Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[C:13]1([C:2]2[O:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1ccco1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Product: c1ccc(-c2ccco2)cc1

Procedure:
2-phenylfuran was prepared by the method of Example 32C from 2-bromofuran (0.93 g, 6.3 mmol), sodium carbonate (18 ml of 2M aqueous solution), phenyl boric acid (0.93 g, 7.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.36 g, 0.32 mmol). Flash chromatography with hexane provided 0.79 g (87% yield) of a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O.CCOCC>O1CCCC1.C(N(CC)CC)C>[Cl:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: COc1c(N2CCOCC2)cc(C(C)=O)cc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1c(N2CCOCC2)cc(C(=O)CCl)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
After dissolving 1-[3-(tert-butyl)-4-methoxy-5-morpholinophenyl]-1-ethanone (9.5 g) in tetrahydrofuran (60 ml), triethylamine (13 ml) and tert-butyl dimethylsilyltrifluoromethanesulfonate (9.8 ml) were added dropwise while cooling on ice. The reaction mixture was stirred for 30 minutes while cooling on ice and then N-chlorosuccinimide (5.3 g) was gradually added. After continuing to stir the reaction mixture for 30 minutes, ether (2 l) was added thereto and the resulting mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (4.87 g) as light yellow crystals.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[O:10]=[C:11]1[C:20]2[CH:21]=[C:22]([S:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][C:19]=2[O:18][CH2:17][C:16]2[CH:15]=[CH:14][S:13][C:12]1=2.[Cl-].[NH4+]>C1COCC1>[CH3:30][O:29][C:27](=[O:28])[CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:19]2[O:18][CH2:17][C:16]3[CH:15]=[CH:14][S:13][C:12]=3[C:11]([OH:10])([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)[C:20]=2[CH:21]=1
Reactant: COC(=O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1sccc1CO2
Yield: 18.1 %

Procedure:
A Grignard reagent prepared from magnesium (2.8 g, 116 mmol), 4-chloro-1-methylpiperidine (15.5 mL, 116 mmol), and THF (180 mL) was ice-cooled, and a THF (120 mL) solution of the compound obtained in Example 22 (18.5 g, 58 mmol) was added dropwise thereto. After allowing the mixture to react for 30 minutes, a saturated ammonium chloride was added thereto, and a product was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated ammonium chloride and with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give 4.4 g (18%) of the captioned compound.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:12]C(=O)C(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[I:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(C(F)(F)F)cc1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1ncc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
N-(3-iodo-5-(trifluoromethyl)pyridin-2-yl)pivalamide (16.8 g, 45.1 mmole) was taken up in H2SO4 (24 wt. %, 392 ml) and the mixture was stirred for 60 minutes under reflux. After cooling to RT the mixture was neutralised with 4 N NaOH and solid NaHCO3, the aqueous phase was extracted with DCM (3×200 ml) and the combined organic phases were dried over MgSO4. After filtration the solvent was removed on a rotary evaporator. 3-iodo-5-(trifluoromethyl)pyridin-2-amine (13 g, 100%) was obtained as a cream-coloured solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([O:55][CH3:56])=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:37])=[O:38])[C:41]([O:55][CH3:56])=[N:42][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 4.9 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.16 mmol) was treated with 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (124 mg, 0.27 mmol), a solution of sodium carbonate (2 M, 365 μl, 0.73 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (5 mg, 0.01 mmol) according to the method described in Preparation 17. The residue was purified by reverse phase using SP1® Purification System to give 5 mg (5% yield) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:19][CH:20]([C:25](=[O:41])[NH:26][CH:27]([C:37](=[O:40])[NH:38][CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12]C(=O)C(F)(F)F)[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CO>[CH3:1][O:2][P:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)([CH2:19][CH:20]([C:25](=[O:41])[NH:26][CH:27]([C:37](=[O:40])[NH:38][CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:4]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(NC(=O)C(F)(F)F)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(N)c1)OC
Yield: 64 %

Procedure:
{2-[2-(4-Methoxyphenyl)-1-methylcarbamoylethylcarbamoyl]-4-methyl-pentyl}-[3-(2,2,2-trifluoroacetylamino)benzyl]phosphinic acid methyl ester (prepared from the appropriate starting materials using the procedures described in Example 2/Steps A-D) (105 mg, 0.18 mmole) was treated with potassium carbonate (242 mg, 1.75 mmole) in 10% aqueous methanol (10 ml) for 18 hours. 1N Sodium hydroxide (1 ml) was added and after 3 hours the reaction mixture was concentrated and ethyl acetate (25 ml) and water (5 ml) added. The ethyl acetate layer was removed and the water extracted with ethyl acetate (3×20 ml). The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated to give 56 mg (64%) of (3-aminobenzyl){2-[2-(4-methoxy phenyl)-1-methylcarbamoylethyl carbamoyl]-4-methylpentyl}phosphinic acid methyl ester as a light yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[N:13]2[C:8]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)=[N:7]1.[I-].[K+].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14](=[O:15])[N:13]4[C:8]([CH2:9][O:10][C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=54)=[N:7]3)[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1n(CCCCCl)nc2n1-c1ccccc1OC2
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=c1n(CCCCN2CCN(c3ccccc3)CC2)nc2n1-c1ccccc1OC2

Procedure:
A solution of 2-(4-chlorobutyl)-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one (see example 4, part 1), (1.40 g.; 0.005 mole), potassium iodide (0.83 g.; 0.005 mole) and N-phenylpiperazine (1.79 g.; 0.011 mole) was stirred at 100° C. for 5 hours. The reaction mixture was cooled, poured into water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with dilute brine solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed through 125 g. of silica gel, using a 2% v/v diethylamine in ethyl acetate as eluting liquid. The eluted product thus obtained, titled above, was crystallized in the manner described in example 1, hereinabove, from an ethyl acetate/Skellysolve®B hexane mixture to give 1.56 g., m.p. 89°-90° C. and 0.115 g., m.p. 85°-87° C. of the named, titled compound hereinabove. The analytical sample had melting point 89°-90.5° C.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg), potassium carbonate (300 mg) and methyl bromoacetate (400 mg) in 2-butanone (10 ml) is heated under reflux for 1 hour. The reaction is filtered and concentrated, and the crude product is purified by prep. TLC to yield methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH2:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30](=[O:31])[CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)CC2CCNCC2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3, Step (b) from tert-butyl 4-({N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(methylsulfonyl)-amino]phenyl}piperidyl)-2-oxoethyl]-carbamoyl)methyl)-piperidinecarboxylate (Step a) (330 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (242 mg). MS (EST, pos. ion) m/z: 561 (M+1); (ESI, neg. ion) m/z: 559 (M−1). Calc'd for C28H37ClN4O4S: 560.22. Anal. Calcd for C28H37ClN4O4S.1.6C2HF3O2: C, 50.40; H, 5.23; N, 7.53. Found: C, 50.54; H, 5.53; N, 7.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:28])([F:27])[C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:21]3([C:20]([F:28])([F:27])[F:19])[CH2:23][CH2:22]3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-trifluoromethyl-cyclopropanecarboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=396.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH:20]([C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:29][C:28](=[O:34])[NH:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:20]([O:19][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1)[CH3:21])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(C)O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC(C)[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Temperature: 90 °C

Procedure:
A mixture of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.05 g, 0.193 mol), tert-butyl ((3S)-2-hydroxy-5-methylhexan-3-yl)carbamate (0.067 g, 0.290 mmol), Cs2CO3 (0.315 g, 0.966 mol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (8.21 mg, 0.019 mol) and Pd(OAc)2 (2.60 mg, 0.012 mol) were taken in Toluene (2 mL) and heated overnight at 90° C. After cooling the reaction mixture was concentrated, then diluted with ethyl acetate and water. Ethyl acetate layer was collected, dried over Na2SO4, filtered and concentrated which afforded tert-butyl((3S)-2-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5-methylhexan-3-yl)carbamate, (70 mg, 0.154 mmol, 80% crude yield) as brown solid. The crude product was used for next step without further purification. LC/MS (ESI) m/e 454.2 [(M+H)+, calcd for C26H36N3O4, 454.3]; LC/MS retention time (method D): tR=0.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[NH2:14][C:13]1[C:8]([NH:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1NCc1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Nc1cccnc1NCc1ccc(Cl)cc1

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 5.00 g of 2-(4-chloro-benzyl)amino-3-nitropyridine (prepared as described in Preparation 52), 21.4 g of tin(II) chloride dihydrate, 0.36 g of sodium borohydride and 150 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 3.55 g of the title compound, melting at 123°-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:36])[CH2:32]C([O-])=O)([CH3:29])([CH3:28])[CH3:27].[K+].[Cl-].[Mg+2].[Cl-]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:15][C:16](=[O:18])[CH2:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:36])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC(=O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Temperature: 10 °C

Procedure:
Into a one-liter four-necked flask were poured 43.9 g (0.125 mole) of (3R)-5-benzyloxycarbonylamino-3-(2-tetrahydropyranyloxy)pentanoic acid (2-c) obtained in the above process B and 290 ml of acetonitrile. Furthermore, 19.6 g (0.121 mole) of N,N'-carbonyldiimidazole was added to the contents over a period of 15 minutes in a nitrogen stream with stirring. Gas evolution was observed. Approximately 30 minutes later the gas evolution was nearly complete. Then, the contents were cooled to approximately 10° C., and 35.2 g (0.178 mole) of potassium malonate tert-butyl ester and next 11.4 g (0.119 mole) of magnesium chloride were separately added thereto. After stirring for 1 hour at the same temperature, the contents were heated to 50° C. and allowed to react for 2 hours. After removing acetonitrile by distillation, 150 ml of ethyl acetate and 200 ml of a 5 wt % aqueous hydrochloric acid solution were added to thereby adjust the pH to 4.5. After separating the aqueous layer, the organic layer was neutralized by adding 25 ml of a 5 wt % aqueous sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution and then dried with magnesium sulfate. The solvent was then removed by distillation, to thereby obtain 72.3 g of a crude oily product. The crude product was purified with a silica gel column using hexane/ethyl acetate=1/1 as an eluent to obtain the intended oily product (1). The yield was 57.8 g (79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>CCO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Compound 89A (150 mg, 0.36 mmol), phenylboronic acid (57 mg, 0.47 mmol) and 2N aqueous Na2CO3 (1.25 mL, 2.5 mmol) in a mixed solvent of toluene (1.5 mL) and EtOH((0.5 mL) were stirred at RT for 30 min while N2 was allowed to bubble through the mixture, and then tetrakis(triphenylphosphine)-palladium (0) (30 mg) was added. The mixture was stirred at 90° C. under N2 for 1 h. After cooling to RT, the mixture was extracted with EtOAc (15 mL×3), and organic extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (10-50%) in hexane to give the title compound (80 mg, 67%) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)C(=O)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-methyl-piperazin-2-one. ES-MS m/e (%): 505 (M+Na+, 31), 483 (M+H+, 100).
Reaction SMILES: [CH3:1][Si:2]1([CH3:18])[CH2:7][CH:6]2[CH:4]([N:5]2[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][Si:2]1([CH3:18])[CH2:7][CH2:6][CH:4]([NH:5][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2C3C[Si](C)(C)CC32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC2CC[Si](C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 3,3-dimethyl-6-[(4-methylphenyl)sulfonyl]-6-aza-3-silabicyclo[3.1.0]hexane (0.5 g, 1.8 mmol) in THF (10 ml) was added lithium aluminum hydride (11.0M THF, 5.33 mL, 5.33 mol). After stirring at rt overnight, the reaction was quenched by the sequential addition of H2O (0.2 mL), 1N NaOH (0.2 mL), and H2O (0.6 mL). The mixture was filtered through a pad of celite and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20](O)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[CH2:11]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A chilled solution of 4-nitrophenol (3.9 g, 28 mmol) and 1-benzyl-3-pyrrolidinol (7.5 g, 42 mmol) in THF was treated with diisopropyl azodicarboxylate (8.3 mL, 42 mmol), stirred at ambient temperatures, under nitrogen, for 45 minutes, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was twice purified by flash chromatography with 40% ethyl acetate in hexane to give 1-benzyl-3-(4-nitro-phenoxy)-pyrrolidine as a dark yellow gum, 7.2 g (86% yield), Mass spectrum (+APPI, [M+H]+) m/z 299. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.23-7.29 (m, 4H), 7.17-7.21 (m, 1H), 7.02-7.07 (m, 2H), 4.97-5.02 (m, 1H), 3.56 (s, 1H), 2.80-2.84 (m, 1H), 2.61-2.71 (m, 2H), 2.28-2.41 (m, 2H), 1.73-1.79 ppm (m, 1H).