Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:32][CH2:33][O:29][C:30]4=[O:34])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C1NCCO1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(N2CCOC2=O)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 64.6 %

Procedure:
To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.5 g), which is the intermediate described in Preparation Example 24, oxazolidin-2-one (313 mg), potassium carbonate (829 mg) and copper (I) iodide (114 mg) were added toluene (3 mL) and N,N′-dimethylethylenediamine (130 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (982 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5](I)[C:3]=1[NH2:4].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>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.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[C:5]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:3]=1[NH2:4]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)c1cc(Cl)c(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(S(C)(=O)=O)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 1308.5 %

Procedure:
To the suspension of 2-chloro-6-iodo-4-methanesulfonylaniline (886.9 mg, 2.7 mmol.), Pd(PPh3)2Cl2 (94.5 mg, 0.13 mmol), and CuI (24.3 mg, 0.13 mmol.) was added triethyl amine (2 mL), and the suspension was slowly treated with (trimethylsilyl)acetylene (0.22 mL, 0.16 mmol.) at 0° C. The reaction mixture was stirred at room temperature for ˜16 h. Solvent was removed under vacuum. The residue was diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with saturated NaCl, water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using 20% ethyl acetate—hexane to give 2-chloro-4-methanesulfonyl-6-trimethylsilanylethynyl-phenylamine (632 mg, 78%). The 1H NMR (500 MHz, CDCl3) spectrum was: 0.27 (s, 9H), 3.01 (s, 3H), 5.17 (s, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=O>C(O)(=O)C>[C:21]([O:20][C:18]([C:10]12[CH2:16][C:14]3([OH:25])[CH2:13][CH:12]([CH2:17][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH2:15]3)[CH2:9]1)[CH2:11]2)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=O
Reactant: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C12CC3CC(O)(C1)CC(C(=O)OC(C)(C)C)(C3)C2

Procedure:
A mixture of 10 mmol of the obtained 1.3-di(t-butoxycarbonyl)adamantane, 2 mmol of NHPI, 0.1 mmol of acetylacetonatocobalt Co(AA)2, and 25 ml of acetic acid was stirred in an atmosphere of oxygen at 75° C. for 6 hours. As a result, there was obtained 1,3-di(t-butoxycarbonyl)-5-hydroxyadamantane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:25]4[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 17, 0.35 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.25 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.3 g of desired product. MS (electrospray): 386 (M+1) for C16H16FN9O2. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.4 (s, 1H) 11.30 (s, 1H) 9.15 (s, 1H) 9.00 (s, 1H) 8.80 (s, 2H) 6.10 (d, 1H) 5.25 (m, 1H), 1.90 (m, 1H) 1.60 (d, 3H) 1.00 (m, 2H) 0.80 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([CH3:33])[C:3]=1[Cl:34].S(=O)(=O)(O)O>CC(OC(C)=O)=O.CO>[C:14]([N:1]([C:11](=[O:20])[CH3:12])[C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:24])=[O:25])[CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])[N:5]=[C:4]([CH3:33])[C:3]=1[Cl:34])(=[O:15])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)ON=C(CCN2C(=O)c3ccccc3C2=O)n2nc(C)c(Cl)c2N)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N(C(C)=O)c1c(Cl)c(C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Yield: 94.5 %

Procedure:
2.62 g (5.2 mmol) of 5-amino-4-chloro-3-methyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole in 15 ml of acetanhydride, to which 0.15 ml of concentrated sulphuric acid has been added, are heated to boiling point and then cooled down. After careful hydrolysis the solid obtained is ground up with methanol and boiled in methanol. The crystals which are produced are filtered off under suction and washed with a little methanol. 1.44 g (47%) of 5-bisacetylamino-4-chloro-3-methyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole with a m. pt. of 143°-147° C. are obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:7]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[OH-].[NH4+]>C1C=CC=CC=1>[Cl:3][CH:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:7]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14]
Reactant: OC(c1ccccc1Cl)C(c1ccccc1Cl)n1ccnc1
Reactant: O=S(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Clc1ccccc1C(Cl)C(c1ccccc1Cl)n1ccnc1
Yield: 94.8 %

Procedure:
A solution of 6 g (0.05 mole) of thionyl chloride dissolved in 20 ml of benzene is added dropwise to a solution containing 11 g (0.033 mole) of 1-[2-hydroxy-1,2-di-(2-chlorophenyl)ethyl] imidazole and 150 ml of benzene at room temperature. The reaction mixture is heated to reflux for 3 hours and is then made basic with 10% ammonium hydroxide solution. The organic product is extracted with ether and the combined ether extracts are washed with water, saturated sodium chloride solution, and dried over magnesium sulfate. Solvent is evaporated to give 11 g of a brown oil. This material is further purified by converting to its hydrochloride salt and back neutralized to the free base to give 8.2 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:10]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[C:10]([CH3:18])=[CH:11][C:12]([C:16](=[NH:17])[NH:21][OH:22])=[CH:13][C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Yield: 95.2 %

Procedure:
A solution of 3-(4-cyano-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (4.1 g, 15.8 mmol), hydroxylamine hydrochloride (1.65 g, 23.7 mmol) and triethylamine (3.20 g, 31.6 mmol) in methanol (40 mL) is refluxed for 2 h before the solvent is removed in vacuo. The residue is taken up in isopropyl acetate (50 mL) and washed twice with water (50 mL). The org. extract is dried over MgSO4, filtered, evaporated and dried to give 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (4.4 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[CH:20]([Br:23])[CH2:21][Br:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[CH:20]([Br:23])[CH2:21][Br:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C(=O)CCl)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)COc1ccc(Cl)cc1)C(Br)CBr
Temperature: 100 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
70.7 g (0.55 mole) of 4-chlorophenol and 75.9 g (0.55 mole) of potassium carbonate are heated under reflux in 500 ml of toluene for 2 hours, using a water separator. 133 g (0.433 mole) of 1-chloro-4,5-dibromo-3,3-dimethyl-2-pentanone in 100 ml of toluene are then added at 70° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool, and is washed with water and dilute sodium hydroxide solution, dried over sodium sulphate and concentrated. 109.2 g (63.3% of theory) of 1-(4-chlorophenoxy)-4,5-dibromo-3,3-dimethyl-2-pentanone of refractive index nD20 1.5363 are obtained. ##STR108##
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH3:14])=[CH:7]2)([OH:3])=[O:2].Br[CH2:16][C:17](C)=[CH2:18]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][C:17]([CH3:18])=[CH2:16])=[CH:7]2)([OH:3])=[O:2]
Reactant: C=C(C)CBr
Reactant: CCc1cc2cc(C(=O)O)ccc2[nH]1
Product: C=C(C)CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
Refer to 36a) using 3-bromo-2-methylpropene as the alkylating agent.
Reaction SMILES: Cl.C1C2(CCN(C(OC(C)(C)C)=O)CC2)CNCC1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCCC#C.[CH2:31]([N:35]1[CH2:40][C:39]2([CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]2)[CH2:38][CH2:37][CH2:36]1)[CH2:32][C:33]#[CH:34].C(N(CC)CC)C.[CH3:60][C:61]1([CH3:68])[C:65]([CH3:67])([CH3:66])[O:64][BH:63][O:62]1>C(OCC)(=O)C.ClCCl.[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].C(#N)C>[CH3:60][C:61]1([CH3:68])[C:65]([CH3:67])([CH3:66])[O:64][B:63](/[CH:34]=[CH:33]/[CH2:32][CH2:31][N:35]2[CH2:40][C:39]3([CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)[CH2:38][CH2:37][CH2:36]2)[O:62]1
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC1(C)OBOC1(C)C
Agent: [Zr+2]
Agent: C#CCCBr
Agent: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
Add tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (46.07 mmol) and cesium carbonate (115.2 mmol) to a solution of acetonitrile (200 mL). After stirring at room temperature for 20 minutes, add 4-bromobutyne (69.1 mmol) and heat the mixture to reflux with stirring overnight. Cool to room temperature and dilute with ethyl acetate (200 mL). Filter the reaction through a glass frit rinsing with ethyl acetate (2×100 mL). Concentrate the crude mixture under reduced pressure, then add ethyl acetate (200 mL) and wash the organics with water (200 mL) and brine (200 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (13.6 g, 44.4 mmol): MS (m/z): 307.2 (M+H). To a round bottom flask under nitrogen, add tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (44.4 mmol), triethylamine (4.44 mmol), zirconocene chloride (4.44 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (48.8 mmol). Heat this mixture to 60° C. for 3 hours, then stir overnight at room temperature. Dissolve the mixture in dichloromethane (20 mL) and purify by flash chromatography (330 g silica gel cartridge) eluting with 15-85% ethyl acetate in hexanes to yield the final title compound, tert-butyl 4-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (29.9 mmol) as a light yellow oil: MS (m/z): 435.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:15][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (2.80 g, 12.7 mmol) in DCM (20 mL) was added DIPEA (6.62 mL, 38.00 mmol). The reaction mixture was cooled to 0° C. tert-Butyldimethylsilyl chloride (3.82 g, 25.3 mmol) was added dropwise and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with DCM and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl(dimethyl)-{[3-nitro-5-(trifluoromethyl)benzyl]oxy}silane (3.71 g, 87%) as a white solid. 1H NMR (400 MHz,CDCl3, HCl salt) δ: 8.35-8.41 (m, 2H), 7.92 (s, 1H), 4.88 (s, 2H), 0.97 (s, 9H), and 0.15 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12](I)=[C:7]2[CH:6]=[C:5]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[CH3:22][N:23](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:22]#[N:23])[C:7]=2[CH:6]=[C:5]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c(CCc2ccccc2)cc2c(I)ccnc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(=O)n1c(CCc2ccccc2)cc2c(C#N)ccnc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 1-acetyl-4-iodo-2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.56 mmol), zinc cyanide (246 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (148 mg, 0.128 mmol) and N,N-dimethylformamide (20 mL) was stirred under an argon atmosphere at 80° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1), and crystallized from hexane to give the title compound (472 mg, yield 64%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:18][CH2:17]2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure D, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone (32 mg, 0.079 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.176 mmol) to afford the desired product (24.5 mg, 64%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.34 (d, J=2.0 Hz, 2H), 7.99 (dd, J=8.7, 2.0 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.62 (s, 2H), 4.27-4.20 (m, 1H), 2.80-2.74 (d, J=6.9 Hz, 2H), 2.71-2.63 (m, 9H), 2.37 (d, J=12.8 Hz, 2H), 1.99 (d, J=13.2 Hz, 2H), 1.89-1.85 (m, 1H), 1.70-1.58 (m, 2H), 1.33-1.21 (m, 2H). ESI MS m/z 486 [C26H29Cl2N3O2+H]+; HPLC 97.9% (AUC), tR=10.81 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]([O-:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.CCOCC>[S:8]([OH:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)[O-])s2)CC1
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)s2)N1OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
TFA (0.20 mL) was added to a mixture of sodium (2S,5R)-2-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-6-yl sulfate after lyophilization (33 mg, 0.064 mmol) in dry DCM (0.60 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2-3 hrs and then diluted with ether (˜10 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-7-oxo-2-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (10 mg) as aTFA salt. ESI-MS (EI+, m/z): 391.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]1[C:29](F)=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34].O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([O:22][C:29]2[C:28]([F:31])=[C:27]([F:32])[C:26]([F:33])=[C:25]([F:34])[C:24]=2[F:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)c(F)c1F
Reaction time: 20 h
Yield: 14.53 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 4.0 g) in 75 ml of dimethylformamide was added a solution of 22.69 g of 1-benzyl-4-hydroxy-4-phenyl piperidine in 100 ml of dimethylformamide. The mixture was heated with a heat gun to initiate evolution of gas. When evolution had ceased, the mixture was cooled to ice bath temperature and 18.61 g of hexafluorobenzene was added, dropwise, and the reaction was allowed to proceed for 20 hours. The reaction mixture was then poured into 500 ml of iced water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane) to yield 5.36 g, (14.53%) of 1-benzyl-4-(2,3,4,5,6,-pentafluorophenoxy)-4-phenyl piperidine, m.p. 80°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[NH:17][CH2:16][CH2:15][S:14]1)=[O:12].Cl[S:36]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37]>N1C=CC=CC=1.Cl>[C:42]([C:41]1[CH:40]=[C:39]([S:36]([N:17]2[CH2:16][CH2:15][S:14][C@H:13]2[C:11]([O:10][C@H:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:19]=2)[CH2:8][C:7]2[C:6]([Cl:33])=[CH:5][N+:4]([O-:34])=[CH:3][C:2]=2[Cl:1])=[O:12])(=[O:38])=[O:37])[CH:47]=[CH:46][CH:45]=1)([OH:44])=[O:43]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (209 mg, 0.390 mmol) was dissolved in pyridine (4 ml). 3-(chlorosulfonyl)benzoic acid (172 mg, 0.781 mmol) was added slowly at 0° C., and the reaction was stirred at RT for 8 hours. The reaction mixture was diluted with HCl 1N, filtered, and the precipitate was dissolved in DCM. The organic phase was washed with HCl 1N (2×) and brine, dried over Na2SO4 and concentrated under vacuum to give 4-((S)-2-((S)-3-(3-carboxyphenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (100 mg, 0.139 mmol, 35.6% yield), that was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2].Cl>>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][CH2:7][CH2:6]2
Reactant: N#Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: Cl
Product: NCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from N-(6-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 8, Step F) by catalytic hydrogenation and HCl salt formation as described in Example 2. MS (+ESI m/z): 514 (M+H)+.