=1
Reactant: Nc1ncc(C2CCNC2)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(pyrrolidin-3-yl)pyridin-2-amine (20 mg, 0.083 mmol) in DCM in ice bath was added DIEA (57.7 μl, 0.330 mmol) and methanesulfonyl chloride (7.08 μl, 0.091 mmol). The reaction mixture was stirred in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was used for next step without purification. LCMS (m/z): 320.0/322.0 (MH+), 0.363 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O-:38])=[O:37])[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[S:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:49]>>[ClH:49].[CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[S:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)[O-])C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5 N hydrogen chloride-ethyl acetate solution is dissolved 0.1 g of 3(R)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3 hours. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.076 g of 3(R)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetic acid hydrochloride as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.N>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: N
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3
Yield: 50.2 %

Procedure:
The title compound (55.9 mg, 50%) was prepared by the method of Example 89 Step C from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (94 mg, 0.25 mmol) and 2,4-dichlorophenylboronic acid (95 mg, 0.5 mmol) as a white amorphous solid. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=O)[OH:3].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([O:3][C@@H:2]1[CH2:4][C:5](=[O:7])[O:8][C:1]1=[O:9])(=[O:12])[CH3:11]
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: CC(=O)Cl
Product: CC(=O)O[C@@H]1CC(=O)OC1=O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
A mixture of D-malic acid (10 g, 75 mmol, Major Chemicals Co. Ltd. lot #KS00404) in acetyl chloride (30 mL, Aldrich cat #11, 418-9) was heated to 45° C. for 6 h. The excess acetyl chloride was evaporated in vacuo and the residue was taken up in dichloromethane (10-15 mL). The volatiles were removed in vacuo and the residual oil was stored at 4° C. for 18 h. Under cold storage, the oil crystallized, giving rise to (R)-(+)-2-acetoxysuccinic anhydride (95a) as a white solid (11.7 g, quant yield); m.p. 52° C.; [α]D+23.82° (c 5.44, acetone); 1H-NMR (300 MHz, CDCl3) δ: 5.51 (dd, 1H, J 6 Hz, 9 Hz), 3.36 (dd, 1H, J 19 Hz, 9 Hz), 3.00 (dd, 1H, J 19 Hz, 6 Hz), 2.17 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 169.61 (+), 167.66 (+), 166.21 (+), 67.51 (−), 35.10 (+), 20.16 (−).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7](=O)([O:10][CH:11]([CH3:13])[CH3:12])[O:8]C>CO>[C:7](=[O:8])([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)OC(C)C
Reactant: CN(C)CCO
Solvent: CO
Product: CC(C)OC(=O)OCCN(C)C

Procedure:
reacting 2-(N,N-dimethylamino)ethanol with the methyl isopropyl carbonate formed in step i) in the presence of a transesterification catalyst to form isopropyl 2-dimethylaminoethyl carbonate and methanol, under such conditions that the 2-(N,N-dimethylamino)ethanol also reacts with the di-isopropyl carbonate formed in step i) to form more isopropyl 2-dimethylaminoethyl carbonate,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:13].[CH3:15][C:16]1[N:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:19][C:20]=1[CH:21]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:21][C:20]2[S:19][C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[N:17][C:16]=2[CH3:15])=[CH:8][C:7]=1[CH3:13]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: COC(=O)CCc1ccc(N)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.14 g, 0.70 mmol) and 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.19 g, 0.71 mmol) in anhydrous CH2Cl2 (5 mL) is added 4 Å molecular sieves followed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RT for 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, and the mixture is stirred at RT for 12 h. The reaction is quenched with saturated NaHCO3. The organics are separated and washed with saturated NaHCO3 and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound (0.21 g, 68%).
Reaction SMILES: O1CCCC1.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.CC(C)([O-])C.[K+].[CH3:27][N:28]=[C:29]=[S:30]>O>[CH3:27][NH:28][C:29](=[S:30])[C:17]([C:14]1[CH:13]=[CH:12][C:11]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)=[CH:16][CH:15]=1)([C:18]#[N:19])[CH3:20]
Reactant: CN=C=S
Reactant: CC(C#N)c1ccc(-n2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)C(C)(C#N)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To a 10 ml tetrahydrofuran solution containing 1.00 g (5.1 mmole) of 2-[4-(1-imidazolyl)-phenyl]propionitrile was added a 10 ml tetrahydrofuran solution containing 0.69 g (6.2 mmole) of potassium tert-butoxide at 0 C. After stirring for 0.5 hour, a 5 ml tetrahydrofuran solution containing 0.45 g (6.2 mmole) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture and the mixture was extracted with 20 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and condensed. The resulting condensate was suspended in 30 ml of toluene and the suspension was refluxed under heating for 0.5 hour and a solid was collected by filtration to obtain 0.75 g (yield: 54 %) of N-methyl-2-[4-(1-imidazolyl)-phenyl]-2cyanothiopropionamide as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].[CH3:17]O>Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: CC(C(=O)O)c1c(F)cc([N+](=O)[O-])cc1F
Agent: Cl
Product: COC(=O)C(C)c1c(F)cc([N+](=O)[O-])cc1F
Yield: 89 %

Procedure:
Compound (27b) (3.6 g, 15.6 mmol) was dissolved in a solution of a catalytic amount of concentrated hydrochloric acid (0.14 mL) in methanol (72 mL) and treated in the same manner as in (c) in Production Example 1 to give 3.4 g (89%) of compound (28b) as pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1.[CH2:14]([OH:16])[CH3:15]>>[ClH:2].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:16][CH2:14][CH3:15])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1
Reactant: CCOc1cc(Cl)ccc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(Cl)cc1OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Hydrogen chloride gas was passed through a solution of 4-chloro-2-ethoxy-benzonitrile (670 mg, 3.689 mmol) in anhydrous ethanol (25 mL) cooled to 0° C. After 45 min, the hydrogen chloride gas was stopped and the reaction vessel was sealed with a Teflon stopper. It was stirred at room temperature for 5 d. The reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 4-chloro-2-ethoxy-benzimidate hydrochloride (913 mg, 94%). It was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:24])[F:23])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)#[C:2][CH3:3]>[Pd].CCO>[CH2:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:23])[F:24])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)[CH2:2][CH3:3]
Reactant: CC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reaction time: 2 h
Yield: 50 %

Procedure:
To a Paar bottle was added 8-prop-1-ynyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in Example 21 d, Step 2 (150 mg, 0.409 mmole), 10% Pd/C (75 mg) and absolute EtOH (10 mL). The mixture was hydrogenated at 30 psi for 2 h. The catalyst was filtered, the solvent was removed in vacuo and the resulting oily solid triturated with hexanes to give 76 mg (50% yield) of the product as an off-white solid: ESHRMS m/z 369.0559 (M−H, C15H11F6O4, Calc'd 369.0556). 1H NMR (dmso-d6, 300 MHz) 13.38 (brs, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 7.26 (s, 1H), 5.99 (q, 1H, J=7.3 Hz), 2.51-2.66 (m, 2H), 1.48-1.60 (m, 2H), 0.86 (t, 3H, J=7.3 Hz).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:3]2[N:4]=[C:5]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]3[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:28][CH2:27]1
Reactant: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1
Reactant: OC1CCNCC1
Product: O=c1[nH]ccc2nc(N3CCC(O)CC3)nc(Nc3cccc(C(F)(F)F)c3)c12

Procedure:
The title compound was prepared as described in Example 1g by starting from 2-(methylthio)-4-(3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (100 mg, 0.26 mmol) and 4-hydroxypiperidine to yield the title compound (73 mg) as white solids. MS m/z: 406 (M+H)+, 1H NMR (300 MHz), δ ppm 1.21-1.35 (m, 4H), 3.76-3.78 (m, 1H), 4.26-4.28 (m, 4H), 6.17 (d, J=7.2 Hz, 1H), 7.38-7.68 (m, 4H), 7.90 (s, 1H), 8.61 (s, 1H), 11.42 (s, 1H), 12.10 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.O=[C:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[NH2:11][C:10]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[N:1]=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccc(N)c(C#N)n1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc(OC)nc2c1N

Procedure:
Prepared as in Example 2a from 3-amino-6-methoxypicolinonitrile (Example 11b) and ethyl 3-oxobutanoate as an off white solid (45%). MS 262 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[OH:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1nc(/C(=N/O)C(=O)OCCS(=O)(=O)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)OCCS(=O)(=O)c1ccccc1)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11. After a serial addition of 4.0 g (0.0205 mole) of t-butyl bromoacetate, 0.3 ml of water and 7.7 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for 1.5 hours. After completion of the reaction, the insoluble matter was filtered off and 100 ml of water and 100 ml of ethyl acetate were added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue, whereupon white crystals separated out. After cooling, the crystals were collected by filtration to give 4.1 g (yield, 62%) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH:20]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:24][C:23]=1[CH3:33])=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:20]([C:22]4[C:23]([CH3:33])=[CH:24][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:26][C:27]=4[CH3:28])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: CC(=O)Nc1cc(C)c(C=O)c(C)c1
Solvent: CO
Product: CC(=O)Nc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.8 mL in 0.2 M DMSO solution), N-(4-formyl-3,5-dimethyl-phenyl)-acetamide (0.8 mL in 0.2 M toluene solution) and FeCl3 (0.4 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(4-acetylamino-2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 427 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][CH:10]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)OC2CCCCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1

Procedure:
To 1-tert-butyldimethylsilyloxy-2-tetrahydropyranyloxy-2-(4-tertbutylphenyl)ethane (0.4 g, 1.01 mmol) is added tetrabutylammonium fluoride solution (1M TBAF in THF, 5 ml, 5.0 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted in ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 97.3 %

Procedure:
To a solution of tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 3 (0.23 g, 050 mmol) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 4 (0.18 g, 93%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:26]=1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][NH:23][CH3:22])[CH:26]=3)[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CNCc1cccc(C2CCNC2)c1
Product: CNCc1cccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)c1
Yield: 55 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.52 g, 1.7 mmol) and N-methyl-3-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.44 g, 55%) as a yellow solid, mp>270° C.
Reaction SMILES: [CH:1]([CH:4]1[C:13](=O)[C:12]2[C:11]([C:15](OC)=[O:16])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][CH:5]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>>[CH:1]([CH:4]1[C:13]2=[N:26][NH:27][C:15](=[O:16])[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]=32)[NH:6][CH:5]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:2])[CH3:3]
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(C(C)C)C(c1ccccc1)N2
Solvent: O
Product: CC(C)C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
Methyl 3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (35 mg, 1 mmol) and hydrazine monohydrate (20 mL) were added and the mixture was stirred under 40° C. for 3 h. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated, purified with prep-HPLC. 7 mg of solid 9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained (yield: 15%). 1H-NMR (400 MHz, DMSO-d6): δ 0.82-0.83 (d, J=5.2 Hz, 3H), 1.15-1.17 (d, J=5.2 Hz, 3H), 1.89-1.93 (m, 1H), 2.71-2.73 (d, J=6.0 Hz, 1H), 4.83 (s, 1H), 7.11-7.26 (m, 7H), 7.51-7.54 (m, 2H), 12.11 (s, 1H). LC-MS (ESI) m/z: 306 (M+1)+.