Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[N+:13]([O-])([OH:15])=[O:14]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) (Ark # AK-27735) in methylene chloride (29.5 mL), 2.0 M nitric acid in methylene chloride (25 mL) was added and the mixture was stirred for 15 min at RT. The mixture was poured into ice-cold water and extracted with methylene chloride to give the crude product, 4.42 g, 93%.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[C:24]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:1][CH:2]([CH2:3][N:34]1[CH2:35][CH2:36][N:31]([CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:33]1)[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 91.4 %

Procedure:
Using the procedure of Example 28 of Step C, 3.08 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide of step B of Example 28, and 5.2 g of 1-(diphenylmethyl)piperazine were reacted to obtain after chromatography over silica (eluant: chloroform/ethyl acetate 7:3), 5.12 g of 2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1H-indol-4-yl)benzamide, and then 3.22 g of its neutral oxalate from 4.36 g of base melting at 170° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:23])[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([O:24]C)[C:12]([O:26]C)=[C:11]([O:28]C)[CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:23])[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([OH:24])[C:12]([OH:26])=[C:11]([OH:28])[CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccccc3)c(=O)c2c(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(O)c(O)c(O)c12
Reaction time: 0.5 h

Procedure:
Similar to the preparation of 1d, the reaction of 2,3-diphenyl-5,6,7-trimethoxychromone with boron tribromide in methylene chloride at ° C. for 30 min and then at room temperature for 3 hr produces the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2ccc(C)cc21
Reactant: ClCCCCBr
Product: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:42][C:43]([N:45]1[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]1([CH3:54])[CH3:53])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]2([CH3:54])[CH3:53])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.9 mg) was obtained.
Reaction SMILES: [Cl-:1].[Ca+2].[Cl-].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:13]=3[CH2:12][CH:11](O)[C:10]=2[CH:22]=1)[CH3:5].Cl>C1C=CC=CC=1>[Cl:1][CH:11]1[C:10]2[CH:22]=[C:6]([CH2:4][CH3:5])[CH:7]=[CH:8][C:9]=2[S:15][C:14]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:13]=2[CH2:12]1
Reactant: [Cl-]
Reactant: CCc1ccc2c(c1)C(O)Cc1ccc(F)cc1S2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CCc1ccc2c(c1)C(Cl)Cc1ccc(F)cc1S2
Reaction time: 1 h

Procedure:
Powdered anhydrous calcium chloride (9 g) was added to a solution of 9.4 g of the foregoing alcohol in 120 ml of benzene and the suspension saturated over 2 hours under stirring with anhydrous hydrogen chloride. After 1 hour standing, the mixture was filtered, and the filtrate evaporated under reduced pressure. The required 10-chloro-8-ethyl-3-fluoro-10,11-dihydrodibenzo(b,f)thiepin was obtained in an almost theoretical yield (10.0 g); crystallization from petroleum ether yielded the pure substance melting at 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[C:3](/[C:9](=[N:36]/[OH:37])/[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(F)ncc1Cl)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(F)ncc1Cl)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(5-chloro-2-fluoro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow oil, MS (ESI−): m/z=487.3 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([N+:12]([O-])=O)[CH3:11]>C1COCC1.[Ni].CCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:15][CH3:16])[CH:10]([NH2:12])[CH3:11]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(c1ccc(Cl)cc1Cl)C(C)N
Reaction time: 23 h
Yield: 100 %

Procedure:
2,4-dichloro-1-(1-methoxy-2-nitro-propyl)-benzene (132.2 g, 0.500 mol), was dissolved in THF (3.6 l). The solution was deaerated, RaNi-EtOH (133 g) catalyst was added, and the mixture was hydrogenated at 50 bar at ambient temperature for 23 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure. 117.1 g (100% of theory) of 2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethylamine (compound Z1.14) was obtained in the form of a colourless oil as a mixture of diastereomeres.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21]([NH:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])=[O:22])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccnc(NC(=O)Nc2cccc(Cl)c2Cl)c1
Yield: 91.3 %

Procedure:
A solution of 2-amino-4-tert-butylpyridine (192 mg) and 2,3-dichlorophenyl isocyanate (240 mg) in anh. toluene (15 mL) was heated at 70° C. under argon for 24 h. The resulting mixture was diluted with EtOAc (200 mL) then washed with water (125 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give a gum. Trituration of the gum with hexanes afforded N-(4-tert-butylpyridyl)-N′-(2,3-dichlorophenyl) urea as a white solid (394 mg, 91%): TLC (2:1 hexanes/ethyl acetate) Rf 0.40; FAB-MS m/z 338 ((M+H)+). B2a. Reaction of a Heterocyclic Amine with N,N′-Carbonyldiimidazole Followed By Reaction with a Substituted Aniline
Reaction SMILES: C[CH:2](C)[CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15].NCCC[OH:22]>>[OH:22][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCCO
Reactant: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1

Procedure:
4-(3-Hydroxy-propylamino)-3-nitro-benzonitrile was prepared as described for 4-(3-methyl-butylamino)-3-nitro-benzonitrile using 3-amino-propan-1-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of 3.53 g. (0.01 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine, 2.07 g. (0.01 mole) of γ-piperidinobutyric acid hydrochloride, 2.16 g. (0.0105 mole) of N,N'-dicyclohexylcarbodiimide, and 160 ml. of dried methylene chloride was stirred overnight at room temperature. The reaction mixture was cooled at approximately 5° C. for several hours and was filtered to remove dicyclohexylurea. The filtrate was evaporated in vacuo and the residue was dissolved in 12.5 ml. of methylene chloride and 50 ml. of cyclohexane. After standing overnight in the cold room (approximately 5° C.), the mixture was filtered again and the filtrate was evaporated in vacuo. The residue was recrystallized from methylene chloride/ether, giving 4.1 g. of the product, m.p. 134°-137°.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27].[H-].[Na+]>C1COCC1>[CH3:23][O:24][CH2:25][CH2:26][O:27][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1
Reactant: Cc1cc(C#Cc2cn(-c3cncc(Cl)n3)c(C)n2)ccn1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cncc(-n2cc(C#Cc3ccnc(C)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=350.4 (M+H+) was prepared by treatment of 100 mg 0.32 mmol) 2-chloro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazine (27) with 3 equiv. of 2-methoxyethanol and 3 equiv. of sodium hydride in 5 ml of THF (1 h, 50° C.). The compound, after extraction with methylene chloride/water, was purified by chromatography. Yield: 45 mg (0.13 mmol, 40%).
Reaction SMILES: O[NH:2][C@H:3]([C:12](N)=[O:13])[CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(Cl)(Cl)=[O:16]>C1COCC1>[NH2:2][C@H:3]([C:12]([OH:13])=[O:16])[CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NO)C(N)=O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
HO-Asp(But)-NH2 (20.0 g, 105.7 mmol) was suspended in 300 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (105 mL, 211.4 mmol) was added to the amino acid suspension, and the amino acid dissolved over the course of approx. 1 hr, forming a clear solution. The solution was concentrated on by rotary evaporation, transferred to a beaker, and hexane was added to precipitate the product. The white solid was isolated by filtration and dissolved in anhydrous THF. The solution was filtered over a bed of Celite to remove any insoluble material. An excess of hexane was added on the top of the filtrate and the bilayer solution was left in the freezer overnight. The NCA was isolated by filtration and dried in vacuo. 15.0 g (66% yield) of Asp(But) NCA was isolated as a white, crystalline solid. 1H NMR (d6-DMSO) δ 8.99 (1H), 4.61 (1H), 2.93 (1H), 2.69 (1H), 1.38 (9H) ppm.
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 87.4 %

Procedure:
Using the general method of Example 146. Part B, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (4.0 g, 12.3 mmol) was reacted with phenyl isocyanate (1.34 mL, 12.3 mmol) to provide 4.77 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[F:26][C:27]([F:39])([F:38])[S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:38][C:27]([F:26])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)C(F)(F)F)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-trifluoromethanesulfonyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 565.3 [(M+H)+]; mp 207° C.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:27])[O:6][C:7]=1[P+](C1CC=CCC=1)(C1CC=CCC=1)C1CC=CCC=1.[CH:34]([C:36]1[CH2:37][S:38][C@@H:39]2[C@H:59]([NH:60][C:61](=[O:69])[CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:58](=[O:70])[N:40]2[C:41]=1[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=O>ClCCl.C(=O)([O-])O.[Na+]>[CH3:2][C:3]1=[C:4]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:5](=[O:27])[O:6]/[C:7]/1=[CH:34]/[C:36]1[CH2:37][S:38][C@@H:39]2[C@H:59]([NH:60][C:61](=[O:69])[CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:58](=[O:70])[N:40]2[C:41]=1[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: CC1=C([P+](C2=CCC=CC2)(C2=CCC=CC2)C2=CCC=CC2)OC(=O)C1c1ccccc1
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
2,5-Dihydro-4-methyl-2-oxo-3-phenylfuran-5-yl-triphenylphosphonium bromide (2.21 g) and diphenylmethyl 3-formyl-7β-phenylacetamidoceph-3-em-4-carboxylate (2 g) in dichloromethane (30 mls) and saturated aqueous sodium hydrogen carbonate (30 mls) were stirred vigorously atroom temperature for ca 20 mins. T.l.c. analysis showed all the starting material had been consumed. The organic layer was separated and washed with dilute hydrochloric acid, brine and then dried. After removal of solvent, the residue was flash chromatographed on silica gel eluting with 40% ethyl acetate/hexane. After trituration with ether, the title compound was obtained as a pale yellow crystalline compound, (0.643 g, 25%), m.p. 180°-183° C. (decomp.) ethyl acetate/hexane. (Found: C, 71.93; H, 5.10; N, 4.17; S, 4.54.%. C40H32N2O6S requires C, 71.84; H, 4.82; N, 4.19; S, 4.79%); νmax (CH2Cl2) 1785, 1760, 1715, 1680, 1490 and 1365cm - ; δH (CDCl3) 1.99 (3H,s), 3.44 (2H,ABq, J18.7Hz), 3.67 (2H,ABq,J16.1Hz), 5.02 (1H,d,J4.9Hz), 5.93 (1H,dd,J4.9,8.9Hz), 6.08(1H,d,J8.9Hz), 6.28(1H,s), 6.97 (1H,s) and 7.1-7.5 (20H,m); [mass spectrum: +ve ion (3-NOBA, Na+) MNa+, 691].
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[N:9]=[CH:10][N:11]2[C:16]=1[C:15](=[O:17])[N:14]1C=N[CH:20]=[C:13]1[C:12]2=[O:21].N[C@@H]1C[CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:25][C@H]1O>CN(C)C=O>[OH:21][C@H:12]1[C@H:13]([NH:14][C:15]([C:16]2[NH:11][CH:10]=[N:9][CH:8]=2)=[O:17])[CH2:20][CH2:27][N:26]([CH:29]([CH3:49])[CH2:30][C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:32]([N:34]([CH3:35])[CH3:36])=[O:33])[CH2:25]1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=c1c2cncn2c(=O)c2cncn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cnc[nH]2)[C@H](O)C1
Reaction time: 8 h
Yield: 23 %

Procedure:
2.8 Parts of N,N-diethylethanamine were added to a solution of 1 part of 5H, 10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione in 36 parts of N,N-dimethylformamide. The thus obtained suspension was added dropwise to a stirred and heated (70° C.) solution of 3.95 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 18 parts of N,N-dimethylformamide. Upon complete addition, stirring was continued overnight at 70° C. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was pulverised and evaporated again, yielding 1.13 parts (23%) of trans-3-hydroxy-4-[(1H-imidazol-5-yl)carbonylamino] -N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 155.0° C. (compound 43).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N+:14]([C:17]1[S:21][C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:14]([C:17]1[S:21][C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:26][CH2:27]2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncc([N+](=O)[O-])s3)CC2)cc1
Yield: 171.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.5 g), 1-(5-nitrothiazol-2-yl) piperazine (0.5 g) and potassium carbonate (0.5 g) in dimethylformamide (15 ml) was stirred at 80° C. for 3.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow solid (1.5 g). The obtained pale-yellow solid was crystallized from ethyl acetate to give the title compound (0.5 g) as yellow crystals, m.p.=151-152° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Product: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 28.5 %

Procedure:
4-{[4-(2-aminoethyl)phenyl]sulfonyl}-N-hexyl-1-piperidinecarboxamide (0.53 g, 1.34 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.461 g, 1.14 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.260 g, 0.325 mmol).
Reaction SMILES: COCCOC.[BH4-].[Na+].[C:9]([CH:13]([O:15][C:16]([C:19]([C:22]([C:25]([C:28]([C:31](OC)=[O:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])[F:14])([F:12])([F:11])[F:10].S(=O)(=O)(O)O>O>[C:9]([CH:13]([O:15][C:16]([C:19]([C:22]([C:25]([C:28]([CH2:31][OH:32])([F:29])[F:30])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])[F:14])([F:12])([F:11])[F:10]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Temperature: 80 °C
Yield: 76.1 %

Procedure:
A 5-L round-bottom flask equipped with a mechanical stirrer and nitrogen bubbler was charged with 1 L of 1,2-dimethoxyethane and sodium borohydride (76 grams, 2.0 moles) and heated to 80° C. CF3CFH—O—(CF2)5COOCH3 (713 grams, 1.67 mole), prepared as described in Part A, was added to the stirred slurry over a period of one hour. A mixture of concentrated sulfuric acid (198 grams) and water (1.0 L) was added to the reaction mixture. The lower phase was separated, and the solvent was removed by distillation. Further distillation provided 506 grams of CF3CFH—O—(CF2)5CH2OH (boiling point 173° C.), the structure of which was confirmed by Fourier Transform Infrared Spectroscopy (FTIR) and 1H and 19F Nuclear Magnetic Resonance (NMR) Spectroscopy.