Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)=[O:19])[CH:22]([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OCC(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1

Procedure:
A solution of Example 131B (2.8 g, 8.37 mmol) and 4M aqueous NaOH (10 mL) in 1:1 THF/methanol (40 mL) was heated to reflux for 18 hours, and concentrated. The concentrate was diluted with water and adjusted to pH 1 with concentrated HCl, treated with isobutyl chloroformate (3 mL), slowly adjusted to pH 12 with NaOH, and adjusted to pH 2 with HCl. The mixture was filtered and the filter cake was dried under vacuum to provide the desired product. MS (ESI(−)) m/e 305 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.[Cl-].[Na+].O>[Br:15][C:16]1[CH:17]=[C:18]([C:19]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[N:1]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Temperature: 25 °C

Procedure:
2-amino-4-phenylphenol (30) (250 mg, 1.20 mmol) and 3-bromo-benzoyl chloride (31) (265 mg, 1.20 mmol) were heated in NMP at 150° C. overnight. The reaction was cooled to ambient temperature then K2CO3 (aq) and brine were added, and the aqueous extracted with EtOAc (×5). The organic layer was washed with brine, dried (Na2SO4), and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with a mixture of 1:1 DCM in heptane to yield the title compound. Yield: 210 mg, 49%; LC-MS tr 2.02 min; HPLC Purity: 67%; MS (ES+) m/z 350, 352 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4(O)[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:50])CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[C:29]5[C:24](=[CH:25][C:26]([C:30]6([F:50])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)=[CH:27][N:28]=5)[N:23]=[CH:22][CH:21]=4)=[N:16][N:17]=3)[N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(-c2ccc3nnc(CNc4ccnc5cc(C6(F)CCNCC6)cnc45)n3n2)c1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of tert-butyl 4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (30 mg, 51 μmol) in 0.5 mL of DCM was cooled to −78 C. Then added DAST (13 μl, 102 μmol) and let stir to room temperature over 30 min. TFA was then added to the reaction mixture and stirred for 30 min. The solvent was then removed by rotary evaporation and the residue was redissolved in MeOH and free based through a cation exchange column. Purification via MPLC (DCM/MeOH+1% NH4OH) yielded the title compound (15 mg, 60% yield). M/Z=491.2 [M+H], calc 490.18 for C25H21F3N8.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:3])=[O:2]
Reactant: Oc1ccc2ncccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
A solution of triflic anhydride (42.8 g, 0.15 mol) in CH2Cl2 (100 mL) was added dropwise to a 0° C. solution of 6-hydroxyquinoline (20.00 g, 0.138 mol) and pyridine (23 g, 0.277 mol) in CH2Cl2 (500 mL). The cooling bath was removed and the resulting solution was stirred at RT for 4 h. The reaction mixture was washed with water (3×300 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum to afford crude quinolin-6-yl trifluoromethanesulfonate (40 g, >100% yield) as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 9.00 (d, 1H, J=2.8 Hz), 8.50 (d, 1H, J=8.0 Hz), 8.21 (d, J=2.8 Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.80 (m, 1H), 7.64 (m, 1H); MS (ESI) m/z: 277.9 (M+H+).
Reaction SMILES: C(OO)(C)(C)C.C([O:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([OH:24])[C:18]([CH3:26])([CH3:25])[CH2:17]1)(=O)C1C=CC=CC=1.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>[Mo](=O)(=O)=O.O>[OH:15][CH:16]1[CH2:17][C:18]([CH3:25])([CH3:26])[N:19]([O:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]([CH3:22])([CH3:23])[CH2:21]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCCCCCCC
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
A solution of 121.8 grams (946 mmol) of 70% aqueous tert-butyl hydroperoxide is added over a 3-hour period to a mixture of 101.5 grams (367 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 1.3 gram of molybdenum trioxide, and 650 ml of n-octane that is preheated to 120° C. The reaction mixture is maintained at reflux temperature throughout the addition, and water is collected in a Dean-Stark trap. The reaction mixture is heated at reflux for 8.5 hours after the addition is complete in order to discharge the red color of the nitroxyl starting material. The crude reaction mixture is purified by flash chromatography (50:1 heptane: ethyl acetate ) and then hydrolyzed using potassium hydroxide in ethanol to obtain the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Reaction time: 17 h
Yield: 83.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (450 mg, 1.52 mmol), 2-piperidin-4-ylpropan-2-ol (239 mg, 1.67 mmol) and 4 Å powdered molecular sieves (450 mg) in DCE (10 mL) was stirred for 6 h before the addition of sodium triacetoxyborohydride (644 mg, 3.04 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-4%) affording the title compound as a cream solid (538 mg, 84%). LCMS (method H): RT 2.02 min [M+H]+ 423.3
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1(O)[CH2:16][CH2:15][CH2:14][CH:13]=1.C1(O)CCCC1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OC1=CCCC1
Agent: OC1CCCC1
Product: Clc1nc(Cl)c2ncn(C3=CCCC3)c2n1

Procedure:
2,6-Dichloro-9-cyclopentenylpurine is prepared from 2,6-dichloropurine and cyclopentenol essentially as described in Example 1, Scheme A, step a, but substituting cyclopentenol for cyclopentanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][C:3]=12.Br[C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1>>[CH2:38]([N:36]1[CH:37]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH:12]=4)=[CH:10][C:3]=23)[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35]1)[CH3:39]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc(N3CCOCC3)c2)cc2c(Br)ccnc21
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(N4CCOCC4)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with 4-bromo-2-[3-(4-morpholinyl)phenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Using this product crude and following the procedure in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 676.4
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([O:19]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][NH2:23]>C(O)C>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([NH:22][NH2:23])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: NN
Solvent: CCO
Product: NNC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
A solution of ethyl 3-phenyl-7-benzofuranacetate, 2.0 g., and hydrazine, 1 g., in 15 ml. of ethanol is heated overnight at reflux. The mixture is cooled and the white precipitate collected. Recrystallization from benzene gives 3-phenyl-7-benzofuranacethydrazide, m.p. 158°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[N:25]1[O:29][N:28]=[C:27]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:26]=12.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:31]1[CH:32]=[CH:33][C:26]3[C:27]([CH:30]=1)=[N:28][O:29][N:25]=3)=[CH:8]2)=[O:4]
Reactant: OB(O)c1ccc2nonc2c1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc2c(cc(-c3ccc4nonc4c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 36.7 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), benzo[1,2,5]oxadiazole-5-boronic acid (51 mg, 0.31 mmol), K3PO4 (87 mg, 0.41 mmol), H2O (7.4 mg, 0.41 mmol), SPhos (4.2 mg, 0.010 mmol) and Pd(OAc)2 (4.2 mg, 0.0062 mmol) in toluene (5 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added with stirring until pH was about 3, and the organic layer was dried over MgSO4 and concentrated. The crude product was first purified by silica gel chromatography (0-60% EtOAc/hexanes+1% AcOH), then by preparative TLC (20% EtOAc/CH2Cl2) to give 33 mg of the title compound. MS: (+) m/z 429.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([OH:24])=O)[CH:9]=2)[C:5]([Br:25])=[CH:4][N:3]=1.CC[N:28](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([NH2:28])=[O:24])[CH:9]=2)[C:5]([Br:25])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CCc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 169.9 %

Procedure:
Crude 5-(2-amino-5-bromopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxylic acid (200 mg, 0.47 mmol) in DMF (2 mL) and DIPEA (0.332 mL, 1.89 mmol) was stirred at 0° C. EDCl (180 mg, 0.94 mmol) and HOBT.NH3 (143 mg, 0.94 mmol) were added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured into saturated solution of sodium hydrogen carbonate. The solid was filtered with suction and the panel washed thoroughly with water and dried under vacuum in an oven at 50° C. The crude compound may be purified by flash chromatography (DCM/MeOH 95/5) to give the title compound (336 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH:12]=O)=[CH:6][C:5]=1[O:14][CH3:15].[CH2:17]([O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23])[CH3:18]>N1CCCCC1>[CH2:17]([O:19][C:20](=[O:24])[C:21]([C:22]#[N:23])=[CH:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([O:14][CH3:15])[CH:6]=1)[CH3:18]
Reactant: COC(=O)c1c(OC)cc(C=O)cc1OC
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc(OC)c(C(=O)OC)c(OC)c1
Temperature: 120 °C

Procedure:
A mixture of 11.2 g. of 2,6-dimethoxy-4-formyl-benzoic acid methyl ester, 6.3 g. of cyanoacetic acid ethyl ester and three drops of piperidine was heated in an open vessel with stirring to 120°C. and stirred at this temperature for an additional 15 minutes. The residue was recrystallized from ethyl acetate and yielded α-cyano-3,5-dimethoxy-4-methoxycarbonyl-cinnamic acid ethyl ester, having a m.p. of 142°-144°C.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>C(Cl)Cl>[C:33]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@@H:14]2[N:13]3[C:3]4[C:2]5[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=5)[N:6]=[CH:5][C:4]=4[N:11]=[C:12]3[CH2:17][O:16][CH2:15]2)=[CH:20][CH:21]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(C[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccc(C[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
4-[(11S)-10,11-Dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethyl]phenol (2.62 g, 7.91 mmol) was suspended in 50 mL of dry CH2Cl2 and stirred under N2. The solution was treated with triethylamine (2.2 mL, 15.8 mmol) and acetic anhydride (0.89 mL, 9.45 mmol). After 18 hours, the reaction mixture was treated with 50 mL of H2O. The layers were separated, and the organic portion was washed with H2O and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-[(11S)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethyl]phenyl acetate (2.95 g) as a white solid.
Reaction SMILES: C1(C[NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:11][C@H:10]2[OH:24])C=CC=CC=1.[H][H]>[Pd].CO>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:11][C@H:10]1[OH:24]
Reactant: O[C@@H]1CN(CCNc2ncccn2)CC[C@H]1NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O
Yield: 86.9 %

Procedure:
A mixture of 10.6 parts of trans-4-[(phenylmethyl)amino]-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated, yielding 6.6 parts (86.9%) of trans-4-amino-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol as a residue (interm. 19).
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].N[C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[C:16]#[N:17].[BrH:20]>C(O)(=O)C>[Br:20][C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: Br
Reactant: Cc1ccc(N)cc1C#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Br)cc1C#N
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
Conc. sulfuric acid (60 mL) is added to sodium nitrite (5.75 g, 83.4 mmol). The temperature rises to 70° C. and solution is effected. After cooling to 20-40° C., the above solution is added dropwise to a mechanically stirred solution of 5-amino-2-methylbenzonitrile (10.0 g, 75.8 mmol) in acetic acid (150 mL). The temperature is maintained at 20-40° C. throughout the addition. The reaction mixture is cooled to 16-20° C. and a solution of cuprous bromide (24 g, 167 mmol) in conc. hydrobromic acid (150 mL) is added keeping the temperature between 16-20° C. After 45 min, the reaction mixture is poured onto ice (500 g) and the solids are collected by filtration then dissolved in dichloromethane (600 mL), washed with brine, dried, filtered and concentrated to give 5-bromo-2-methylbenzonitrile (see also, Dressler, J. et al. EP 0 594 019) (11.5 g, 77%) as a brown solid. 1H NMR (CDCl3, δ ppm): 7.72 (1H, s), 7.60 (1H, dd), 7.20 (1H, dd), 2.50 (3H, s).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: c1ccc(C2(c3ccco3)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2ccco2)CC1
Yield: 32 %

Procedure:
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3-Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.21 g (0.54 mmol, 32% for two steps) of 3-(4-phenyl-4-(furan-2-yl)piperidin-1-yl)propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.13 g, 0.45 mmol, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:16]([N:22]=[C:23]=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[N:12]([C:23]([NH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]cc(-c2ccc(F)cc2)c(=O)[nH]1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1cc(-c2ccc(F)cc2)c(=O)[nH]c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 6, starting from 5-(4-fluorophenyl)-1H-pyrimidine-2,4-dione (0.10 g, 0.48 mmol); 4.5 equivalents of hexyl isocyanate were used herein, splitted into two aliquots (2.2 equiv each) and the reaction mixture was heated under microwave irradiation to 110° C. for 1 hr (2 cycles of 30 min each). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 84:16) to afford the title compound (0.03 g, 22% over two steps) as white powder. 1H NMR (400 MHz, CDCl3) δ 0.91 (d, J=6.3 Hz, 3H), 1.27-1.42 (m, 6H), 1.58-1.68 (m, 2H), 3.41 (td, J=7.1, 5.6 Hz, 2H), 7.06-7.17 (m, 2H), 7.45-7.63 (m, 2H), 8.35 (s, 1H), 8.55 (s, 1H), 8.93-9.16 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 14.41, 22.33, 26.62, 29.26, 31.38, 41.46, 115.62, 126.97, 130.27, 135.83, 149.57, 150.60, 160.93, 162.81 (d, J=250.5 Hz). MS (ESI) m/z: 207 [M-H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][S:32]([CH3:31])(=[O:34])=[O:33])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Yield: 31.8 %

Procedure:
7-(2-Thienyl)acetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.46 g.) was suspended in methylene chloride (100 ml.). To the suspension was added bis(trimethylsilyl)acetamido (4.06 g.) and the mixture was stirred to give a solution. To the solution was added methanesulfonyl chloride (1.15 g.) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was added to 5% hydrochloric acid at 0°-5° C. White precipitates in the solution were collected by filtration, dried and then recrystallized with aqueous acetone to give 7-(2-thienyl)acetamido-3-(5-mesylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (910 mg.). m.p. 139°-145° C (dec.).