Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 92.4 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 90%).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=CC=1)(O)=O.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:11]([N:12]([CH2:29][C:30]1[CH:31]=[CH:32][C:23]([CH2:14][CH2:13][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:24][CH:25]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[C@@H:23]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=2[CH2:24]1)[CH3:10]
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: C1CCNCC1
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 39 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and piperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Temperature: 70 °C

Procedure:
Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoate (35 g, 96 mmol) from Step 5 above was dissolved in MeOH (250 mL) and to the solution was added 2 N NaOH (100 ML, 200 mmol). The stirred mixture was warmed to 70° C. for 3 h. The solution was cooled to ambient temperature, concentrated under reduced pressure, cooled to 0° C. and 0.5M aqueous citric acid solution (300 mL) was added. To the suspension was added EtOAc (500 mL) and water (300 mL). The EtOAc layer was separated and the aqueous phase was washed with EtOAc (200 mL). The combined EtOAc layers were washed with brine (250 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid as a foam that solidified on standing in vacuo (HPLC (method A) retention time= 8.46 min).
Reaction SMILES: ClCCl.Cl[CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7].[CH2:23]([SH:25])[CH3:24].C(N(CC)CC)C>O>[CH2:23]([S:25][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7])[CH3:24]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Reactant: CCS
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(NC(=O)c1ccccc1OC(C)=O)C(Cl)(Cl)Cl
Yield: 90.3 %

Procedure:
50 ml of dichloromethane was added to 7.9 g of N-(1,2,2,2-tetrachloroethyl)-2-acetoxybenzamide. 1.3 g of ethyl mercaptan was add to the solution under stirring and then 2.0 g of triethylamine was added dropwise thereto at 10°-15° C. After effecting the reaction at room temperature for one hour, water was added thereto and the solution was allowed to stand. Then the dichloromethane layer was separated out, dried with unhydrous sodium sulfate and concentrated to obtain 7.0 g of N-(1-ethylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide as white crystals.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=3[Cl:26])[CH:12]=[CH:11][C:10]=2[OH:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]([Cl:26])[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([OH:27])=[C:9]([S:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)(=[O:8])=[O:7])[CH:14]=2)=[C:21]([Cl:22])[CH:20]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)NC3CCC3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)NC3CCC3)c2)c(Cl)c1
Reaction time: 3 h
Yield: 128.7 %

Procedure:
To a solution of N-Cyclobutyl-5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxy-benzenesulfonamide (403 mg, 0.73 mmol) in ethanol (10 mL) at room temperature was added 10% palladium on carbon (60 mg), and the resulting mixture was placed on Parr shaker for 3 hours under 50 psi. hydrogen gas at room temperature. The reaction solution was filtered through Celite®, and the filtrate was concentrated to afford the title compound (379 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ8.32 (s, 1H), 7.07-7.04 (dd, 1H), 6.95 (m, 2H), 6.67 (s, 2H), 4.68 (d, 1H), 3.81-3.68 (m, 1H), 2.16-2.08 (m, 2H), 1.7-1.58 (m, 4H). MS (APCI−) Calc: 402.1, Found: 401.3 (M−1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C[O:18][C:19]1[C:20](=O)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1>CO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:25]3[C:19](=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 122.2 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-piperazine (2.3 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (2.0 g) in methanol (50 ml) was refluxed for 24 hr and evaporated. The residue was chromatographed on silica gel (100 g) using ethyl acetate. The eluates were evaporated and crystallized from ethyl acetate-benzene to give the title compound (4.08 g): mp 112°-114° C.; ir (CHCl3) 1570 cm-1 ; uv max (MeOH)350 (ε=10575) and 256 nm (ε=31730); nmr (CDCl3)δ 3.5 (m, 8H) and 7.0 (m, 9H); and Anal. Calcd for C18H17F3N2O: C, 64.66% H, 5.12% N, 8.38% and Found: C, 64.84% H, 5.17% N, 8.54%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:15][O:14][C:12]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([Br:16])[N:4]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cccnc2c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2cccnc2c1O
Reaction time: 1 h

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1 Step 2 (5.0 g, 24.49 mmol) in CH2Cl2 (100 ml) at room temperature was added N-bromo succinimide (4.36 g, 24.49 mmol). The reaction was stirred for 1 hr. The solids were collected by filtration and dried in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([N:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[O:41])[CH:39]=1)[C:6]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:10]([OH:29])[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)C(=O)OC(C)(C)C)=[O:7])#[N:2].[Cl:49]CCl.Cl>CO>[ClH:49].[CH2:30]([C@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:39]=[C:38]([C:40]([N:42]([CH2:43][CH2:44][CH3:45])[CH2:46][CH2:47][CH3:48])=[O:41])[CH:37]=1)[C@H:10]([OH:29])[CH2:11][NH:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN(Cc2cccc(OC)c2)C(=O)OC(C)(C)C)c1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2R,3S)-3-({3-cyano-5-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate (XXXVI, EXAMPLE 585, 0.080 g, 0.122 mmol), dichloromethane (1 mL), and methanol saturated with hydrochloric acid (1 mL) is stirred for 8 hours, after which time the solvents are removed under reduced pressure. A few drops of methanol, followed by ether, gives the title compound, MS (ESI+) for C33H40N4O4 m/z (M+H)+=557.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)C.C(OC(C1C=CC2N(C(CC3C=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1)=C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:14]1[N:18]2[N:19]=[C:20]([C:23](=[O:25])[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: C=C(OCC)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Product: CC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1

Procedure:
The title compound was prepared as a white solid in analogy to the synthesis of compound 39.4 from 6-(1-ethoxyvinyl)-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine. LCMS (method B): [MH]+=324, tR=2.41 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[C:16](=O)[C:15]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)N(C1CCN(Cc3ccccc3)CC1)C(=O)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccn(C3CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A 2 M solution (0.47 ml) of a diborane/dimethyl sulfide complex in tetrahydrofuran was added to a solution of 1-(1-benzylpiperidin-4-yl)-6-methoxyindoline-2,3-dione (110 mg) in tetrahydrofuran (2 ml) followed by stirring for 1 hr and then heating under reflux for 4.5 hr. After the completion of the reaction, an aqueous solution of sodium bicarbonate was added to the reaction solution, which was then extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate andthe solvent was removed. The residue was dissolved in pyridine and stirred for 4.5 hr. After evaporating off pyridine, ethyl acetate and an aqueous solution of sodium bicarbonate were added thereto. The ethyl acetate layer was separated and dried over magnesium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give 1-(1-benzylpiperidin-4-yl)-6-methoxyindole (28 mg) (yield: 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:4]=1.C(C1C=C(OC)C=CC=1CC(O)=O)(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2C)c1
Agent: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2)c1
Product: COc1ccc(CC(=O)O)c(Cc2ccccc2C)c1

Procedure:
According to the procedure of Preparation 10 (c), except substituting 4-methoxy-2-(2-methylbenzoyl)phenylacetic acid for the 2-benzoyl-4-methoxyphenylacetic acid, the title compound was obtained as a viscous oil: MS (ES) m/e 288.2 (M+NH4)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[O:3].[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]3[CH:34]=[N:33][CH:32]=[N:31][C:27]=3[NH:28]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[O:3])=[CH:17][C:16]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]3[CH:34]=[N:33][CH:32]=[N:31][C:27]=3[NH:28]2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(N)cc1-c1ccc2c(c1)[nH]c1ncncc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 25 °C

Procedure:
To 1-isocyanato-3-(trifluoromethyl)benzene (8.7 μl, 0.062 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)aniline (17.0 mg, 0.062 mmol) and DIPEA (16 μL, 0.089 mmol) in THF (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 3-4 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (16.7 mg, 46.9%). 1H NMR (400 MHz, CDCl3): δ 13.0 (bs, 1H), 9.65 (s, 1H), 9.15 (s, 2H), 8.93 (s, 1H), 8.37 (d, 1H), 8.01 (s, 1H), 7.4-7.6 (m, 5H), 7.2-7.4 (m, 3H), 2.21 (s, 3H). MS (EI) m/z=462 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (30 g, 163 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (20 g, 163 mmol), diisopropylethylamine (50 mL, 300 mmol) and 1-butanol (100 mL) was heated to 80° C. for 2 h. The solvents were removed on a rotary evaporator and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine and dried over magnesium sulfate. The residue was concentrated on a rotary evaporator to give the desired product (40.7 g, 92%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:4]=[CH:5]1
Reactant: CI
Reactant: Cc1cc(C)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ccn(C)c2c1
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A solution of the 4,6-dimethylindole (750 mg, 5.2 mmol) in DMF (20 mL) was cooled to 0° C. under nitrogen and treated with 60% sodium hydride in mineral oil (413 mg, 10.3 mmol). After stirring for 15 minutes, iodomethane (0.4 mL, 6.2 mmol) was introduced and the cooling bath was removed (reaction became light purple). After 30 minutes the solution was subsequently quenched with water (5 ml) and then concentrated to reduce the volume of DMF. The reaction was poured into water (200 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organics were washed with water (3×) and then dried (MgSO4), filtered and concentrated. The residue was purified by silica gel flash column chromatography with 10% EtOAc in Hexane as the eluent to afford the title compound (700 mg, 80%) as a white solid.
Reaction SMILES: O[CH2:2][C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@H:4]([OH:6])[CH3:5].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:36][O:35][CH2:34][C@@H:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[NH:11][C:10]([C:8]3[O:9][CH2:2][C@@H:3]([C@H:4]([OH:6])[CH3:5])[N:7]=3)=[CH:14][CH:13]=2)[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])[CH:18]=1)[CH3:37]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
N-[(2S,3R)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (1.70 g, 3.18 mmol) synthesized in Example (114a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.78 g, 4.48 mmol) and triethylamine (1.50 mL, 10.76 mmol) were added at 0° C., followed by stirring at the same temperature for 1.5 hours under nitrogen atmosphere, followed by stirring at 50° C. overnight. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-4%) to afford the desired compound (1.30 g, yield 79%) as a white foam.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=[N:32][O:33][CH3:34])[C:7]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([O:19]CC4C=CC([N+]([O-])=O)=CC=4)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:8])[N:3]=[N:2]1>CO.O1CCCC1.[C].[Pd]>[S:1]1[CH:5]=[C:4]([C:6](=[N:32][O:33][CH3:34])[C:7]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:8])[N:3]=[N:2]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csnn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csnn1
Reaction time: 3.5 h
Yield: 24.8 %

Procedure:
10% Palladium carbon (0.85 g.) was added to a solution of p-nitrobenzyl 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem-4-carboxylate (syn isomer, 1.65 g.) in methanol (70 ml.) and tetrahydrofuran (90 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 3.5 hours. After removing the catalyst from the reaction mixture by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was adjusted to pH 7 to 8 with sodium bicarbonate, washed with ethyl acetate, adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was pulverized with diethyl ether. The precipitates were collected by filtration and the dried to give yellow power of 7-{2-(1,2,3-thiadiazol-4-yl)-2-methoxyiminoacetamido}-3-cephem- 4-carboxylic acid (syn isomer, 0.3 g.), m.p. 200° to 210° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[N:10]([C:24](=[O:25])[NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]2=[O:14])[CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)NC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 50 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then cyclohexylisocyanate (626 mg., 5 mmoles) were added. The reaction mixture was stirred for 19 hours at room temperature, washed in sequence with two portions of 1N sodium hydroxide, two portions of 1N hydrochloric acid and once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. Recrystallization from toluene gave purified 5-(5-chloro-2-methoxyphenyl)-3-cyclohexylcarbamoyloxazolidine-2,4-dione [435 mg., m.p. 150°-153° C., ir (KBr) 1818, 1761, 1527, 1493, 1364 cm-1 ].
Reaction SMILES: [C-]#N.[Na+].[CH:4]([C:6]1[C:7]([OH:20])=[CH:8][C:9]2[O:14][C:13]([CH3:15])=[CH:12][C:11](=[O:16])[C:10]=2[C:17]=1[O:18][CH3:19])=[O:5].[C:21](O)(=[O:23])C>CO.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[OH:20][C:7]1[C:6]([C:4]([O:23][CH3:21])=[O:5])=[C:17]([O:18][CH3:19])[C:10]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1c(C=O)c(O)cc2oc(C)cc(=O)c12
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cc2oc(C)cc(=O)c2c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
2.6 g (53 mmol) of sodium cyanide and then 18.50 g (223 mmol, 25 eq.) of activated manganese dioxide are added to 2 g (8.5 mmol) of 6-formyl-7-hydroxy-5-methoxy-2-methyl-4H -benzopyran-4-one (A. SCHONBERG, N. BADRAN and N. A. STARKONSKY, J. Am. Chem. Soc., 1953, 75, 4992) suspended in 105 ml of methanol acidified with 2.6 ml of acetic acid. After having been stirred for 4 hours at room temperature, the reaction mixture, diluted with 200 ml of ethyl acetate, is filtered to remove insoluble material (excess MnO2) and the solvents are evaporated. The powdery residue is taken up in water and filtered. 1.80 g of a beige powder are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH:16]([CH3:23])[CH2:17][C:18]([O:20]CC)=O)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.[NH3:24]>CO>[CH3:23][CH:16]1[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:2][NH:24][C:18](=[O:20])[CH2:17]1
Reactant: N
Reactant: CCOC(=O)CC(C)n1c(CCl)nc2cnc3ccccc3c21
Solvent: CO
Product: CC1CC(=O)NCc2nc3cnc4ccccc4c3n21

Procedure:
A solution of ethyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (8.22 g, 24.8 mmol) in 7 N ammonia in methanol (140 mL) was stirred overnight at room temperature. The volatiles were removed under reduced pressure, and the residue was further dried under high vacuum and purified by automated flash chromatography (eluting with a gradient of dichloromethane/methanol/concentrated ammonium hydroxide in a gradient from 100:0:0 to 50:47.5:2.5) to provide 12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one as an orange solid. Automated flash chromatography was carried out using a combination of a COMBIFLASH system (an automated high-performance flash purification product available from Teledyne Isco, Inc., Lincoln, Nebr., USA) and a HORIZON HPFC system (an automated high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA).