Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([CH3:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a mixture of 4-(benzyloxy)aniline hydrochloride (4.10 g) and 2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA (7.27 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was heated to 60° C. After stirring at 60° C. overnight, K2CO3 (4.81 g) was added to the mixture. The mixture was heated to 100° C. and stirred at 100° C. overnight. The mixture was poured into water and the mixture was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-30% AcOEt in hexane) to give N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as a red solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45]1([CH2:48]Br)[CH2:47][CH2:46]1.[CH3:50]N(C)C=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:3]1([CH2:2][O:8][C:9]2[C:17]3[N:16]=[C:15]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:50][CH2:48][CH2:45][CH2:47][CH2:46]1
Reactant: CN(C)C=O
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCC4CCCCC4)cccc32)CC1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Cyclopropylmethyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanol (0.24 mL, 4.0 mmol), and triethylamine (1.5 mL, 11 mmol) in anhydrous THF (15 mL) was added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (850 mg, 77%): ESI MS m/z 298 [C8H9BrFNO3S+H]+.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:26]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Fc1ccc(/C=C/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 80.3 %

Procedure:
A solution of 1 (10.4 mg, 0.0315 mmol) in 0.4 mL of 95% aqueous ethanol was added dropwise to a solution of 4-fluorostyrene (9.8 mg, 0.080 mmol) and palladium(II) acetate (0.2 mg, 0.0009 mmol) in 0.10 g of 95% aqueous ethanol. The reaction mixture was heated on an oil bath at 70° C. for 5 h. After cooling, the mixture was filtered through a pad of Celite 545 and purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2b (8.2 mg, 77% yield) as colorless crystals; m.p. 85.0-86.2° C. IR (ATR): {tilde over (v)}=1593, 1508, 1236, 1159, 1099, 964, 831, 818 cm−1. MS (GC, EI): m/z=324 [M+], 197 [M+ SF5], 177. 1H NMR (500 MHz, CDCl3): δ=7.73 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.51 (dd, J=8.8, 5.4 Hz, 2H), 7.15 (d, J=16.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.01 (d, J=16.4 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=162.8 (C), 152.3 (C), 140.4 (C), 132.6 (C), 130.7 (CH), 128.4 (2CH), 126.3 (2CH), 126.2 (2CH), 126.2 (CH), 115.8 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.9 (quint, J=150.2 Hz, 1 F), 63.0 (d, J=150.2 Hz, 4 F), −112.7 (m, 1 F) ppm.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl[C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.[CH4:23]>CO>[C:17]1([N:20]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:5]=[CH:4][CH:3]=[CH:2][CH:23]=3)=[N:21]2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Reaction time: 22 h

Procedure:
A mixture of 10 g (54.3 mmol) of ethyl trifluoroacetoacetate and 9.72 g (54.3 mmol) of 4-chlorophenylhydrazine and 1 mL of concentrated HCl in 130 ml of methanol was refluxed with stirring for 22 hours. After adding activated charcoal with stirring, the hot mixture was filtered, diluted with water, and the resulting white solid was filtered. The solid was washed with hexane and dried to afford 19 g of 2,4-dihydro-2-(4-chlorophenyl)-5-trifluoromethyl-3H-2-pyrazol-3-one (Formula III: R1 =4-Cl--Ph; R2 =CF3 ; R3 =H) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[C:30]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])=[O:21])[S:17][CH:18]=2)=[CH:7][CH:6]=1>[Li+].[OH-]>[CH:32]1([C:30]([C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[NH:22][C:20](=[O:21])[NH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:10][CH:9]=3)[N:15]=2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)Cc1ccc(OCCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCOc3ccc(CC(=O)O)cc3)cs2)c(C(=O)C2CCCC2)c1
Yield: 82.1 %

Procedure:
[4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy)-phenyl]acetic acid (25 mg, 86%) was prepared from [4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy)-phenyl]acetic acid methyl ester (0.03 g, 0.06 mmol) and 2.5M LiOH (20 uL) following the general procedure J.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[CH3:15][NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH3:15])=[O:11])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)N(C)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
0.995 g of terphthalic acid monomethyl ester chloride and 0.756 g of methyl 4-(methylamino)-benzoate were dissolved in 25 ml of acetone and treated with 0.691 g of anhydrous potassium carbonate. The reaction mixture was stirred at room temperature for 30 hours and was evaporated. The residue was treated with water and the crystals were filtered off yielding N-(4-methoxycarbonyl-phenyl)-N-methyl-terephthalamic acid methyl ester in the form of colourless crystals, MS: m/z 327 (M+).
Reaction SMILES: [CH:1](=[N:6][OH:7])[C:2]([CH3:5])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[CH:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH2:17].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[C:2]([C:1]1[CH2:17][CH:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[O:7][N:6]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C=NO
Reactant: C=CP(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C1CC(C(C)(C)C)=NO1

Procedure:
The procedure is analogous to that of Example 25 using 15.2 g (0.15 mol) of pivalaldoxime, 22.0 g (0.165 mol) of N-chlorosuccinimide, 0.5 ml of pyridine, 27.1 g (0.165 mol) of diethyl vinylphosphonate and 22.9 ml (0.165 mol) of triethylamine in dichloromethane. The product is obtained as an oil after the usual working up.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:7]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:32])[C@:19]4([CH3:31])[CH2:20][CH2:21][C@H:22]5[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C@:23]5([CH3:30])[C@H:18]4[CH2:17][CH2:16][C@@H:15]3[C@@:10]2([CH3:33])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][OH:6].[N:34]1C=CC=CC=1.C(N(CC)CC)C.[C:47](Cl)(=[O:51])[C:48]([CH3:50])=[CH2:49]>ClCCl.C(OCC)C>[C:47]([NH2:34])(=[O:51])[C:48]([CH3:50])=[CH2:49].[CH3:1][C@@H:2]([C@@H:7]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:32])[C@:19]4([CH3:31])[CH2:20][CH2:21][C@H:22]5[C:27]([CH3:29])([CH3:28])[CH2:26][CH2:25][CH2:24][C@:23]5([CH3:30])[C@H:18]4[CH2:17][CH2:16][C@@H:15]3[C@@:10]2([CH3:33])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: c1ccncc1
Reactant: C=C(C)C(=O)Cl
Agent: C[C@H](CCCO)[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(C)CCCC(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@H]12
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(N)=O
Temperature: 25 °C

Procedure:
Into a one-liter, 3-neck flask equipped with a reflux condenser, a pressure equalizing addition funnel and a magnetic stirrer are charged 200 g (0.07 mole) of Monol I, 22 g (0.28 mole) of pyridine and 200 ml of anhydrous diethyl ether. Under a static nitrogen purge with cooling to ~2° C., 14.4 g of toluene sulfonyl chloride dissolved in 25 ml of diethyl ether is added with stirring over a period of one half of an hour. The reaction mixture is allowed to warm to room temperature and stirred for 12 hours. Thereafter, the diethyl ether is removed under reduced pressure at temperatures less than 40° C. The reaction mixture is filtered to remove pyridine hydrochloride and then charged into a one-liter, 3-neck flask equipped with a reflux condenser, gas sparge addition tube and a magnetic stirrer. To this flask is added with stirring 200 ml of dichloromethane and anhydrous ammonia is sparged through the reaction mixture for 11/2 hours followed by sparging with nitrogen for 2 hours. The reaction mixture is filtered and then subjected to reduced pressure to remove dichloromethane. Into the aforementioned flask are added the reaction product, 200 ml of dichloromethane and 7.0 g (0.07 mole) of triethylamine. To the resulting solution is added with stirring and refluxing, 7.9 g (0.075 mole) of methacryloyl chloride diluted in 25 ml of dichloromethane over a period of 30 minutes and stirred overnight. The resulting product is cooled and subjected to reduced pressure to remove dichloromethane. To this product is added 200 ml of diethyl ether, then filtered and subjected to reduced pressure to remove diethyl ether thereby providing the aforementioned desired adduct.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)C)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Isopropylamine (2 mL, 48.72 mmol) was added to a solution of Example 57k (0.3 g, 0.59 mmol) in DMF (5 mL) and stirred at 80° C. for 3 h. The reaction mixture was concentrated, treated with water, and extracted with chloroform. The organic layer was washed with water, brine and concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 2% methanol/chloroform). Yield: 0.16 g, (55.17%); 1H NMR (CDCl3,): δ 1.10 (d, 6H, 2CH3), 2.7 (s, 3H, CH3), 2.8 (q, 1H, CH), 2.86 (t, 2H, CH2), 3.41 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.38 (d, 1H, Ar), 7.46 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[NH:32][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[N:25]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Product: c1ccc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)nc2c1
Temperature: 130 °C
Yield: 0.7 %

Procedure:
A mixture of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (400 mg, 1.20 mmol), 1,2-diaminobenzene (129 mg, 1.20 mmol) and polyphosphoric acid (2 g) was heated at 130° C. for 2 days. The cooled reaction mixture was partitioned between dichloromethane (20 ml) and aqueous ammonia (20 ml). The aqueous layer was further extracted with dichloromethane (2×50 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC on Fraction-Lynx® eluting with water:acetonitrile:TFA (95:5:0.1) to provide the title compound (3.5 mg, 1%). 1H NMR (400 MHz, CDCl3) δ 1.92-1.96 (m, 2H), 2.06-2.21 (m, 4H), 2.40-2.46 (m, 2H), 2.96-3.00 (m, 4H), 3.05-3.09 (m, 2H), 3.16-3.20 (m, 2H), 3.57-3.65 (m, 4H), 3.93 (d, 2H), 5.45 (d, 2H), 7.06 (d, 2H), 7.45 (d, 2H), 7.71-7.74 (m, 2H). LCMS ESI+ m/z 406 [MH]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:15]([CH2:29][CH3:30])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][NH:21][CH2:20]1)[CH3:14].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:29]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:20]1)[CH3:30]
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: CCN(CC)CCOC1CNCCC1(OC)OC
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 7.5 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 10.5 parts of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine, 7 parts of N,N-diethylethanamine, 1 part of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 17 hours at 60° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The whole was evaporated and the residue was taken up in acetonitrile. The solution was evaporated, yielding 14 parts (75%) of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl]-4,4-dimethoxy-3-piperidinyl]oxy]ethanamine as a residue (intermediate 115).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(C(=O)N3CCCC3)c21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1C(=O)N1CCCC1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A mixture of 6-(2-hydroxyphenyl)-5-[(pyrrolidin-1-yl)carbonyl]-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 8-1, 65.0 mg, 0.179 mmol), methyl iodide (11.1 μL, 0.178 mmol) and potassium carbonate (49.5 mg, 0.358 mmol) was suspended in anhydrous N,N-dimethylformamide (1.5 mL), and the reaction mixture was stirred at 50° C. overnight. After cooling down, it was diluted with ethyl acetate (100 mL). The whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (42.5 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[SH:20][C:21]1[S:25][C:24]([S:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[N:23][N:22]=1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:20][C:21]3[S:25][C:24]([S:26][CH2:27][C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])=[N:23][N:22]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C(CSc1nnc(S)s1)N1CCOCC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(SCC(=O)N4CCOCC4)s3)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Mixed were 0.68 g of 7-ACA, 0.18 g of water and 0.90 g of 5-mercapto-2-morpholinocarbonylmethylthio-1,3,4-thiadiazole, and 4.0 ml of acetonitrile was added to the mixture, 2.52 g of diphosphoryl tetrachloride was added to the mixture under stirring in a dry ice/acetone bath at -20° to -40° C. over a period of about 10 minutes, and the cooling bath was removed. After the temperature was allowed to increase at 0° C., the reaction solution was stirred in a warm water bath at 40° C. for 20 minutes, cooled with ice and adjusted to pH 4.3 with aqueous concentrated ammonia following the addition of 5 ml of water. There was obtained 1.10 g (89.9% of yield) of 7-amino-3-(2-morpholinocarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid thus produced.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1([O:11][C:12]2[CH:34]=[CH:33][C:15]3[C:16]4[N:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:19]=[C:18]([C:24]2[N:25]([CH:30]([CH3:32])[CH3:31])[N:26]=[C:27]([CH3:29])[N:28]=2)[N:17]=4)[CH2:10][CH2:9]1)=[O:7]>CO.O>[CH:30]([N:25]1[C:24]([C:18]2[N:17]=[C:16]3[N:20]([CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([O:11][C:8]5([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]5)[CH:34]=[CH:33][C:15]=43)[CH:19]=2)=[N:28][C:27]([CH3:29])=[N:26]1)([CH3:32])[CH3:31]
Reactant: COC(=O)C1(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Yield: 80.9 %

Procedure:
Lithium hydroxide monohydrate (141 mg, 3.44 mmol) was added to a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid methyl ester (730 mg, 1.72 mmol) in MeOH (10 mL) and water (2 mL) and the mixture was heated at 50° C. for 1 h. Volatiles were removed under reduced pressure and the pH of the resulting residue was adjusted to 4 by addition of 1N HCl. A precipitate formed which was collected by filtration and washed with water affording 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid (570 mg, 81%). LCMS: RT 2.71 min [M+H]+ 410.2
Reaction SMILES: B(F)(F)F.CCOCC.C([NH2:13])(=O)C.[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@H:25]([C:53]([O:55][CH3:56])=[O:54])[CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]([O:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=3)=O)=O)=[CH:29][CH:28]=2)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CC(=O)OCC>[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@@H:25]([CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]3[O:33][CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)[N:13]=3)=[CH:29][CH:28]=2)[C:53]([O:55][CH3:56])=[O:54])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(N)=O
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To boron trifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallized from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8. found 597.0 [M+H]+, tR=3.11 min. (Method 4).