Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:10][C:4]=2[O:3]1.[H][H]>>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:18]([Cl:32])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=3[Cl:23])=[CH:10][C:4]=2[O:3]1
Reactant: [H][H]
Reactant: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)cc2O1
Product: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(O)cc3Cl)cc2O1

Procedure:
As depicted in scheme 1, for example the known compound 2,6-dichloro-4-phenylmethoxyphenol (A) was reacted with a haloalkane of suitable chain length, such as 1-bromo-4-chlorobutane, under basic conditions, affording the corresponding 4-chlorobutoxy derivative (A1). Intermediate (A1) was in turn was reacted under basic conditions with the known hydroxy compound 2,2-dimethylbenzo[d]1,3-dioxolan-4-ol yielding the corresponding coupled compound 2-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-5-oxy)butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (A2). Intermediate (A2) wha then treated with hydrogen gas under catalytic hydrogenation conditions, providing the deprotected intermediate 4-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-5-yloxy)butoxy]-3,5-dichlorophenol (A3). Intermediate (A3) was then reacted with 1,1,1,3-tetrachloropropane, affording a compound of formula I, such as 5-(3,3-Dichloroprop-2-enyloxy)-2-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-4-yloxy)butoxy]-1,3-dichlorobenzene. Example 1 set forth below describes in detail the method by which compounds of formula I were prepared as shown in scheme 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.O>CS(C)=O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[C:4](=[O:8])[CH2:3]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Reaction time: 1 h

Procedure:
3,3-Dimethylcyclohexanone (5.60 mL) was added to sodium bis(trimethylsilyl)amide (45.3 mL, 1M in tetrahydrofuran), and the reaction was stirred for 1 hour. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (11.1 g) in dimethylsulfoxide (30 mL) was added, and the reaction was stirred at 50° C. for 24 hours. The reaction was cooled, poured into water (300 mL), extracted three times with ether, and the combined extracts were washed three times with water, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 5-20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@H:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 79.2 %

Procedure:
To a solution of N-CBZ-cis-4-hydroxy-L-proline ethyl ester (6.4 g, 22 mmol) and anhydrous pyridine (5.3 mL, 5.2 g, 65 mmol) in CHCl3 (35 mL) was added p-toluenesulfonyl chloride (8.3 g, 44 mmol) in one portion. After stirring at room temperature for 7 days, the reaction was diluted with CH2Cl2 (100 mL) and pyridine removed by extraction with 10% HCl (4×13 mL). The organic layer was dried (MgSO4) and concentrated to a yellow oil which was purified by flash chromatography (silica gel, using 5:4 petroleum ether-ether) affording 7.8 g (80%) of 5 as colorless needles: mp 91°-92° C.; TLC Rf 0.15 (4:2 ethyl ether-petroleum ether); [α25D -26° (c 1.1, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.75 (app d, J=8.4 Hz, 2 H), 7.34-7.28 (m, 7 H), 5.18-5.04 (m, 3 H, PhCH2 and H-4), 4.52-4.41 (m, 1 H, H-2), 4.20-4.02 (m, 2 H, CO2CH2CH3), 3.78-3.62 (m, 1 H, H-5), 2.48-2.37 (m, 2 H, H-3), 2.45+2.44 (s, 3 H, PhCH3, two rotamers), 1.22+1.14 (t, J=7.1 Hz, 3 H, CO2CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 170.89, 170.57, 154.20, 153.89, 145.12, 145.09, 136.11, 133.88, 129.91, 129.85, 128.38, 128.32, 128.03, 127.98, 127.86, 127.77, 127.58, 78.62, 77.74, 67.21, 67.15, 61.47, 57.53, 57.30, 52.25, 51.99, 37.07, 35.98, 21.59, 13.92, 13.85; IR (CHCl3) 2995, 1745, 1700, 1415, 1360, 1175, 1120, 1050, 1020 cm1. Anal. Calcd for C22H25NO7S: C, 59.05; H, 5.63; N, 3.13. Found: C, 59.08; H, 5.54; N, 3.11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[Br:18]Br>BrCCBr.[W]>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Reactant: BrBr
Agent: [W]
Solvent: BrCCBr
Product: O=C1c2cc(CBr)ccc2COc2ccccc21
Temperature: 0 °C

Procedure:
To a stirred and irradiated (Tungsten lamp) solution of 2.0 gm of the 9-methyl compound of Step B in 5 ml of 1,2-dibromoethane, add a solution of 1.7 gm of bromine in 5 ml of 1,2-dibromoethane dropwise over a period of 1 hour at 150° C. Cool the reaction mixture, pour into ice water and extract with water and dry over sodium sulfate. Concentrate to dryness and crystallize the residue from isopropyl ether to obtain the title product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9]CCCN)[CH:5]=[CH:6][C:7]=1Cl.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C=O.[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:39][CH2:38][N:37]([CH:40]([CH2:53][C:54]2[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH2:44])[CH2:36][CH2:35]1)(=[O:32])[CH3:31].C(=O)C1C=CC=CC=1>>[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:35][CH2:36][N:37]([CH:40]([CH2:53][C:54]2[CH:55]=[C:56]([C:64]([F:65])([F:66])[F:67])[CH:57]=[C:58]([C:60]([F:62])([F:61])[F:63])[CH:59]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH:44][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:38][CH2:39]1)(=[O:32])[CH3:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: NCCCCc1ccc(Cl)c(Cl)c1
Agent: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=Cc1ccccc1
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the (3,4-dichlorophenyl)butylamine and the 3,5-bis-(trifluoromethyl)benzaldehyde used therein with 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine and benzaldehyde, respectively, the title compound was prepared; mp 65°-67° C.; NMR: 7.85 (s,1), 7.75 (s,1), 7.65 (s,1), 7.45 (s,1), 7.40-6.95 (broad m,10), 3.85 (d,1, J=15.9), 3.65 (d,1 J=13.6) 3.56 (d,1, J=15.9), 3.42 (d,1, J=13.6), 3.05 (m, 1), 2.75-2.40 (m,4), 2.35-2.18 (m, 2), 2.18-1.95 (m,4), 1.85 (s,3); MS: m/z=750(M+1,100%). Analysis for C39H39Cl2F6N3O: Calculated: C, 61.10; H, 5.13; N, 5.48; Found: C, 61.12; H, 5.34; N, 5.65.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:53])C(=O)C1>CC#N.C(Cl)Cl>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[C:9]=1[Br:53]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Solvent: ClCCl
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (128 mg, 0.199 mmol) in CH3CN/DCM (3/1 mL) was added NBS (42.5 mg, 0.239 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.6 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow oil (125 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[C:18]([CH:16]1[CH2:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:17]1)=[O:19]
Reactant: CNCc1ncccc1C
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cccnc1CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(3-methyl-pyridin-2-ylmethyl)-amine (176 mg, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound 127 mg, 46% yield). Rf=0.30 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C24H30ClN3O2, 427.9, found, 428.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks, δ 4.72, 4.53 (s, 2H), 3.72 & 3.70 (s, 2H), 2.97, 2.93 (s, 3H), 1.76-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks δ 177.6, 175.7, 154.7, 153.6, 146.8, 146.6, 126.5, 126.4, 122.8, 122.7, 73.4, 73.2, 56.7, 56.6, 54.3, 54.2, 51.1, 41.4, 40.9, 35.6, 35.4, 28.9, 28.7, 23.7, 23.6, 18.3, 18.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]([CH2:20][CH2:21][C@@:22]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[C:23]([NH:25][O:26]C4CCCCO4)=[O:24])[C:16](=[O:38])[CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.ClCCl.O.Cl>O1CCOCC1>[OH:26][NH:25][C:23](=[O:24])[C@:22]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:21][CH2:20][N:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]3)=[CH:9][CH:10]=2)=[CH:15][C:16]1=[O:38]
Reactant: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)n1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)cc2)n1
Reaction time: 0.25 h

Procedure:
To (2R)-4-{4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (120 mg, 0.22 mmol) was added dioxane (2 ml), dichloromethane (2 ml), and water (1 ml). The reaction flask was cooled externally with ice then treated with a 4.0M sol of HCl in dioxane (0.55 ml). The reaction mixture was stirred for 15 minutes then concentrated under reduced pressure. IPA (10 ml) was added and concentrated to azeotrope any remaining water to furnish a tan solid (80 mg, 80% TY). MS (LC/MS) m/z 462.3 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.74 (s, 3H) 2.34-2.51 (m, 1H) 2.55-2.81 (m, 1H) 3.13 (s, 3H) 3.96-4.06 (m, 1H) 4.07 (s, 3H) 4.26-4.45 (m, 1H) 6.84-7.00 (m, 2H) 7.49 (s, 1H) 7.75-7.93 (m, 3H) 8.09 (d, J=8.78 Hz, 2H)
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41]N(C)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1ccncc1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccncc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-pyridin-4-yl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C20H21FN3O3: 370.1567. found: 370.1568. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s, 3), 3.23 (t, 2, J=7), 3.90 (t, 2, J=7), 4.20 (s, 2), 4.60 (s, 2), 7.03 (m, 2), 7.21 (m, 2), 7.80 (d, 2, J=6), 8.73 (d, 2, J=6). 13C NMR (125 MHz, CDCl3) δ: 34.55, 34.63, 42.47, 49.04, 51.55, 109.53, 114.58, 115.74, 115.91, 127.10, 129.30, 129.50, 131.76, 141.92, 153.22, 158.36, 160.92, 161.23, 161.43, 163.40, 165.33, 166.13.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[NH:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[H-].[Li+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>C(O)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:22]3[C:23](=[O:25])[N:24]=[C:19]([N:16]4[CH2:17][CH2:18][N:13]([C:10]5[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=5)[CH2:14][CH2:15]4)[NH:20][C:21]3=[O:26])=[CH:40][CH:39]=2)=[CH:32][CH:31]=1
Reactant: ClCc1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
In argon atmosphere, to an N,N-dimethylformamide solution (5 mL) of 6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione (200 mg, 0.69 mmol) synthesized in Reference Synthesis Example 18, lithium hydride (12 mg, 1.51 mmol) was added at 0° C. and the resultant mixture was stirred for 1 hour. To the mixture, 1-chloro-4-{[4-(chloromethyl)phenoxy]methyl}benzene (183 mg, 0.69 mmol) was added and the resultant mixture was stirred at 50° C. for 2 hours and at 70° C. for 3 days. After the completion of the reaction, water and ethanol were added to the reaction solution and a resultant solid was filtered to obtain a crude product of a precursor (66St) of the title compound, which was used as it was in the next reaction below.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2nc1Cl
Temperature: 60 °C

Procedure:
To 2-chloroquinoline-3-carboxylic acid (5 g, 24.08 mmol) was added thionyl chloride (22.83 mL, 313.0 mmol) and DMF (12 drops) and the reaction was heated at 60° C. for 16 hours. The excess thionyl chloride and N,N-dimethyl formamide were removed in vacuo to yield 2-chloroquinoline-3-carbonyl chloride as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([CH:10]1[CH2:20][C:19]2[C:21]3[C:16]([N:17]([CH2:22][C:23]4[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=4)[N:18]=2)=[N:15][C:14]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:13][C:12]=3[S:11]1)#[N:9].CC1C=CC(S(OC(C#N)CC2C3C(=NC(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=3Cl)N(CC3C(C)=C(OC)C(C)=CN=3)N=2)(=O)=O)=CC=1>ClCCl>[NH2:33][C:14]1[N:15]=[C:16]2[C:21]3[C:19]([CH2:20][CH:10]([C:8]#[N:9])[S:11][C:12]=3[N:13]=1)=[N:18][N:17]2[CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SC(C#N)C3)c1C
Agent: COc1c(C)cnc(Cn2nc(CC(C#N)OS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C#N)C3)c1C
Reaction time: 1 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (0.25 mL) was added to a mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 4) of Example 3 (30 mg) and dichloromethane (1 mL). Then, the ice bath was removed and the mixture was stirred for one hour. After confirming that the raw material disappeared, the reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried to obtain the title compound (13.8 mg, 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30](OC)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4].[N:36]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30]([NH:44][CH2:43][CH2:42][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Reactant: NCCN1CCOCC1
Solvent: CO
Product: CN(C)C(=O)c1ccc(-n2c(=O)c(C(=O)NCCN3CCOCC3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1
Yield: 83 %

Procedure:
In a similar manner to that described in example 196, from methyl 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0421 mmol), [2-(4-morpholinyl)ethyl]amine (0.05 mL), and methanol (2 mL), was prepared 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (20 mg, 83% yield) as a tan solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.02 (br s, 1 H), 8.50 (s, 1 H), 7.64 (d, (J=8.4 Hz, 2 H), 7.26 (d, J=8.4 Hz, 2 H), 7.01-6.98 (m, 2 H), 6.94 (m, 2 H), 6.77 (s, 1 H), 3.93 (s, 2 H), 3.71-3.68 (m, 4 H), 3.58 (q, J=12.4, 6.4 Hz, 2 H), 3.15 (s, 3 H), 3.05 (s, 3 H), 2.63 (t, J=6.4 Hz, 2 H), 2.56-2.54 (m, 4 H); MS m/z 574 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([CH2:13][CH3:14])=[N:7][C:6]=2[N:5]([CH3:15])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:15])[C:6]=4[N:7]=[C:8]3[CH2:13][CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 66.9 %

Procedure:
To a solution of 1,3-dimethyl-8-ethylxanthine (416 mg) in DMF (10 ml) were added potassium carbonate (332 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 21 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (ethyl acetate-ether) to provide the title compound as white powder (584 mg, 67%). 1H-NMR (CDCl3) δ: 1.30(3H,t,J=7.6Hz), 2.72(2H,q,J=7.6Hz), 3.40(3H,s), 3.61(3H,s), 5.64(2H,s), 7.21-7.80(8H,m).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:30])[CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[N:32]([O-])=[O:33].[Na+]>C(O)(=O)C.O.CC(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:30])[C:23]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[N:32][OH:33])[C:19](=[O:31])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccncc3)[C@H]2SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccncc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-(pyrid-4-ylacetamido)ceph-3-em-4-carboxylate (3.0 g.) in acetic acid (30 ml.) was stirred, cooled briefly in ice and treated dropwise over 3-4 minutes with a solution of sodium nitrite (1.38 g.), in water (10 ml.). The mixture was stirred at 20° for 30 minutes and was then diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation almost to dryness gave a residue which was dissolved in the minimum volume of acetone and added dropwise to stirred petroleum spirit (bp. 40°-60°). The resulting solid was collected, washed with petroleum spirit and dried to yield the title oxime as a white powder (2.9 g., 91%) which was shown (NMR) to be a syn-/anti-mixture (30:/0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14](N3CCN(C(OC(C)(C)C)=O)CC3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.NC1N=CC([C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])=CC=1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 21 %

Procedure:
Following the procedure described for synthesis of 101i, intermediate 111a and 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 111b in 21% yield. LCMS: (M+H)+ 394. 1H NMR (500 MHz, MeOD) δ 8.84 (d, J=2.5, 1H), 8.42 (d, J=2, 1H), 7.72 (m, 1H), 7.42 (d, J=2, 1H), 7.11 (d, J=8.5, 1H), 3.72 (m, 8H), 3.63 (s, 3H).