Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (0.026 g, 0.098 mmol) (Intermediate 17), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.051 g, 0.118 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.802 mg, 0.982 μmol) and sodium bicarbonate (0.196 ml, 0.196 mmol) in dioxane (0.491 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (only EtOAc) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.015 g, 29%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.68-1.83 (2H, m), 2.13-2.20 (2H, m), 3.58-3.65 (2H, m), 4.05-4.12 (2H, m), 4.41-4.50 (1H, m), 6.94-7.02 (2H, m), 7.18 (1H, d, J=8.0 Hz), 7.84-7.90 (1H, m), 8.09 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.4 Hz), 8.65 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.84 (1H, d, J=2.4 Hz). NH peak was not observed. m/z=533.4 [M+1]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[S:5][CH2:4]1.[Br:15]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:15][CH2:2][CH:3]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[S:5][CH2:4]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CC(CO)CS2
Solvent: CC#N
Product: COc1ccc2c(c1)CC(CBr)CS2

Procedure:
The alcohol (3.43 g, 16.31 mmol) is dissolved in 150 ml of acetonitrile and treated with dibromotriphenylphosphorane (6.88 g, 16.31 mmol). The solvent is removed in vacuo, and the residue is triturated with ether. The solid is removed by filtration and washed with ether. The ether solution is concentrated and the residue is chromatographed (silica gel, 20% EtOAc/hexane) to give 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-benzothiopyran as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[NH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:27][C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:6][CH2:7]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCCl)CC2)cc1
Reactant: Nc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCNc3ncccn3)CC2)cc1

Procedure:
A mixture of equivalent amounts of 1-(3-chloropropyl)-N,α-bis(4-fluorophenyl)-4-piperidinemethanamine, 2-aminopyrimidine, and sodium bicarbonate in 1-butanol is heated at reflux temperature until the reaction is complete. The solvent is removed and the residual material partitioned between water and methylene chloride. The methylene chloride layer is dried and concentrated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=2)[CH:7]=1.[CH3:33][NH2:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:34][CH3:33])[CH2:13][C:12]=3[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cc2c(c(-c3cc(Cl)ccc3OC)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cc(Cl)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.067 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.148 g, 0.31 mmol) and methylamine (0.097 g, 3.1 mmol). mp 169-171° C.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32]>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][P:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: CC(C)P(N=C(Nc1ccccc1C(C)(C)C)c1ccc(C(C)(C)C)cc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.54 g of 4-tert-butyl-N1-(2-tert-butylphenyl)benzamidine (Amidine VII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.9 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)ccn1
Yield: 38.6 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (85 mg, 39%). MS (ISP) 441.5 [(M+H)+]; mp 250° C.
Reaction SMILES: CO[C:3](=[O:22])/[C:4](/[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5](\O)/[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH3:24][C:25]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH2:26][C:27](=[NH:29])[NH2:28].C[O-].[Na+].Cl>CO.O>[CH2:15]([O:14][C:4]1[C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[N:28][C:27]([CH2:26][C:25]([CH3:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:24])=[N:29][C:3]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CC(=N)N)c1ccccc1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
4-tert-Butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (4) (652 mg, 2.12 mmol, Eq: 1.5,) and 3-methyl-3-phenylbutanimidamide hydrochloride (54) (300 mg, 1.41 mmol, Eq: 1.00) were stirred in methanol (7.2 ml). The reaction mixture was cooled to 0° C. and sodium methoxide (229 mg, 4.23 mmol, Eq: 3) (powdered, Aldrich) was added. The reaction mixture was stirred at room temperature. The reaction mixture is a suspension. It was stirred overnight. 5 ml 1N aqueous HCl was added and the mixture was diluted with water, filtered through a sintered glass funnel. The solid was washed with water. The solid was placed under high vacuum to dry to give tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate as a yellow solid (260 mg, 21%) as a 1:1 mixture of tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate (55) and 3-methyl-3-phenylbutanimidamide. The product was used without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: N#Cc1cccc2nc(-c3cccnc3N)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: N#Cc1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture of 1-bromopyrrolidine-2,5-dione (44.5 mg) and 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carbonitrile (59 mg) in tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction was incomplete and further 1-bromopyrrolidine-2,5-dione (44.5 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with acetonitrile (2×2 ml) and dried to a constant weight to afford 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carbonitrile (70.0 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 7.61 (dd, 1H), 7.85 (bs, 2H), 7.96 (dd, 1H), 8.20 (dd, 1H), 8.37 (d, 1H), 8.39 (d, 1H); Mass spectrum: M(+CH3CN)+H+ 356-358.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][CH:15]=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:15]=1[B:26]([OH:31])[OH:27]
Reactant: Fc1cccc(-c2cccnc2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cccnc2)nc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of diisopropylamine (0.531 ml, 3.79 mmol) (Aldrich) in THF (4 mL) was treated with 1.6 M n-butyllithium in hexanes (2.368 ml, 3.79 mmol) (Aldrich) at −40° C. and the pale yellow solution was stirred for 1 h and then cooled to −78° C. A solution of 6-fluoro-2,3′-bipyridine (550 mg, 3.16 mmol) in THF (5 mL) was added by cannula slowly over 2 min. The resulting bright orange solution was stirred at −78° C. for 1.5 h and then a solution of triisopropyl borate (1.089 ml, 4.74 mmol) (Aldrich) in THF (4 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1 N NaOH(aq) (10 mL) and stirred for 30 min. The separated aqueous layer was removed and carefully acidified with 5 N HCl until acidic (pH 5about6) and the resulting cloudy mixture was extracted with EtOAc (20 mL). Most of the product remained in the aqueous phase so the water was removed on the freeze-dryer overnight resulting in a white fluffy product contaminated with salt. m/z (ESI, +ve ion) 219.1 (M+H)+. 1H NMR (400 MHz, MeOH) δ 9.22 (1H, s); 8.62 (1H, d, J=4.5 Hz); 8.51 (1H, d, J=8.0 Hz); 8.12 (1H, t, J=7.9 Hz); 7.89 (1H, dd, J=7.3, 2.8 Hz); 7.59 (1H, dd, J=8.0, 4.9 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[C:40]5[C:35](=[CH:36][C:37]([O:41]COC)=[CH:38][CH:39]=5)[O:34][CH2:33][C:32]4([C:46]4[CH:51]=[CH:50][C:49]([O:52]COC)=[CH:48][CH:47]=4)[CH3:45])=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO.ClCCl>[C:11]([C:9]1[CH:8]=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[C:40]5[C:35](=[CH:36][C:37]([OH:41])=[CH:38][CH:39]=5)[O:34][CH2:33][C:32]4([C:46]4[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][CH:51]=4)[CH3:45])=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCN3CCN(Cc4cc(C(C)(C)C)cc(C(C)(C)C)c4)CC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(CN2CCN(CCOc3ccc(C4c5ccc(O)cc5OCC4(C)c4ccc(O)cc4)cc3)CC2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 53.9 %

Procedure:
(3RS,4SR)-4-{4-{2-{4-{[3,5-Bis(t-butyl)phenyl]methyl}piperazinyl}ethoxy}phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman (150 mg, 0.21 mmol) was dissolved in methanol (1.5 ml), 6N-HCl (2 ml) was added portionwise thereto, and the mixture was stirred at 50–60° C. for 2 hours. The reaction solution was diluted with dichloromethane, which was then basified with saturated sodium bicarbonate solution. This solution was washed with water, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (dichloromethane:methanol=40:1) to give 75 mg (yield: 54%) of a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[C:22]([C:24]4[NH:25][C:26](=[N:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.CO.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:36])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:27][CH:28]=4)[C:18](=[O:37])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCCS(=O)(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCS(=O)(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanolsulfonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (8.0 g.), methanol (160 ml.) and 1 N sodium hydroxide aqueous solution (13.6 ml.) was dropwise added a mixture of sodium borohydride (0.26 g.) and ethanol (15 ml.) over 20 minutes under stirring and ice-cooling. The mixture was further stirred for 1 hour, and then methanol was distilled off. The residue was dissolved in water, and the solution was washed with ethyl acetate. To the aqueous solution was added ethyl acetate, and the mixture was adjusted to pH 2 with 10% hydrochloric acid, and then the ethyl acetate layer was separated from the mixture. The remaining aqueous layer was saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate extract was combined with the separated ethyl acetate layer, washed with a saturated aqueous solution of sodium chloride and then dried. The solvent was distilled off, and the residue was washed with diethyl ether and then dried to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-propanesulfonylimino-1,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (5.5 g.), mp. 160° to 170° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:3]1=2.Br[C:18]1[CH:22]=[C:21]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[O:20][CH:19]=1>>[CH2:28]([O:27][CH:23]([O:24][CH2:25][CH3:26])[C:21]1[O:20][CH:19]=[C:18]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:16])([CH3:1])[C:3]=3[CH:12]=2)[CH:22]=1)[CH3:29]
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CCOC(OCC)c1cc(Br)co1
Product: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1

Procedure:
Prepared according to procedure B from 4,4-dimethyl 2 oxo -1,4-dihydro 2H-benzo[d][1,3]oxazine-6-boronic acid and 3-bromo-5-diethoxymehyl furan. A brown gum: 1H NMR (DMSO-d6) δ10.2 (s, 1H), 8.12(s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88(m, 2H), 5.56(s, 1H), 3.60-3.38(m, 4H), 1.67(s ,6H), 1.2-1.14 (m, 6H). .MS (ESI) m/z 344 [M−H]−. Anal. Calcd. For C19H23NO51/2 H2O: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H, 6.79; N, 3.78.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:11]=1
Reactant: NCCc1cccc(F)c1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
A mixture of methyl 2,6-dichloronicotinate (53.3 g, 0.26 mol), 3-fluorophenethyl amine (37.3 mL, 0.29 mol), K2CO3 (72 g 0.52 mol) and NMP (150 mL) was stirred at 100° C. for 10 hrs. The mixture was diluted with ethyl acetate (2×300 mL) and washed with brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography using hexane-EtOAc (9:1) as eluant to give methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate as an off-white solid (44 g, 54%). LRMS (M+H+) m/z 309.0.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C)C=O.O>[NH:8]1[C:9]2[C:5](=[C:4]([O:3][CH2:14][CH2:15][CH2:16][Cl:17])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
A suspension of 1.6 gm (39.7 mMol) sodium hydride (60% dispersion in mineral oil) in 80 mL dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. To this suspension were added 5.0 gm (37.6 mMol) 4-hydroxyindole in portions over 30 minutes. The reaction mixture was stirred at room temperature for 1.5 hours after this addition was complete. To the resulting mixture was then added dropwise a solution of 5.91 gm (37.6 mMol) 1-bromo-3-chloropropane in dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was diluted with water and then extracted well with ethyl acetate. The ethyl acetate phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.62 gm (59%) of the title compound.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[O:25][N:24]=[C:23]([C:26]([OH:28])=O)[N:22]=1.CNC>O1CCCC1>[CH3:1][N:3]([CH3:4])[C:26]([C:23]1[N:22]=[C:21]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:30])[F:29])[O:25][N:24]=1)=[O:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1noc(-c2cnccc2C(F)(F)F)n1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.8 g of carbonyidiimidazole are initially charged in 90 ml of tetrahydrofuran and, a little at a time, admixed with 9 g of 5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole-3-carboxylic acid. The mixture is stirred at room temperature for 15 min and then heated at 50° C. for 2 h. After cooling to room temperature, 2.3 g of dimethylamine are introduced in a very gentle gas stream over a period of 2 h. After a reaction time of 12 h, the mixture is concentrated and taken up in 200 ml of diethyl ether. The mixture is washed with ice-cold half conc. hydrochloric acid solution, washed neutral with sat. sodium bicarbonate sol., dried over magnesium sulfate and concentrated under reduced pressure. This gives a slightly yellow oil which solidifies after a number of days to a solid of mp. 52-54° C.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:17]=1N)=[O:12])[CH3:9].[ClH:25]>C(#N)C.[Cu]Cl>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:17]=1[Cl:25])=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1N
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C2CCCCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Copper(I) chloride (2.500 g, 25.25 mmol) was suspended in 7.0 mL cold (ice/acetone bath) anhydrous acetonitrile. t-Butyl nitrite (5.75 mL, 90%, 43.56 mmol) was added, followed by a suspension of 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.408 g, 18.58 mmol) in 27.0 mL acetonitrile. The mixture was stirred at room temperature for 45 minutes and then at 70° C. for 1.25 hour. The mixture was cooled to room temperature, slowly added to 6N HCl (17.5 mL) and then extracted with methylene chloride. The organic phase was washed sequentially with water and brine. The aqueous phases were back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude residue was chromatographed by flash chromatography eluting with a gradient of 10-50% ethyl acetate/hexanes to give 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.98 g; 42%). Mass spectrum: m/z: 257.3 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[C:8]2[CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][CH2:23]CCC>CCOCC>[CH2:22]([C:13]([CH3:19])([CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([CH3:20])=[CH:9][CH:10]=1)[C:14]([OH:16])=[O:15])[CH3:23]
Reactant: CCOC(=O)C(C)Cc1ccc(C)n1-c1ccccc1
Reactant: CCCCC
Agent: Cl
Solvent: CCOCC
Product: CCC(C)(Cc1ccc(C)n1-c1ccccc1)C(=O)O
Temperature: 92.5 °C
Yield: 84.7 %

Procedure:
A mixture of (IV) (9.4 g of crude oil, ca. 33 mmol) and Claisen's reagent (18 mL) were heated at 90-95° C. for 1 h. After cooling to room temperature, the solution was diluted with 15 g of crushed ice and acidified to pH 1-2 with 6 N HCl. The brown oily precipitate was dissolved in ether, washed with brine solution, dried over MgSO4, filtered and evaporated to waxy solids. Triteration of the solids with pentane afforded 6.6 g of V as a tan powder (84.7% yield).