Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[CH3:15].[C:16]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:31])[CH2:29]Br)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:2]([O:5][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:31])[CH2:29][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:29][C:28]([N:24]2[CH2:25][CH2:26][CH2:27][C@@H:23]2[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[O:31])[C:9]=1[CH3:15])=[O:20])([CH3:4])([CH3:3])[CH3:1]
Reactant: Cc1c(O)cccc1O
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 0.04 h
Yield: 61 %

Procedure:
To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2 ml dimethylformamide at room temperature was added dropwise a solution of 124 mg (1.0 mmol) 2,6-dihydroxytoluene in 2 ml dimethylformamide. Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol) (R)-(1) -bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml dimethylformamide was added within 1-2 min. The reaction mixture was stirred for additional 3 h at room temperature. The solvent was removed in vacuo and the residue purified by flash-chromatography to yield 335 mg (61 %) of the title compound as a colorless oil. MS m/e (%): 564 (M+NH4+, 100), 491 (27), 435 (71).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31]C)=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[CH:14][C:15]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[CH:14][C:15]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 43.8 %

Procedure:
To a round bottom flask, a mixture of methyl 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (130 mg, 0.30 mmol) in methanol (3 mL) and water (0.6 mL) was treated with a solution of sodium hydroxide (204 mg, 5.1 mmol) in water (0.6 mL). The resultant mixture was heated for reflux for 1 h. The methanol was removed under vacuum. The residue was acidified with 1 M hydrochloric acid to pH=5. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=2:1, 5% methanol) to afford 55 mg (44%) of 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a colorless solid. MS (ESI+APCI) M+1=419.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:25]=[CH2:26])[C@@H:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[NH:10][CH:11]([CH:15]2[CH2:17][CH2:16]2)[CH:12]2[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36].C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:25]=[CH2:26])[C@H:9]([N:10]([CH:11]([CH:12]2[CH2:13][CH2:14]2)[CH:15]2[CH2:16][CH2:17]2)[C:34](=[O:37])[CH:35]=[CH2:36])[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C1CC1)C1CC1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)N(C(C1CC1)C1CC1)[C@H](c1ccc(Cl)cc1)[C@H](C=C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.1 g (5.44 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmethyl)but-3-en-1-amine (Example 115, Step F) and triethylamine (1.89 mL, 13.59 mmol) in THF (30.0 mL) was added acryloyl chloride (0.66 mL, 8.15 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 2 h. When LCMS indicated completion of the reaction, 100 ml of ethyl acetate was added and the combined organics were washed consecutively with water (10 ml), citric acid (10 ml, 1M), NaHCO3 solution (10 ml) and sat. NaCl solution (30 ml), dried over MgSO4, filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate, 90/10 to 20/80) to give the title compound.
Reaction SMILES: [NH:1]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[C@H:2]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:65]([NH:67][C@H:68]([C:74]([OH:76])=[O:75])[CH2:69][CH2:70][C:71](=[O:73])[OH:72])=[O:66])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[H][H].O>CO.C(O)(=O)C.[Pd]>[NH:1]([C:77]([O:79][C:80]([CH3:82])([CH3:81])[CH3:83])=[O:78])[C@H:2]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:65]([NH:67][C@H:68]([C:74]([OH:76])=[O:75])[CH2:69][CH2:70][C:71](=[O:72])[OH:73])=[O:66])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Procedure:
150 Milligrams of Boc-Glu(OBzl)-Ser-Leu-Arg-Ser-Lys(Tos)-Glu-OH was dissolved in a mixture of 30 ml of methanol with 30 ml of 10%-acetic acid, to this solution was added a small amount of palladium black and stirred for 18 hours under the conditions of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, the residue thus obtained was added water and was lyophilized to obtain the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:12]([S:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=3)=[C:13]([S:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)[C:14]([S:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[C:15]3[C:20](=[O:21])[NH:19][C:17](=[O:18])[C:16]=23)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60].C(=O)([O-])[O-:62].[K+].[K+]>CN(C)C=O>[CH2:53]([N:19]=[C:17]([OH:18])[C:16]1[C:15](=[C:14]([S:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:13]([S:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[C:12]([S:42][C:43]2[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=2)[C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:20]([OH:62])=[O:21])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: O=C1NC(=O)c2c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c(Sc3ccc([N+](=O)[O-])cc3)c21
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCN=C(O)c1c(Sc2ccc([N+](=O)[O-])cc2)c(Sc2ccc([N+](=O)[O-])cc2)c(Sc2ccc([N+](=O)[O-])cc2)c(Sc2ccc([N+](=O)[O-])cc2)c1C(=O)O

Procedure:
1 g (1.32 millimols) of tetrakis-(p-nitrophenylthio)-phthalimide (prepared according to Example 10), 0.57 g (2.97 millimols) of 1-bromooctane, 0.68 g (4.96 millimols) of potassium carbonate and 10 ml of N,N-dimethylformamide are stirred at 25° C. for 5 hours. The mixture is concentrated and the residue is acidified and extracted with methylene chloride. After recrystallisation from toluene/cyclohexane, 1.02 g (89% of theory) of the title imide are obtained; melting point 202°-4° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[N:11]=1
Reactant: CN1CCN(C)CC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2nc(Cl)c3ccccc3n2)CC1
Temperature: 150 °C
Yield: 51.3 %

Procedure:
2,4-Dichloroquinazoline (2.00 g, 10.1 mmol, prepared as described in Prasad, M., et al. Org. Process Res. Dev. 2004, 8, 330-340) was slurried in 1,4-dioxane (20.0 mL). 1,4-Dimethylpiperazine (1.44 mL, 10.6 mmol) was added. The mixture was heated in a CEM microwave at about 150° C. for about 5 min. The material was poured into saturated aqueous NaHCO3/water (1:1, 150 mL). The mixture was extracted with EtOAc (5×100 mL). 20 g of silica gel was added to the combined organics and the volatiles were removed under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with a gradient of 2-10% MeOH/DCM to afford 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36 g, 52%): LC/MS (Table 1, Method n) Rt=0.51 min; MS m/z 263 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][C:40]([N:42]1[CH2:48][CH2:47][CH2:46][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][CH2:43]1)=[O:41].C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:52]1([CH2:51][CH2:50][CH2:49][N:45]2[CH2:46][CH2:47][CH2:48][N:42]([C:40]([CH2:39][NH:38][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])=[O:41])[CH2:43][CH2:44]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NCC(=O)N1CCCN(CCCc2ccccc2)CC1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CCCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a suspension of 1.0 g (4.58 mmol.) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mmol.) of N-hydroxysuccinimide in acetonitrile (20 ml) was added, at room temperature, 1.76 g (9.18 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodimide hydrochloride. The mixture was stirred for one hour. To the reaction system was added a solution of 1.91 g (5.48 mmol.) of 1-(aminoacetyl)-4-(3-phenylpropan-1-yl)-2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride, 1.67 g (10.97 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and 0.7 ml (5.0 mmol.) of triethylamine in acetonitrile (20 ml). The mixture was stirred for further one hour. The solvent was distilled off under reduced pressure. To the residue was added water. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure to leave a crude product, which was purified by means of a column chromatography (methanol/ethyl acetate 30-50%) to afford the object compound as an amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(F)c2)c1-c1ccccc1

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids filtered away and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 100° C.-101° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28].S(=O)(=O)(O)O>C(Cl)(Cl)Cl.O.CC(C)=O>[CH2:27]([O:29][C:30](=[O:31])[NH:19][S:16]([C:14]1[CH:13]=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[CH2:6][CH2:7][C:8]=2[CH:15]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Temperature: 25 °C

Procedure:
A mixture of 7.5 g. of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide, 13.9 g. of potassium carbonate, 9.6 ml. of chloroformic acid ethyl ester and 150 ml. of acetone is heated to reflux for 16 hours while stirring, then cooled to 25° C. and poured on to a mixture of 500 ml. of water and 1000 ml. of chloroform. The pH of the aqueous phase is then brought to 2.0 with 6N sulfuric acid while stirring. The chloroform phase is subsequently separated, dried over sodium sulfate and evaporated in vacuo. The evaporation residue is crystallized by the addition of ether. There is obtained [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester of melting point 140°-141° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH2:27]O)[C:22]#[N:23])[CH3:18]>>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([CH2:27][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([CH2:17][CH3:18])[CH:20]=1)#[N:23]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(C#N)ccc1CO
Product: CCc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)OC)ccn1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-ethyl-4-(hydroxymethyl)benzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.6 Hz), 2.73 (2H, q, J=7.6 Hz), 3.96 (3H, s), 5.28 (2H, s), 5.77 (1H, d, J=1.2 Hz), 7.53-7.67 (4H, m), 7.77 (1H, d, J=4.8 Hz), 8.31 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O3, 363. Found, 363.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CNCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(N(C)CCO)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (100 mg, 0.22 mmol), N-methylethanolamine (0.05 mL, 0.66 mmol) were reacted for 2 h to give the crude material, which was purified by preparative hplc to afforded the title compound, 26 mg (27%). LC-MS: 441.2 (MH+, m/z), 2.19 (Rt, min).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC/C(Nc1ccc(NC(C)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-p-phenylenediamine
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C#N)=CC=1>C(O)(=O)C>[O:13]=[C:12]1[N:7]([C:1]2[CH:6]=[CH:5][C:4]([C:24]#[N:23])=[CH:3][CH:2]=2)[CH:8]=[N:9][C:10]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:11]1=2
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: N#Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: N#Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 27 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-aminobenzonitrile (96 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 38 mg (0.12 mmol, 27% yield) of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:35][CH2:34][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:28][CH2:27]2)[C:19](=[O:36])[C:18]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:39]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([CH:26]2[CH2:27][CH2:28][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:34][CH2:35]2)[C:19](=[O:36])[C:18]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)=[CH:42][CH:43]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.32 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24]O)=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][Br:29])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CO)=CC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CBr)=CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-1,2-dihydro-2,2-dimethyl-4-hydroxymethyl-6-phenylquinoline (structure 11, where R1 =phenyl) (230 mg, 0.630 mmol) and carbon tetrabromide (220 mg, 0.662 mmol) in 5 mL of dichloromethane at 0° C. was added triphenylphosphine (174 mg, 0.662 mmol) in 2 mL of dichloromethane. The reaction mixture was allowed to warm to rt and stirred for 1 h. The mixture was concentrated in vacuo to a residue that was subjected to flash chromatography (silica gel, hexane/ethyl acetate, 9:1) to give structure 12, where R1 =phenyl (72 mg, 27%). 1H NMR (acetone d6) 7.67 (m, 3H), 7.52 (dd,J=8.7, 2.1, 1H), 7.45 (t, 2H), 7.32 (m, 2H), 6.07 (s, 1H), 4.60 (s, 2H), 1.55 (s, 6H), 1.53 (s, 9H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12]([NH2:15])[C:13](=[O:14])[N:10]2[C:9]=1[C:18]([OH:20])=[O:19].C(#N)C.[CH2:24]([O:31][C:32](=[O:54])[CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:34](OC1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32]([CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:34]([NH:15][CH:12]1[C:13](=[O:14])[N:10]2[C:9]([C:18]([OH:20])=[O:19])=[C:8]([CH3:7])[CH2:17][S:16][C@H:11]12)=[O:35])=[O:54])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(OCc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
1.8 ml. of pyridine are added to a suspension of 2.17 g. (0.01 mole) of 7-ADCA in 40 ml. of acetonitrile and 2 ml. of water. The obtained solution is cooled to 0° C., 5.6 g. (0.01 mole) of phenylmalonic acid pentachlorophenylester benzylester are added, and the mixture is stirred for 4 hours. The acetontrile is evaporated, the residue is taken up in 50 ml. of ethyl acetate, and the ethyl acetate solution is admixed with saturated sodium bi-carbonate solution. The aqueous phase is washed with ethyl acetate, thereafter it is covered with 50 ml. of ethyl acetate, and acidified to pH=2 with 2 n aqueous hydrochloric acid. The ethyl acetate phase is separated, dried, and evaporated. 3.5 g. (75%) of 7-(α-benzyloxycarbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid are obtained with a purity degree of 95% (determined by titrimetry).