Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[OH-].[NH4+:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:20])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride, and aqueous ammonium hydroxide to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=2)[N+:6]([O-:25])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc2cc(C(F)(F)F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc[n+]([O-])c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 15 mL of a chloroform solution containing 1.06 g of 4-methoxy-7-trifluoromethylquinoline, 1.36 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with 20 mL of an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid, 4-methoxy-7-trifluoromethylquinoline N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.[C:15]1([N:21]2[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([C:25]2[N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:22]=[CH:23][CH:24]=2)[CH:13]=1
Reactant: O=c1ccc(-c2ccccc2F)c[nH]1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: O=c1ccc(-c2ccccc2F)cn1-c1ccnn1-c1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 1.4 %

Procedure:
5-(2-Fluorophenyl)pyridin-2(1H)-one (0.0281 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0802 g) and copper(II) acetate (0.0539 g) were suspended in pyridine (1.48 mL), and the suspension was stirred at room temperature for 12 hr and further at 90° C. for 6 hr. To the reaction mixture were added 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0802 g) and copper(II) acetate (0.0539 g) at room temperature, and the mixture was heated under reflux for 1.5 days. The reaction mixture was cooled to room temperature, purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (0.0007 g).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=O)=O.[C-:32]#[N:33].[K+]>CN(C)C=O>[CH2:18]([N:15]1[C:10]2[C:11](=[O:14])[N:12]([CH3:13])[C:7]([CH2:6][C:32]#[N:33])=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:9]=2[CH:17]=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cn1c(COS(C)(=O)=O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(CC#N)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A suspension of 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4 g, 10.6 mmol) in Dichloromethane (DCM) (50 mL) was treated with Et3N (4.38 mL, 31.5 mmol) and MsCl (1.839 mL, 23.60 mmol) at 0° C. and then stirred for 30 min. The mixture was diluted with Dichloromethane, washed with 0.1N HCl and NaHCO3, dried over Na2SO4, filtered and concentrated to afford (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate as a pale yellow solid (4.8 g, 10.5 mmol, 95% yield) which was used for in next step without any further purification. A solution of (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate (4.8 g, 10.5 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was treated with KCN (6.15 g, 94 mmol) and the resultant was stirred at ambient temperature overnight. The mixture was quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (2.7 g, 7.0 mmol, 67% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.47-7.52 (m, 2H) 7.31-7.35 (m, 3H) 7.27-7.30 (m, 4H) 7.04-7.09 (m, 1H) 5.94-5.98 (m, 1H) 5.83-5.88 (s, 2H) 3.81 (s, 3H) 3.64 (s, 2H); LCMS (m/z) ES+=388 (M+1).
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].[N:15]#[C:16][NH2:17]>>[ClH:1].[CH2:6]([C:5]1[N:13]=[C:16]([NH2:17])[NH:15][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCCCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-non-8-ynoic acid methyl ester hydrochloride (2.02 g, 9.20 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Hept-6-ynyl-1H-imidazol-2-ylamine hydrochloride (1.04 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.17 (s, 1H), δ 2.19 (t, 2H), δ 1.90 (t, 1H), δ 1.86 (m, 2H), δ 1.24-1.13 (m, 6H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 128.3, 108.8, 83.8, 65.5, 28.4, 28.3, 28.2, 24.5, 17.8 ppm; HRMS (ESI) calcd for C10H16N3(M+) 178.1338, found 178.1337.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=1.[Br:12][C:13]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=1[O:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:10]([O:9][C:7]([C:5]1[O:6][C:2]([N:18]2[CH2:19][CH2:20][C@H:16]([O:15][C:14]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:13]=3[Br:12])[CH2:17]2)=[N:3][N:4]=1)=[O:8])[CH3:11]
Reactant: Fc1ccc(Br)c(O[C@H]2CCNC2)c1
Reactant: CCOC(=O)c1nnc(Br)o1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (0.5 g, 2.26 mmol) and (3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidine (0.5 mL, 3.4 mmol) in THF (4.5 mL) was added DBU (0.5 mL, 3.4 mmol). The mixture was stirred at room temperature for 0.5 h then filtered and the filtrate concentrated. Purification by Combiflash (SiO2, gradient elution 70-100% EtOAc/Hexanes) afforded the desired product as solid.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5](=[O:18])/[CH:6]=[CH:7]/[C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:1]=[CH:2][CH:5]([OH:18])/[CH:6]=[CH:7]/[C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC#CCC#C/C=C/C=O
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(O)/C=C/C#CCC#CCCCCC
Temperature: 0 °C

Procedure:
A solution of vinyl magnesium chloride (2.2 Molar in tetrahydrofuran 35 mL) was added to tetrahydrofuran (150 mL) and cooled to -60°. The compound (E)-2-tridecen-4,7-diyn-1-al (12.6 g) dissolved in tetrahydrofuran (50 mL) was added to the above solution over 5-10 min and the cooling bath was removed and the temperature of the reaction mixture was allowed to warm to 0° C. (20 min). Ether (200 mL) was then added followed by a saturated aqueous solution of ammonium chloride (10 mL). After the contents of the flask had been stirred for a further 15 L min, magnesium sulfate was added and after a further 30 min, the solids were filtered off and washed with ether. Removal of the solvents from the combined filtrates and purification of the residue by liquid chromatography (two columns, 10% by volume ethyl acetate in 90% by volume hexane) yielded the pure (E)-1,4-pentadecadien-6,9-diyn-3-ol (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]=3)[CH:23]=[CH:22][N:21]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.37 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.25 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([S:39]([NH:42][CH3:43])(=[O:41])=[O:40])[CH:36]=[N:37][CH:38]=1>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.CN(C=O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:33]3[CH:38]=[N:37][CH:36]=[C:35]([S:39]([NH:42][CH3:43])(=[O:40])=[O:41])[CH:34]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: CNS(=O)(=O)c1cncc(Br)c1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 3.9 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg) was placed in microwave vial with Pd(PPh3)4 (10 mg) and 5-bromo-N-methyl-3-pyridinesulfonamide (24.6 mg) was added. DMF (2 ml) was added and the reaction was heated under microwave irradiation for 15 min at 120° C. The reaction was evaporated to dryness and the residue was dissolved in IPA (2 ml) and 2M NaOH (aq) (1 ml). The reaction was stirred at RT for 3 h then evaporated to dryness. The residue was purified by MDAP (method E) to give the title compound (1.5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:29][CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:57]=[N+:58]=[N-:59])(CCCCCCCC)CCCCCCCC)CCCCCCC>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:59][N:58]=[N:57][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 117.5 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 1-[(2′-cyanobiphenyl-4-yl)-methyl]-2-ethoxybenzimidazole-7-carboxylate [BEC] (228 kg) obtained in Reference Example 5, the residue containing trioctyltin azide [TOTA] obtained in Reference Example 6 and toluene (1148 L) was heated for about 40 hours under reflux (115-120° C.). The reaction solution was cooled and concentrated under reduced pressure. To the residue were added ethanol (764 kg) and sodium nitrite solution (135 kg/460 L) and the solution was adjusted to pH 4.5-5.5 with concentrated hydrochloric acid (about 224 kg). To the solution was added ethyl acetate (735 L) and the solution was adjusted to pH 0.5-1.5 with concentrated hydrochloric acid (about 100 L). To the solution was added hexane (1005 L) and the solution was adjusted to pH 3.5±0.5 with 4% sodium hydroxide solution. The solution was cooled to 10° C. or less and stirred for 1 hour. The crystals were separated and washed with a mixture of ethyl acetate (106 L) and hexane (310 L), followed by hexane (410 L) to give wet MET (396.6 kg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([O:15][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc(O)nn1-c1ccc(Cl)c(Cl)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc(OCCN2CCCCC2)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol (0.41 mmol) was dissolved in methanol (150 mL) at room temperature. A solution of potassium carbonate in water (30 mL) was added dropwise until pH 9. After 15 min under stirring a solution of 1-(2 chloroethyl) piperidine hydrochloride (0.62 mmol) in water (100 mL) was added. The reaction was stirred at room temperature overnight. The methanol was evaporated and after extraction with CH2Cl2 the organic layer was dried over MgSO4 then evaporated and finally purified by chromatography in silica gel to give 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy]ethyl}piperidine (0.03 g, yield 20%) as a dark orange oil. H1NMR (300 MHz, CDCl3, 25° C.) δ: 7.53 (d, J=2.4 Hz, 1H); 7.48 (d, J=8.6 Hz, 1H); 7.23 (dd, J=2.4 Hz, 1H); 4.33 (t, J=5.9 Hz, 2H); 2.71 (t, J=5.9 Hz, 2H); 2.44 (t, J=4.9 Hz, 4H); 2.40 (s, 3H); 1.51 (q, J=5.5 Hz, 4H); 1.34 (m, 2H) ppm. EM (ES+) m/z=355 (100%) [M+H]+. C16H20Cl2N4O (355.26) calc. C, 54.09%; H, 5.67%; N, 15.77%. found C, 53.80%; H, 5.72%; N, 15.48%.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(NC(C)C)(C)C.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30]>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.[Cu]I.O>[CH:31]1([C:29]#[C:30][C:2]2[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=2)[O:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:33][CH2:32]1
Reactant: C#CC1CC1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#CC1CC1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (873 g, 2 mmol), bis(triphenylphosphine)palladium dichloride (140 mg, 0.2 mmol), and CuI (19 mg, 0.1 mmol) were added to 15 mL of degassed diisopropylamine under nitrogen in a screw cap flask. Ethynylcyclopropane (0.25 mL, 3 mmol) was added, and the flask was sealed and heated to 70° C. for 18 hours. The reaction mixture was cooled, poured into water, and extracted into dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 100 g of flash silica (2%-3% MeOH/CH2Cl2) to give 605 mg of 5-(5-cyclopropylethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. MP 225.5-226.8° C.; MS (M+H)=339.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:33]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.5723 g 34%). mp 120-123° C. 1H NMR (300 MHz, DMSO d6) δ 3.83 (bs, 2H), 5.30 (bs, 2H), 6.95-7.06 (m, 4H), 7.28-7.40 (m, 5H), 7.48 (m, 2H), 7.60 (m, 2H), 7.91 (m, 2H), 7.95 (s, 1H). MS (DCI/NH3) m/z 450 (M+H)+, 467 (M+NH4)+. Anal. calc. for C24H20FN3O3S: C, 64.13; H, 4.48; N, 9.35. Found: C, 63.76; H, 4.71; N, 9.02.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:21][CH:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[CH2:23]2)[S:18][CH:19]=1)=[O:14])[CH3:11]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](CO)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Yield: 58.4 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methyl-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (940 mg, 1.28 mmol) (obtained as described in Example 40(1)) in tetrahydrofuran (47 ml) were added acetic acid (221 μl, 3.85 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (3.85 ml, 3.85 mmol) in an ice bath and the mixture was stirred for 3 days at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (99:1 and 9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-((1S)-2-hydroxy-1-methylethylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (462 mg, yield 58%) as a pale yellow solid.
Reaction SMILES: Br[CH:2]1[CH:7]2[CH:8]([OH:13])[CH:9]([OH:12])[CH:10]([OH:11])[C:3]1([CH2:15][OH:16])[O:4][C:5](=[O:14])[NH:6]2.[H][H]>O.[Pd]>[OH:13][CH:8]1[CH:9]([OH:12])[CH:10]([OH:11])[C:3]2([CH2:15][OH:16])[CH2:2][CH:7]1[NH:6][C:5](=[O:14])[O:4]2
Reactant: [H][H]
Reactant: O=C1NC2C(O)C(O)C(O)C(CO)(O1)C2Br
Agent: [Pd]
Solvent: O
Product: O=C1NC2CC(CO)(O1)C(O)C(O)C2O
Reaction time: 8 h

Procedure:
In 100 ml of water is dissolved 2.0 g of 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane, and 400 mg of palladium black is added to the solution, followed by stirring for 8 hours in a stream of hydrogen at room temperature. The catalyst is filtered off and washed with water. The filtrate and washings are combined, adjusted to pH 6 by adding a saturated aqueous solution of sodium hydrogen carbonate, and concentrated under reduced pressure. The residue is chromatographed on a column of 250 ml of MCI Gel CHP 20P (produced by Mitsubishi Chemical Ind., Ltd., Japan), followed by elution with water. The eluate is chromatographed on a column of activated carbon (250 ml), and the column is washed with water, followed by elution with a water-methanol gradient. The eluate containing the objective compound is concentrated under reduced pressure, and methanol is added to the residue, which is then allowed to stand overnight in a refrigerator to give crystals of 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane. Yield of 780 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][C:9]=2[O:17][CH3:18])=[CH:4][CH:3]=1.BrC1C=CC(CC[I:28])=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][I:28])=[CH:10][C:9]=2[O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Brc1ccc(CCI)cc1
Reactant: COc1cc(CCO)ccc1-c1ccc(F)cc1
Product: COc1cc(CCI)ccc1-c1ccc(F)cc1
Yield: 74.5 %

Procedure:
The title compound (549 mg, 74.5%) was prepared from 2-(4′-fluoro-2-methoxybiphenyl-4-yl)ethanol (which may be made as described in Preparation Number 5) following the general procedure described in Preparation 2, Step 1 for 1-bromo-4-(2-iodoethyl)benzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.11 (t, J=8.00 Hz, 2H) 3.33 (t, J=7.81 Hz, 2H) 3.90 (s, 3H) 6.66-6.73 (m, 4H) 6.87 (d, J=8.59 Hz, 2H) 7.27 (s, 1H).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension of NaH (60% in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then 1-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70° C. The resulting mixture was stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature and poured into HCl (1 N). The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaSO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with petroleum ether/EtOAc=50/1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95%). 1H-NMR (CDCl3, 400 MHz) δ 7.92˜7.97 (m, 2H), 7.07˜7.13 (m, 2H), 4.14˜4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J=7.2 Hz, 3H). MS (M+H)+: 211.