Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:27])=[CH:20][CH:21]=1
Reactant: COc1ccc(N2CCN(C3CCN(Cc4ccccc4)CC3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
A mixture of 44 g of 1-(1-benzyl-4-piperidyl)-3-(4-methoxy-phenyl)-imidazolidin-2-one, 320 ml of methanol, 130 ml of water and 12 g of a conc. aqueous solution of hydrochloric acid, with the addition of 10 g of a palladium on charcoal catalyst, is hydrogenated at 30° to 40° C and under reduced pressure until 1 molar equivalent of hydrogen has been taken up. Thereafter the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of isopropyl alcohol and diethyl ether to yield the 1-(4-methoxyphenyl)3-(4-piperidyl)-2-imidazolidinone with a melting point of 140° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.O=S(Cl)[Cl:14]>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(Cl)c1ccc(CBr)cc1

Procedure:
A solution of 4-bromomethyl-benzoic acid (8.6 g, 0.04 mol) in 7.23 mL SOCl2 (0.1 mol) is heated to reflux for 5 h. SOCl2 is removed, and the residue is recrystalized from hexane to afford 4-bromomethyl-benzoyl chloride as a white crystalline solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]/[N:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:12]=2)=[N:6][CH:7]=1.CCO>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: Ic1ccc(N/N=C/c2cccc(OCCN3CCOCC3)c2)nc1
Solvent: CCO
Solvent: ClCCl
Product: Ic1ccc2nnc(-c3cccc(OCCN4CCOCC4)c3)n2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a solution of Example 1 step a (10.93 g, 24.16 mmol) in DCM (100 mL)/EtOH (15 mL), was added Phl(OAc)2 (10.74 g, 33.35 mmol). The reaction was stirred at RT for 72 h, diluted with DCM (25 mL) then washed with aq. sodium hydroxide (1 M, 25 mL) and brine (25 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was triturated with Et2O (10 mL) and the resulting solid was collected by filtration to afford the title compound (9.98 g, 92%) as an off-white solid. LCMS (Method 1): Rt 2.11 min, m/z 451 [MH+]. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (1 H, s), 7.71 (1 H, d, J 9.5), 7.60 (1 H, d, J 9.5), 7.53 (1 H, t, J 7.9), 7.47-7.41 (2 H, m), 7.18 (1 H, d, J 8.1), 4.21 (2 H, t, J 5.7), 3.59 (4 H, t, J 4.5), 2.75 (2 H, t, J 5.7), 2.45 (4 H, m).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1
Reactant: C1=COCCC1
Reactant: Cc1cc2[nH]ncc2c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cnn2C2CCCCO2)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
p-Toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and 3,4-dihydro-2H-pyran (99%, 205 μL, 2.39 mmol) were sequentially added to a suspension of C1 (250 mg, 1.49 mmol) and 4 Å molecular sieves in dichloromethane (10 mL). The reaction mixture was allowed to stir at room temperature for 4 hours, at which time it was filtered, concentrated in vacuo, and washed three times with heptane. Purification via silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 65 mg, 0.26 mmol, 17%. LCMS m/z 252.1 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.08 (d, J=0.9 Hz, 1H), 7.26-7.27 (m, 1H), 5.67 (dd, J=9.1, 2.8 Hz, 1H), 3.99-4.05 (m, 1H), 3.71-3.79 (m, 1H), 2.65 (d, J=0.8 Hz, 3H), 2.06-2.2 (m, 2H).
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].C(ON=C(C1N=C(NC(=O)C(F)(F)F)SC=1)C(N[CH:18]1[C:40](=[O:41])[N:20]2[C:21]([C:37]([OH:39])=[O:38])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=O)C#C.Cl>O>[C:34]([CH2:33][CH2:32][N:31]1[C:27]([S:26][CH2:25][C:22]2[CH2:23][S:24][C@@H:19]3[CH2:18][C:40](=[O:41])[N:20]3[C:21]=2[C:37]([OH:39])=[O:38])=[N:28][N:29]=[N:30]1)([OH:36])=[O:35]
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 8 h
Yield: 111.4 %

Procedure:
A solution of sodium acetate trihydrate (5.97 g) in water (25 ml) was added to 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(3.0 g) and the mixture was stirred overnight. The reaction mixture was adjusted to pH 3 with 10% hydrochloric acid under ice-cooling and precipitates were collected by filtration, washed with water and dried to give 7-[2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.80 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:18]([F:29])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]=2[CH:6]=1)=O.[BH4-].[Na+]>CCO.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:19]2[C:5]([CH2:3][OH:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[N:9][C:8]=3[C:18]=2[F:29])=[C:22]([Cl:28])[CH:23]=1
Reactant: COC(=O)c1cc2c(ncn2CCS(C)(=O)=O)c(F)c1Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(CO)cc21
Reaction time: 96 h
Yield: 79.5 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11 cc (0.300 g, 0.594 mmol) is suspended in a mixture of EtOH (6 mL) and THF (4 mL) under N2. NaBH4 (0.112 g, 2.97 mmol) is added. After approximately 4 days stirring, reaction mixture is quenched by the addition of AcOH until the reaction mixture reaches pH 7. The reaction mixture is concentrated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with water (3×), brine, and dried (Na2SO4). The organic layer is concentrated under reduced pressure until a white precipitate forms which is collected by filtration to give 0.225 g (79%) clean desired product: LC/MS ESI (+) m/z 478, 476 (M+ Br pattern) detected.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 73.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.18 g, 0.29 mmol) prepared in Example 110a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (100 mg, 73%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].N1C=CC=CC=1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C>[O:8]([CH2:7][C@H:6]1[O:5][C@@H:4]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@@H:3]1[CH2:2][OH:1])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a round-bottom flask were placed 10 g of 9-((2R, 3R, 4S)-3,4-bis-hyroxymethyl-oxetan-2-yl)-adenine and 100 mL of pyridine. To the system was added 6.4 g of tert-butylchlorodimethylsilane, and the reaction mixture was stirred under nitrogen at room temperature for 1 day. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated with a rotary evaporator. The residue was purified by column chromatography to afford 9-((2R,3R,4S)-4-t-butyldimethylsiloxymethyl-3-hydroxymethyl-oxetan-2-yl)adenine.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[K].C1(=O)[NH:18]C(=O)C2=CC=CC=C12>CN(C)C=O>[NH2:18][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: ClCC1COc2ccccc2O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: NCC1COc2ccccc2O1

Procedure:
Commercial grade of 2-chloromethyl-1,4-benzodioxane (10.0 g, 54.7 mmol) and phthalimide potassium salt (12.0 g, 65.0 mmol) were added to N,N-dimethylformamide (350 ml) and subjected to reaction overnight under reflux; thereafter, N,N-dlmethylformamide was distilled off under vacuum. Water (250 ml) was added to the residue and the mixture was stirred well, with the floating solids being subsequently recovered by filtration. The solids were dried, then recrystallized from methanol/methylene chloride, thereby yielding (1,4-benzodioxan-2-ylmethyl)phthalimide as a colorless tabular crystal in an amount of 8.43 g. The thus obtained crystal was dissolved in ethanol (500 ml); to the solution, hydrazine hydrate (4.3 g) was added, followed by refluxing under heating for 3 h. The resulting solids were filtered off and ethanol was distilled off under vacuum, followed by addition of water (300 ml). Thereafter, an aqueous solution of 6N sodium hydroxide was added to adjust pH to 12 and the mixture was subjected to 3 cycles of extraction with methylene chloride. The methylene chloride layers were dried with anhydrous sodium sulfate, and concentrated under vacuum, thereby yielding a crude product of 2-aminomethyl-1,4-benzodioxane as a colorless oil (crude product, 4.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][N:23]2[C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccccc1
Reactant: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.4 mL, 15.6 mmol) in CH2Cl2 (37 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 7.8 mL, 15.6 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one (4.0 g, 15.6 mmol) in CH2Cl2 (37 mL) was added over 10 min. Heated to reflux for 12 h, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (70 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×75 L). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-7.5% MeOH in CH2Cl2 gave (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide as a white solid (5.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.59 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.07-6.99 (m, 2H), 6.53 (dd, J=3.6, 8.6 Hz, 1H), 4.70 (t, J=4.9 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H), 3.92-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.55-3.47 (m, 2H), 3.05-2.89 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.88 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=349.1; tR=1.69 min.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O>FC(F)(F)C(O)=O>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CCCCCl)cc1

Procedure:
Triethylsilane (22.5 ml; 0.141 mol) was added dropwise to a cold (~0° C.) stirring mixture of 4-chloro-4'-fluoro-butyrophenone (10 ml; 0.0613 mol) in trifluoroacetic acid (47 ml). The reaction mixture was stirred at room temperature under nitrogen for 6 hours. The reaction was quenched with brine and extracted with diethyl ether. The organic extract was dried (MgSO4) and evaporated under vacuum giving the desired compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])[N:19]=[CH:18]4)/[S:10][C:9]2=[O:36])[N:6]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15](/[CH:14]=[C:11]4/[C:12](=[O:13])[N:8]([CH2:7][C:5]5[N:6]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[S:3][CH:4]=5)[C:9](=[O:36])[S:10]/4)=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1

Procedure:
N-(4-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}-1,3-thiazol-2-yl)acetamide was prepared from (5Z)-3-[(2-amino-1,3-thiazol-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 400) and acetic anhydride following General Procedure U.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H, J=11.3 Hz), 2.52-2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83-1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C32H39N3O2+HCl+0.19CHCl3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][C:9]=1[CH3:11])[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)O)c(C)c1Br
Temperature: 50 °C

Procedure:
2,4-Dimethylbenzoic acid (7.00 g, 46.6 mmol) and NBS (12.4 g, 69.9 mmol) were dissolved in TFA (150 mL). The mixture was then heated at 50° C. for overnight. Analysis by LC as well as TLC (hexanes/EtOAc=1/1) indicated that reaction had gone to completion. The solvent was removed in vacuo and the resulting residue was dissolved in DCM, absorbed onto silica gel, and loaded onto a silica MPLC column for separation. The desired product was separated using the solvent system of hexanes/EtOAc (1/1) to yield 3-bromo-2,4-dimethylbenzoic acid. The undesired isomeric 5-bromo-2,4-dimethylbenzoic acid was also isolated. 1H-NMR (CDCl3, 500 MHz), δ 7.868 (d, J=7.5 Hz, 1H), 7.2 (d, J=7.5 Hz, 1H), 2.793 (s, 3H), 2.526 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]2[NH:19][C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:26][CH2:27][CH2:28][OH:29])[C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:23][CH:24]=1
Reactant: COc1cccc2c(=O)[nH]c(COc3ccc(Cl)cc3)nc12
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCO)c(COc3ccc(Cl)cc3)nc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (239 mg, 9.94 mmol) was added to a solution of 2-(4-chlorophenoxymethyl)-8-methoxy-3H-quinazolin-4-one (3000 mg, 9.47 mmol) in DMF (20 mL) at room temeprature. The reaction mixture was stirred for 30 min, then 3-bromopropanol (1448 mg, 0.94 mL, 10.42 mmol) was added. The reaction mixture was heated at 80° C. for 17 h, cooled to room temperature and diluted with EtOAc. The organic solution was washed with water, sat'd aq NaCl, dried and concentrated. The crude residue was purified using SiO2-gel chromatography (50% EtOAc/hexanes) to give 1.1 g of the desired N-alkylated product. API-MS: 375 (M+1). 1H NMR (300 MHz, CDCl3): d 7.82 (d, 1 H), 7.4 (t, 1 H), 7.2 (m, 3 H), 7.9 (d, 2 H), 5.2 (s, 2 H), 4.36 (t, 2 H), 4.0 (s, 3 H), 3.58 (t, 2 H), 2.0 (t, 2 H).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH:12]([OH:15])[CH2:13][CH3:14].Cl[O-].[Na+]>ClCCl>[OH:15][CH:12]([C:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH2:13][CH3:14]
Reactant: C#CC(O)CC
Reactant: ON=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCC(O)c1cc(-c2ccccc2)no1

Procedure:
In 12.5 ml of dichloromethane, were dissolved 2.5 g (20.7 mmol) of benzaldoxime and 2.1 g (25.0 mmol) of 1-pentyne-3-ol. Under ice cooling, 14.5 g of a 12.0% aqueous solution of sodium hypochlorite were added dropwise addition, they were reacted at room temperature for 3 hours, followed by the extraction of the organic layer with dichloromethane. The extract was washed with water and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby the target compound, namely, 5-(1-hydroxypropyl)-3-phenylisooxazole was obtained as crystals.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:21][C@@H:22]1[C@H:27]([NH:28][C:29]([C:31]2[NH:32][C:33]([CH2:37][CH3:38])=[C:34]([Cl:36])[N:35]=2)=[O:30])[CH2:26][CH2:25][N:24]([C:39]2[S:40][C:41]3[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH2:23]1.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Cl:36][C:34]1[N:35]=[C:31]([C:29]([NH:28][C@@H:27]2[CH2:26][CH2:25][N:24]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:23][C@@H:22]2[NH:21][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:30])[NH:32][C:33]=1[CH2:37][CH3:38]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(CC)CC)C3)sc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.5 %

Procedure:
3-Pentanone (68.9 μL, 0.65 mmol) and sodium triacetoxyborohydride (165 mg, 0.78 mmol) were added four times every two hours to a mixed solution of ethyl 2-[(3S,4R)-3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl]-1,3-benzothiazole-7-carboxylate obtained in Example (202e) (62.0 mg, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluate: hexane:ethyl acetate=1:1 v/v) to obtain 48 mg of the title compound (68%) as a colorless solid.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[C:10]([CH3:11])=[C:9](Br)[CH:8]=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[C:6]=1[CH3:17].C([O-])(=O)C.[Na+].[H][H]>[Pd].O>[Cl:4][C:5]1[C:6]([CH3:17])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1c(Br)cc(S(C)(=O)=O)c(C)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(C)(=O)=O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
30 ml of ethanol was added to 1.0 g of the crude 2-chloro-4-bromo-6-methylsulfonyl-m-xylene obtained in Example 3, and 0.1 g of 5% palladium active carbon and 1.0 g of anhydrous sodium acetate were further added thereto. The reactor was sealed, and was substituted with hydrogen, then stirring at room temperature for 7 hours. 30 ml of water was added to the reaction liquor, and was concentrated under reduced pressure. 30 ml of EDC was further added thereto, and the resultant mixture was filtered. The EDC layer was taken out from the filtrate, and was washed with 20 ml of water and then with 10 ml of a saturated aqueous solution of common salt, and was dried over anhydrous sodium sulfate. The EDC layer thus obtained was concentrated under reduced pressure and was dried to a solid to obtain 0.7 g of a crude product of the above-identified aimed compound (purity measured by gas chromatography: 75.6%). The crude product thus obtained was recrystallized by methanol to obtain the above-identified aimed compound.