Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:15]=2)[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[BH4-].[Na+]>CO>[CH2:1]([CH:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH:15]=2)[NH:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cnc3c(c2)C(=Cc2ccccc2)C(=O)N3)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(c2)C(Cc2ccccc2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
To a solution of 3-benzylidene-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (41 mg, 0.106 mmol) in a mixture of MeOH (2 ml), THF (1 ml) and water (0.3 ml) was added sodium borohydride (40 mg, 1.06 mmol). The reaction was stirred at room temperature for 10 min after which it was quenched by the addition of 1 N HCl and partitioned between water and DCM. The residue was purified by preparatory HPLC to yield the title compound (5.2 mg, 13%).
Reaction SMILES: [CH3:1][CH:2]([N:4]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][C@H:6]1[CH2:8][O:7]1)[CH3:3].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>CO.[OH-].[Na+]>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:8][C@@H:6]([OH:7])[CH2:5][N:4]([CH:2]([CH3:3])[CH3:1])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)N(C[C@H]1CO1)S(C)(=O)=O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)N(C[C@H](O)COc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Yield: 88.7 %

Procedure:
To a solution of (S)-N-(1-methylethyl)-N-(methylsulfonyl)oxiranemethaneamine (86.98 g) and 4-benzyloxyphenol (100 g) in 100 ml methanol was added potassium t-butoxide (5.04 g) and the mixture was stirred under reflux for 16 hours, whereupon 150 ml 2N sodium hydroxide was added and the reaction turned to a solid mass. It was diluted further with 1 L 1N sodium hydroxide solution and stirred for 1 hour to digest the solids which were then removed by filtration, washed with 1N sodium hydroxide and with water. The still wet crude material was taken up in dichloromethane, and the solution was dried over sodium sulfate and partially evaporated in vacuo to a thick oil (wt 250 g) which was then diluted with stirring using 1 L of ether. The mixture was chilled and the product filtered to give 157.1 g of (S)-1-(4-benzyloxyphenoxy)-3-[N-mesyl-(1-methylethyl)amino]-2-propanol, mp 96°-97°.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCNCC2)no1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N1CCN(C(=O)N2CCCC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1-(piperazine-1-carbonyl)-piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (60 mg; 0.165 mmol) in THF (1 mL) is added propionyl chloride (0.015 mL; 0.17 mmol), followed by N,N-diisopropylethylamine (0.03 mL; 0.17 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate and water. The layers are separated and the organic layer is concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 420 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36])[NH2:30].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1c(Cl)cc(N)cc1Cl
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1c(Cl)cc(NC(=O)c2ccc(C(=O)OC)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
5-(Methoxycarbonyl)-2-pyridine carboxylic acid (50 mg, 276 μmol) was dissolved in DMF (2 mL) and treated with CDI (60 mg, 370 μmol). The reaction mixture was stirred at RT for 2 h. 3,5-Dichloro-4-ethoxyaniline (2) (57 mg, 276 μmol) and DIPEA (96 μL, 552 μmol) were added sequentially and the reaction mixture was stirred at RT overnight, then at 70° C. for 19 h. The reaction mixture was partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallised from methanol to afford methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (46 mg, 45%) as a white solid: m/z 369 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 3.94 (3H, s), 1.37 (3H, t).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][N:4]=[C:5]([NH2:26])[NH:6][C:7]1[S:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)[N:11]=1.[CH3:29][NH2:30]>>[F:28][C:2]([F:1])([F:27])[CH2:3][N:4]=[C:5]([NH2:26])[NH:6][C:7]1[S:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:30][CH3:29])=[N:20][S:21]([CH3:24])(=[O:22])=[O:23])[N:11]=1
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)NCCCCc1nc(NC(N)=NCC(F)(F)F)sc1C
Product: CNC(=NS(C)(=O)=O)NCCCCc1nc(NC(N)=NCC(F)(F)F)sc1C
Reaction time: 8 h

Procedure:
To the 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]-5-methylthiazole was added a 30% w/v ethanolic solution of methylamine (5 ml.) and the mixture allowed to stand overnight at ambient temperature. It was then evaporated to dryness and 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]-5-methylthiazole (0.17 g.) was isolated as the maleate salt from acetone, m.p. 165°-166°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:31]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccccc1Cl
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O>>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:6]2[S:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccsc1
Reactant: O=Cc1cccc(Br)c1
Product: CCc1csc(Cc2cccc(Br)c2)c1

Procedure:
3-Ethylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 281/283 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3C(=O)C(F)(F)F)=[C:7]3[C:14]4=[C:15]([CH2:23][CH:24]5[CH2:28][CH2:27][CH2:26][N:25]5C(=O)C(F)(F)F)[C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=5[N:13]4[CH2:12][CH2:11][N:8]32)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[C:7]3[C:14]4=[C:15]([CH2:23][CH:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=5[N:13]4[CH2:12][CH2:11][N:8]32)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(F)(F)F)c2ccc(F)cc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Fc1ccc2c(CC3CCCN3)c3n(c2c1)CCn1c-3c(CC2CCCN2)c2ccc(F)cc21
Temperature: 60 °C

Procedure:
A mixture containing 28 (1.94 g, 2.97 mmol) and K2CO3 (2.05 g, 14.8 mmol) in MeOH (60 mL) was heated at 60° C. for 1.5 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.57 g (quant.) of 29 as a yellow solid which was used without further purification. TLC analysis, 1:1 hexane/EtOAc, Rf(28)=0.9; Rf(29)=0.01. 1H NMR (CDCl3, 300 MHz) δ7.65 (m, 1H), 6.98 (app d, J=8.2 Hz, 1H), 6.90 (app t, J=8.3 Hz, 1H), 4.31 (s, 2H), 3.97 (br s, 3H), 3.54 (m, 1H), 3.31 (m, 1H), 3.14 (m, 1H), 2.97 (m, 1H), 1.83 (m, 1H), 1.68 (m, 2H), 1.42 (m, 1H) ppm. 13C NMR (CDCl3, 75 MHz) δ160.6 (d, JC—F=238.7 Hz), 136.2 (d, JC—F=12.0 Hz), 127.1, 125.4, 120.8 (d, JC—F=10.2 Hz), 109.8, 108.9 (d, JC—F=24.6 Hz), 95.3 (d, JC—F=26.3 Hz), 59.6, 45.6, 41.6, 31.0, 30.7, 24.5 ppm.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[C:7]=1[F:29].[OH-].[K+].O.Cl>O1CCCC1>[F:29][C:7]1[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)COc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To [2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetic acid methyl ester (P-1465, 20.0 mg, 0.049 mmol) in tetrahydrofuran (8.0 mL) were added potassium hydroxide (100.0 mg, 1.8 mmol) and water (3.0 mL). The reaction was stirred at room temperature overnight and then poured into water, acidified to pH=5 with 1 N HCl, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound as light yellow solid (P-1468, 9.1 mg, 47%). MS (ESI) [M+H+]+=396.2.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[N:50][CH:51]=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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: Brc1ccc(-c2ccncc2)nc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccncc5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.50 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.83 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.74 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (0.97 g, yield 56%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:43][CH:44]([CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:45][S:46][CH2:47][CH2:48][C:49](O)=[O:50])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:49](=[O:50])[CH2:48][CH2:47][S:46][CH2:45][CH:44]([O:43][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 4-arninobenzoylphenylalanine t-butyl ester (170 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (208 mg, yield 86%) as a colorless wax-like substance.
Reaction SMILES: [NH2:1][OH:2].[OH-].[K+].Cl[C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=2[N:10]=1>CO>[OH:2][NH:1][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: ONc1nc2ccc(C(F)(F)F)cc2s1
Temperature: 20 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
0.88 g of hydroxylamine hydrochloide is added to a solution of 0.7 g of potassium hydroxide in 15 ml of methanol and the reaction mixture is brought to reflux for 10 minutes. 0.5 g of 2-chloro-6-(trifluoromethyl)benzothiazole is then added and reflux is continued for 8 hours. After cooling to a temperature in the region of 20° C., the insoluble material is filtered off, the filtrate concentrated to dryness and the residue taken up in dichloromethane. The organic phase is washed with water and then dried and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa). The crude product thus obtained is purified by flash chromatography on a silica column, an ethyl acetate/cyclohexane (40/60 by volume) mixture being used as eluent. 0.35 g of 2-hydroxyamino-6-(trifluoromethyl)benzothiazole is thus obtained in the form of an orangey powder, the melting point of which is greater than 260° C. (Analysis % calculated C: 41.03, H: 2.15, N: 11.96, S: 13.69; found C: 41.4, H: 1.6, N: 12.3, S: 13.9) [1H N.M.R. spectrum (200 MHz, d6-(CD3)2SO, δ in ppm): 7.2 (broad s, 1H, aromatic CH), 7.53 (d, J=7 Hz, aromatic CH, 8.0 (broad s, 1H, aromatic CH), 10.07 (s, 1H, NH, 11.05 (s, 1H, OH)].
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:22](=[O:24])[CH3:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Commercial available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetic anhydride (2.22 g, 20.8 mmol) were added in drops. The mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, the mixture was filtered using dichloromethane and crystallized to give the title compound (4.50 g, 18.6 mmol)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]1>>[OH:24][CH2:23][C:19]1([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC1(CO)CCC1
Product: O=C(NC1(CO)CCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-amino-cyclobutanemethanol (CAN 180205-34-9, 66.02 mg, 0.64 mmol) as starting materials, and isolated (50 mg, 36.86%) as off white solid; LC-MS (UV peak area, ESI) 97.56%, 318.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cccc(OC)c2)cc1
Yield: 99.7 %

Procedure:
Using m-anisidine (0.99 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.50 g (99.7%) of the title compound in the form of light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]2[C:8]([O:13][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:10]
Reactant: Cc1ccc(C(=O)O)c(C(=O)O)n1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(n1)C(=O)OC2=O
Temperature: 110 °C
Yield: 68 %

Procedure:
A mixture of 6-methylpyridine-2,3-dicarboxylic acid (19.75 g) and acetic anhydride (51 ml) was stirred and heated in an oil bath (bath temperature 110° C.) for 5 hours. The solvent was removed in vacuo and a 2:1 mixture of dichloromethane and ether was added, giving a dark brown solid. A solution of this solid in dichloromethane was passed through a pad of silica gel, eluting with dichloromethane, and the solvent was then evaporated to give partially purified 6-methylpyridine-2,3-dicarboxylic acid anhydride (12.1 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[S:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>CN(C=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH3:28])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[S:10]
Reactant: CN=C=S
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Potassium carbonate (0.75 g, 5.4 mmol) and methyl isothiocyanate (0.39 g, 5.4 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.00 g, 3.6 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carbothioamide (0.35 g, yield: 37.7%) mp: 63-65° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.87 (d, J=0.6 Hz, 3H), 3.21 (d, J=4.9 Hz, 3H), 6.14 (q, J=0.6 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.36 (m, 1H), 8.80-9.05 (m, 1H).
Reaction SMILES: BrC[CH2:3][C:4]1[CH2:5][S:6](=[O:31])[C@@H:7]2[CH:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18](=[O:30])[N:8]2[C:9]=1[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].CS(C)=[O:34].O>C1C=CC=CC=1.CS(C)=O>[OH:34][CH2:3][C:4]1[CH2:5][S:6](=[O:31])[C@@H:7]2[CH:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18](=[O:30])[N:8]2[C:9]=1[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11]
Reactant: CS(C)=O
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CCBr)CS(=O)[C@H]12
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CO)CS(=O)[C@H]12
Reaction time: 168 h

Procedure:
To a solution of 0.461 (0.82 mmole) of 2,2,2-trichloroethyl 3-bromoethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 20 ml of 1:1 benzene-dimethylsulfoxide (DMSO) is added 0.150 ml (8.2 mmoles) of water and the mixture is stirred at 25° for 7 days. Then the mixture is poured into 100 ml of H2O and extracted with ethyl acetate. The ethyl acetate is dried (MgSO4) and evaporated in vacuo to yield 2,2,2-trichloroethyl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide, which can be purified by recrystallization from methanol.