Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].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>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c(Br)ccc(N)c1C#N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Yield: 36.3 %

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-6-methylbenzonitrile, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene was heated at 90° C. for about 20 hours. After this time, the reaction mixture was stirred with 100 mL of water, and the organic layer was separated. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 30/65/5 and 20/60/20 methylene chloride/petroleum ether/ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 1.0 gram of 2-amino-6-methyl-5-[3,5-di(trifluoromethyl)phenyl]benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].O=[C:14]1O[C@H]([C@H](CO)O)[C:17](O)=[C:15]1O.O[CH2:26][C@@H:27]([C@H:29]([C@@H]([C@@H](CO)O)O)O)O.OCC([C@@H]([C@H]([C@@H](CO)O)O)O)=O>>[CH3:14][C:15]1([CH3:17])[O:4][C@:3]2([O:12][CH2:11][C@@H:9]3[O:10][C:27]([CH3:29])([CH3:26])[O:8][C@@H:7]3[C:5]2=[O:6])[CH2:2][O:1]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@H](O)[C@@H](O)[C@H](O)CO
Product: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Yield: 95 %

Procedure:
L-sorbose is an important intermediate for the synthesis of L-ascorbic acid (vitamin C) by the Reichstein method (see FIG. 1). When D-sorbitol is chemically oxidized, approximately a half of the product becomes D-sorbose, whereas when D-sorbitol is brought into contact with a microorganism having an SLDH activity, only an L-enantiomer is obtained in a yield of about 95%. Therefore, a fermentation method has been conventionally used for converting D-sorbitol to L-sorbose.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]2=[N:4][CH:3]=1.N1[C:45]2[C:40](=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38]1.[CH3:49][CH:50](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:41]3[CH:42]=[CH:43][CH:44]=[C:45]4[C:40]=3[CH:39]=[N:38][CH:50]=[CH:49]4)=[CH:3][N:4]=[C:5]2[NH:10][CH:9]=1)=[O:31])([CH3:35])([CH3:34])[CH3:36]
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3cccc4ccncc34)nc12
Temperature: 100 °C
Yield: 292.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.5 g, 0.928 mmol), 1H-indazol-4-ylboronic acid (165 mg, 1.02 mmol), Pd(PPh3)4 (214 mg, 0.186 mmol), X-Phos (177 mg, 0.371 mmol) and Na2CO3 (295 mg, 2.78 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 hours under N2 atmosphere. Reaction mixture was concentrated and the residue was purified by preparative-TLC (eluting with methanol:dichloromethane=1:100) to afford N-tert-butyl-2-(isoquinolin-8-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (375 mg, 70%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 10.37 (s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 7.55-7.49 (m, 3H), 7.30-7.26 (m, 9H), 7.22-7.18 (m, 6H), 1.53 (s, 9H). LCMS: (M+H)+=577.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>Cl.CO.CC(=O)OCC.O>[OH:1][CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:39])([F:41])[F:40])[CH:32]=1)[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.104 mmol) was dissolved in 2N HCl/MeOH (5 mL). The reaction was stirred at RT for 1 h then diluted with EA (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(1-hydroxy-3-methylbutyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 38.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.59 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.98-6.92 (m, 3H), 5.62-5.60 (m, 2H), 4.54 (t, J=5.2 Hz, 1H), 4.06-4.01 (m, 2H), 3.60 (s, 3H), 3.46-3.52 (m, 2H), 1.92-1.90 (m, 1H), 1.80-1.72 (m, 3H), 1.24-1.19 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H). LCMS: MH+ 498 and TR=3.186 min.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[C:19]3[C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:24][CH3:25])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=O)=O.Cl.[NH2:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+]>CO>[NH2:32][C:31]1[NH:33][C:3](=[O:2])[C:5]2[CH2:10][C:9]([C:11]3[C:19]4[C:18]5[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=5[O:16][C:15]=4[C:14]([O:24][CH3:25])=[CH:13][CH:12]=3)([C:26]#[N:27])[CH2:8][CH2:7][C:6]=2[N:30]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc(N)[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in example 1 (200 mg, 0.53 mmol), guanidine HCl (127 mg, 1.326 mmol) and sodium methoxide (100 mg) in 2 ml methanol was stirred overnight at room temperature. The solvent was evaporated under vacuum and the crude residue was purified by column chromatography to get 150 mg (73.3% yields) as a white solid product. MP-decomposes at 300° C.
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][N:2]=1.[CH3:12][I:13]>C1C=CC=CC=1>[I-:13].[CH3:12][N+:2]1[CH2:3][CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH:1]=1
Reactant: C1=CC2(C=NCCC2)CCC1
Reactant: CI
Solvent: c1ccccc1
Product: C[N+]1=CC2(C=CCCC2)CCC1
Product: [I-]
Yield: 93 %

Procedure:
A solution of 2-azaspiro-[5.5]-undeca-1,7-diene (14.0 g.; 0.10 mole) is dissolved in dry benzene (150 ml.) and methyl iodide (21.3 g.; 0.15 mole) is added. The mixture becomes warm and a solid separates. The precipitate is filtered, washed with ether and air-dired to afford 27.0 g. (93% yield) of 2-methyl-2-azoniaspiro-[5.5]undeca-1,7-diene iodide, m.p. 193°-194° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Br:19]N1C(=O)CCC1=O.O>ClCCl.C(#N)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[Br:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1Br
Reaction time: 3 h
Yield: 70.6 %

Procedure:
5.34 g (0.02 mol) of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) is dissolved in 60 mL of dichloromethane and 5.34 g (0.03 mol, 1.5 eq) of N-bromosuccinimide in 60 mL of acetonitrile is added dropwise at −8±2° C. in 30 min. The reaction mixture is stirred for 3 hours at this temperature and then is poured into 150 mL of water. The product is extracted with 2×60 mL of dichloromethane. The organic layer is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:methanol=7:3) to give 4.89 g (71%) of the title compound (IIIb) as an orange solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(C)cc2)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CN2CCC(C(=O)O)CC2S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyIoxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6g (61%); off white solid, mp 204° C.; MS: 514.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]([CH2:11][CH:12]=O)[C:5](=[O:14])[C:4]=2[CH:3]=1.[CH2:15]([N:17]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[C:19]2[CH:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[CH:31]=[CH:32][C:18]1=2)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(=O)C)C.[ClH:65]>C(OCC)(=O)C.ClCCCl.C(O)(=O)C>[ClH:65].[ClH:65].[CH2:15]([N:17]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[C:19]2[CH:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:12][CH2:11][N:6]3[CH:7]=[CH:8][C:9]4[O:10][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]3=[O:14])[CH2:38][C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[CH:31]=[CH:32][C:18]1=2)[CH3:16]
Reactant: Cc1cc2c(=O)n(CC=O)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN(CCn3ccc4oc(C)cc4c3=O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methyl-4-oxo-4H-furo[3,2-c]pyridin 5-yl)acetaldehyde(0.18 g) and acetic acid(0.1 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione(0.38 g). The mixture was stirred for 30 minutes at room temperature. sodium triacetoxyborohydride(0.32 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=1:0→9:1). The purified product was condensed under reduced pressure. A 6N-hydrogen chloride ethyl acetate solution(1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound(0.43 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]=O)=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.C([N:21](CC)CC)C.Cl.NO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:21])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Agent: Cl
Agent: NO
Solvent: O
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbaldehyde (Preparation 1, 60 g, 194 mmol) in MeCN (1.5 L) was added triethylamine (68.5 mL, 485 mmol) and hydroxylamine hydrochloride (20 g, 291 mmol). The reaction was heated at 60° C. for 3 hours. The reaction was cooled to 0° C., further triethylamine (220 mL, 1.55 mol) was added and TFAA (109 mL, 776 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2 hours. Water (2 L) was added to the reaction mixture and the resulting solid was collected by filtration. The solid was dissolved in DCM (1 L) and the resulting solution was washed with water (2×500 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (58.59 g) in a 99% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[F:30][C:31]([F:36])([F:35])[C@@H:32]([OH:34])[CH3:33]>CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:34][C@@H:32]([CH3:33])[C:31]([F:36])([F:35])[F:30])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Reactant: C[C@H](O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](Oc1cc(C[C@@H]2CSC[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 24j, starting from [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.409 g, 1 mmol), KOH (0.06 g, 1.05 mmol) and (S)-1,1,1-trifluoro-propan-2-ol (0.583 g, 5 mmol) and was obtained as a yellow oil, which was used as such in the next step: TLC (hexane-EtOAc 1:1) Rf=0.37; HPLC RtA=2.36 min; ESIMS [M+H-isobutylene]+=443.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(OCC)C>C(Cl)Cl>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To phenylmethyl(2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.78 g, 3.32 mmol) in CH2Cl2 (10 mL) was added Et3N (0.92 mL, 6.63 mmol) followed by TsCl (0.664 g, 3.48 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was poured onto water and diethyl ether (Et2O). The aqueous layer was separated and the organic layer was washed with saturated aqueous NaHCO3 followed by brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (0.85 g, 66%) as a colorless oil. LC-MS (ES) m/z=390 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[S:18][C:17]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:16][CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[S:10]([CH3:13])(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(N(CCN2CCOCC2)S(C)(=O)=O)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of tert-butyl 5-(N-(2-morpholinoethyl)-methylsulfonamido)-thiophene-2-carboxylate (Int. 58) (1.3 g, 3.33 mmol) in DCM (50 ml), TFA (2.56 ml, 33.3 mmol) was added drop-wise at 0° C. and then the brown solution was stirred at RT overnight. Additional TFA (7.69 ml, 99.9 mmol) was added in two portions over 4 hours, cooling to 0° C. and stirring at RT. The volatiles were removed under vacuum to afford 5-(N-(2-morpholinoethyl)methylsulfonamido)thiophene-2-carboxylic acid 2,2,2-trifluoroacetic acid salt (Int. 59) (1.436 g, 3.21 mmol, MS/ESI+335.0 [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][OH:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:19]([C:21]([CH2:28][CH3:29])([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])[CH3:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:22](=[O:23])[C:21]([CH2:28][CH3:29])([CH2:19][CH3:20])[C:25](=[O:26])[O:10]2)=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)NO)cc1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)cc2)C1=O

Procedure:
A mixture consisting of 1.67 g (0.0107 mol) of 4-methoxybenzohydroxamic acid, mp 158-159° C (dec.)(lit. mp 156-157° C. (dec.), Beilstein Handbook of Organic Chemistry, series H, vol 10, p. 170), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 2.107 g (0.0107 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.19 g (70.4%) of crude 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue Recrystallization of the solid from absolute ethanol gave pure 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 116-118° C.; IR (Nujol) 1810 (s,C=0), 1750 (s, C=0), 1690 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) 7.83 (d, 2H), 6.98 (d, 2H), 3.89 (t, 3H), 1.95 (q, 4H), 1.01 (t, 6H); High resolution MS, calc'd for: C15H17NO5 : 291.1102. Found: 291.1106. Anal Calc'd for: C15H17NO5C, 61.84; H, 5.88; N, 4.81. Found: C, 61.83; H, 5.76; N, 4.76.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=3)=[O:9])[CH:3]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Examples 73-87 using (5-aminopyridin-3-yl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 103) and 4-chlorophenylacetic acid to afford the title compound as a white solid in 66% yield, 223 mg.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=O.C(C1C=CC(C(O)=O)=CC=1O)#N.[N+](CC)([O-])=O.[NH2:30][C@@H:31]([C:34]([OH:36])=[O:35])[CH2:32][SH:33]>C([O-])(=O)C.[Na+].C(O)(=O)C>[OH:12][C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:3]=1[C:1]1[S:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[N:30]=1
Reactant: O=Cc1ccc(C(=O)O)cc1O
Reactant: N[C@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: N#Cc1ccc(C(=O)O)cc1O
Agent: [Na+]
Solvent: CC[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C2=N[C@@H](C(=O)O)CS2)c(O)c1

Procedure:
The key step of the synthesis of (S)-4,5-dihydro-2-(2-hydroxy-3-methoxyphenyl)-4-thiazolecarboxylic acid (6) was cyclocondensation of D-cysteine with 2-hydroxy-3-methoxybenzonitrile. The cyano intermediate was obtained from o-vanillin by treatment with nitroethane in sodium acetate and acetic acid. (S)-4,5-Dihydro-2-(2-hydroxy-4-carboxyphenyl)-4-thiazolecarboxylic acid (7) was synthesized by a similar reaction sequence. 4-Formyl-3-hydroxybenzoic acid was converted to 4-cyano-3-hydroxybenzoic acid using nitroethane in sodium acetate and acetic acid; cyclization with D-cysteine completed the synthesis of dicarboxylic acid chelator 7.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=O)[N:8]2[C@@H:3]1[CH2:4]C[C:6](Cl)=[C:7]2C(O)=O.C[Si]([I:19])(C)C.C[Si](N[Si](C)(C)C)(C)C.C1N2CCN(CC2)C1>C(#N)C>[CH2:3]1[N:8]2[CH2:9][CH2:2][N:1]([CH2:6][CH2:7]2)[CH2:4]1.[IH:19]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12
Reactant: C[Si](C)(C)I
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-carboxylic acid (8c), as produced in Example 13a, was converted to the carbacephem (9a) through reaction with trimethylsilyl iodide (TMSI). Specifically, the carboxylic acid (8c) (0.726 g, 2 mM), was combined with 5 ml acetonitrile (ACN), HMDS (1.06 ml, 5 mM), and TMSI (0.72 ml, 5 mM), and the mixture was stirred for 4 hours at room temperature. DABCO (0.56 g, 5 mM) in 5 ml ACN was added and the solution stirred overnight at room temperature, yielding a DABCO-HI precipitate. Both reactions appeared normal and the DABCO reaction (elimination) gave an HPLC ratio of product to starting material of 39.1/12.0 for a conversion of about 77%. 5 ml of 1N HCl was added and the mixture stirred for 30 min. at room temperature. The pH was at 3.55. The DABCO-HI precipitate dissolved and the desired carbacephem product (9a) appeared as a precipitate. The product was filtered and washed successively with 10 ml of ACN/H2O (2/1), 5 ml of H2O, and 5 ml of ACN. Vacuum drying at 50° C. yielded 0.275 g of a nearly white solid. Yield was about 63.5%. NMR was excellent in DMSO (d-6) with trifluoroacetic acid (TFA) to dissolve. NMR (DMSO d-6, TFA): δ1.95 (m, 2), 2.67 (m, 2), 3.94 (m, 1), 4.83 (d, 1), 8.87 (bs, 5).