Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]=[C:7]1[C:12](=[O:13])[C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:10][NH:9][CH2:8]1>C(O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[C:11]1[CH:12]([OH:13])[C:7](=[CH:6][C:5]2[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=2[F:3])[CH2:8][NH:9][CH2:10]1
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (36 mg, 0.96 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in ethanol at 0° C., in portions. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated to dryness. The residue was dissolved in chloroform, and the organic phase was washed with brine and water. The organic layer was dried over sodium sulfate, and concentrated to dryness. The crude product was passed through silica column, and eluted with 70% ethyl acetate in hexanes. The title compound 10 was obtained as colorless thick syrup (296 mg, 98% yield). Rf (60:40 ethyl acetate:hexanes)=0.10. 1H NMR (300 MHz, CDCl3): δ 7.25 (s, 1H), 7.00 (q, 2H, Ar—H, J=7.4), 6.93 (t, 2H, Ar—H, J=7.8), 6.86 (t, 2H, Ar—H, J=7.0), 6.81 (t, 2H, Ar—H, J=7.6), 6.39 (s, 2H, C═CH), 4.66 (s, 1H), 3.61 (d, 2H, J=14.8), 3.25 (d, 2H, J=14.8). 13C NMR (75 MHz, CDCl3): δ 161.42 (d, J=246.2), 144.36, 130.74, 128.50, 128.60, 128.49, 124.31, 124.12, 123.64, 115.43, 115.14, 75.62, 45.68. ESI Mass calculated for C19H17F2NO (M)+313.13. found 313.87.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:4][C:3]=1[F:13].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH2:8][C@@H:9]2[CH2:10][O:11][C:15]([CH3:20])([CH3:16])[O:12]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@@H](Cc2cnc(Cl)c(F)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 967.5 %

Procedure:
A suspension of 3 (2.50 g, 12.2 mmol) in dimethoxypropane (25 mL) was cooled with an ice bath and treated with paratoluene sulfonic acid monohydrate (0.23 g, 1.22 mmol). The ice bath was removed and the solution was stirred at room temperature for 16 hrs, cooled to 5° C. and treated with aqueous sat. NaHCO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to afford 2.90 g of 31 (97%) as an oil. 1HNMR (CDCl3) δ 1.34 (3 H, s), 1.42 (3 H, s), 2.87 (2 H, d, J=6.0 Hz), 3.62 (1 H, t, J=7.0 Hz), 4.08 (1 H, t, J=6.0 Hz), 4.30 (1 H, q, J=6.0 Hz), 7.46 (1 H, d, J=9.0 Hz), 8.12 (1 H, s). LC/MS (M+1) 247.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C[OH:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]#[CH:19])=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:17][C:18]#[CH:19])=[O:8])=[CH:12][CH:11]=1
Reactant: CO
Reactant: C#CCSc1ccc(C)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: C#CCS(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In 250 mL of water, was subsequently added and dissolved 68.7 g (321 mmol) of sodium periodate. A methanol solution (250 mL) of 49.6 g (306 mmol) of 4-methyl-1-prop-2-ynylthiobenzene [general formula (XI)] was dropped and stirred at room temperature for 2.5 hours. After 2.5 hours, the mixture was filtered, and the solids were washed with 100 mL of ethyl acetate. The filtrate was vacuum concentrated, and 200 mL of water was added. The resulting mixture was extracted with ethyl acetate (150 mL) three times. The obtained organic layers were washed with 150 mL of water, dried with magnesium sulfate and vacuum concentrated to provide 50.6 g (crude yield 93%) of 4-methyl-1-(prop-2-ynylsulfinyl)benzene.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
6-Bromohexanoyl chloride (16.2 g) was dissolved in methylene chloride (50 ml), and aluminum chloride (10.6 g) was added, which was followed by stirring at room temperature for 30 min. The reaction mixture was ice-cooled, and benzene (5.0 g) was dropwise added, which was followed by stirring for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 18.2 g of 6-bromo-1-phenyl-1-hexanone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: C=C(NC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1)C(=O)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C=C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(=O)OC
Temperature: 80 °C
Yield: 18.4 %

Procedure:
Methyl 2-(3-(4-nitrophenyl)isoxazole-5-carboxamido)acrylate (1.2 g, 3.78) was dissolved in EtOH (20 ml), THF (8 ml) and water (8 ml). Then ammonium chloride (601 mg, 11.34 mmol)) and iron (529 mg, 9.45) were added and refluxed at 80° C. for 1.5 hours. Reaction mixture was cooled and filtered through celite and solvent was removed under reduced pressure to get dark brown residue. Residue was taken in water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated to get dark brown residue, which was purified by column chromatography using EtOAc and petroleum ether to yield 200 mg (18%) of the title compound. MS: ES (+): m/z 288 (M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 10.115 (s, 1H), 7.577 (d, 2H), 7.558 (s, 1H), 6.640 (d, 2H), 6.011 (s, 1H), 5.873 (s, 1H), 5.642 (s, 2H), 3.753 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].CN(C=O)C>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.COCCOC>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)cc1OC

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(3,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 37%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccccc1C=CC1CCCCC(=O)N1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCC1CCCCC(=O)N1

Procedure:
The title material of Example 79 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[C@H:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C@@H:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CNC(=O)[C@@H](C)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](C)N1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), (R)-2-bromo-N-methylpropanamide (100.0 mg, 0.60 mmol), and triethylamine (102.0 μL, 0.60 mmol) in 2 mL of DMF was heated at 150° C. in a microwave reactor for 30 min. The reaction mixture was directly purified by preparative RP-HPLC to afford (S)-2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-N-methylpropanamide; ESMS m/z 501.2 (M+H+).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([SiH2:12][O:13][C:14]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:15]([CH:22]=[CH2:23])[C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][O:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[CH:15]([C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:13][SiH2:12][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:22]=[CH2:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(C(C)(C)C(=O)O)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CC(C(C)(C)C(=O)OC)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trimethylsilyl diazomethane (29 mL, 2 M in hexanes, 57.78 mmol) was added to a stirred solution of Example 5G (15.58 g, 39.3 mmol) in toluene (100 mL) and methanol (20 mL). After one hour at room temperature, acetic acid (1.5 mL) was added to quench the excess reagent. The solvent was evaporated and the crude product was dissolved in diethyl ether and washed with NaHCO3 solution brine, dried (MgSO4), filtered, and evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14](=[S:17])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[C:21](O)(=O)C>O>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14]([S:17][CH3:21])=[N:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (13.79 g) was added to a stirred solution of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (22.66 g) and sodium hydroxide (8.0 g) in water (250 ml), and the mixture was heated at 70° for 1 hour and stirred at room temperature overnight. Acetic acid was added until pH 5 and the volume of the mixture was evaporated to a volume of 50 ml. The solid was filtered off and was recrystallised from ethanol-acetic acid to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (10.16 g) m.p. 197°-197.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
2.91 g of 8-amino-6-phenyl-1H-s-triazolo[4,3-a] [1,5]-benzodiazepine-1,5-dione and 1.02 g of acetic anhydride in 50 ml pyridine is stirred for 12 hours then refluxed for 30 minutes. The reaction is evaporated; the residue is taken up in chloroform, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.Cl.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C(O)CCC>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=2)=[CH:19][CH:18]=1
Reactant: C=C(OCC)c1c(C)nc(C)nc1Cl
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: C=C(OCC)c1c(C)nc(C)nc1NCc1ccc(Br)cc1
Yield: 55.6 %

Procedure:
A mixture of 4-chloro-2,6-dimethyl-5-(1-ethoxyvinyl)pyrimidine (3.00 g, 0.0141 mol), 4-bromobenzylamine hydrochloride (3.45 g, 0.0155 mol), NaHCO3 (2.37 g, 0.0282 mol), and n-butanol (20 mL) was heated under reflux for 70 h. The mixture was concentrated, taken up in EtOAc, washed with water, dried MgSO4), and concentrated. Trituration with ether/hexane gave 2.84 g (56%) of product as a white solid. An analytical sample was recrystallized from ether/hexane, mp 111°-113° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH2:14])[NH:8]2)=[C:4]([O:15][CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:3]=1.C1(=O)N([O:36][C:37](=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][C@H:49]2[C@@H:57]3[C@@H:52]([NH:53][C:54]([NH:56]3)=[O:55])[CH2:51][S:50]2)C(=O)CC1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH:13]([NH2:14])[C:37](=[O:36])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][C@H:49]3[C@@H:57]4[C@@H:52]([NH:53][C:54]([NH:56]4)=[O:55])[CH2:51][S:50]3)[NH:8]2)=[C:4]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[CH:29][CH:30]=2)[N:3]=1
Reactant: NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(CCC(N)C(=O)CCCCCNC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)[nH]c2n1
Yield: 82.6 %

Procedure:
Amine 41 (Example 24, 10 mg, 0.023 mmol) and N-(+)-biotinyl-6-aminocaproic acid succinimidyl ester (50, 10 mg, 0.023 mmol) are dissolved in 650 μL DMF with 5 μL TEA and left at room temperature over night. The product is purified by reverse phase MPLC by using a linear gradient from water to acetonitrile (0.08% TFA) to yield 15.1 mg (0.019 mmol, 86%) of the title compound. MS (ESI) m/z 763.0 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:28]2[S:29][CH:30]=[C:31]([Si](C)(C)C)[N:32]=2)[OH:27])=[C:22]([O:37][CH3:38])[CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[OH:27])=[C:22]([O:37][CH3:38])[CH:21]=1
Reactant: COc1cc(Cl)ccc1C(O)c1nc([Si](C)(C)C)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(O)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Tetrabutylammonium fluoride (0.58 mL, IM solution in THF) was added to a solution of Example 685A (96 mg, 0.29 mmol) in THF (2 mL). The resulting solution was stirred at room temperature for 1 hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to provide 65 mg (88%) of the title compound. MS (ESI) m/e 256 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][CH:4]([CH:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:4]([Cl:3])([CH:13]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1ccccc1)C(Cl)C(COCc1ccccc1)OCc1ccccc1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Cl)(Br)C(COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (16.0 g., 0.1 m.) in 100 ml. of chloroform is added dropwise to a stirred solution of 39.5 g. (0.1 m.) of 2-chloro-3,4-dibenzyloxybutyrophenone and 0.2 g. of dibenzoyl peroxide in 650 ml. of chloroform. After stirring for 30 minutes at 25°C., the reaction mixture is washed with water, aqueous saturated sodium bicarbonate and again with water. The chloroform solution is dried and concentrated in vacuo to leave a residue of α-bromo-2-chloro-3,4-dibenzyloxybutyrophenone.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)OCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)OCC)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-n-pentyl-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>>[Cl:9][CH2:10][CH2:11][C:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(F)cc1
Product: O=C(CCCl)Nc1ccc(F)cc1

Procedure:
By using 4-fluoroaniline and 3-chloropropionyl chloride, the title compound was obtained by similar procedures to those of Example 42a (yield: 57%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:29]([NH:28][C:10]3[CH:11]=[C:12]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)[CH:19]=[CH:18][N:17]=4)[CH:13]=[CH:14][C:9]=3[F:8])=[O:38])=[CH:35][CH:34]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1cc(Nc2nccc(-c3cccnc3)n2)ccc1F)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Nc3cc(Nc4nccc(-c5cccnc5)n4)ccc3F)cc2)CC1
Yield: 95.7 %

Procedure:
1-Methylpiperazine (0.58 g, 5.77 mmol) and N-[4-fluoro-3-(4-chloromethylbenzoyl amino)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.31 mmol) were reacted according to the same procedure as Example 1 to give 4-(4-methylpiperazin-1-ylmethyl)-N-[2-fluoro-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.1 g).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18]Cl)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[I-:46].[Na+].[C:48]([NH2:56])(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1.C(OC(C)C)(C)C>CN(C)C=O>[I-:46].[CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18][N+:52]4[CH:53]=[CH:54][C:49]([C:48](=[O:55])[NH2:56])=[CH:50][CH:51]=4)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccncc1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc[n+](CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate 1-oxide (syn isomer) (2.5 g) and sodium iodide (3.4 g) in N,N-dimethylformamide (20 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added isonicotinamide (0.91 g) under ice-cooling and the mixture was stirred for 2 hours at the same temperature. The mixture was poured into diisopropyl ether to give an oil. The oil was separated by decantation and triturated with water. The solid was dissolved in tetrahydrofuran, dried over magnesium sulfate, concentrated under reduced pressure, and triturated in diisopropyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6].[H-].[Na+].[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Br)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=2)=[O:6])=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: O=C(O)CCCn1cc(C(=O)c2cccc(O)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(Oc2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
A solution of 4-[3-(3-hydroxybenzoyl)indol-1-yl]butyric acid (500 mg) in N,N-dimethylformarnide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 136 mg) in N,N-dimethylformamide (10 ml) at 25°. The mixture was stirred at 25° C. for 1 hour, and a solution of bis (4-isobutylphenyl)bromomethane (1.11 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirred at 25° C. overnight, the mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with 2% methanol in chloroform to give 4-[3-[3-[bis(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyric acid (120 mg) as colorless crystals.