Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][N:12]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: N#CC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 79.7 %

Procedure:
A solution of 4-(4-chlorophenyl)piperidine-4-carbonitrile hydrochloride (0.055 g, 0.2155 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.033 g, 0.2155 mmol) and triethylamine (0.150 ml, 1.0775 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 2 days. Concentration and trituration with methanol (3 ml) gave a white solid (0.058 g, 80%). LC-MS (LCT2) m/z 338 [M+H+], Rt 6.17 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCO
Reactant: Cc1occc(=O)c1OCc1ccccc1
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 1-amino-4-hydroxybutane under substantially similar conditions to those described under Example 11 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one as white crystals, m.p. 126°-128° C.; νmax (nujol) 1630, 3350 cm-1 ; δ(d6DMSO) 1.5 (m, 4H), 2.45 (s, 3H) 3.35 (t. 2H), 4.30 (t, 2H), 7.25 (d 1H), 8.2 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.[OH-].[Na+]>CN(C=O)C>[Si:11]([O:10][CH2:9][C:7]1[N:8]=[C:3]([CH2:2][NH2:1])[CH:4]=[CH:5][CH:6]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCc1cccc(CO)n1
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6-aminomethypyridine-2-methanol (5 g, 36.2 mmol) in anhydrous DMF (25 mL) at 0° C. was treated with tert-butyldimethylsilyl chloride (5.728 g, 38 mmol) and imidazole (2.584 g, 38 mmol), stirred at room temperature for 20 h, poured into 1.5-M aqueous NaOH (100 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with water (4×10 mL), brine (2×20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil; NMR δH (400 MHz, CDCl3) 0.82 (9H, s), 0.87 (6H, s), 1.81 (2H, s), 3.84 (2H, s), 4.73 (2H, s), 7.03 (1H, d, J 8.0 Hz), 7.28 (1H, d, J 7.5 Hz) and 7.57 (1H, t, J 8.0 Hz); M/Z 253 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:2]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[O:7])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(c1ccc(O)cc1)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1
Yield: 50 %

Procedure:
A mixture of 2-thienyl-(4-hydroxy-phenyl)ketone (M.p. 112° C.; 65 g), ethyl bromoisobutyrate (62 g) and potassium carbonate (88 g) in 2-butanone (500 ml) is refluxed for 24 hours. After removing the solid by filtration in the hot, the solvent is removed. The unreacted phenol is extracted from the residue with an alkaline aqueous solution. The usual treatments give, in a yield of 50%, the ester which melts at 45° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[N+:29]([O-:31])=[O:30])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[N+:29]([O-:31])=[O:30])[NH:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3n2S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
A mixture of 1-benzenesulfonyl-6-methoxy-2-(4-methoxy-2-nitrophenyl)-1H-indole (2.0 g), tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (11.4 ml) and tetrahydrofuran (40 ml) was stirred for 5 hours at 80° C. The reaction mixture was diluted with water, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](N2CCOCC2)[C:9]#N)[CH:5]=[CH:6][CH:7]=1.[O:17]1CCCC1.[OH-].[K+].[C:24](#[N:28])[C:25](C)=[CH2:26]>CO.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([CH2:9][CH:25]([CH3:26])[C:24]#[N:28])=[O:17]
Reactant: N#CC(c1cccc(Cl)c1)N1CCOCC1
Reactant: C1CCOC1
Reactant: C=C(C)C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C#N)CC(=O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 11.8 g. of α-(m-chlorophenyl)-4-morpholineacetonitrile in 50 ml. of tetrahydrofuran is added 60 drops of a 30% solution of KOH in methanol. To the solution is added 4.62 ml. of methacrylonitrile (temperature rose to 42° C.). After stirring for 1 hr., the mixture is concentrated to dryness and the residue dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate and the eluent concentrated to give 15.5 g. of a yellow oil. The oil is heated (steam bath) with a mixture of 75 ml. of acetic acid and 5 ml. of water for 1 hr. and the solvent removed under vacuum. Addition of water to the residue gives 11.2 g. of crystals, m.p. 72°-75° C. Recrystallization from methylene chloride-hexane gives 8.95 g. of crystals, m.p. 79.5°-80.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[NH2-].[Na+].ClC1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>C1C=CC=CC=1.C(O)CCC.Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCO
Product: Fc1ccc(Cc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 100 g (740 mmol) of 4-fluorophenylacetonitrile in 200 ml of benzene was added to a cooled (0° C.) slurry of 40 g (945 mmol) of sodium amide in 600 ml of the same solvent. After the addition was complete the solution was warmed to ambient temperature and stirred for one-half hour. The reaction mixture was again cooled to 0° C., 73.2 g (370 mmol) of solid 4,7-dichloroquinoline was added in increments, and the mixture was then stirred at ambient temperature overnight. Quenching with NH4Cl followed by workup gave the crude disubstituted acetonitrile, which was dissolved in 500 ml of n-butanol saturated with anhydrous HCl. The acidic solution was heated at reflux for 18 hours. The majority of the solvent was removed via distillation, and the residue was diluted with solvent, and washed with 10% NaOH. The organic layer was dried, and the solvent was removed in vacuo. Purification via HPLC gave 67 g of the title product. Yield: 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1.N>>[Cl:31][C:28]1[S:27][C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(Br)s1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(Cl)s3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-bromo-5-chlorothiophene in place of 4-bromothioanisole (yield: 150 mg, 45%). mp 249-251° C. 1H NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 6.92 (d, J=9 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 2H), 7.58 (d, J=6 Hz, 1H), 7.94 (d, J=9 Hz, 2Hz, 2H), 8.04 (s, 1H). MS (DCI/NH3) m/z 477 (M+H)+, 494 (M+NH4)+. Anal. calc. for C21H14Cl2N2O3S2.H2O: C, 50.9; H, 3.03; N, 5.60. Found: C, 50.5; H, 2.79; N, 5.26.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2=[N:14][N:15]=[CH:16][N:7]2[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:12][C:13]2[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:17])[N:7]3[CH:16]=[N:15][N:14]=[C:8]3[C:9]=2[N:10]=1
Reactant: CC(C)Cn1c(=O)n2cnnc2c2nc[nH]c21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n2cnnc2c2nc(Br)[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-isobutyl-6,7-dihydro-5h-[1,2,4]triazolo[3,4-i]purin-5-one (9.4 mg, 40 mmol) in THF (5 ml) was added N-bromosuccinimide (8 mg, 44.7 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method A) to provide the desired product. LCMS calculated for CO10H12BrN6O (M+H): 311.0. found 310.9, 313.0.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:20](=[O:23])([O-])[O-].[Na+].[Na+].O.[CH2:27]([OH:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([C:20]1[O:23][C:2]2[C:1]([C:4]3[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:6]([CH3:7])[CH3:5])[C:5]=3[O:16][CH2:17][CH2:18][CH3:19])=[CH:3][CH:9]=[CH:4][C:1]=2[CH:2]=1)(=[O:29])[CH3:28]
Reactant: CCO
Reactant: O=C([O-])[O-]
Reactant: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of (3,5-diisopropyl-2-propoxy-phenyl)-boronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of Pd(Ph3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-7-(3,5-diisopropyl-2-propoxyphenyl)-benzo[b]furan as a clear yellow pasty solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6]>O.O1CCOCC1.C(OCC)(=O)C>[Cl:2][C:3]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cnc1Cl
Reactant: N
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of ammonia in water was treated with a solution of 2-chloro-5-(trifluoromethyl)nicotinoyl chloride (as prepared in the previous step, 1.18 g, 4.8 mmol) in dioxane. After stirring at ice bath temperature for 1 hour, the resulting precipitate was dissolved in ethyl acetate and the organic extract dried over anhydrous sodium sulfate. Concentration in vacuo followed by drying on the high vacuum afforded the product as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:27])[NH:16][C:17]2[S:18][C:19]3[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=3[N:25]=2)[CH:10]=1)(C)(C)C.[ClH:29]>C(Cl)Cl.CCOCC.CCCCCC>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=2[N:25]=1)=[O:27].[ClH:29].[ClH:29].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][C:24]=2[N:25]=1)=[O:27]
Reactant: CN1CCc2nc(NC(=O)c3cccc(CNC(=O)OC(C)(C)C)c3)sc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1CCc2nc(NC(=O)c3cccc(CN)c3)sc2C1

Procedure:
To a solution of [3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (3.56 g, 8.76 mmol) in anhydrous DCM (175 mL) at rt add HCl (44 mL 4M solution in 1,4-dioxane, 175 mmol) and stir the reaction at rt for 24 h. Dilute the solid suspension with Et2O (300 mL) and hexane (500 mL), stir vigorously for 20 min Filter and wash with Et2O and hexane to afford the desired product 3-aminomethyl-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-benzamide dihydrochloride as a solid (3.28 g, 8.64 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])(=[O:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:22])(=[O:15])=[O:14])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.66 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-(4-morpholinylsulfonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 66; 250 mg, 0.66 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h. The organic phase was evaporated in vacuo to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (62.3 mg, 0.66 mmol) and diisopropylethylamine (0.12 ml, 0.66 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C1COCC1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15]>O>[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:2]=[O:4])[CH2:18][CH2:17]1)=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CCC(=O)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCC(C=O)CC1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To dried MTP 50.0 g (146 mmol), THF 500 ml was added, and potassium-t-butoxide 18.0 g (160 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (100 ml) of 4-oxocyclohexane carboxylic acid methylester 21.9 g (140 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 500 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). Such resulting purified material was stirred in mixed solvent of 2N-hydrochloric acid 500 ml and acetone 500 ml for 5 hours at room temperature, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-formylcyclohexane carboxylic acid methyl ester 18.8 g (111 mmol). The yield was 79.2% from 4-oxocyclohexane carboxylic acid methylester.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH2:11][C:12]#[C:13][C:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:16][N:15]=2)[CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:30]/[OH:31])=[C:4]([O:10][CH2:11][C:12]#[C:13][C:14]2[C:18]([C:19]([F:21])([F:20])[F:22])=[C:17]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:16][N:15]=2)[CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O/N=C/c1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Yield: 96.4 %

Procedure:
A mixture of 4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde (Preparation 62D, 0.050 g, 0.111 mmol), hydroxylamine hydrochloride (9.26 mg, 0.133 mmol), and sodium acetate (0.018 g, 0.222 mmol) in methanol (2.0 mL) was heated at reflux for 30 min. The solvent was removed under reduce pressure, and the residue was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (E)-4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde oxime (0.050 g, 0.107 mmol, 97% yield) as a white solid. The product had an HPLC with a ret. time=3.26 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=466.8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.O>C(O)(C)(C)C>[ClH:7].[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nsc2ccccc12
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(C)(C)O
Product: Cl
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
Anhydrous piperazine (49.4 g, 0.57 mol) and t-butanol (10 mL) were added to a dry, 300 mL round bottom flask equipped with a mechanical stirrer, thermometer, condenser topped with a nitrogen inlet, and pressure-equalizing dropping funnel. After the flask was purged with nitrogen, it was heated to 100° C. in an oil bath. A solution of 3-chloro-1,2-benzisothiazole (19.45 g, 0.11 mol) in t-butanol (10 mL) was added to the addition, funnel, and then slowly added to the reaction flask over 20 minutes to moderate an exothermic reaction (112-118° C.). Once addition was complete the yellow solution was heated to reflux (121° C.) and then maintained at reflux for 24 hours. Thin-layer chromatography showed that the reaction was complete. The reaction mixture was cooled to 85° C. and 120 mL of water was added. The hazy solution was filtered and the filter cake rinsed with 60 mL of t-butanol/water (1:1) solution. The pH of the combined filtrate and wash was adjusted to 12.2 with 50% aqueous caustic. The aqueous solution was extracted with toluene (200 mL), the layers were separated, and the aqueous layer was extracted with fresh toluene (100 mL). The combined toluene layers were washed with water (75 mL), and then the toluene solution was concentrated in vacuo at 48° C. to 90 mL. Isopropanl (210 mL) was added to the concentrate and then the pH was slowly adjusted to 3.8 with 7.6 mL of concentrated hydrochloric acid. The resulting slurry was cooled to 0° C., granulated for 45 min, and then filtered. The filter cake was washed with cold isopropanol (50 mL) and then dried in vacuo at 40° C. to afford 23.59 g (80% yield) of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride as an off white solid.
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[C:5](=[O:10])[O:6][CH:7](Cl)[CH3:8])([CH3:3])[CH3:2].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH:7]([O:6][C:5]([N:4]([CH:11]([CH3:13])[CH3:12])[CH:1]([CH3:3])[CH3:2])=[O:10])[CH3:8])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CC(Cl)OC(=O)N(C(C)C)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)OC(=O)N(C(C)C)C(C)C
Yield: 16.8 %

Procedure:
In the same manner as in step b) in Example 125, 92 mg of the title compound was prepared from 247 mg of 1-chloroethyl N,N-diisopropylcarbamate and 400 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:8]=[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19]2)[C:3]=1[C:4]([OH:6])=[O:5].[CH2:34]1COCC1>CO>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:8]=[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19]2)[C:3]=1[C:4]([O:6][CH3:34])=[O:5]
Reactant: C1CCOC1
Reactant: Nc1nc(-c2ccccc2O)cc(C2CCCN(C(=O)OCc3ccccc3)C2)c1C(=O)O
Solvent: CO
Product: COC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a solution of 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinic acid (1.1 g, 2.5 mmol) in THF (10 mL) and MeOH (5 mL) was added dropwise trimethylsilyldiazomatane (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hrs, and the reaction was quenched by acetic acid. The mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3:1) followed by recrystallization from a mixture of CH2Cl2 and hexane to give methyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinate as a yellow solid (0.39 g, yield; 34%).