Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[C:9](O)=[O:10])([CH3:5])([CH3:4])[CH3:3]>>[C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[C:9]([NH2:1])=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O

Procedure:
In the manner of Example 7, ammonia was reacted with 3,5-di-t-butyl-4-hydroxybenzoic acid to produce 3,5-di-t-butyl-4-hydroxybenzamide; melting point 263°-265°C. When tested by the procedure of Example 2, this compound lasted 1000 hours, about 2.5 times as long as the control.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([CH2:10]OS(C)(=O)=O)[CH2:9][CH2:8]1>>[CH:7]1([CH2:10][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)[CH2:9][CH2:8]1
Reactant: Nc1nc[nH]n1
Reactant: CS(=O)(=O)OCC1CC1
Product: Nc1ncn(CC2CC2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and methanesulfonic acid cyclopropylmethyl ester (Journal of the American Chemical Society 128, 3118 (2006)). The title compound was obtained as a brownish solid (Yield=25%). MS ISP (m/e): 138.1 (100) [M+].
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:14]S(C(F)(F)F)(=O)=O)([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8].[C:22]([O:26][C:27]([C:29]1([CH2:38]O)[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([C:29]1([CH2:38][O:14][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)N1CCC(CO)(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(COS(=O)(=O)C(F)(F)F)(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A mixture of 2.0 ml (250 mmol) of pyridine and of 20 ml of dichloromethane is cooled to −78° C. under nitrogen. Triflic anhydride (2.10 ml, 12.5 mmol) is added drop by drop. After 10 min, a solution of 1.29 g of the compound from step 2 (5.0 mmol) in 15 ml of CH2Cl2 is added drop by drop. The mixture is stirred for 2 hours at −78° C. The organic phase is washed with 1N HCl, H2O, sat. NaCl, dried over Na2SO4 and concentrated at reduced pressure to produce 1.68 g of the expected product (yield: 86%) used as it is for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc([N+](=O)[O-])c[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc([N+](=O)[O-])c[nH]c1=O)c1ccccc1

Procedure:
A solution of 100 mg. of 3-amino-5-nitro-2-pyridone in 1.5 ml. of pyridine was cooled and treated with 200 mg. of benzoyl chloride. After 2 hours water was added. The oil that separated was washed with water and triturated with ether. The resultant solid was recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone, m.p. 267°-268° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[NH:11]1.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:26](=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[NH:11]1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: COc1ccc(N)cc1Nc1cc(=O)n(-c2c(Cl)cc(Cl)cc2Cl)[nH]1
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(OC)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1

Procedure:
The 1-(2,4,6-trichlorophenyl)-3-(2-methoxy-5-aminoanilino)-5-pyrazolone prepared in the above procedure was reacted with myristic acid chloride prepared using Method (3) of Synthesis Example 1 to give the desired product having a melting point of 89°-93°C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[N:16]1([C:22]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2CN(C(=O)N3CCOCC3)CC2C1
Yield: 100 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring, and potassium carbonate (0.397 g, 2.88 mmol) was then added to the solution in an ice-water bath, followed by morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol). Upon completion of the addition, the reaction mixture was stirred overnight in an ice-water bath, then the solvent was evaporated, and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][CH2:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].[C:42]([OH:45])(=[S:44])[CH3:43]>C1COCC1>[C:42]([S:44][CH2:33][CH2:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])(=[O:45])[CH3:43]
Reactant: OCCC(CCO)CCO
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCC(CCO)CCO
Temperature: 0 °C
Reaction time: 0.92 h
Yield: 37.7 %

Procedure:
To a solution of triphenylphosphine (1.77 g, 6.8 mmol) in anhydrous THF (15 mL) was added diethyl azodicarboxylate (2.2 M in toluene, 2.4 mL, 5.4 mmol) dropwise at 0° C. After stirred at 0° C. for 55 minutes, a solution of 3-(2-hydroxyethyl)pentane-1,5-diol (740 mg, 5 mmol) and thioacetic acid (335 μL, 4.5 mmol) in dry THF (7 mL) was added dropwise. After 1 hour the ice/water bath was removed and the reaction was stirred at room temperature for 16 hours. The solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography (CHCl3/MeOH, 20:1, 15:1, 10:1, 4:1) to give 3-(2-acetylthioethyl)pentane-1,5-diol as white solid (350 mg) and recovered starting material triol (406 mg). 1H NMR (400 Hz, CDCl3): δ 3.65-3.63 (m, 4H), 3.45 (bs, 2H), 2.84-2.80 (m, 2H), 2.28 (s, 3H), 1.73-1.67 (m, 1H), 1.55-1.49 (m, 6H). MS (ESI): m/z 229.0 (M+Na)+.
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[N:33]1([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:38]CN[CH2:35][CH2:34]1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6](=[O:32])[N:5]3[CH2:4][CH2:38][N:33]([C:39]4[N:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:34][CH2:35]3)=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCN(c2ncccn2)CC1

Procedure:
Compound 107 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-(piperazin-1-yl)pyrimidine. LCMS (+ESI) m/z=540.4 [M+H]+. 1H NMR (CDCl3) δ 8.33 (d, J=4.8 Hz, 2H), 8.00 (d, J=9.6 Hz, 1H), 7.47-7.52 (m, 1H), 7.30-7.33 (m, 1H), 7.19-7.26 (m, 1H), 6.56 (t, J=4.8 Hz, 1H), 4.90 (d, J=9.6 Hz, 1H), 4.82 (s, 2H), 4.00-4.06 (m, 1H), 3.63-3.96 (m, 9H), 3.18 (br, 2H), 1.11 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:27][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:24][CH2:23][CH2:22]2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1cccc2c1C(N)CCC2
Product: COc1cccc2c1C(Nc1ccc3c(N)cccc3n1)CCC2

Procedure:
The title compound, MS: m/e=320.4 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline and 8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-amine (CAS 535935-61-6).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([SH:10])[N:9]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>CN(C=O)C>[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([S:10][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[N:9]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc(S)nc2c1CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (125 mg) in dry DMF (5 ml) was added a solution of the product from example 3, step (a) (0.57 g) in DMF (10 ml). The mixture was allowed to stir for 30 mins. To the solution was added 2,3-difluorobenzyl bromide (0.39 ml) and the mixture stirred for 2 hours. Poured into water and the crude product extracted into ethyl acetate. Chromatography on silica eluting with 10% ethyl acetate/dichloromethane afforded the title compound (0.35 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br>C(#N)C>[CH2:4]([CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:2][N:1]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCCBr
Reactant: NCC(Cc1ccccc1)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1cccc(C(Cc2ccccc2)CN2CCCC2)c1

Procedure:
To 3-(1-amino-3-phenylpropan-2-yl)phenol (0.6 g, 2.6 mmol) dissolved in 40 ml acetonitrile was added triethylamine (0.81 ml, 5.8 mmol) followed by 1,4-dibromobutane (0.37 ml, 3.2 mmol). The mixture was heated to reflux for 3 h then poured on ice-water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and the solvent evaporated to obtain a yellow oil. m=665 mg (90%)
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH2:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1)[CH3:9]
Reactant: CCc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-ethyl-1,3-thiazole (5.2 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (700 mg, 3.6 mmol), and triethylamine (1.5 mL, 11 mmol) in absolute ethanol (40 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (900 mg, 78% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 2H, J=7.5 Hz), 2.76 (m, 2H, J=7.5 Hz), 4.65 (s, 2H), 6.65 (s, 1H), 8.88 (s, 1H); M+ 322.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-Hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (55.5 mg, 85% yield). 1HNMR (500 MHz, CDCl3) δ: 11.98 (1H, s), 7.95 (1H, t, J=5.19 Hz), 7.49 (1H, td, J=7.33, 1.83 Hz),7.40–7.38 (2H, m), 7.29 (1H, dd, J=7.63, 1.83 Hz), 7.15 (1H, dd, J=8.24, 1.83 Hz), 7.07 (1H, t, J=8.24 Hz), 4.51 (2H, d, J=6.41 Hz), 3.82 (3H, s), 3.35 (3H, s). HRMS (ESI) calcd for C20H18Cl2N3O4 (M+H): 434.0675; found: 434.0674.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].Cl>[OH-].[Na+]>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)CCl
Reaction time: 0.5 h

Procedure:
18 mL (221 mMol) chloracetylchloride was added dropwise to 20 g (153 mMol) 6-aminohexanoic acid dissolved in 80 mL cold NaOH solution (2 N) at RT. The reaction mixture was stirred for 30 minutes while the pH of the solution was kept between 10 and 11 with occasional addition of NaOH solution (6 N). The pH of the reaction mixture was then altered to pH 5 with HCl (2 N) and the residue was filtered. The residue was then washed with water until the pH of the water was neutral. The product, dried over phosphorus pentoxide, was re-dissolved in 300 ml chloroform and filtered to remove the undissolved residue. Heptane was added to the filtrate and a syrup was obtained by stirring under cooling. The product was filtered, dried and was then crystallized from water.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].C([O:13][C:14]1O[CH:17]=[N:16][CH:15]=1)C>>[CH3:7][O:6][C:4]([C:3]1[CH:17]=[N:16][CH:15]=[C:14]([OH:13])[C:2]=1[C:1]([O:9][CH3:10])=[O:8])=[O:5]
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: CCOc1cnco1
Product: COC(=O)c1cncc(O)c1C(=O)OC

Procedure:
Dimethyl fumarate (781 mg; 1.1 eq.) was added to 5-ethoxyoxazole (557.3 mg; 4.9 mmol), and the mixture was reacted at 120° C. for 1.5 hours. The reaction residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane 2:1), to give crude crystals of the title compound. Yield: 730 mg (70.2%). The crude crystals were recrystallized from dichloromethane-hexane, to give colorless plates.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([OH:28])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:20]1[CH:19]=[CH:18][C:17]([CH3:16])=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(C)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (113 mg), ethyl 5-methylsalicylate (632 mg), and 4-dimethylaminopyridine (435 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (64.1 mg, yield 35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH2:15](C([Sn])=C(CCCC)CCCC)[CH2:16]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:15]=[CH2:16])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of 4-bromo-2-nitro-benzoic acid methyl ester (1 g, 3.85 mmol) in dioxane (5 mL) were added tributylvinyltin (1.7 mL, 5.76 mmol) and Pd(Ph3P)2Cl2 (275.4 mg, 0.385 mmol). The reaction mixture was stirred at 80° C. for 18 h, was cooled to r.t. and was diluted with EtOAc. After removal of the precipitate by filtration, the solution was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes→1:1 hexanes:EtOAc) to provide the title compound (820 mg, 100%, 97% purity by HPLC) as a yellow oil. ESI-MS: m/z 208.2 [M+H]+, rt 5.14 min.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C(N)C.[C:43](N1C=CN=C1)([N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1)=[O:44]>C1COCC1.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:43]([N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[O:44])[CH2:34][CH2:33]3)=[O:31])=[CH:38][CH:39]=2)=[N:16]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
A solution of dihydrochloride of Compound 18 (400 mg, 1.09 mmol) in THF (20 mL) was added with ethylamine (177 mg, 2.18 mmol) and 1,1′-carbonyldiimidazole (352 mg, 2.18 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative thin-layer chromatography (chloroform/acetone=1/1) to obtain Compound 48 (350 mg, 44%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
To a solution of N-[(1,3-dimethyl-indole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (209 mg, 0.33 mmol) in CH2Cl2 (5.0 ml) was added Dess-Martin periodinane (181 mg, 0.43 mmol) and the solution stirred for 10 min. at room temperature. The reaction was quenched with Na2S2O4, diluted with EtOAc, washed with NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (1:1 EtOAc/hexane) to give the titled product as a white solid (135 mg, 64%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].[OH-].[Na+]>C(O)(C)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:28]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:27]=2)=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1ccc(NC(=N)N)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 104130488 %

Procedure:
3-Dimethylamino-1-(3-pyridyl)-2-propen-1-one (20 g, 0.1 μmol), 4-methyl-3-nitrophenyl-guanidine nitrate (32 g, 0.12 mol), and sodium hydroxide (6.8 g, 0.17 mol) were dissolved in isopropanol, and reacted under reflux for 28 hours. The reaction solution was cooled to 0° C., filtered, washed with isopropanol, water and ethanol, and dried to give N-(4-methyl-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (32 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[CH:14]([C:20]([OH:22])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)=CS[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Reaction time: 5 h
Yield: 73.3 %

Procedure:
A suspension of palladium carbon (20 g.) in acetic acid (50 ml.) was added to a solution of 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylic acid (19.0 g.) in acetic acid (150 ml.) and water (50 ml.). The solution was subjected to catalytic reduction in the presence of hydrogen gas of 20 kg./cm2 at 70° C. for 5 hours. After filtration, the filtrate was concentrated in vacuo. The residue was dissolved in aqueous solution of sodium bicarbonate, washed with ethyl acetate, adjusted to pH 3.0 and then extracted with ethyl acetate. The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (14 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[N:10][OH:11])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:20]#[C:21][CH2:22][CH3:23]>CCOCC>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]2[CH:20]=[C:21]([CH2:22][CH3:23])[O:11][N:10]=2)=[CH:5][N:6]=1
Reactant: C#CCC
Reactant: ON=C(Cl)c1cnc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1cc(-c2cnc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5,6-Dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (0.85 g, 3.8 mmol) was dissolved with stirring in ether (60 mL) and a solution of triethylamine (0.8 g, 7.9 mmol) in ether (50 mL) added dropwise to the solution while 1-butyne was bubbled through the reaction mixture. The mixture was stirred at room temperature overnight, filtered, and the filtrate evaporated to dryness under reduced pressure. Recrystallisation of the residue from hexane gave the desired product (0.83 g, 90%) as a cream solid, melting point. 98-9° C.