Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.[C:24](O)(=[O:27])[CH2:25][SH:26]>C(#N)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[S:26][CH2:25][C:24](=[O:27])[NH:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[C:5]2=3)=[C:17]([CH3:23])[CH:16]=1
Reactant: O=C(O)CS
Reactant: Cn1nc(-c2ccccn2)cc1N
Reactant: Cc1cc(Br)ccc1C=O
Solvent: CC#N
Product: Cc1cc(Br)ccc1C1SCC(=O)Nc2c1c(-c1ccccn1)nn2C
Temperature: 150 °C
Yield: 68 %

Procedure:
A mixture of 1-methyl-3-(2-pyridyl)pyrazol-5-amine (1.74 g, 10 mmol), 4-bromo-2-methylbenzaldehyde (2.0 g, 10 mmol, Ark Pharm Inc.), and thioglycolic acid (3.90 g, 32 mmol) in acetonitrile (15 mL) was heated, in a sealed microwave vessel, for about 25 min, at about 150° C., in a microwave. After cooling to rt the precipitated solid was collected by filtration and washed with acetonitrile and diethyl ether to afford 4-(4-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (2.92 g, 6.8 mmol, 68%), which was used as such. 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s), 3.29 (1H, d, J=15 Hz); 3.37 (1H, d, J=15 Hz); 3.95 (3H, s); 6.58 (1H, s); 6.66 (1H, d, J=8 Hz); 7.03 (2H, m); 7.24 (1H, d, J=11 Hz); 7.56 (1H, dt, J=8 Hz, 2 Hz); 7.75 (1H, m), 8.30 (1H, d, J=4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[N:27][C:28]([O:32][CH2:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35]3)=[CH:29][C:30]=2[CH3:31])[CH:5]=[N:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[N:27][C:28]([O:32][CH2:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:35][CH2:36][CH2:37]3)=[CH:29][C:30]=2[CH3:31])[CH:5]=[N:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1cnc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1cnc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Reaction time: 60 h
Yield: 61.9 %

Procedure:
In trifluoroacetic acid (3.1 mL) and water (0.3 mL) was dissolved 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl]oxy)methyl}cyclobutanecarboxylic acid (312 mg), and the mixture was allowed to stand at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid, isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-[({5′-chloro-4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (151 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[CH3:17])([CH3:3])[CH3:2].[NH2:23][NH:24][C:25]([NH2:27])=[O:26].C([O-])(=O)C.[Na+]>C(O)C>[CH3:16][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([CH3:17])[C:8]=1[O:7][C:6]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)[CH:12]=[N:23][NH:24][C:25]([NH2:27])=[O:26]
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(C=NNC(N)=O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-benzaldehyde (19 mg, 0.063 mmol) in ethanol (1 ml) at room temperature was added semicarbazide (7.7 mg, 0.69 mmol) and sodium acetate (5.1 mg, 0.063 mmol). After stirring at room temperature for about one hour, the solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (5 ml). The ethyl acetate solution was washed with water (3×5 ml), brine (5 ml), dried, filtered, and concentrated to afford the title compound (20 mg) as a yellow solid which was used directly in the next step without further purification. MS (APCI−) Calc: 355.2, found: 354.3 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.[F:37][C:38]1[C:43](O)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][C:43]1[C:42]([F:45])=[C:41]([F:46])[C:40]([F:47])=[C:39]([F:48])[C:38]=1[F:37])=[O:20])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pentafluorphenyl 6-n-heptyloxy-2-naphthoate is prepared as follows. To a suspension of 6-n-heptyloxy-2-naphthoic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h. Any precipitate is removed by filtration. The filtrate is washed twice with water and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gives the desired pentafluorphenyl 6-n-heptyloxy-2-naphthoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:6][CH:7]=1)#[N:21]
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(OCCNS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, was dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) was added. This was stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) was added. Stirring continued for another hour. The reaction mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (1/1 CH2Cl2/EtOAc) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl} methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11]([NH:25][CH2:26][Si](C)(C)C)=[N:10][C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[C:11]([NH:25][CH3:26])=[N:10][C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(NC[Si](C)(C)C)=NC(=O)N2c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC1=NC(=O)N(c2cccc(F)c2)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 60 °C

Procedure:
To a 50 ml THF solution of 1.04 g (2.41 mmol) tert-butyl 1-(3-fluorophenyl)-2-oxo-4-{[(trimethylsilyl)methyl]amino}-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (prepared in the same manner as Intermediate 5-1 above) was added 3.61 mL (3.61 mmol) of a 1.0M tetrabutylammonium fluoride in THF solution over 5 m and the reaction warmed to 60° C. overnight. The reaction was concentrated to dryness in vacuo and the residue treated with 100 mL CH2Cl2. The organic layer was washed with water (1×25 mL), brine (1×25 mL), dried over Na2SO4, filtered and concentrated to dryness in vacuo to give a crude oil (1.6 g). Purification by flash chromatography (0-7.5% MeOH in CH2Cl2 over 25 m) afforded tert-butyl 1-(3-fluorophenyl)-4-(methylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate 6-2 as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 1H), 7.12 (m, 1H), 7.03 (d, J=7.95 Hz, 1H), 6.97 (m, 1H), 5.70 (br s, 1H), 3.54 (m, 2H), 3.11 (d, J=4.76 Hz, 3H), 2.02 (m, 2H), 1.92 (m, 2H), 1.42 (s, 9H). High resolution mass spec (FT/ICR): calc M+H=377.1984. found 377.2010
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:24])[C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])=[N:5][CH:4]=1)=[O:2].Cl.C(OCC)C>C(Cl)Cl>[NH2:16][C@@H:14]([CH3:15])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 137.6 %

Procedure:
Following the procedure as described in Example 68, except using material from Example 69 (265 mg, 0.743 mmol), CH2Cl2 (50 mL), HCl, 11.0M in diethyl ether (5 mL, 5.00 mmol) and stirring at room temp for 2.5 days, 262 mg (quantitative yield) of the title compound is obtained as a pale yellow solid, as a bis HCl salt by weight. LC/MS (Condition A): ret. T=0.93 min, (M+H)+ 257.14.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[O:12])[CH2:8]2.Cl.[Cl-].[NH4+:16].[C-:17]#N.[K+]>O>[C:17]([C:7]1([OH:12])[CH2:6][CH:5]2[N:4]([CH2:3][CH:2]([F:1])[F:13])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)#[N:16]
Reactant: O=C1CC2CCC(C1)N2CC(F)F
Reactant: [C-]#N
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N#CC1(O)CC2CCC(C1)N2CC(F)F
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A 50 ml 3-necked round bottom flask was fitted with a pressure equalised dropping funnel, bubbler and magnetic stirrer. 8-(2,2-Difluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (4.82 g, 25 mmol) was charged to the reaction flask and suspended in water (5 ml). Hydrochloric acid (5 ml, 5M) was added followed by solid ammonium chloride (2.23 g, 41 mmol) and the mixture stirred until the ammonium chloride had dissolved (5 minutes). The mixture was cooled to 5° C., a solution of potassium cyanide (5.03 g, 65 mmol) in water (7.5 ml) was added over 0.25 hour then the reaction was stirred at 0° C. for 3 hour. After this time, the lower oil phase was separated from the solid precipitate/aqueous phase to give 3-cyano-3-hydroxy-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]octane as an oil which darkened on standing (5.32 g). The product was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:38])([CH:36]=[CH2:37])[CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1.[Cl-].[NH4+]>C(Cl)Cl>[CH3:28][C:29]([CH3:38])([CH:36]=[CH2:37])[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: C=CC(C)(C)Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (1.5 mL, 53 mmol) followed by of trityl chloride (9 g, 32 mmol) were added to a 0° C. solution of 4-(2,2-dimethylbut-3-en-1-yl)-1H-imidazole (4 g, 27 mmol) in methylene chloride (40 mL). After stirring at ambient temperature for 3 h, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:6]([CH:8]=[C:9]([CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[N:10]=2)[N:7]=1.C([O-])=O.[NH4+]>C1COCC1.CO.CCOC(C)=O.[Pd]>[O:25]1[CH2:24][CH2:23][N:22]([C:4]2[C:5]3[N:6]([CH:8]=[C:9]([CH:11]4[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]4)[N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3nc(Cl)cc(N4CCOCC4)c3n2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2cn3nccc(N4CCOCC4)c3n2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Compound 19b (430 mg, 1.09 mmol) and ammonium formate (344 mg, 5.45 mmol) were placed in a 20 mL vial equipped with a stir bar and dissolved in a mixture of THF (8 mL) and MeOH (4 mL). 10% Pd/C (116 mg, 0.109 mmol) was then added. The reaction mixture was stirred at 70° C. for 3 h, cooled to rt, and filtered through a pad of diatomaceous earth. The solids were washed with MeOH (2×10 mL). The combined filtrates were concentrated under reduced pressure and the residue obtained was dissolved in EtOAc (100 mL) and washed with water (2×25 mL) and brine (25 mL). The combined aqueous washings were extracted once with EtOAc (25 mL) and the organic extracts were combined, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to obtain compound 19c. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H25N5O3: 360.2 (M+H). found: 360.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(CO)c2)n1
Reaction time: 0.42 h
Yield: 54.4 %

Procedure:
In a hard walled glass tube, a solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (250 mg, 0.75 mmol), 3-(hydroxymethyl)phenylboronic acid (137 mg, 0.9 mmol) and Na2CO3 (79.7 mg, 0.75 mmol) in acetonitrile/water (6 mL, 2:1) is degassed over nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (43.5 mg, 0.04 mmol) is added and the tube is sealed and set in a microwave for 25 minutes at 130° C. The reaction is dilute with 25 mL of water and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate, filtered and concentrate in reduced pressure. The residue is purified by chromatography (SiO2 packed column), eluted with EtOAc/DCM to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol [165 mg, Example 78 (a)]. LCMS: RT=2.24 minutes, MS: 405 (M+H); 1H NMR (300 MHz, CDCl3): □8.05 (1H, s), 7.95 (1H, b)), 7.48 (3H, b), 7.42 (1H, s), 7.2 (1H, s), 6.45 (1H, s), 4.95 (1H, b), 4.78 (2H, b), 4.05 (3H, s), 3.72 (2H, b), 3.1 (2H, t, J=3.5 Hz); and to afford (3′-chloro-4′-{2-[6-(3-hydroxymethyl-phenyl)-2-methoxy-pyrimidin-4-ylamino]-ethyl}-biphenyl-3-yl)-methanol [110 mg, Example 78(b)]. LCMS: RT=2.12 minutes, MS: 477 (M+H).
Reaction SMILES: [N:1]1([S:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:15](C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17]>C(Cl)Cl>[O-:18][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:15].[CH3:19][N+:3]1[CH:4]=[CH:5][N:1]([S:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH:2]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(N1CCCCC1)n1ccnc1
Solvent: ClCCl
Product: C[n+]1ccn(S(=O)(=O)N2CCCCC2)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 1-H (79.6 mg, 0.37 mmol) in CH2Cl2 (2 mL), cooled to 0° C., was added methyl triflate (46 μL, 0.407 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was evaporated under reduced pressure to afford compound 1-I as a white solid. MS (method 2): m/z 229.9 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(O[C:29](N(C)C)=[N+:30](C)[CH3:31])C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>ClCCl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[N:30]([CH3:31])[CH3:29])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
(R)-2-(tert-Butoxycarbonylamino)propanoic acid (1.0 g, 5.3 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.8 g, 5.6 mmol) were dissolved in 13 mL of dichloromethane. Dimethylamine hydrochloride (0.64 g, 7.8 mmol) and N,N-diisopropylethylamine (3.6 mL, 20.8 mmol) were added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and water was added. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 1.16 g (100%) of ((R)-1-dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C@@H:13]([O:14][CH2:15][C:16](=[O:27])[C:17](=[N+]=[N-])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:12][C:11]1=[O:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.O1CCCC1.[Hg]>[C:1]([NH:9][C@H:10]1[C:11](=[O:28])[N:12]2[C@@H:13]1[O:14][CH2:15][C:16]([OH:27])=[C:17]2[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Agent: [Hg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(O)CO[C@@H]2[C@@H](NC(=O)c3ccccc3)C(=O)N12
Yield: 16.6 %

Procedure:
An anhydrous and degassed solution of 78 mg (0.2 mmol) of tert.-butyl 4-[3(R)-benzoylamino-2-azetidinon-4-(R)-yloxy]-2-diazo-3-oxo-butyrate in 25 ml of benzene:tetrahydrofuran 3:1 was irradiated in a nitrogen atmosphere at 20° C. for 1 hour with a 450 W mercury vapour lamp with a Pyrex filter. The solvent was evaporated off in vacuo and the residue was purified by chromatography on 8 g of silica gel (toluene:ethyl acetate 35:65). 12 mg (17%) of the title compound were obtained as a colorless rigid foam.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: CON=Cc1ccc(NC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(NC(C)=O)cc1

Procedure:
Reduction of 4-acetamidobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a waxy solid (100% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.16 (3H, s, CH3), 3.49 (3H, s, OCH3), 4.00 (2H, s, NCH2), 7.26 (1H, broad s, NH), 7.29 (2H, m, aromatics), 7.46 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 186–188° C. (dec.). Anal. calcd. for C10H14N2O2—HCl—H2O: C, 50.87; H, 6.66; N, 11.87. Found: C, 50.77; H, 6.44; N, 12.16.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCCCC(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
In a vessel sufficiently replaced with nitrogen, 0.40 g (3.0 mmol) of (-)-2-fluoroheptanol and 1.00 g (13 mmol) of dry pyridine were placed and stirred for 30 min. under cooling on an ice bath. Into the solution, 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride was added, and the mixture was stirred for 5 hours. After the reaction, 10 ml of 1N-HCl was added, and the resultant mixture was subjected to two times of extraction with 10 ml of methylene chloride. The extract liquid was washed once with 10 ml of distilled water and dried with an appropriate amount of anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 0.59 g (2.0 mmol) of (+)-2-fluoroheptyl p-toluenesulfonate.
Reaction SMILES: [Mg].BrC(Br)C.[CH:6]([O:8][CH2:9][CH2:10]CCl)=[CH2:7].[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[C:14]1=[O:23])[CH2:20]2>O.OS(O)(=O)=O.C1COCC1>[CH:6]([O:8][CH2:9][CH2:10][C:14]1([OH:23])[CH:15]2[CH2:21][CH:19]3[CH2:18][CH:17]([CH2:22][CH:13]1[CH2:20]3)[CH2:16]2)=[CH2:7]
Reactant: C=COCCCCl
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(Br)Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=COCCC1(O)C2CC3CC(C2)CC1C3

Procedure:
(Step-2) Magnesium metal(2.6 g) and anhydrous tetrahydrofuran (hereinafter referred to as THF(100 mL)) were added to a round bottom flask. Next, after dripping a small quantity of dibromoethane into the round bottom flask containing the resulting mixture to promote the reaction, 3-chloropropyl vinyl ether (12 g, 0.1 mol) and anhydrous THF(100 mL) were added drop-wise thereto. Then, the mixture was reacted for 2 hours. After dripping an adequate quantity of THF containing 2-adamantanone (15 g, 0.1 mol) in the mixture, the resulting mixture was refluxed for 12 hours. After the reaction was completed, the reaction mixture was slowly dissolved in excessive water and neutralized with thin H2SO4 solution. Then, the organic layer was extracted from the reaction solution using an adequate quantity of diethyl ether and then dried with anhydrous sodium sulfate. Next, after evaporating the solvent to obtain an oily residue using a rotary evaporator, the product was separated using a column chromatography method (hexane:ethyl acetate=3:1). (Yield: 60%)
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[N:26]([CH3:27])[CH3:28])[CH:18]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CN(C)S(=O)(=O)c1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Product: Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.73 g) and 3-(aminomethyl)-N,N-dimethylbenzenesulfonamide obtained in Step 1 (1.0 g) in ethanol (10 ml) was added potassium carbonate (0.65 g) at room temperature, and the mixture was stirred overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (306 mg).