Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]([CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25].CCCCCC>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]([NH:23][C:17]2[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: OC(CBr)C1COc2ccccc2O1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Yield: 106.6 %

Procedure:
1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (formula H) (12 g) prepared according to J. Med. Chem. 13, 169, (1970), is treated with 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (14 g) in 500 ml of ethanol. The remainder of the procedure is described in Example 1 above and 21 g of the 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is obtained from hexane. The dihydrochloride salt has a melting point of 175°-176° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])=[CH:17][CH:18]=2)[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:12][C:11]1([CH3:33])[CH3:32])(=[O:9])[CH3:8]>C1COCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]([CH2:22][CH2:23][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[O:24])=[CH:17][CH:18]=2)[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:25])[CH2:12][C:11]1([CH3:33])[CH3:32])(=[O:9])[CH3:8]
Reactant: C=CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Reactant: CCOCCO
Solvent: C1CCOC1
Product: CCOCCOCCC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Michael addition of 2-ethoxyethanol (19 mg) and 1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (8 mg) in THF (1 mL) was performed according to the method described in example 65.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Solvent: O
Product: CN(C)C(=N)NC(=N)N
Temperature: 50 °C

Procedure:
The Metformin Resin Complex was prepared by first dissolving 225 g of metformin HCl in 4 L of purified water, and then slowly adding 735 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 25%. KOLLICOAT™ SR-30D (250 g) was first mixed with 150 g of purified water and the mixture was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried in a 50° C. VWR™ convection oven to the moisture content about 20%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and drying continued at 50° C. until the moisture content was between 3-7%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Yield: 123.5 %

Procedure:
A solution of compound 11d (303 mg, 0.79 mmol), and LiOH.H2O (132.7 mg, 3.16 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 11e (249 mg). MS m/z (M+H+) 256.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:27][CH2:28]4)[CH:21]=3)[CH:17]=1)[N:5]=2)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.453 mmol) produced in Example C29(iv) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (54 μL, 0.68 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide as a colorless solid.
Reaction SMILES: CCCCCCOC(/[N:10]=[C:11](\N)/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=O.NC1C=C(C=CC=1NC)C(N(C1C=CC=CN=1)CCC(OCC)=O)=O.C(C1C=CC(NCC(O)=O)=CC=1)#N>O1CCCC1>[C:11]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:14][CH:13]=1)#[N:10]
Reactant: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Agent: N#Cc1ccc(NCC(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1

Procedure:
Dabigatran etexilate was first described in U.S. Pat. No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps (see Scheme 1). Example 58 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and N-(4-cyanophenyl)glycine (compound III) in the presence of N,N′-carbonyldiimidazole (CDI) in tetrahydrofuran to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Finally, example 113 describes the reaction between compound V and n-hexyl chloroformate (compound VI), in the presence of potassium carbonate, in a mixture of tetrahydrofuran and water, to give dabigatran etexilate after work-up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate.
Reaction SMILES: C=O.[CH:3]([CH:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]([O:8][CH3:9])=[O:7])=O>CO.C(O)(=O)C.CNC>[C:6]([O:8][CH3:9])(=[O:7])[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH2:3]
Reactant: COC(=O)CC(C=O)C(=O)OC
Agent: C=O
Agent: CNC
Solvent: CO
Solvent: CC(=O)O
Product: C=C(CC(=O)OC)C(=O)OC
Temperature: 50 °C
Reaction time: 7 h
Yield: 96.5 %

Procedure:
60 g of paraformaldehyde are added to a solution of 6.0 g of acetic acid and 6.75 g of dimethylamine in 800 g of methanol, after which 348 g of dimethyl 2-formylsuccinate are added dropwise in the course of 20 minutes. The mixture is stirred for 7 hours at 50° C. and allowed to cool, and methanol and methyl formate are distilled off. The residue is taken up in ethyl acetate and the solution is washed with 100 g of 10% strength sulfuric acid and distilled. 305 g of isomer-free dimethyl itaconate of boiling point 42°-43° C. under 0.3-0.4 mbar are obtained, corresponding to a yield of 96.4% of theory.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.CS(C)=O>C(#N)C>[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:41]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(OC)c2)C3)cc1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
In a glass tube was weighed 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 (0.32 mmol), acetonitrile (2.5 mL), 4-methoxybenzylamine (0.66 mmol), and dimethylsulfoxide (1.11 mmol). The stirred solution was heated at 80° C. for 20 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (5 mL), washed twice with water, dried over anhydrous sodium sulfate, and evaporated. Flash chromatography on silica gel using hexane/ethyl acetate/dichloromethane (3:1:1) provided 0.155 g (86%) of the title compound as a white solid, which was recrystallized from ethyl acetate/hexane, m.p. 178-179° C. MS [(+)ESI, m/z]: 570 [M+H]+Anal. Calcd for C36H33N3O4: C, 75.64; H, 5.82; N, 7.35. Found: C, 75.31; H, 5.83; N, 7.27.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=2)[CH:20]=[O:21])=[CH:11][CH:10]=1)#[N:8]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.N1C=CC=CC=1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=2)[C:20]([OH:2])=[O:21])=[CH:26][CH:27]=1)#[N:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C=O)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1
Reaction time: 1 h
Yield: 125.2 %

Procedure:
Potassium permanganate (6.18 g, 39.1 mmol) was added in portions to a stirred solution of 13.8 g (48.9 mmol) of 5-(4-cyanobenzyloxy)-2-nitrobenzaldehyde and 1.58 g (4.89 mmol) of tetrabutylammonium bromide in 70 mL of pyridine. After 1 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. Sodium hydrogen sulfite was added to destroy excess permanganate and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with 1N sodium hydrogen sulfate, brine, dried over anhydrous magnesium sulfate, and concentrated to give 14.6 g of 5-(4-cyanobenzyloxy)-2-nitrobenzoic acid as a powder, used without further purification. 1H NMR (300 MHz, d6 -acetone) d 8.07 (1H, d, J=8.8 Hz, O-Ar-H), 7.86 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.78 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.39 (1H, d, J=2.9 Hz, O-Ar-H), 7.36 (1H, dd, J=8.8, 2.9 Hz, O-Ar-H), 5.48 (2H, s, ArCH2O).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>>[C:17]([C:3]1[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([C:2]=1[NH:1][C:27](=[O:28])[CH2:26][Cl:25])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)CCl)c2ccc(Cl)cc21

Procedure:
The titled compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (Example 1, step 2) and chloroacetyl chloride.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1>C(O)(C)C.O1CCOCC1.C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCO
Product: Brc1ccc(N2CCCNCC2)nc1
Temperature: 70 °C
Yield: 117.1 %

Procedure:
6 ml of a solution of hydrogen chloride (6N) in isopropanol are added to a solution of 1.63 g (4.4 mmol) of 1,1-dimethylethyl 4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, obtained in step 11.1, in 12 ml of dioxane and 4 ml of ethanol. This reaction mixture is maintained at 70° C. for 3 hours. The mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. 1.32 g of a white solid are obtained after crystallization from acetone. These crystals are taken up in 10 ml of dichloromethane and the reaction medium is basified to pH=14, by adding 28% ammonia solution. The organic phase is recovered by filtration through a hydrophobic cartridge and the filtrate is concentrated under reduced pressure. 0.96 g of product is obtained in the form of an oil, and is used without further purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][CH:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH:21]([O:20][CH2:18][CH3:19])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:33][CH:32]=2)=[CH:12][CH:13]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.6 %

Procedure:
Compound (c) (1.03 g; 4.34 mmole) and (b) (1.03 g; 4.34 mmole) were dissolved in dichloromethane under argon at room temperature. Azodicarbonyl dipiperidine (1.65 g; 6.5 mmole) and thereafter triphenylphosphine (1.37 g; 5.2 mmole) were added. After stirring at room temperature for 6 hours the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (2:1) as eluant gave 1.78 g (yield 89%) of the desired product.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][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].[O:27]1[CH2:31][CH:28]1[CH2:29][OH:30].CN(C)P(N(C)C)(N(C)C)=O.CCOCC>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:28]([OH:27])[CH2:29][OH:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][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: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.6 g. of 4-(n-hexadecylamino)benzoic acid and 1.0 g. of 2,3-epoxypropan-1-ol in 100 ml. of hexamethylphosphoramide is heated at 90° C. for 8 hours. After addition of ether and water, the ether layer is separated and the ether extraction repeated several times. Following evaporation of the ether extracts, the mixture of starting material and desired, 2,3-dihydroxypropyl ester is separated by chromatography on silica gel and recrystallization from acetonitrile.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[C:12]([Cl:18])[S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1nc2sccc2c(=O)n1CCC
Solvent: c1ccncc1
Product: CCCCc1nc2sc(Cl)cc2c(=O)n1CCC
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
In a sulfonation flask, 2.0 g (8 mmol) of 2-n-butyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are added, with stirring, to 15 ml of absolute pyridine. The internal temperature is then raised to 80° C. and then 1.87 g (14 mmol) of N-chlorosuccinimide (NCS) are added in smallish portions. After stirring for 3 hours at 90° C. 1.0 g of NCS is added and the mixture is stirred another 3 hours at 90° C. The pyridine is removed in a water-jet vacuum and the crude product so obtained is purified by column chromatography over silica gel (eluant:n-hexane/tert.butylmethylether=3:1), giving 0.9 g of 2-n-butyl-6-chloro-3-propyl-3H-thieno-[2.3-d]pyrimidin-4-one in the form of a beige powder having a melting point of 67-69° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1)\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: COc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1
Temperature: 23 °C
Yield: 46.6 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 3-methoxy-phenol (6.24 g, 0.050 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (5.50 g, 46%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:27]5[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C(F)(F)F)cc5)cn4)CC3)nc2)cc1
Yield: 40.6 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-trifluoromethylphenylboronic acid (227.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as colorless needles (melting point: 236.0-238.0° C.) (110.0 mg, yield: 40%).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][C@@H:6]1[O:11][C:9](=[O:10])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:16]([F:18])[CH:17]=2)[CH2:7]1)=[O:3].[S:25](=[O:29])(=[O:28])([OH:27])[OH:26]>C1COCC1>[CH3:1][C:2]([NH:4][CH2:5][C@@H:6]1[O:11][C:9](=[O:10])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:16]([F:18])[CH:17]=2)[CH2:7]1)=[O:3].[S:25]([O-:29])([O-:28])(=[O:27])=[O:26]
Reactant: O=S(=O)(O)O
Agent: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of linezolid are dissolved at about 40° C. in 150 ml of THF. The solution is kept at about 40° C. and 0.85 ml of concentrated sulfuric acid (98% w/w H2SO4) are added, thus immediately causing linezolid sulfate to precipitate as a white solid. The mixture is refluxed, under stirring, for about 30 minutes, then left to cool first to room temperature then on an ice-water bath, stirring for about 30 minutes. A white solid precipitates, which is filtered with suction, washed with 5 ml of THF and dried under vacuum at about 50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12].[ClH:20]>O1CCOCC1>[ClH:20].[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH2:13])[CH3:12]
Reactant: C=C(C)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)c1ccc([C@H](C)N)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.02 g, 3.60 mmol) was added dioxane (7 mL). To this homogenous solution was then added HCl in Dioxane (1.80 mL, 7.20 mmol, 4 M). Resulting reaction mixture allowed to stir 10 min at room temperature. Volatiles removed. Et2O was added and mixture sonnicated briefly. Volatiles removed again. Et2O was added and the solid collected and washed with Et2O to afford a white HCl salt of (S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethanamine (742 mg, 3.44 mmol, 96% yield). 1H NMR (400 MHz, D2O) δ 1.65 (d, J=6.94 Hz, 3H) 2.12 (s, 3H) 5.23 (s, 1H) 5.50 (s, 1H) 7.37 (d, J=13.06 Hz, 1H) 7.43 (m, 2H). LCMS m/z 163.2 (deamino fragment) (M+H)+, Rt 0.56 min.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH2:17][Br:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(Cc3ccccc3)sc2c1
Temperature: 25 °C
Yield: 25 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.51 mmol), NBS (0.5 g, 2.63 mmol), AIBN (40 mg, 0.25 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the combined organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.2 g, 69%). MS (ES+) m/z: 319 (M+H)+.