Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:32][CH3:33])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[CH:18]=[C:17]2[NH:23][C:24]1[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=1[Cl:31]>>[C:1]([O:4][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:32][CH3:33])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[CH:18]=[C:17]2[NH:23][C:24]1[C:25]([Cl:31])=[CH:26][N:27]=[CH:28][C:29]=1[Cl:30])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCOC(C)=O

Procedure:
The title compound can be prepared from potassium acetate and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 2H), 7.84 (d, 1H), 7.16 (d, 1H), 4.77 (s, 1H), 4.16 (t, 2H), 4.11 (t, 2H), 3.98 (s, 3H), 2.02 (s, 3H), 1.91 (m, 2H), 1.84 (m, 2H); MS (ESI): 466.9.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(OCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using p-cresol and 1-bromo-3-chloropropane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:10]=2)[N:5]=[C:4]([CH3:18])[CH:3]=1.[C:19]1([CH:25]2[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCCO)C.[OH-].[Na+]>[CH3:18][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2cc(N3CCCC3=O)ccc2n1
Reactant: c1ccc(C2CCNC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N3CCCC3=O)ccc2n1
Temperature: 250 °C
Yield: 28.1 %

Procedure:
A mixture of 1-(4-chloro-2-methylquinolin-6-yl)pyrrolidin-2-one (0.2 g; see Preparation 6 above) and 3-phenylpyrrolidine (0.282 g) in 2-ethoxyethanol was heated in a microwave at 250° C. for 20 minutes. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. Trituration from ether gave the title compound as a white powder (0.08 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21](OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[CH2:27]([Al+]CC(C)C)[CH:28](C)[CH3:29].CCCCCC.[Cl-].[NH4+].[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.C([Li])CCC>O1CCCC1.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH:21]=[C:28]([CH3:29])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)C[Al+]CC(C)C
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
After cooling a methylene chloride solution (400 ml) of 1,4-dibenzyl-2-ethoxycarbonylpiperazine (19.57 g) to −78° C., diisobutylaluminum hydride (a 0.95 mole hexane solution, 121.7 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 2.5 hours. A saturated aqueous solution of ammonium chloride and methylene chloride were added and then, the water layer was extracted three times. The organic layers were combined, washed with distilled water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was provided for the subsequent reaction without purification. After cooling a tetrahydrofuran solution (300 ml) of isopropyltriphenylphosphonium iodide (25.0 g) to −78° C., n-butyl lithium (a 1.53 mole hexane solution, 37.8 ml) was added dropwise, followed by stirring at −78° C. for 30 minutes. A solution of the residue, which had been obtained above, in tetrahydrofuran was added dropwise to the reaction mixture. The resulting mixture was heated gradually from −78° C. and stirred overnight. A saturated aqueous solution of ammonium chloride was added to terminate the reaction. Ethyl acetate was added and the water layer was extracted three times. The organic layers were combined, washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure The residue was subjected to chromatography on a silica gel column (ethyl acetate:hexane=1:20), whereby the title compound (6.0 g) was obtained as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[C:9]1[S:10][CH:11]=[C:12]([Br:14])[N:13]=1>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:14][C:12]1[N:13]=[C:9]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:10][CH:11]=1
Reactant: Brc1csc(Br)n1
Reactant: Oc1ccccn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1csc(Oc2ccccn2)n1
Temperature: 140 °C
Yield: 37.9 %

Procedure:
According to Scheme 3, Step 2: Pyridin-2-ol (4.12 mmol, 0.39 g) and then silver carbonate (4.94 mmol, 1.36 g) were added to a solution of 2,4-dibromothiazole (4.12 mmol, 1.00 g) in DMF (18 mL) and the reaction mixture was heated at 140° C. overnight. After evaporation of the solvent, the reaction mixture was dissolved in DCM and was filtered through celite. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6](OC)=[O:7].[NH2:15][NH2:16]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH:15][NH2:16])=[O:7]
Reactant: NN
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Solvent: O
Product: COc1ccc(C(=O)NN)cc1OC

Procedure:
A mixture of 9.8 g (0.05 mol) of methyl 3,4-dimethoxybenzoate and 15 ml of 85% water containing hydrazine was refluxed for 2.5 hours with stirring. The reaction mixture was cooled and the crystals formed were recovered by filtration and washed with water to provide 3,4-dimethoxybenzoic acid hydrazide. The yield was quantitative.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CN1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2CCNC2C1

Procedure:
10.3 g (47.6 mmol) of 2-benzyl-7-methyl-2,7-diazabicyclo(3.3.0]octane in 200 ml of ethanol are hydrogenated on 2.5 g of palladium/active carbon (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[S:9][CH:8]=1)[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][CH:3]([C:7]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[S:9][CH:8]=1)[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(C(=O)O)c1csc2cc(F)ccc12
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(C(=O)Cl)c1csc2cc(F)ccc12

Procedure:
A solution of 2.70 g (10.7 mM) of α-methoxy-α-(6-fluoro-3-benzothienyl)acetic acid (from Preparation 1) in 60 ml of benzene containing 2.8 ml of oxalyl chloride and 4 drops of N,N-dimethylformamide was stirred under nitrogen at 25° C. for two hours. The solvent was then removed by evaporation under reduced pressure to give α-methoxy-α-(6-fluoro-3-benzothienyl)acetyl chloride. The acid chloride was dissolved in 60 ml of acetone and added dropwise over five minutes to a stirred cold (5° C.) solution of 2.41 g (11.3 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 60 ml of acetone and 120 ml of water containing 2.84 g (33.8 mM) of sodium bicarbonate. The reaction mixture was stirred for two hours at 5° C. and then warmed to 25° C. and stirred for an additional two hours. The reaction mixture was diluted with 1N hydrochloric acid to pH 7.5 and stored at 0° C. for twelve hours. Following removal of acetone from the reaction mixture by evaporation, the aqueous mixture was acidified to pH 2 with 1N hydrochloric acid, and the aqueous acid layer was extracted several times with dichloromethane. The organic extracts were combined, washed with brine, dried, and the solvent was removed by evaporation under reduced pressure to provide 5.02 g (100%) of 7-[α-methoxyimino-α-(6-fluoro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (CDCl3): δ2.24 (s, 3H); δ4.04 and 4.15 (two singlets, 3H); δ5.08 and 5.11 (two dd, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), β-alanine (1.06 g, 11.9 mmol) and NaOMe solution (18 mL, 8.96 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude residue was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a white solid. MS: (+) m/z 393.00 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.OO.C(O)(=O)C.[CH:18](=[O:22])[CH2:19][CH2:20]C>C1(C)C=CC=CC=1.Cl[Cu]>[CH2:18]([O:22][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:19][CH3:20]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCC=O
Agent: Cl[Cu]
Agent: OO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C

Procedure:
1.8 g 2,2,6,6-tetramethyl-piperidin-4-ol (intermediate product of Ciba Specialty Chemicals Inc.) are suspended in 7 ml of toluene. 3.6 ml of a 30% aqueous hydrogen peroxide solution and 0.41 g acetic acid are added at 5° C. and the solution is stirred at room temperature over night. 4.2 ml butanal and, after 15 min., 50 mg CuCl are added. The reaction mixture is stirred for 18 h at room temperature. The two phases are separated and the organic one is washed with 0.05M hydrochloric acid, sodium bisulfite solution, water, diluted sodium hydroxide solution, water and finally saturated sodium chloride solution. The organic phase is dried over sodium sulfate and finally evaporated to complete dryness under vacuum to afford 0.38 g product.
Reaction SMILES: F[C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1)=[O:5].[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]=1)=[O:5]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3F)n2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3N)n2)CC1
Temperature: 120 °C
Yield: 76 %

Procedure:
A microwave vial was charged with tert-butyl 4-(1-(2-fluoronicotinoyl)isoquinolin-3-yl)piperazine-1-carboxylate (8 mg, 0.018 mmol) and a saturated aqueous solution of ammonium hydroxide (3 ml). The reaction mixture was heated under microwave irradiation at 120° C. for 30 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (6 mg, 76% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([O:35][C:36]([N:38]1[CH:42]=[CH:41][CH:40]=[C:39]1B(O)O)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:39]1[N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:42]=[CH:41][CH:40]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccn2C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C19H19N2O3 (M+H): 323.1390. Found 323.1384.
Reaction SMILES: B#B.[C:3]([C:18]1[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[NH:21][CH:22]=1)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.O>O1CCCC1>[CH2:3]([C:18]1[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[NH:21][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A solution (30 ml, 90 mmol) of ca. 3M diborane in tetrahydrofuran was added to 1.80 g (5.4 mmol) of methyl 4-tetradecanoylpyrrole-2-carboxylate prepared in Synthetic Example 6, and then 1 ml of boron trifluoride-diethyl ether complex was further added thereto. The mixture was allowed to stand overnight at room temperature. Methanol and water were successively added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/3) to obtain 0.22 g (13% yield) of methyl 4-tetradecylpyrrole-2-carboxylate, m.p. 80°-82° C.
Reaction SMILES: [CH2:1]([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]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][NH2:26])(=[O:24])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([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:26][NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CS(=O)(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.67 g, 2.42 mmol) in dry DCM (60 mL) were added methanesulfonohydrazide 187 (0.40 g, 3.63 mmol), 1-hydroxybenzotriazole (0.44 g, 3.63 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.63 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)-6-(benzyloxy)-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 188 (0.37 g, 42%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C[N:18](C=O)C.[OH-].[NH4+]>S(Cl)(Cl)=O.CC(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([Cl:16])=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2,4-Dinitro-5-chlorobenzoic acid (7.00 g, 28.4 mmol) was suspended in 40 mL thionyl chloride containing 3 drops of DMF. The suspension was warmed to reflux for four hours. After cooling to room temperature, solvent was removed by rotary evaporation leaving a golden yellow liquid. This was diluted with 30 mL acetone and added dropwise over 20 minutes to a 0° C. solution of 20 mL concentrated ammonium hydroxide. The reaction was stirred at 0° C. for 30 minutes, then poured into 250 g of ice. The yellow orange precipitate was collected by filtration and washed well with water. The solid was dried first by water aspirator then under high vacuum to furnish 5.9 g (24 mmol, 84% yield) of product. NMR (400 MHz; acetone-d6): δ 8.75, s 1H, 8.25, s 1H; mp 201-203° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](OC)=[O:20].[H-].[Na+].O>CN(C=O)C>[OH:20][CH:19]=[C:11]([S:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CSc1cccc(-c2ccccc2)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=CO)Sc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 15.4 %

Procedure:
Methyl (3-phenylthiophenoxy)acetate (6.60 g) and methyl formate (30.78 g) were dissolved in DMF (30 ml) and added dropwise at 0° C. to sodium hydride (0.83 g, 50% dispersion in oil) in DMF. The reaction mixture was stirred at 0° C. for 45 minutes and then left at room temperature under nitrogen over the weekend. The reaction mixture was then poured into water (300 ml) and washed with diethyl ether (3×150 ml). The aqueous phase was adjusted to pH 7 with hydrochloric acid and then extracted with diethyl ether (3×100 ml). The combined organic extracts were washed successively with water (3×100 ml) and brine (2×75 ml) and then dried. Filtration and evaporation of the solvent under reduced pressure gave methyl 3-hydroxy-2-(3'-phenylthiophenoxy)propenoate (1.13 g) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])=[N:16][C:15]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[N:18][C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])=[N:16][C:15]=3[CH:14]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(C=C3CN(C(=O)OC(C)(C)C)C3)cc2n1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CC3CN(C(=O)OC(C)(C)C)C3)cc2n1
Reaction time: 65 h
Yield: 52.9 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.51 mmol) in EtOH (30 mL) was added 10% Pd/C (275 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with EtOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange oil (0.71 g, 53%). LCMS (method A): RT 3.22 min [M+H]+ 535.4
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:18])[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:18])[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[N:14]2[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)CC[C@@](C)(c2cc(F)cc(F)c2)NC1=O
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)C(C)(C)CC[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (6S)-6-(3,5-difluorophenyl)-3,3,6-trimethylpiperidin-2-one (540. mg, 2.13 mmol) in THF (20 mL), chilled to 0° C. was added potassium hydride (approximately 86 mg, 2.13 mmol, as a 30% suspension in oil) under a constant stream of nitrogen. The reaction was allowed to stir for 30 minutes at which time methyl bromoacetate (391 mg, 2.56 mmol) was added at 0° C. An LCMS after one hour indicated that the reaction was incomplete, thus more potassium hydride was added (approximately 43 mg, 1.06 mmol, as a 30% suspension in oil) at 0° C. The reaction was sealed well and was stirred for an additional 16 hours, during which time the bath temperature warmed to ambient temperature. The reaction was judged to be 46% complete by LCMS analysis. The reaction was chilled to 0° C. and saturated aqueous ammonium chloride (5 mL) was added to quench the potassium hydride. To the reaction was added 1M aqueous HCl (5 mL) and the reaction was diluted with ethyl acetate. The organic layer was washed once with brine and then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes-10:90 to 75:25, to give the title compound. MS: m/z=326 (M+1).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH:13]([CH3:15])[CH3:14].[Cl:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28](Cl)=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[Cl:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([CH2:27][C:28]([NH:1][N:2]4[C:11](=[O:12])[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=[C:3]4[CH:13]([CH3:15])[CH3:14])=[O:29])([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(Cl)(C3)C1)C2

Procedure:
3-Amino-2-isopropyl-4(3H)-quinazolinone and the product of Example 21A were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21-1.26 (m, 6H), 1.51-1.74 (m, 6H), 1.99-2.19 (m, 8H), 2.25 (s, 2H), 3.08-3.17 (m, 1H), 7.51-7.56 (m, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 1H), 8.13 (dd, J=7.9, 1.6 Hz, 1H), 10.89 (s, 1H) ppm; MS (DCI/NH3) m/z 414 (M+H)+; Elemental Analysis: Calculated for C23H28ClN3O2: C, 66.74; H, 6.82; N, 10.15. Found: C, 66.65; H, 6.82; N, 10.03.