Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: Clc1ncc(OC[C@@H]2CCCN2)cc1-c1ccccc1
Yield: 83 %

Procedure:
The compound from step 84a was deprotected and converted to the salt by treatment with HCl in ethanol to give the title compound (189 mg, 83% yield). mp 75°-80° C. MS (DCI/NH3) m/z 289 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl·1.6 HCl: C, 55.53; H, 5.25; N, 7.96. Found: C, 55.53; H, 5.40; N, 8.07. [α]25D =+9.88° (c 0.27, MeOH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:11][CH2:12][CH2:13][CH:14]1[O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH:2]=[O:1]
Reactant: C1=COCCC1
Reactant: O=Cc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
This alcohol (0.44 mole) was dissolved in CH2Cl2 (500 mL). DHP (50 g, 59 mole) and PTSA (1 g, 5 mmol) were added and the mixture was stirred overnight at r.t. After concentration in vacuo, the residue was purified by flash chromatography (5%→15% EtOAc in toluene) to give 85 g of the title compound.
Reaction SMILES: S1CCCC1.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[C:15]1([CH:21]=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]2[CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1CCSC1
Product: Clc1ccc(C2OC2c2ccccc2)cc1
Yield: 26 %

Procedure:
To a stirred solution of tetrahydrothiophene (0.1 mmol), rhodium (II) acetate (0.01 mmol) and p-chlorobenzaldehyde (1 mmol) in dichloromethane (4 ml) was added a solution of phenyldiazomethane (1 mmol in 6 ml of tert-butylmethyl ether) at room temperature over a period of 24 hours. After addition was completed the solvent was removed in vacuo and the residue was chromatographed over silica to provide the title oxirane in 26% yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[OH:49][C:50]([CH3:57])([CH2:55][CH3:56])[CH2:51][C:52](O)=[O:53]>>[OH:49][C:50]([CH3:57])([CH2:55][CH3:56])[CH2:51][C:52]([N:43]1[CH2:42][CH2:41][C:38]2([C:37](=[O:46])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)[CH2:45][CH2:44]1)=[O:53]
Reactant: CCC(C)(O)CC(=O)O
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CCC(C)(O)CC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 3-hydroxy-3-methyl-pentanoic acid. Light brown oil. MS (ESI): 429.2 (MH+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[CH:17][C:18]([CH3:29])=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.CCOC(C)=O.C(Cl)Cl>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:24]([O:23][C:22]([NH:21][C:19]1[CH:20]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:16]=[CH:17][C:18]=1[CH3:29])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(Br)cc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 65.3 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (5.47 g, 29.4 mmol), tert-butyl 5-bromo-2-methylphenylcarbamate (2.8 g, 9.78 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.233 g, 0.489 mmol), diacetoxypalladium (0.066 g, 0.294 mmol), and Reactant 5 (9.56 g, 29.4 mmol) (Cs2CO3) in Toluene (45 mL) was heated at 100-110° C. for 2 days. After the solvent was removed, the residue was dissolved in ethyl acetate and washed with water. After the EtOAc was removed, the residue was purified by column with DCM, then EtOAc/DCM (2%) to give tert-butyl 4-(3-(tert-butoxycarbonylamino)-4-methylphenyl)piperazine-1-carboxylate (2.5 g, 6.39 mmol, 65.3% yield, white solid). 1H-NMR (CDCl3, 500 MHz): δ 7.57 (1H, s), 7.00 (1H, d, J=8.55 Hz), 6.55 (1H, d, J=8.24 Hz), 6.31 (1H, s), 3.56 (4H, m), 3.09 (4H, m), 2.15 (3H, s), 1.52 (9H, s), 1.48 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([O:18][CH3:19])[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:29][CH:30]([NH2:39])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1.Cl>C1COCC1>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH:30]([NH:39][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3)[N:5]=[C:4]([O:18][CH3:19])[N:3]=2)[CH3:29])=[CH:37][CH:36]=1
Reactant: CC(N)Cc1ccc(Cl)cc1
Reactant: COc1nc(Cl)cc(-c2ccc(OC)c(OC)c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1nc(NC(C)Cc2ccc(Cl)cc2)cc(-c2ccc(OC)c(OC)c2)n1
Yield: 25.5 %

Procedure:
To a solution of 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methoxy-pyrimidine [140 mg, 0.5 mmol, Intermediate (50)] and N,N-diisopropylethylamine (392 μL, 2.25 mmol) in THF (1.7 mL) is added DL-p-chloroamphetamine hydrochloride (154.6 mg, 0.75 mmol, Intermediate (51)]. The mixture is heated to reflux for 2 hours and quenched with water (20 mL) and extracted twice with EtOAc (20 mL). The combined extracts are concentrated and the residue is subjected to flash column chromatography on silica gel eluting with 0 to 50% EtOAc in heptane gradient to afford [2-(4-chloro-phenyl)-1-methyl-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-methoxy-pyrimidin-4-yl]-amine [52.7 mg, 25.5%, Example 43(a)]. LCMS: RT=2.66 minutes, MS: 414 (M+H). 1H NMR (300 MHz, CDCl3): δ 7.65 (1H, d, J=0.066 Hz), 7.53 (1H, dd, J=0.066, 0.028), 7.28 (2H, d, J=0.028 Hz), 7.14 (2H, d, J=0.028 Hz), 6.93 (1H, d, J=0.028 Hz), 6.31 (1H, s), 4.72 (1H, s), 4.34 (1H, s), 4.04 (3H, s), 3.99 (3H, s), 3.95 (3H, s), 2.89 (2H, qd, J=0.045, 0.022 Hz), 1.79 (1H, s), 1.24 (3H, d, J=0.22 Hz). IC50=1726 nM
Reaction SMILES: CN1C2C=CC([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([CH2:42][CH:43]=[CH2:44])[C:20]5[C:25]([C:26]=4[CH:27]=3)=[CH:24][C:23](C3C=CC4N(C)C6C(C=4C=3)=CC=CC=6)=[CH:22][CH:21]=5)=CC=2C2C1=CC=CC=2.C1COCC1.[Cl:50][SiH:51]([Cl:53])[Cl:52]>C1(C)C=CC=CC=1>[Cl:50][Si:51]([Cl:53])([Cl:52])[CH2:44][CH2:43][CH2:42][N:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:27]=2
Reactant: C=CCn1c2ccc(-c3ccc4c(c3)c3ccccc3n4C)cc2c2cc(-c3ccc4c(c3)c3ccccc3n4C)ccc21
Reactant: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)CCCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
To a three-neck flask fitted with a reflux condenser and a dropping funnel were added the 3,6-bis(9-methylcarbazol-3-yl)-9-allylcarbazole (10 g), anhydrous THF (100 g), and platinum (0) 1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (250 mg of a 0.05% solution in anhydrous toluene). Then, trichlorosilane (30 g) was slowly added. When the addition of trichlorosilane was completed, the mixture was heated to 60° C. and maintained at that temperature for two hours. Then, the mixture was distilled at 0.02 torr to remove volatiles and gave 9-(3-trichlorosilylprop-1-yl)carbazole with a yield of about 5.6 g, at a concentration of about 90% by weight. 1 H NMR (CDCl3) δ 8.53 (d, 2 H, J=1.5 Hz); 8.46 (d, 2 H, J=1.2 Hz); 8.21 (d, 2 H, J=7.8 Hz); 7.87 (m, 4 H); 7.48 (m, 8 H); 7.27 (m, 2 H); 6.10 (m, 1 H); 5.40 (d, 1 H, J=9.0 Hz); 5.14 (d, 1 H, J=15.9 Hz); 5.00 (m, 2 H); 3.91 (s, 6 H).
Reaction SMILES: [C:1]([N:3]=[C:4](OC)[CH2:5][CH2:6][CH3:7])#[N:2].Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CO>[C:1]([N:3]=[C:4]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH2:5][CH2:6][CH3:7])#[N:2]
Reactant: COC(=O)CN
Reactant: CCCC(=NC#N)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCC(=NC#N)NCC(=O)OC
Temperature: -5 °C
Reaction time: 17 h

Procedure:
Methyl N-cyanobutyrimidate (240 g, 1.90 mol) from Example 2 was dissolved in absolute methanol (1.5 L) and glycine methyl ester HCl (250 g, 1.99 mol) added to the reaction mixture. The suspension was cooled to -5° C. and triethylamine (211 g, 2.09 mol) added over a period of 15 minutes. The resulting solution was stirred at 20° C. for 17 hours, then concentrated under reduced pressure to an oily-solid residue (690 g). The residue was taken up in ethyl acetate and the insoluble salts removed by filtration. The filtrate was washed with water followed by 10% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This product (370 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](O[K])(C)(C)[CH3:16].[I-].ClCC[S+](C)C.O>CC(O)(C)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12]2([CH2:16][CH2:15]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)O[K]
Agent: C[S+](C)CCCl
Agent: [I-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C2(CC2)C1
Reaction time: 16 h
Yield: 17.8 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) was dissolved in tBuOH (10 ml) with tBuOK (1.1 g, 10 mmol) and stirred for 15 minutes before portionwise addition of (2-chloro-ethyl)-dimethyl-sulfonium iodide (Tet. Lett. 1984, 25, 5501) (1.1 g, 5 mmol) over 1 h. The reaction was stirred for 16 h after which time it was partioned between water and CH2Cl2, the organic collected, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:n-heptane 1:9-3:7) afforded the titled product (0.2 g, 19%) as a colourless oil. MS: 130.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane (5.0 g, 26.5 mmol) from Example 1, Step C and benzyl bromide (4.7 mL, 40 mmol) in DMF (130 mL) was added 60% sodium hydride in mineral oil (0.77 g, 32 mmol). The reaction was stirred at room temperature for 24 h was then diluted with ether and slowly quenched into aq. sodium bicarbonate. After three ether extractions, the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FC (2–5% ethyl acetate in hexanes) to afford the title compound (7.1 g).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(=O)c2ccccc21
Temperature: 22 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
In a 250 mL flame dried round bottom flask equipped with a stir bar, tert-butyldimethylsilyl chloride (4.5 g, 30 mmol) is dissolved in 150 mL dichloromethane. To this solution, in a single portion, isatin (2.2 g, 15 mmol) and 4-dimethylaminopyridine (0.18 g, 1.5 mmol) are added. The flask is sealed with a rubber septum and purged with nitrogen. Triethylamine (6.3 mL, 45 mmol) is added in one portion through a syringe and mixture is allowed to stir for 24 h at 22° C. The volatiles are removed in vacuo and the resultant dark orange solid is purified by silica gel chromatography (hexanes to 1:1 hexanes:dichloromethane to dichloromethane) to afford an orange solid, which is recrystallized from hot EtOH (details below) to afford 14a (2.6 g, 9.9 mmol, 67% yield) as an orange crystalline solid. Please note that for long-term storage, N-tert-butyldimethylsilyl protected isatins should be kept under an inert atmosphere at −15° C. 1-(tert-Butyldimethylsilyl)indoline-2,3-dione (14a): M.p.=123-124° C. IR (neat): 2929 (w), 2853 (w), 1731 (s), 1603 (m), 1589 (m), 1463 (m), 1325 (m), 1252 (m), 1170 (m), 1139 (m), 927 (m), 835 (s), 796 (m), 752 (s), 686 (m), 466 (m), 424 (m) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.63-7.61 (1H, m), 7.53-7.49 (1H, m), 7.10-7.03 (2H, m), 1.02 (9H, s), 0.56 (6H, s); 13C NMR (100 MHz, CDCl3): δ 184.2, 164.9, 155.4, 138.3, 125.6, 123.4, 120.0, 115.1, 26.4, 19.7, −3.3; HRMS Calcd for C14H20NO2Si [M+H]+: 262.12633. Found: 262.12608.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1O.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:14]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cccc(F)c1O
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2cccc(F)c2o1
Temperature: 200 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-fluoro-phenol (0.586 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The precipitate was filtered, washed with water, diethyl ether, and dried. The compound was stirred in THF during 2 days, the insoluble was filtered, the filtrate was concentrated to dryness and dried under vacuum to give 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.475 g). NMR Spectrum: (DMSOd6) 7.37-7.48 (m, 2H), 7.69 (dd, 1H), 7.83 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[CH:10][C:11]=1[F:12].Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:13]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1nccc(F)c1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12

Procedure:
Under argon, 500 mg (1.97 mmol) of 3-[(2,6-difluorobenzyl)oxy]-4-fluoropyridine-2-amine Example 268A were initially charged in 10 ml of ethanol, 500 mg of powdered molecular sieve 4A and 3.24 g (19.67 mmol) of ethyl 2-chloroacetoacetate were added and the mixture was then heated at reflux for 48 h. All volatile components were evaporated at 85° C. under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate=9/1 isocratic). This gave 368 mg (39% of theory; purity about 76%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([O-:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11].[Na+]>O.N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3cccc(O)c3)[C@H]2SC1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Yield: 52.5 %

Procedure:
Ethyl chloroformate (10.9 g.) was dropwise added by small portions with stirring and ice-cooling to a solution of sodium 7-[2-hydroxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (16.3 g.) in a mixture of water (80 ml.) and pyridine (80 ml.), and the mixture was stirred for 1 hour at the same temperature. Water (200 ml.) was added thereto and the mixture was washed with ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and with a sodium chloride aqueous solution and dried over magnesium sulfate. After treating with activated charcoal, the solvent was distilled off and the residual oil was pulverized with a mixture of diisopropyl ether and ether. The powder was collected by filtration, dried and suspended in water (150 ml.). To the suspension was added sodium bicarbonate (1.7 g.). The solution was adjusted to pH 6 with dilute hydrochloric acid and treated with activated charcoal. Dilute hydrochloric acid was added thereto with cooling and stirring and precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxycarbonyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (9.4 g.).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.N1C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH2:73])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH:73][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45]
Reactant: N#CSCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCSC#N)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 16 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.69 g of the product of Step A, 0.685 g of pyridine hydroiodide, 1.16 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-eme-4-carboxylate and 1.36 g of dicyclohexylcarbodiimide was admixed with 17 ml of dimethylformamide and the mixture was cooled to 16° C. for 30 minutes and was then vacuum filtered. 400 ml of ether were added to the filtrate and the mixture was stirred for 5 minutes and allowed to stand for one hour. The mixture was decanted and the gum was washed with ether and was added to 50 ml of ether. The mixture was kneaded until concretization and was vacuum filtered. The product was washed with ether and dried to obtain 1.92 g of raw product which was chromatographed over silica gel. Elution with a 91-9 chloroform-acetonitrile mixture yielded 790 mg of amorphous syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-thiocyanatoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[CH3:15][N:16]([CH3:19])/[CH:17]=[CH:1]/[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27]
Reactant: Cc1ncc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ncc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 204.7 %

Procedure:
A solution of tert-butyl 4-[4-(6-methyl-5-nitropyridin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (7.7 g) and N—N-dimethylformamide-dimethylacetal (DMF-DMA) (10g) in 50 ml of DMF was heated at 90° C. overnight and cooled to room temperature. The solvent was evaporated and the residue dissolved in DCM, which was washed with sat. NaHCO3 and brine, and evaporated to give a red solid, 9.0 g of crude product.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12]([CH3:18])([CH3:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[C:12]([CH3:18])([CH3:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1O
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.456 g, 12.0 mmole) was added to the stirred solution of 1-benzyl-3,3-dimethylpiperidin-4-one [{prepared according to literature procedure described in U.S. Pat. No. 5,846,980} 5.4 g, 24.0 mmole] in methanol (25 ml) at 0-5° C. over a period of 15 min, and stirring was continued for 30 min. The reaction mixture was concentrated to dryness, triturated with water (25 ml) and extracted with ethyl acetate (2×100 ml). The extract was dried (sodium sulphate) and concentrated to dryness to furnish 1-benzyl-3,3-dimethyl-4-hydroxypiperidine as oil. Yield 5.2 g (96%), C14H2,NO, m/z 220 (M+1), PMR (CDCl3): 0.83 (3H, s, CH3), 1.13 (3H, s, CH3), 1.29 (1H, m, H5), 1.62-1.9 (2H, m, H2 & H5), 2.14 (1H, m, H6), 2.38 (1H, d, H2, j=12 Hz), 2.8 (1H, m, H6), 3.12 (1H, m, H4), 3.46 (2H, s, N—CH2), 7.3 (5H, m, ArH).