Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[O:17][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]([OH:22])[CH2:20][N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[C:10]1([C:16]2[O:17][CH:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:19]([O:22][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:20][N:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Yield: 61.2 %

Procedure:
Phenyl isocyanate (0.33 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (0.4 g) in 1,2-dichloroethane (10 cc). The solution obtained is stirred under reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 5 to 11, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in petroleum ether, (5RS, 6SR)-2,6-diphenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.36 g), m.p. 111° C., is obtained.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:2]#[CH:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:25](=[O:26])[CH2:24][Cl:23])[C:2]#[CH:3]
Reactant: O=C(Cl)CCl
Reactant: C#CCNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CCN(CC(OC)OC)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-dimethoxyethyl)amine (9 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was cooled to a temperature of 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. Stirring was then continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase, was washed with water and was dried. The dried solution was then filtered and the filtrate stripped of solvent to yield the desired product N-propargyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide as the residue.
Reaction SMILES: C1C2C=CC3C4C=CC=CC=4C=CC=3C=2OC=1CO.[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[C:25](OCC)=[O:26]>C(Cl)Cl.CCCCCC>[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[CH2:25][OH:26]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2s1
Agent: OCc1cc2ccc3c4ccccc4ccc3c2o1
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1cc2ccc3c4ccccc4ccc3c2s1
Yield: 98 %

Procedure:
Using the procedure outlined in 14A, ethyl phenanthro[1,2-b]thiophene-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 98.0% yield of phenanthro[1,2-b]thiophene-2-methanol, mp 169°-170.5° (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:14]([OH:34])([PH2:32]=[O:33])[CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:16](O)=[O:17])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:36][C@H:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH3:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:42]([O:41][C:39](=[O:40])[CH:37]([NH:36][C:16](=[O:17])[CH:15]([C:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13])([OH:34])[PH2:32]=[O:33])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH3:38])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(NC(=O)OCc1ccccc1)C(O)([PH2]=O)C(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(O)([PH2]=O)C(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
The compound from step 1 (0.9 g) is solubilised in 10 ml of DMF in nitrogen, and t-butyl alaninate hydrochloride (450 mg), 2.5 ml of DIEA (6 eq) and 1.98 g of TBTU (3 eq) are successively added. The mixture is stirred for 15 min at ambient temperature and the reaction is processed as in step 4 of example 3. 1.10 g of expected product (97%) is obtained.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([O:12][C:13](=[O:23])[NH:14][C@H:15]1[CH2:20]C[CH2:18][C@H:17](CO)[CH2:16]1)([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:8]([O:12][C:13]([NH:14][C@H:15]1[CH2:16][CH2:17][CH2:18][C@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:20]1)=[O:23])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Acetic anhydride (0.85 mL, 9.012 mmol) was added at 0° C. to a mixture of racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester (1.69 g, 7.37 mmol) and pyridine (0.78 mL, 9.646 mmol) in 20 mL of DCM. The resulting mixture was stirred at 0° C. to RT overnight and then at 50° C. for 4 hours before being cooled to RT and partitioned between DCM and aqueous 1M HCl. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 2 g of racemic trans acetic acid 3-tert-butoxycarbonylamino-cyclohexylmethyl ester (>95% yield).
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][C:26]4[C:25](=O)[C:24]([CH3:40])([C:36](OC)=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[OH2:41].[NH2:42][NH2:43]>C(O)C>[C:9]([O:41][C:6](=[O:5])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][C:26]4[C:25]5=[N:42][NH:43][C:36](=[O:37])[C:24]5([CH3:40])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)([CH3:13])([CH3:12])[CH3:10]
Reactant: COC(=O)C1(C)CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C3=NNC(=O)C3(C)CC4)cc2)CCC1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of methyl 2-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-6-methyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (54 mg, 0.10 mmol) in anhydrous ethanol (1300 μL) was added hydrazine monohydrate (8 μL, 0.16 mmol). The reaction mixture was heated to reflux under a nitrogen atmosphere for 5 hours, additional hydrazine monohydrate (40 μL, 0.82 mmol) added, and the mixture heated at reflux for 18 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as a yellow solid (12 mg, 23% yield). 1H-NMR (500 MHz, CDCl3) δ 8.72 (1H, s), 8.09 (1H, s), 7.34 (2H, d), 7.30 (2H, d), 7.23-7.28 (3H, m), 7.16-7.22 (2H, m), 5.05 (1H, br s), 3.32-3.44 (1H, m), 3.19-3.32 (1H, br m), 2.41-2.60 (4H, br m), 2.26-2.35 (1H, dd), 1.97-2.11 (2H, m), 1.74-1.86 (1H, m), 1.45 (3H, s), 1.14-1.44 (9H, br m). LCMS (Method A) RT=6.60 min, M+H+=523.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([OH:21])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([O:21][C:29]([CH2:28][CH2:27][CH2:26][Br:25])=[O:30])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCBr
Reactant: CC12CC3(C)CC(O)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Solvent: CN(C)C=O
Product: CC12CC3(C)CC(NC(=O)OCc4ccccc4)(C1)CC(OC(=O)CCCBr)(C2)C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(benzyloxy-carbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (100 mg) in DMF (0.4 mL) was added 4-bromobutyryl chloride (0.3 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was purified by thin layer chromatography eluting with ethyl acetate and hexane (½, v/v) to afford an oily product. 1H NMR (DMSO-d6, ppm): 7.38-7.29 (m, 5 H, C6H5), 7.12 (brs, 1 H, NH), 4.95 (s, 2 H, OCH2), 3.53-3.49 (t, 2 H, J=6.6 Hz, COCH2), 2.36-2.32 (t, 2 H, J=7.7 Hz, CH2Br), 2.10 (s, 2 H), 2.00-1.96 (m, 2 H, CHCH2CH2), 1.66 (s, 4 H), 1.59-1.41 (dd, 4 H, J=11.5, 51.7 Hz), 1.08-1.07 (d, 2 H, J=3.8 Hz), 0.87 (s, 6 H, 2×CH3).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[NH2:11][CH:12]1[C:30](=[O:31])[N:14]2[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]3[N:25]([CH3:26])[N:24]=[N:23][N:22]=3)[SH:20])[CH2:17][S:18][C@H:13]12>C(#N)C.C(N1C=CN=C1)=C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH:19]([C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[SH:20])[CH2:17][S:18][C@H:13]23)=[O:10])[O:4][N:3]=1.[CH3:7][C:8]([O:10][CH2:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH2:12][C:30](=[O:31])[N:14]2[C:15]=1[C:27]([OH:29])=[O:28])=[O:9]
Reactant: Cc1noc(CC(=O)O)n1
Reactant: Cn1nnnc1C(S)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C=Cn1ccnc1
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Product: Cc1noc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(C(S)c4nnnn4C)CS[C@H]23)n1

Procedure:
Using the same procedure, 4 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 4 mmol of 7-amino-3-(1-methyltetrazol-5-yl-mercaptomethyl)-3-cephem-4-carboxylic acid (90% purity) in 35 ml of dry acetonitrile and 0.1 ml of N-vinyl-imidazole were reacted for one hour at room temperature and two hours at 50° C. to obtain a 37% yield of almost pure 7-[3-methyl-1,2,4-oxadiazol-5-yl-acetamido]-3-[1-methyltetrazol-5-yl-mercaptomethyl]-3-cephem-4-carboxylic acid with a 41% recovery of the starting cephalosporanic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])O.[K+].CI>CN(C)C=O.O>[CH3:19][O:17][C:16]([CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:18]
Reactant: O=C([O-])O
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a solution of 28.83 g of (±)-N-benzyloxycarbonyl-2-pyrrolidine carboxylic acid in 180 ml of N,N-dimethylformamide, 23.23 g of potassium hydrogen carbonate and 10.8 ml of methyl iodide were added. After stirring at room temperature for 15 hours, the reaction solution was diluted with water and then extracted twice with diethyl ether. After the extract was washed with an aqueous 5% sodium hydrogen sulfite solution and water and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 26.52 g of the desired compound as a yellowish oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[CH:3]=1.[NH2:24][C:25]1[N:30]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:29](=[O:38])[N:28]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:27](=[O:46])[C:26]=1[N:47]=O.C([C:51]1[CH:59]=[CH:58][C:54]([C:55]([OH:57])=[O:56])=[CH:53][CH:52]=1)=O>>[CH:32]1([CH2:31][N:30]2[C:25]([NH2:24])=[C:26]([NH2:47])[C:27](=[O:46])[N:28]([CH2:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:29]2=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:17]1([CH2:16][N:5]2[C:4](=[O:23])[C:3]3[N:24]=[C:25]([C:53]4[CH:52]=[CH:51][CH:59]=[CH:58][C:54]=4[C:55]([OH:57])=[O:56])[NH:1][C:2]=3[N:7]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]2=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (1.00 g) and immediately condensed with 4-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid an off-white solid (720 mg, 54%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(Cl)(Cl)Cl.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]([CH3:34])[C:14]=1[C:35]#[N:36]>O>[NH2:12][C:13]1[C:14]([C:35]#[N:36])=[C:15]([CH3:34])[C:16]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:18]=1[NH:19][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(C#N)c(N)c(N)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)c(N)c(NC(=O)C(C)(C)C)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Reaction time: 3 h
Yield: 43 %

Procedure:
With cooling with ice, pivaloyl chloride (0.46 ml, 3.73 mmol) was dropwise added to a chloroform (40 ml) solution of 4,5-diamino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-methylbiphenyl-3-carbonitrile (I-269) (1.25 g, 3.73 mmol). After stirring for 3 hours, water was added to the reaction liquid to stop the reaction, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform/methanol (95:5, v/v) to obtain the entitled compound (675 mg, 43%) as a brown amorphous substance.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH2:27][C@H:28]([CH3:31])[CH2:29][OH:30].FC(F)(F)C(O)=O>C(O)CCC>[OH:30][CH2:29][C@H:28]([N:27]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:31]
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2cccnc2)ccn1
Reactant: C[C@@H](N)CO
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CO)n1cnnc1-c1cccc(NC(=O)c2cc(-c3cccnc3)ccn2)c1
Temperature: 150 °C
Yield: 23 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (210 mg, 0.61 mmol), (R)-2-amino-1-propanol (0.3 mL), and trifluoroacetic acid (0.05 mL) in n-butanol was heated in a microwave to 150° C. for 1 hour. The solvent was removed under reduced ressure and the residue was purified by reverse-phase HPLC to give (R)—N-(3-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (55 mg, 0.138 mmol, 23% yield).
Reaction SMILES: Cl[S:2]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:4])=[O:3].C([N:31]([CH2:34]C)[CH2:32][CH3:33])C.C[CH2:37][O:38][C:39]([CH3:41])=O>ClCCl>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]2[S:2]([N:31]([CH2:32][CH2:33][NH:7][S:15]([C:18]1[CH:23]=[CH:41][C:39]([O:38][CH3:37])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH3:34])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(F)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)N(C)CCNS(=O)(=O)c2ccc(OC)cc2)c2cc(F)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Step A above (1 equivalent) was combined with the product from Step C above (1 equivalent) and triethylamine (3 equivalents) in dichloromethane and stirred at room temperature for 1.5 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO3 and brine and dried over Na2SO4. Concentrating in vacuo gave the titled compound. ESI+ MS: 640 [MH—CH3]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-])=O.N1CCOCC1>C(O)C.CO.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[NH2:17]
Reactant: Cc1ccc(/C=C\c2ccccc2Br)c([N+](=O)[O-])c1
Agent: [Rh]
Solvent: C1COCCN1
Solvent: CCO
Solvent: CO
Product: Cc1ccc(CCc2ccccc2Br)c(N)c1
Yield: 92.7 %

Procedure:
A solution of the above nitrobenzene (9.68 g, 30.3 mmol) in ethanol (110 ml) and methanol (40 ml) was hydrogenated 2 h at 3 MPa in the presence of morpholine (0.6 ml) and Rh/C (KO 319) catalyst (2 g). The catalyst was filtered off, the filtrate evaporated in vacuo and the residue was stripped with toluene (3×20 ml). The oily residue crystallized after standing at room temperature. After washing the solid with petroleum ether and drying, 2-(2-(2-bromophenyl)ethyl)-5-methylaniline (8.15 g, 92%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.[Br:18][C:19](Br)=[N:20][OH:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:21][N:20]=[C:19]([Br:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ON=C(Br)Br
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CC(Br)=NO1

Procedure:
To a solution of N-tert-butoxycarbonyl allyl amine, 20 gm, in 700 ml of ethyl acetate and containing 65 gm of NaHCO3 and 50 ml of water, was added portion-wise 80 gm of dibromoformaldoxime at room temperature with vigorous stirring. After completion of the reaction, the organic portion was washed with water (2×100 ml), 100 ml each of 5% NaHCO3, brine and dried over anh. MgSO4 and concentrated to give an oil. Purification by chromatography on silica gel gave the desired product as an oil which solidified on standing. IR(KBr): 3322, 2988, 1680, 1529 cm-1. 1H NMR (80 MHz, CDCl3): delta 1.45 (s, 9H, t-butyl), 2.8-3.5 (m, 4H, CH2CHO, CH2N), 4.6-5.1 (broad s, superimposed on a multiplet, 2H, NH, CHO).
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12.O1CCCC1.C(=O)(O)[O-].[Na+].[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44](Cl)=[O:45])=[O:41]>C(OCC)(=O)C>[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44]([NH:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:45])=[O:41]
Reactant: O=COC(C(=O)Cl)c1ccccc1
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2SC1
Temperature: 5 °C
Yield: 51.2 %

Procedure:
To a cooled (5° C.), stirred solution of 0.270 g. of benzhydryl 7-amino-3-acetyl-3-cephem-4-carboxylate in 20 ml. of dry tetrahydrofuran was added 0.0612 g. of sodium bicarbonate and dropwise, a solution of 0.144 g. of 2-formyloxy-2-phenylacetyl chloride in 2 ml. of tetrahydrofuran. The reaction mixture was allowed to stir with cooling for 30 minutes after which time it was transferred to a separatory funnel with the aid of cold ethyl acetate and washed with water, and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a residue which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.194 g. (51.2 percent) of the title product as a white froth:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)[C@@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-D-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.2 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+].COCCOC>ClCCl.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
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: COCCOC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 138 %

Procedure:
A mixture of 6-bromo-3-pyridinol (36 g, 207 mmol), [4-(methylsulfonyl)phenyl]boronic acid (50 g, 250 mmol), 2M Na2CO3 (315 mL) and DME (500 mL) was degassed with N2 for 30 min, and then Pd(PPh3)4 (12 g, 10 mmol) was added and the mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to room temperature and was diluted with dichloromethane (500 mL) and water (500 mL) and stirred for 30 min. The reaction was filtered and the solids were rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic extracts were extracted with 1 N NaOH (2×600 mL), and then cooled to 5° C. and the pH was adjusted to ˜8 with 6N HCl. The resulting precipitate was collected by filtration (water wash) and air-dried to afford a yellow solid. This procedure was repeated and the solids were combined to provide (71.2 g, 68%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol. 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.25 (d, 1H, J=2.7 Hz), 8.21 (d, 2H, J=8.5 Hz), 8.00-3H), 7.27 (dd, 1H, Ja=8.7 Hz, Jb=2.8 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 250 (M+H).