Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:20]\[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: O=Cc1cccnc1
Reactant: COc1cc2c(cc1N1CCN(C)CC1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N1CCN(C)CC1)C/C(=C\c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 253 (0.1 g, 0.384 mmol) in MeOH/H2O (1:1) was added nicotinaldehyde (0.049 g, 0.461 mmol) and NaOH (0.03 g, 0.768 mmol) was added to the reaction mass, which was then stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one 254.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.Cl.[C:22]([O:26][N:27]=[C:28]1[CH:32]([CH2:33][NH2:34])[CH2:31][NH:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2.O>C(#N)C>[NH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29][C:28]1=[N:27][O:26][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)ON=C1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)ON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
141 mg (0.5 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 143 mg (0.55 mmole) of 4-aminomethyl-pyrrolidin-3-one t-butyloxime dihydrochloride were thoroughly suspended in 2.5 ml of acetonitrile. Then, 230 mg (1.5 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was slowly added dropwise thereto. The reaction mixture was stirred for 30 minutes at room temperature, and after adding 1 ml of water, was then vigorously stirred for 10 minutes and filtered. The filtered solid product was successively washed with acetonitrile-water (4:1 v/v, 2 ml) and acetonitrile (2 ml×2) and then with ether and dried to obtain 132 mg (Yield: 61%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.[CH2:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH2:51])[CH3:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH:51][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:26][CH2:27]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:42])[F:1])=[CH:4][CH:5]=1)=[O:39])[CH3:44]
Reactant: CCN1CCCC1CN
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (200. mg, 0.325 mmol, Example (16e)), (1-ethylpyrrolidin-2-yl)methanamine (83 mg, 0.65 mmol, Acros), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (216 mg, 0.487 mmol, Aldrich), and DIEA (0.170 mL, 0.975 mmol, Aldrich) in DCM (2 mL) reacted under the condition of Example 16(f) and Example 16(g) to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 596 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1B1OC(C)(C)C(C)(C)O1)([CH3:13])([CH3:12])[CH3:11]>CO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Temperature: 25 °C

Procedure:
A solution of 37.0 g (129 mmol) of Na2CO3(H2O)10 in a mixture of 200 ml of methanol and 600 ml of water was added to a mixture of 9.58 g (51.5 mmol) of 6-bromopyridine-2-carbaldehyde, 17.5 g (51.5 mmol) of tert-butyl{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}amine and 3.00 g (2.60 mmol) of Pd(PPh3)4 in 1000 ml of toluene by vigorous stirring at room temperature. The resulting mixture was stirred at 80° C. for 12 h. Further on, this mixture was cooled to room temperature; the organic layer was separated and evaporated to dryness. The residue was dissolved in 700 ml of 2 M HCl, and this solution was extracted with 3×200 ml of toluene. To the aqueous layer a solution of K2CO3 was added to pH 9, and the product was extracted with 2×300 ml of dichloromethane. This organic extract was dried over MgSO4 and then evaporated to dryness. Yield 15.2 g (46%). Anal. calc. for C21H22N2O: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.30; H, 7.14; N, 8.65. 1H NMR (CDCl3): 10.18 (s, 1H, CHO), 8.07 (m, 1H, 3-H in Py), 8.02 (m, 1H, 4-H in Py), 7.92 (m, 1H, 8-H in naphthyl), 7.88 (m, 1H, 5-H in naphthyl), 7.71 (m, 1H, 5-H in Py), 7.66 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.45 (m, 1H, 7-H in naphthyl), 7.36 (m, 1H, 6-H in naphthyl), 7.28 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 3.53 (m, 2H, CH2N), 1.55 (br. s, 1H, NH), 0.94 (s, 9H, tBu).
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].[C:15](OC(=O)C)(=[O:17])C>C(O)(=O)C>[C:15](=[N:5][C@@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]([OH:3])=[O:1])=[O:17]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C=N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
In another exemplary particular, L-DOPA is reacted with a carboxylic anhydride (e.g., a mixture of acetic acid and acetic anhydride), to thereby produce a N-carbonyl L-DOPA derivative (e.g., N-acetyl L-DOPA).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:15]([C:21]([F:24])([F:23])[F:22])([C:17]([F:20])([F:19])[F:18])[OH:16])[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[N+:25]([O-])([OH:27])=[O:26]>O>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:15]([C:21]([F:24])([F:22])[F:23])([C:17]([F:18])([F:19])[F:20])[OH:16])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([N+:25]([O-:27])=[O:26])=[CH:13][CH:14]=1)[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccccc1
Solvent: O
Product: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of 4-(1-methylethyl)-5-phenyl-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanol (1.75 g) in 40 ml of water was added 2.5 ml of concentrated nitric acid in a dropwise manner. The mixture was stirred for 30 minutes, and the nitrate salt, 1.51 g) was filtered off. The solid in 5 ml of concentrated sulfuric acid was heated at reflux for 2 hours. The reaction mixture was poured into 50 ml of ice-water. The mixture was basified to a pH of 8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to afford a yellow solid which was purified by flash chromatography on silica gel (85:15 hexane/ethyl acetate) to afford (0.98 g, 50%) of the title compound as a pale yellow solid, m.p. 157°-160° C.
Reaction SMILES: O.[CH2:2]([OH:4])C.C(O)(=O)C.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][N:11]=1.[O:20]1[CH2:24][CH2:23]C[CH2:21]1>[Ni]>[Cl:16][C:15]1[CH:14]=[C:13]([NH:17][CH2:23][CH:24]([O:20][CH3:21])[O:4][CH3:2])[CH:12]=[N:11][C:10]=1[Cl:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: C1CCOC1
Reactant: CCO
Agent: [Ni]
Solvent: CC(=O)O
Solvent: O
Product: COC(CNc1cnc(Cl)c(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a Parr bottle was charged Raney Nickel (10.1 g), water (40.0 g), tetrahydrofuran (166.3 g), ethanol (32.0 g) and acetic acid (2.5 g). A solution of 2,3-dichloro-5-nitropyridine (40.0 g) in tetrahydrofuran (40.1 g) was added to the Parr bottle in four portions and the mixture was hydrogenated at 40 psi and 35° C. for about 1 hour after each addition. The reaction mixture was cooled to room temperature, and then glyoxal-1,2-dimethyl acetal (47.2 g of 50 wt % aqueous), tetrahydrofuran (35.6 g) and water (80.4 g) were added and the mixture was hydrogenated at 40 psi and 50° C. for about 12 hours. The reaction was cooled to room temperature and then filtered through a bed of Hy-Flo. The pH of the filtrate was adjusted to 7 with 5% aqueous phosphoric acid, and then the mixture was concentrated. Isopropyl acetate (79 g) was added, this was concentrated, and then more isopropyl acetate (485 g) was added. After warming to 50° C. to dissolve the solids, the solution was washed with 5% aqueous phosphoric acid (3×215 g) and then washed with 20% aqueous sodium chloride solution (231 g). The organic solution was concentrated to about 78 mL and heptane (124 g) was added. After heating to 83° C. to dissolve everything, the solution was slowly cooled to room temperature. More heptane (124 g) was added and then the suspension was cooled to 5° C. After filtering, the wetcake was washed with cold heptane/isopropyl acetate and then dried in the vacuum oven. 1H NMR (400 MHz/CDCl3) δ 7.71 (d, J=2.7 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 4.53 (t, J=5.2 Hz, 1H),4.05 (s, br, 1H), 3.42 (s, 6H), 3.22 (d, J=5.21 Hz, 2H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O[CH2:17][CH2:18]O)C.FCCC(CCF)=C[O:25][P:26]([O-])([O-:28])=[O:27].[OH-].[Na+]>>[CH2:1]([NH:13][CH2:17][CH2:18][P:26](=[O:25])([OH:28])[OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOCCO
Reactant: O=P([O-])([O-])OC=C(CCF)CCF
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCNCCP(=O)(O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 93 parts by weight of laurylamine and 93 parts by weight of ethyleneglycol monoethyl ether and heated to 80° C. Then, 117 parts by weight of Vini-eight (bisfluoroethylvinylphosphate available from Daihachi Chemical Co., Ltd.) was added dropwise thereto for 30 minutes and reacted for 3 hours. After cooling, 300 parts by weight of a 10% sodium hydroxide solution was added and kept at 100° C. for 2 hours to hydrolize it. The resultant mixture was concentrated, to which 500 parts by weight of water and 500 parts by weight of toluene were added and then neutralized with a 10% hydrochloric acid solution. The aqueous layer was removed and the organic layer was concentrated to obtain 2-laurylaminoethylphosphonic acid monomer chloroethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][CH:22]([OH:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.[Cl:28][C:29]1[O:33][C:32]([CH:34]=O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[O:33][C:32]([C@H:34]2[C:10]3=[C:11]4[N:12]([CH3:20])[C:13](=[O:19])[N:14]([CH3:18])[C:15](=[O:17])[C:16]4=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]3[CH2:21][C@H:22]([CH2:23][N:24]([CH3:26])[CH3:25])[O:27]2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: CN(C)CC(O)Cn1cc2c(c1-c1cccc(Cl)c1)c(=O)n(C)c(=O)n2C
Product: CN(C)C[C@H]1Cn2c(-c3cccc(Cl)c3)c3c(=O)n(C)c(=O)n(C)c3c2[C@H](c2ccc(Cl)o2)O1

Procedure:
The title compound was prepared from 5-(3-chlorophenyl)-6-(3-(dimethylamino)-2-hydroxypropyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 5-chlorofuran-2-carbaldehyde analogously to Example 12, step 2. The first eluted diastereomer (by Agilent Prep. System (10-35%, low pH) was isolated and separated by SFC under the following conditions to yield the title compounds as single enantiomers.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:17])([CH3:16])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[C:8]1=[O:15])([CH3:4])[CH3:3].[CH2:18]=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(O)(=O)C>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:18][C:14]#[C:13][CH2:12][N:9]1[CH2:10][CH2:11][C@H:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:17])[CH3:16])[C:8]1=[O:15])[CH3:21]
Reactant: CCNCC
Reactant: C#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Reactant: C=O
Solvent: CC(=O)O
Product: CCN(CC)CC#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3.0 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinone, 0.9 g of paraformaldehyde, 2.5 ml of diethylamine, 3.5 ml of acetic acid and 0.050 g of cuprous chloride is stirred at room temperature for 15 minutes, followed by heating at reflux temperature for 30 minutes. The reaction is cooled, Concentrated in vacuo, made basic (pH 10) with ammonium hydroxide and partitioned between methylene chloride and water. The layers are separated, the aqueous layer reextracted and the methylene chloride extracts are combined. The organic solution is dried and concentrated in vacuo with 100 ml of toluene as co-solvent. The residue is purified by chromatography (alumina, activity grade 2.5, 1-5% methyl alcohol/methylene chloride) to give 3.0 g of (S)-1-[4-(diethylamino)-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone as a yellow oil. [α]D26° =-56 (methylene chloride).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][CH:6]([F:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Br:5])[F:12])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)Br
Solvent: OCCO
Solvent: CCO
Product: CC(C)NC(=O)C(F)Br
Reaction time: 2 h

Procedure:
A solution of 14.8 grams (0.25 mole) isopropyl amine in 25 milliliters ethanol was added dropwise to a solution of ethyl bromofluoroacetate, 40 grams (0.22 mole), and 5 drops ethylene glycol in 100 milliliters ethyl alcohol at 10°-15° C. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time the solution was evaporated to leave a liquid, 41.8 grams, nD30 1.4629, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (4.5 g, 12.05 mmol) in DCM (60.3 mL) was added TFA (60.3 mL). The reaction mixture was stirred for 2 h. After diluted with toluene (30 mL), the volatile materials were removed in vacuo twice to provide 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (5.2 g, 12.06 mmol, 100%) as a TFA salt. The crude product was used for the next step without further purification. LCMS (m/z): 318.5 (MH+), 0.55 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH:11]=[CH:12][C:3]=12
Reactant: COc1ncc(Br)c2cc[nH]c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235 mL) was stirred at room temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), and the reaction mixture was stirred for 10 min. P-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was then added portion-wise, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was quenched carefully with water and the resulting beige solid collected by vacuum filtration on a Buchner funnel, and washed with water. The solid was collected and dried in a vacuum oven at 50° C. to provide 12.4 g (100%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:31][S:41]([CH3:44])(=[O:43])=[O:42])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][O:11][S:41]([CH3:44])(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](COCc1ccccc1)OS(C)(=O)=O
Reaction time: 8 h

Procedure:
2,3,4,6-Tetra-O-benzyl-D-glucitol (45 g) was dissolved in pyridine (200 ml) and added over 30 min to a solution of mesyl chloride (15 ml) in pyridine (100 ml) at 0° C. The clear solution was stored at 4° C. overnight, after which time TLC analysis showed completion of the reaction. The reaction mixture was partitioned between ethyl acetate and water/ice. The organic fractions were washed with 5% hydrochloric acid then saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and concentrated to a yellow/orange oil. The oil was azeotroped with toluene and used directly in the next stage.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:36]CCCl>>[ClH:36].[NH2:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:22]=[CH:23][C:24](=[O:27])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH2:10]1
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1

Procedure:
1-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-2,3-dihydro-1H-pyridin-4-one hydrochloride is prepared from {3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester following the method described for Example 3 using 25% TFA in DCE. MS (m/z): 288 [M−HCl+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C@H:3]1[C:9](=[O:10])[N:8]2[C@@H:4]1[CH2:5][C:6](=O)[C@@H:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:48]([NH:51][CH2:52][CH2:53][SH:54])(=[O:50])[CH3:49]>CN(C)C=O.C(OCC)(=O)C>[C:48]([NH:51][CH2:52][CH2:53][S:54][C:6]1[CH2:5][C@H:4]2[N:8]([C:9](=[O:10])[C@@H:3]2[N:2]([CH3:1])[CH3:25])[C:7]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:50])[CH3:49]
Reactant: CN(C)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](N(C)C)[C@H]2C1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
69 mg (0.21 mmol) of p-nitrobenzyl (2R,5R,6R)-6-dimethylamino-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate [34] was dissolved in 1.5 ml of dimethylformamide. The solution was cooled to -35° C., and 45 microliters (0.32 mmol) of triethylamine and 58 microliters (0.28 mmol) of diphenylphosphoryl chloride was added, and the mixture was reacted at the above temperature for 30 minutes. The progress of the reaction was determined by the formation of a spot showing a UV absorption at an Rf of 0.46 in silica gel TLC developed with ethyl acetate, and the subsequent reaction was carried out. Specifically, 0.5 ml of a dimethylformamide solution of 54 microliters (0.38 mmol) of triethylamine and 46 mg (0.38 mmol) of N-acetylcysteamine was gradually added dropwise to the reaction mixture at -35° C. The reaction was carried out at the same temperature for 30 minutes. The reaction mixture was poured into 50 ml of ethyl acetate, and washed with 30 ml of 0.1M phosphate buffer (pH 8.9) and 20 ml of a saturated aqueous solution of sodium chloride. The washings were again extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The extracts were combined, and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure to remove the solvent and 26 mg of crystals of the captioned compound were collected by filtration. The mother liquor was dried under reduced pressure, and dissolved in methylene chloride. The solution was adsorbed on a column of silica gel (7 g). The column was eluted with ethyl acetate, acetone and ethyl acetate/methanol (2/1). Those fractions in the eluates which had a UV absorption at an Rf of 0.15 in silca gel TLC developed with acetone were collected and dried under reduce pressure to give 49 mg (yield 83%) of the captioned compound.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:8])(=O)=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH2:6][C@@H:7]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:8])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Product: C[C@@H](CNC1CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
(S)-2-(Benzyloxycarbonylamino)propyl methanesulfonate (48 mmol) and cyclopropyl amine (480 mmol) were mixed together and stirred at room temperature for 48 h. The remaining cyclopropyl amine was removed by rotary evaporator and the residual mixture was added to 500 ml of ethyl acetate and washed with 5% Na2CO3 aqueous solution and brine. After drying (K2CO3) and removal of the solvent, the residual semi-solid was recrystallized from CH2Cl2 and petroleum ether to afford the target compound in 60% yield.