Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])[C:5]1=[O:30].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])[C:5](=[O:30])[N:4]3[CH2:3][CH2:2][NH:1][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.72 (s, 1 H), 3.13-3.20 (m, 3 H), 3.31 (s, 4 H), 3.45-3.50 (m, 5 H), 3.50-3.58 (m, 5 H), 4.13 (s, 2 H), 4.28 (t, J=6.39 Hz, 2 H), 6.77 (t, J=5.40 Hz, 1 H), 7.14 (t, J=8.84 Hz, 2 H), 7.41 (dd, J=8.49, 5.55 Hz, 2 H), 8.26 (s, 1 H), 8.55 (d, J=0.70 Hz, 1 H), 10.42 (t, J=5.62 Hz, 1 H); ES+ MS: 528 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C(N)=O)ncn23)c1

Procedure:
A mixture of 1.62 g. of 4-amino-5-imidazolecarboxamide hydrochloride, 3-dimethylamino-3'-methoxyacrylophenone, 0.82 g. of sodium acetate and 25 ml. of glacial acetic acid is refluxed for 10 hours. The mixture is evaporated to dryness and the residue worked up to give 4-(m-methoxyphenyl)imidazo[1,5-a]pyrimidine-8-carboxamide. This compound is treated as for Example 29 with trifluoroacetic anhydride to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C)C=O>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:18]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,1′-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257 ° C. dec.; UV (pH 1) λmax 243 nm (ε=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR δ5.41 (s, 2 H, ArCH2), 6.13 (s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 10.46 (s, 1 H, exchanges with D2O), 11.04 (s, 1 H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2: 257.0912. Found: 257.0914. Anal. (C12H11N5O2. {fraction (1/2+L )} H2O) C, N, H.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.7 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.[NH2:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]2)=[C:20]2[CH2:26][CH2:25][O:24][C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[C:20]3[CH2:26][CH2:25][O:24][C:21]3=[N:22][CH:23]=2)=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2
Reactant: CCc1ccc2cc(N)c(C(=O)O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCO4)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
3-Amino-7-ethylquinoline-2-carboxylic acid (24.5 mg, 0.113 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (38.3 mg, 0.114 mmol) and HATU (136.1 mg, 0.3579 mmol), DMF (2.00 mL) was added, followed by DIPEA (152.9 mg, 1.183 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. To the resulting residue DCM (2.0 mL) was added followed by T (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a yellow solid (5.7 mg, 12%). LCMS calc. for C24H29N6O2 (M+H)+: m/z=433.2. found 433.2. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.65-7.61 (m, 2H), 7.51 (s, 1H), 7.37 (dd, J=8.6, 1.5 Hz, 1H), 6.81 (s, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.46-3.39 (m, 2H), 3.22-3.17 (m, 1H), 3.17-3.10 (m, 1H), 3.07-3.00 (m, 1H), 2.88-2.81 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.67-2.59 (m, 1H), 2.00-1.92 (m, 1H), 1.92-1.79 (m, 2H), 1.28 (t, J=7.5 Hz, 3H), 1.26-1.20 (m, 1H) ppm.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Fc1ccc(Br)cc1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 1-bromo-4-fluorobenzene
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([O:40][CH2:41][C:42](O)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([O:40][CH2:41][C:42]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxymethoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto is added morpholine (30 μl). After addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (66 mg) and 1-hydroxybenzotriazole hydrate (46 mg) under ice-cooling, the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(morpholin-4-yl)-2-oxoethoxy]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (138 mg). MS (m/z): 727 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:22]([OH:37])[CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:20][C@@H:21]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C@H:22]([OH:37])[CH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:19])[C:13]([CH3:14])([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Yield: 25.9 %

Procedure:
In a manner analogous to that described in Example 6, 68 mg (0.26 mmol) of N-benzyloxycarbonyl-3-methyl-L-valine were coupled with 90 mg (0.26 mmol) of 2(S)-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide to give 40 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-3-methyl-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 90° C. (decomposition); MS m/e 594 [M+H]+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH:41]=[CH2:42].O>C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:42][CH:41]=[CH2:40])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate [Step A of Example 14], 3.51 g of potassium carbonate, 15 ml of diemethylformamide and 7 ml of allyl iodide was stirred under an inert atmosphere at room temperature for 5 hours and then 250 ml of water and 150 ml of ethyl acetate were added thereto with stirring. The mixture was decanted and the aqueous phase was washed and reextracted with ethyl acetate. The extracts were dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallizaton was started. The mixture was cooled in an ice bath with stirring for half an hour and was then vacuum filtered. The crystals were rinsed with ethanol to obtain 4.72 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetate. 215 mg of the product were dissolved in 2 ml of ethanol and 2 ml of methylene chloride and the mixture was filtered. The filtrate was concentrated and diluted with ethanol. Crystallization was effected in an ice bath and the mixture was vacuum filtered. The crystals were rinsed with ethanol and dried to obtain 70 mg of the pure product which melted at 90° C. (pasty) and 160° C. (pure).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17].C(N(C(C)C)CC)(C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].[OH-].[Na+].Cl>O1CCCC1>[C:28]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(CCN)c(C(=O)O)[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(CCNC(C)=O)c(C(=O)O)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-aminoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (1.90 g) and tetrahydrofuran (38.0 mL) were added diisopropylethylamine (6.45 mL) and acetic anhydride (1.42 mL), followed by stirring at room temperature overnight. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution (50.0 mL), followed by stirring for 1 hour and acidifying by the addition of 1 M hydrochloric acid (90.0 mL). This mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration and the filtrate was concentrated under reduced pressure to obtain 3-(2-acetamidoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (2.21 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:7]=[C:6]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[N:5]=1)=[O:3].C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[C:6]([C:19]2[S:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[N:24]=2)[N:5]=1)=[O:3]
Reactant: CS(=O)c1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
tert-Butyl 3-[2-(methylsulfinyl)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.12 g, 0.28 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.095 g, 91%) as white crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[OH:31][CH2:32][C:33]1[CH:38]=[C:37]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:36]=[CH:35][CH:34]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of (3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate). (3.0 g, 6.0 mmol), 3-hydroxymethylphenylboronic acid (1.5 g, 10 mmol), K3PO4 (3.0 g) and Pd(PPh3)4 (0.30 g) in dioxane (30 ml) was heated to reflux. After 3 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc, dried, concentrated to give an oil which was purified by column chromatography (eluent 30% EtOAc/Hexane) to give the title compound as a foam (2.6 g, 96%); MS (ESI) m/z 407([M+H]+); 1H NMR (DMSO) δ 9.149 (s, 1H), 8.33 (d, 1H, J=7.1 Hz), 7.96 (d, 1H), 7.8 Hz), 7.80 (t, 1H, J=7.4 Hz), 7.62 (d, 2H, H=7.1 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.40-7.28 (m, 5H), 7.18-7.14 (m, 1H), 5.23 (t, 1H, J=5.6 Hz), 4.41 (d, 1H, J=5.6 Hz).
Reaction SMILES: O.[ClH:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].[CH3:12]O>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:6]1[CH:7]=[CH:8][N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1
Reactant: CO
Reactant: O=C(O)c1ccccn1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
H2O (18 mL) was added dropwise to a stirred suspension of picolinic acid hydrochloride, compound 1 (157.9 g, 1.0 mol) in thionyl chloride (400 mL). The resulting mixture was heated under reflux for 4 days giving a clear orange solution. After cooling to ambient temperature, the solution was concentrated to a syrup and the residue coevaporated with toluene (2×500 mL). The residue was dissolved in toluene (1 L) and cooled to 0-5° C. Methanol (44.0 g, 1.0 mol) was added dropwise to the ice cold reaction mixture giving a heavy white precipitate. This precipitate was collected by filtration, washed with toluene (3×100 mL) and dried at 40° C. for 24 hr to give 176.5 g (85%) of compound 2 as a white crystalline solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.N1C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH2:73])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH:73][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45]
Reactant: N#CSCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCSC#N)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 16 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.69 g of the product of Step A, 0.685 g of pyridine hydroiodide, 1.16 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-eme-4-carboxylate and 1.36 g of dicyclohexylcarbodiimide was admixed with 17 ml of dimethylformamide and the mixture was cooled to 16° C. for 30 minutes and was then vacuum filtered. 400 ml of ether were added to the filtrate and the mixture was stirred for 5 minutes and allowed to stand for one hour. The mixture was decanted and the gum was washed with ether and was added to 50 ml of ether. The mixture was kneaded until concretization and was vacuum filtered. The product was washed with ether and dried to obtain 1.92 of raw product which was chromatographed over silica gel. Elution with a 91-9 chloroform-acetonitrile mixture yielded 790 mg of amorphous syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-thiocyanatoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=O)[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[S:43])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=S)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.25 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disufide; 0.21 g) in xylene (10 mL) was refluxed overnight. The mixture was cooled to about 50° C. and water (15 mL) was added and refluxed for 2 h. The mixture was stirred at room temperature overnight and evaporated. The residue was partitioned between EtOAc and water. The EtOAc layer was washed with water, dried and evaporated to yield 0.25 g of N-(2,6-dichlorothiobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 504 (MH+).