Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:19])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:18]2)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)C2
Yield: 87.7 %

Procedure:
1.85 g (6.20 mmol) of 2-(t-butoxycarbonylaminomethyl)5-hydroxyindan was dissolved in 20 ml of acetone, to which were added 1.52 g (11.0 mmol) of potassium carbonate and 1.10 g (6.60 mmol) of ethyl bromoacetate, and refluxed for 3.5 hours. After cooling, the precipitates were filtrated, and the residue obtained by condensing the filtrate was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 1.90 g of colorless crystals. Yield: 80%
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8]O)[CH2:5][CH2:4][O:3]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:12][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)CC(CO)CCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(CBr)CCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (2.50 g) in dichloromethane (30 mL) were added carbon tetrabromide (6.80 g) and triphenylphosphine (5.40 g), and the mixture was stirred at room temperature for 20 hr. Water was added and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (1.10 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][NH2:38]>>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:41]=1)[CH2:37][NH:38][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:31])[F:29])[C:9]=3[CH:17]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=672.90 (M+H+); retention time=1.11 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:20][CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)CCNC2=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 42.6 %

Procedure:
To 5-tert-Butyl-indan-1-one (15.7 g, 83.4 mmol) in dichloromethane (150 mL) was added methanesulfonic acid (100 mL) and the resulting mixture was cooled to 0° C. Then sodium azide (10.83 g, 2 eq) was added carefully portion-wise over 15 minutes. The resulting mixture was stirred at 0° C. for about 2.5 hours. TLC analysis confirmed that all of the 5-tert-Butyl-indan-1-one had been consumed. With stirring at 0° C. was added very carefully a solution of aqueous sodium hydroxide (20%) until pH=14. Then added dichloromethane (1000 mL) and water (500 mL) which results in a large emulsion. The layers were separated and the aqueous layer was further extracted with dicholormethane (2×200 mL). Finally the combined dichloromethane layers were washed with brine (9×200 mL), dried over magnesium sulfate and filtered through a bed of celite. After concentrating and pumping to dryness there was 13.5 g of crude product as a tan solid. Purification on a 400 g Analogix Column eluting with a gradient of 10% to 60% ethyl acetate in hexane provided the correct isomer as a white powder (7.22 g) ((M+H)+=204) and the undesired isomer (1.555 g) as a white powder.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[O:8][CH:7]([CH3:9])[CH2:6][NH:5][CH2:4]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:24]=O.Cl>C(O)C>[ClH:1].[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:23])[CH:21]([CH3:24])[CH2:22][N:5]2[CH2:6][CH:7]([CH3:9])[O:8][CH:3]([CH3:2])[CH2:4]2)=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC1CNCC(C)O1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CC1CN(CC(C)C(=O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Yield: 26.9 %

Procedure:
57.6 g (0.5 mole) of 2,6-dimethylmorpholine hydrochloride, 95.2 g (0.5 mole) of p-tert.-butyl-propiophenone and 25 g (0.83 mole) of paraformaldehyde were heated under reflux in 200 ml of ethanol for 1 hour. After adding 0.7 ml of concentrated hydrochloric acid, the reaction mixture was stirred under reflux for a further 15 hours. It was then concentrated, the residue was taken up in chloroform and the chloroform mixture was washed twice with water, dried over sodium sulphate and concentrated. The solid residue was suspended in hot ethyl acetate, filtered off and dried. 47.6 g (30% of theory) of p-tert.-butyl-2-methyl-3-(2,6-dimethylmorpholin-4yl)-propionphenone hydrochloride were obtained and were dissolved in aqueous sodium bicarbonate solution and the solution and 25 g (0.83 mole) of paraformaldehyde were heated under reflux in 200 ml of ethanol for 1 hour. After adding 0.7 ml of concentrated hydrochloric acid, the reaction mixture was stirred under reflux for a further 15 hours. It was then concentrated, the residue was taken up in chloroform and the chloroform mixture was washed twice with water, dried over sodium sulphate and concentrated. The solid residue was suspended in hot ethyl acetate, filtered off and dried. 47.6 g (30% of theory) of p-tert.-butyl-2-methyl-3-(2,6-dimethylmorpholin-4yl)-propionphenone hydrochloride were obtained and were dissolved in aqueous sodium bicarbonate solution and the solution was then extracted with ethyl acetate and the product phase concentrated. A quantative yield of the free base of boiling point 145°-48° C./0.12 mm Hg column was obtained. ##STR59##
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C:12]2=O)([CH3:4])([CH3:3])[CH3:2].[CH:21](=O)[CH:22](C)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.C(OCC)C>[C:1]([Si:5]([O:6][C@@H:7]1[C@H:8]2[C@@:13]([CH3:17])([C:12](=[CH:21][CH3:22])[CH2:11][CH2:10][CH2:9]2)[CH2:14][CH2:15][CH2:16]1)([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@]2(C)C(=O)CCC[C@@H]12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC=C1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 3 h
Yield: 95 %

Procedure:
A suspension of 11.8 g (31.7 mMol) of ethyltriphenylphosphoniumbromide in 64 ml of tetrahydrofuran is treated under stirring and argon atmosphere with 31.9 ml of a one molar solution of potassiumtertiobutylate and the resulting orange suspension treated with a solution of 3.17 g (10.7 mMol) of (4aR,5S,8aS)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-octahydro-naphtalen-1-one in 64 ml of tetrahydrofuran and kept at room temperature for 3 hours. An additional 11.8 g (31.7 mMol) of ethyltriphenylphosphoniumbromid and 31.9 ml of a one molar solution of potassiumtertiobutylate in tetrahydrofurane are added and the reaction mixture kept overnight. Isobutyraldehyde (5.4 ml) is added, the reaction is stirred for 10 minutes, diluted with diethylether and filtered over Florisil using diethylether as eluent. After evaporation in vacuo, the residue (4.79 g) is chromatographed over 120 g of silica gel with hexane to yield 3.15 g (95%) of pure (1S,4aS,8aR)-tert-Butyl-(5-ethylidene-4a-methyl-decahydro-naphtalen-1-yloxy)-dimethyl-silane (E/Z 4/1) as an oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:55][CH2:54][C@H:53]([NH:56]C(=O)OC(C)(C)C)[CH2:52]1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:48][CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][C@H:53]([NH2:56])[CH2:52]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCCO)C1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: N[C@H]1CCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-tert-butyl 1-(3-hydroxypropyl)pyrrolidin-3-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.92 (s, 2 H), 8.34 (s, 1H), 8.08 (s, 2 H), 7.39-7.29 (m, 4 H), 4.42-4.31 (m, 2 H), 3.90-3.79 (m, 1 H), 3.26 (dd, J=9.8, 6.6 Hz, 1H), 3.09-2.99 (m, 2 H), 2.98-2.86 (m, 2 H), 2.50-2.36 (m, 2 H), 2.15-2.05 (m, 2 H), 1.82-1.71 (m, 1 H); MS (ESI) m/z 465.1 (M−H)−; MS (ESI) m/z 467.0 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:24]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)=[N:24][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(OC)c3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(OC)c4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(3-methoxybenzoyl)-1H-pyrazolo-[3,4-b]pyridine was refluxed overnight in 75 ml of pyridine containing 7.0 g of hydroxylamine hydrochloride. The pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product thus obtained was recrystallized from methanol to give 5.94 g, mp 130°-131° C.
Reaction SMILES: [N:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)=[C:2]=O.C1C=C(OC(OC2N=CC=CC=2)=[S:23])N=CC=1.NC1C(C)=C2C(C=CC=N2)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:14][C:13]1[C:4]([N:1]=[C:2]=[S:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N=C=O)ccc2cccnc12
Agent: CN(C)c1ccncc1
Agent: Cc1c(N)ccc2cccnc12
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-Isocyanato8-methylquinoline. To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.02 g) in methylene chloride (50 mL) is added dropwise a solution of 7-amino-8-methylquinoline (1.3 g) in methylene chloride (50 mL). The mixture is stirred for 5 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexanes to afford 8-methyl-7-quinolinylisothiocyanate as a pale yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:28][CH2:27][C@@H:26]([OH:29])[C:22]2[N:23]=[CH:24][S:25][C:21]=2[C@H:20]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].N1([C:43]([N:45]2[CH2:50][CH2:49][CH:48]([N:51]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[NH:53][C:52]3=[O:60])[CH2:47][CH2:46]2)=[O:44])C=CN=C1>CN(C)C=O>[O:60]=[C:52]1[NH:53][C:54]2=[N:55][CH:56]=[CH:57][CH:58]=[C:59]2[N:51]1[CH:48]1[CH2:47][CH2:46][N:45]([C:43]([O:29][C@H:26]2[C:22]3[N:23]=[CH:24][S:25][C:21]=3[C@@H:20]([NH:30][C:31]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:37])[C@H:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=3[F:11])[CH2:28][CH2:27]2)=[O:44])[CH2:50][CH2:49]1
Reactant: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
NaHMDS (0.228 mL, 0.228 mmol) was added to a dimethylformamide (1 mL) solution of tert-butyl (4R,7S,8S)-7-(2,3-difluorophenyl)-4-hydroxy-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-8-ylcarbamate (20.1 mg, 0.051 mmol) and 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (23.7 mg, 0.076 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h and rt for 2 h before quenching with water. The reaction was diluted with ethyl acetate and the organic layer was separated, washed with water and brine and then dried (sodium sulfate), filtered and concentrated. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (18.2 mg, 56%): LCMS (M+H=641.38); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.64 (1H, s), 8.07 (1H, d, J=5.0 Hz), 7.31-7.56 (1H, m), 6.93-7.12 (4H, m), 6.22 (1H, d, J=7.5 Hz), 5.24-5.34 (1H, m), 4.96-5.07 (1H, m), 4.32-4.71 (3H, m), 3.61-3.77 (1H, m), 2.88-3.15 (2H, m), 2.29 (4H, d, J=10.5 Hz), 1.83-1.97 (4H, m), 1.30 (9H, s).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(O)CCCCCCC.[C:21]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[SiH4]>C(O)CCCCCCCCC.C(O)CCCCCCC.C(N(CC)CC)C>[C:21]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])(=[O:31])[C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25].[C:21]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:31])[C:22]1[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25]
Reactant: CCCCCCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: [SiH4]
Solvent: CCCCCCCCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)c1ccccc1C(=O)O
Product: CCCCCCCCOC(=O)c1ccccc1C(=O)O

Procedure:
Solution I, a 50 percent solution of octyl hydrogen phthalate and decyl hydrogen phthalate in mixed 1-decanol/1-octanol was prepared by heating a mixture of 82.4 g. of Epal 810 (a commercially available mixture from Ethyl Corporation of approximately half 1-decanol and half 1-octanol), 29.6 g. of phthalic anhydride and 1 g. of triethylamine up to 120° C. Then 1.46 parts by weight of solution I was combined with 1 part by weight of the 50 percent hydrolyzed silane (1) solution described in Example 7 to give solution II containing 1 mole of carboxylic acid per mole of primary amino group.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1>C1(CCCN)C=CC=CC=1>[C:8]1([CH2:6][CH2:7][CH2:2][NH:3][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=3)[C:5]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2cc(Cl)ncc2-c2ccncc2)c1
Agent: NCCCc1ccccc1
Product: Cc1cccc(-c2cc(NCCCc3ccccc3)ncc2-c2ccncc2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-chloro-4-(3-methylphenyl)-5-(4-pyridyl)pyridine (13 mg) and 3-phenylpropylamine (5 drops) was heated to 160° C. for 2 hr. The cooled reaction mixture was subjected to chromatographic purification (silica gel, methanol/methylene chloride) to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][C:11]([Br:19])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate (1.81 g, 6.70 mmol) obtained in Example 47 (b) was dissolved in dimethylformamide (20 ml), and N-bromosuccinimide (1.27 g, 7.11 mmol) was added thereto in an ice bath followed by stirring under a nitrogen atmosphere for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:2) to afford the title compound (2.32 g, 99% yield).
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]CCl>>[ClH:26].[CH2:1]([C:8]1[O:12][N:11]=[C:10]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(Cc2ccccc2)n1
Product: Cl
Product: c1ccc(Cc2nc([C@@H]3CCCCN3)no2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2S)-2-(5-benzyl-1,2,4-oxadiazol-3-yl)-1-piperidinecarboxylate (10.59 g) [see Preparation 6] was dissolved in dichloromethane (150 ml) and cooled to 0° C. Hydrogen chloride gas was then bubbled through until the point of saturation. The reaction mixture was then stirred for 30 mins. at 0° C., the solvent was removed under reduced pressure and the product azeotroped with dichloromethane to afford 5-benzyl-3-[(2S)-2-piperidyl]-1,2,4-oxadiazole hydrochloride (8.3 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].N1C(C)=CC=CC=1C.[Si:23](OS(C(F)(F)F)(=O)=O)([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25].O>C(Cl)Cl>[CH3:12][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(CCCC=O)CCCC(C)(C)O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCCC(C)CCCC=O
Temperature: -50 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of aldehyde 15 (16.5 mg, 82.5 μmol) and 2,6-lutidine (24 μL, 206 ,μmol) in anhydrous CH2Cl2 (1.1 mL) was added dropwise Et3SiOTf (42 μL, 165 μmol) at −78° C. The mixture was stirred for 2 hours at −78° C. and for one additional hour at −50° C. Water and CH2Cl2 were added, the organic layer was washed with water, dried over MgSO4, and evaporated. The residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (99.7:0.3) as an eluent to give oily aldehyde 16 (22 mg, 85%). An analytical sample was obtained using HPLC (10 mm ×25 cm Zorbax-Sil column, 4 mL/min) with a hexane/EtOAc (98:2) solvent system. Analytically pure aldehyde 16 was collected at Rv=33 mL.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:39][C:40]([NH2:42])=[S:41].C([O-])(=O)C.[Na+].O1CCCC1>O.C(OCC)C>[NH2:42][C:40]1[S:41][CH:2]=[C:3]([C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:39]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 91 %

Procedure:
A solution of benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.2 g), thiourea (0.5 g) and sodium acetate )trihydrate) (0.7 g) in water (20 ml) and tetrahydrofuran (20 ml) was stirred at 30° C. for 3.5 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether to obtain benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.05 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].FC(F)(F)C([N:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=O>CO.O>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1cccc([N+](=O)[O-])c1
Yield: 46.9 %

Procedure:
K2CO3 (1.5 g, 11 mmol) was added to a solution of 52B (800 mg, 2.2 mmol) in MeOH/H2O (2:1, 9 mL) and the mixture was refluxed for 2 h. Volatiles were removed in vacuo and the remaining aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 100% EtOAc in hexanes) to yield 52C (275 mg, 47%) as a clear oil. MS (ESI) m/z 267.1 (M+H)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][N:36]=2>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][CH:38]=[CH:37][N:36]=4)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Brc1cnc2ncccc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3ncccc3c2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 3-bromo-1,8-naphthyridine. MS (ESI): mass calcd. for C24H22FN3O2S, 435.14; m/z found, 436.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.46 (s, 1H), 9.23 (s, 1H), 8.89 (s, 1H), 8.85 (d, J=7.2, 1H), 8.18-8.14 (m, 1H), 7.94-7.90 (m, 1H), 7.80 (m, 1H), 7.70-7.65 (m, 1H), 7.62-7.57 (m, 1H), 7.49-7.40 (m, 3H), 1.11 (s, 9H).