Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=O)=O.O[C@H]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1>O1CCCC1>[SH:9][C@@H:8]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:38][CH2:39]2)=[O:33])[CH2:15]1
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
89 μl of triethylamine and 50 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 321 mg of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 3.2 ml of dry tetrahydrofuran, and the resulting mixture was stirred at between 0° C. and 5° C. for 30 minutes and then at room temperature for a further 1 hour. At the end of tis time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate; the mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 345 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH2:10])[CH:3]=1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23.7 h

Procedure:
To a solution of 82 mg (0.3 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 3 mL of dichloromethane (under a blanket of argon) was added 0.05 mL (36 mg, 0.34 mmol) of triethylamine followed by 0.3 mL (0.3 mmol) of tert-butyldimethylsilylchloride (1M in dichloromethane). The resultant yellow solution was stirred at ambient temperature overnight (23.7 hours), concentrated in vacuo and purified by flash chromatography (silica, 100% hexane) to give the title compound as a clear, colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]4)[O:23][C:22]3=[O:33])=[CH:17][C:16]=2[F:34])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:34][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]3)[O:23][C:22]2=[O:33])[CH:19]=[CH:20][C:15]=1[N:13]1[CH:14]=[C:10]([CH2:9][OH:8])[N:11]=[CH:12]1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-n4cnc(CO[Si](C)(C)C(C)(C)C)c4)c(F)c3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(C[C@H]2CN(c3ccc(-n4cnc(CO)c4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
(5R)-3-{4-[4-(tert-Butyl(dimethyl)silyloxymethyl)-1H-imidazol-1-yl]-3-fluorophenyl}-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Intermediate 31) (1.4 g, 2.88 mmol) was dissolved in tetrahydrofuran (15 ml), and tetrabutylammonium fluoride (3.2 ml, 1.0 M solution in THF) was added. The solution was stirred for 2 hours at room temperature and water (50 ml) was added. The precipitate was collected by filtration and purified by chromatography on silica gel with 3-6% methanol in dichloromethane to give the title compound (0.36 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: Cn1ncc(C=O)c1Cl
Reactant: CC(C)(C)[S@@](N)=O
Solvent: C1CCOC1
Product: Cn1ncc(/C=N/[S@@](=O)C(C)(C)C)c1Cl
Temperature: 25 °C
Yield: 88.7 %

Procedure:
5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 3.46 mmol) was suspended in THF (20 ml), Ti(OEt)4 (1.51 ml, 7.26 mmol) was added followed by (S)-(+)-2-methyl-2-propanesulfinamide (440 mg, 3.63 mmol) and the reaction heated to reflux for 6 hours. The reaction was then cooled to room temperature, poured onto EtOAc:Brine (20 ml: 20 ml) filtered through celite and washed through with EtOAc (2×20 ml). The organic layer was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give the title compound as a brown viscous oil (760 mg, 88.7% yield). 1H NMR (400 MHz, CDCl3) 1.22-1.23 (9H s) 3.88 (3H s) 7.92 (1H s) 8.43 (1H br. s) MS (ESI/APCI) m/z 248 (M+H)+
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:31][C:2]([F:1])([F:30])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
To a solution of tert-butyl 4-(2-(2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate (650 mg, 1.476 mmol) in dichloromethane (DCM) (4 mL) was added TFA (1 mL, 12.98 mmol), and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and the residue was dissolved in DCM (20 mL). The resulting solution was washed with 10% NaHCO3 aqueous solution. The organic phase was collected and dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 470 mg of product as oil. MS: (M+H)+=341.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.33-1.79 (m, 7H), 1.93-2.10 (m, 2H), 2.27-2.59 (m, 1H), 2.84-3.06 (m, 2H), 3.15-3.25 (m, 1H), 3.66 (t, J=7.20 Hz, 2H), 7.09-7.41 (m, 5H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:11][C:12]#[N:13])#[N:2].[H][H]>O1CCOCC1>[NH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:8][CH2:7][CH2:6][N:5]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCN(CCCN)CCCN
Yield: 87.7 %

Procedure:
20.05 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,3-propanediamine, 2.01 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 150° C. for 3 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 18.57 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][C:12]#[CH:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27](OCC)=[O:28].N1CCCCC1>C(O)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:26]1[C:27](=[O:28])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][C:12]#[CH:13])[CH:9]=2
Reactant: CCOC(=O)Cc1nc2ccccc2s1
Reactant: C#CCN(c1ccc(C=O)c(O)c1)C(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: C#CCN(c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1)C(C)C
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution in which the 2-hydroxy-4-(isopropyl(prop-2-ynyl)amino)benzaldehyde (1.8 g, 8.28 mmol) compound of Chemical Formula 4 was dissolved in ethanol (15 mL), ethyl 2-(benzo[d]thiazol-2-yl)acetate (1.83 g, 8.28 mmol) and piperidine (1.63 mL, 16.56 mmol) were added consecutively at room temperature. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and 3-(benzo[d]thiazol-2-yl)-7-(isopropyl(prop-2-ynyl)amino)-2H-chromen-2-one (1.54 g, 50%) was obtained by filtering the precipitated solid. 1H NMR (500 MHz, CDCl3) d 8.94 (s, 1H), 8.02 (d, 1H, J=8.2 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.54 (d, 1H, J=8.7 Hz), 7.47-7.50 (m, 1H), 7.35-7.38 (m, 1H), 6.88 (dd, 1H, J=2.3, 8.7 Hz), 6.80 (d, 1H, J=2.3 Hz), 4.21-4.26 (m, 1H), 4.04 (d, 2H, J=2.3 Hz), 2.26 (t, 1H, J=2.2 Hz), 1.34 (d, 6H, J=6.4 Hz); 13C NMR (125 MHz, CDCl3) d 161.5, 161.0, 156.7, 152.6, 152.4, 142.0, 136.4, 130.6, 126.2, 124.7, 122.3, 121.7, 113.9, 111.0, 109.8, 98.8, 80.0, 72.3, 49.5, 33.5, 20.2 (2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>>[F:8][C:4]1[C:3]2[NH:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2cccc(F)c2[nH]1

Procedure:
The title compound was prepared by the method of Preparation 24 from 1,2-diamino-3-fluorobenzene [J.O.C. 1969, 34(2), 384] and 1,1′-carbonyldimidazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[C:17](/[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=3)\[C:18]#[N:19])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc2c(c1)CCO2
Product: COc1ccc(/C(C#N)=C/c2ccc3c(c2)CCO3)cc1OC
Yield: 49.5 %

Procedure:
2,3-Dihydrobenzofuran-5-carboxaldehyde (150 mg) was condensed with 3,4-dimethoxybenzyl cyanide (180 mg) through Method A (production step 2), to thereby yield the target product (yield: 154 mg, 50%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:37])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([C:28](=[O:36])[NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22][C:23]([CH3:27])=[N:24]3)=[CH:19][CH:18]=2)=[CH:13][N:12]=1)[C:5]([O:7]C)=[O:6].O1CCCC1.Cl>CO>[CH3:3][C:4]([CH3:37])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([C:28](=[O:36])[NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22][C:23]([CH3:27])=[N:24]3)=[CH:19][CH:18]=2)=[CH:13][N:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4)cc(C)nc3c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Reaction time: 12 h
Yield: 60 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (2.0 mL) was added to a solution of methyl 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoate B-16 (94.0 mg, 0.20 mmol) in a 1:1 mixture of tetrahydrofuran:methanol (5.0 mL) at room temperature. After 12 h of stirring, the aqueous layer was acidified to pH 0 with a 1 N aqueous hydrogen chloride solution and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (54.7 mg, Yield=60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (s, 6H), 2.75 (s, 3H), 4.30 (s, 2H), 6.93 (d, J=8.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.41 (t, J=9.5 Hz, 1H), 7.64 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.29 (s, 1H), 8.51 (s, 2H), 8.67 (m, 1H), 10.86 (s, 1H); MS (ESI) [M+1]+ 456.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:32][CH3:33])=[C:9]([CH:31]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([S:21]([NH:24][C:25]([NH:27][CH3:28])=S)(=[O:23])=[O:22])[CH:20]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH:34]O.Cl>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:32][CH3:33])=[C:9]([CH:31]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:29][CH3:30])=[C:19]([S:21]([NH:24][C:25]([NH:27][CH3:28])=[O:34])(=[O:22])=[O:23])[CH:20]=1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=S)NS(=O)(=O)c1cc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)ccc1OC
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)NS(=O)(=O)c1cc(CCNC(=O)c2cc(C(C)(C)C)ccc2OC)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.252 g (0.5 mmol) of 1-[[5-[2-(5-tert-butyl-2-methoxybenzamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (Example 1) were dissolved in 2.5 ml of 2 N aqueous sodium hydroxide solution and admixed with ice-cooling with 0.25 ml of 30% strength hydrogen peroxide. The solution was stirred at room temperature for 24 h and poured into a mixture of ice-water and 2 N hydrochloric acid. Drying in the air gave white crystals of melting point 209-212° C.
Reaction SMILES: C(O[C:4]([NH:6][CH2:7][C:8]([C:10]1[N:17]2[C:13]([S:14][CH:15]=[CH:16]2)=[N:12][C:11]=1[CH3:18])=O)=[O:5])C.O.[NH2:20][NH2:21]>C(O)C>[CH3:18][C:11]1[N:12]=[C:13]2[N:17]([C:10]=1[C:8]1[CH2:7][NH:6][C:4](=[O:5])[NH:20][N:21]=1)[CH:16]=[CH:15][S:14]2
Reactant: CCOC(=O)NCC(=O)c1c(C)nc2sccn12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2sccn2c1C1=NNC(=O)NC1

Procedure:
A mixture of 7 g of 5-ethoxycarbonylaminoacetyl-6-methylimidazo[2,1-b]thiazole, 100 ml of ethanol and 8 ml of 100% hydrazine hydrate is refluxed under heating for 2 days. After cooling, crystals are collected by filtration and recrystallized from a mixed solvent of chloroform and methanol to give 3.4 g of 6-(6-methylimidazo[2,1-b]thiazol-5-yl)-4,5-dihydro-2H-1,2,4 triazin-3-one as white crystals, melting at 293°-295° C. with decomposition.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:22]1([P:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1ccc(Br)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1.0 mole of n-butyllithium in hexane at -78° C under an inert atmosphere is added dropwise and with efficient stirring 236g of p-dibromobenzene in dry tetrahydrofuran (total volume 500 ml). The resulting solution is stirred at -78° C for 1 hour, then treated dropwise at this temperature with 220.5g of chlorodiphenylphosphine. When this addition is complete, the mixture is allowed to warm to room temperature, then solvent is removed under vacuum. The residue is triturated with two 400-ml portions of methanol, then distilled through a Vigreux column. The cut with bp 165°-170° C (0.15 mm) is recrystallized from ethanol to give 100.5g of p-diphenylphosphinobromobenzene, mp 78°-80° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OCc5nc(=O)c(O)c[nH]5)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (65 mg) (0.11 mmol), 22.5 mg (0.143 mol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 27 mg (0.143 mmol) of p-toluenesulphonic acid hydrate are dissolved in 2 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed in a high vacuum and the residue is treated with water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 55 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].O.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH2:32][CH3:33])=[CH:40][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 80 °C

Procedure:
{4′-Bromo-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (14.5 g, 30.6 mmol) was dissolved in DME (100 mL) and water (50 mL) along with 2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.1 g, 36.5 mmol) and potassium carbonate (10.7 g, 77.4 mmol) under N2 atmosphere. The mixture was purged with N2, and then tetrakis(triphenylphosphine)palladium(0) (0.500 g, 0.43 mmol) was added and the reaction was heated to 80° C. The reaction was monitored by analytical LCMS and when the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-35% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>[Pd].CO>[CH2:32]([C:13]1[CH:14]=[C:15]([C:16]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=1)[CH3:33]
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (62.0 mg, 0.140 mmol) and palladium on activated carbon (Aldrich, St. Louis, Mo. 10% Pd, 19.1 mg) were added to MeOH (2.0 mL) and TFA (0.30 mL). The reaction flask was evacuated and back-filled with hydrogen, and the reaction was stirred at room temperature for one hour. Then, the hydrogen balloon was removed, and stirring was continued at room temperature, without the balloon of hydrogen, for 90 minutes. Then, the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (45° C.-50° C.), and stirring was continued under nitrogen overnight. The reaction was cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH and a couple of drops of TFA. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (50° C.). Then, the material was washed with Et2O, MeOH, and Et2O, collected, and dried under high vacuum overnight to give 5-ethyl-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (17.8 mg, 35% yield). MS (ESI pos. ion) m/z 362 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.53 (s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=2.54 Hz, 1H), 8.22-8.13 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 2.85 (s, 3H), 2.65 (q, J=7.37 Hz, 2H), 1.26 (t, J=7.53 Hz, 3H).
Reaction SMILES: CS([C:5]1(C)[C:8](=[C:9]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C@H:22]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:22]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)[N:6]2[CH2:7][C:8](=[C:9]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:5]2)=[CH:24][CH:25]=1
Reactant: C1CSCCN1
Reactant: CC1(S(C)(=O)=O)C(=C(c2cc(F)cc(F)c2)S(C)(=O)=O)CN1[C@@H](c1ccc(Cl)cc1)c1ccc(CCl)cc1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCSCC3)cc2)C1)c1cc(F)cc(F)c1
Yield: 79.4 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of methylsulfonyl methyl 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of thiomorpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.038 g of 1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 2.60 to 2.75 (mt, 8H) 2.80 (s, 3H), 3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].