Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].S(=O)(=O)(O)[OH:17]>>[NH:6]1[C:7]2[C:15](=[CH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[C:3](=[O:17])[C:4]1=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc2c(c1)CCC2
Product: O=C1Nc2cc3c(cc2C1=O)CCC3
Temperature: 80 °C
Yield: 77 %

Procedure:
Add 2-hydroxyimino-N-indan-5-yl-acetamide (4.66 g, 22.84 mmol) in small portions at 65° C. to concentrated sulfuric acid (22 mL) and heat the mixture at 80° C. for 15 minutes. Cool to room temperature, pour into ice water (200 mL) and filter the precipitate. Dissolve the solid in warmed ethanol and leave to cool overnight. Filter the precipitate and wash with ethyl ether. Dry the solid to yield the title compound (3.3 g, 77%). 1H NMR (dimethyl sulfoxide-d6, 300 MHz) δ 1.98 (quintuplet, J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 6.74 (s, 1H), 7.28 (s, 1H). MS (ES−): 186 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[C:19]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:18]=[CH:17][C:16]=1OS(C(F)(F)F)(=O)=O)[CH:9]=[CH:8]2)=[O:4].[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Li+].[Cl-]>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[C:16]([C:40]3[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:17][CH:18]=[C:19]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:20]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1

Procedure:
Compound 21 (320 mg, 0.63 mmol), 4-chloro-phenylboronic acid (Compound 22, 148 mg, 0.94 mmol), 500 mg (2.35 mmol) of K3PO4, 27 mg (0.63 mmol) of LiCl and 36.5 mg (0.031 mmol) of Pd(PPh3)4 were dissolved in 30 mL dioxane (degassed). The mixture was refluxed under argon overnight. The black solution was filtered through a Celite pad, and evaporated to dryness to give Compound 23 as yellow oil which was used without further purification. MS: 471.16 (M+H+).
Reaction SMILES: Cl.[O:2]=[C:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[CH3:9])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)CCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CC(=O)CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 7.5 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxopentanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 123, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxopentanoyl)pyrrolidine-2-carboxamide (2.2 mg, 7.5%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.88 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.45 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 2.60-2.69 (m, 3H), 2.57-2.59 (m, 2H), 2.44-2.53 (m, 2H), 2.45 (s, 3H), 1.92 (m, 2H). MS (EI) for C29H29FN2O4. found 489.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16]Cl)[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1.[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][O:25][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1
Reactant: CCCCC(CC)CO
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(CC)COCc1cc(C)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
2-(5-Chloro-2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (5.0 g, 16 mmol) is suspended in a mixture of 2-ethylhexanol (20.0 g, 154 mmol) and acetone (5 g) and stirred at 80° C. for 15 minutes. Sodium carbonate (3.4 g, 32 mmol) is added. The slightly yellow reaction mixture is stirred at 80° C. for 3 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.9 g of 2-(5-Chloro-benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.[C:11]1(Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:9]23[C:1](=[O:10])[O:2][CH2:3][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: O=C1OCC2CCCCC12
Product: O=C1OCC2CCCCC12c1ccccc1

Procedure:
The title compound was prepared from hexahydro-isobenzofuran-l-one (10 g, 1.3 eq) and phenyl bromide (5.4 mL, 51.27 mmol) according to General Procedure K. It was obtained as a clear oil (7.40 g, 67%). HPLC Rt (5-100-8)=9.8 min. 1H NMR (CDCl3, δ): 7.4-7.2 (m, 5H), 4.05 (dd, 1H), 3.90 (dd, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). 13C NMR (CDCl3, δ, mult): 178.6 (0), 140.5 (0), 128.8 (1), 127.3 (1), 126.3 (1), 70.3 (2), 52.5 (0), 41.0 (1), 34.2 (2), 27.5 (2), 23.4 (2), 23.2 (2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:31])([F:30])[F:29])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=O)[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:29])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:27])[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Reactant: NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O)NCC(F)(F)F
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in DCM (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIEA (0.15 ml, 0.93 mmol) at RT, and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:3]
Reactant: Nc1cnc2ccccc2c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
3.2 ml of methyl chloroformate am added dropwise to 5.0 g of 3-aminoquinoline in 30 ml of methylene chloride and 15 ml of pyridine at 0° C. in the course of 30 min. The mixture is subsequently stirred for a further 30 min and then worked up in the customary manner. The title compound is obtained as a crystalline solid: Rf (H)=0.41.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 107F (0.033 g, 0.052 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 1 hour, concentrated, and partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[C:16]([C:17]=2[O:18]C)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OCC)(=O)[CH3:24]>S(=O)(=O)(O)O.C(O)C.O>[CH2:23]([O:22][C:20]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1)=[O:21])[CH3:24]
Reactant: CCOC(C)=O
Reactant: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Cc2ccccc2)c(O)c2ccccc12
Yield: 62 %

Procedure:
A solution of the compound of Example 95 (2.55 g, 9.2 mmole) and concentrated sulfuric acid (3 drops) in ethanol (125 mL) was heated at reflux for 80 hours. The mixture was cooled and diluted with water, and the crude product was isolated by extraction with ethyl acetate. This was chromatographed (9:1 hexane/ethyl acetate) and recrystallized (hexane) to provide the title compound (1.74 g, 62%) as white needles, mp 79°-80°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([N+:18]([O-:20])=[O:19])[CH:8]=1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(Cl)Cl.CCOC(C)=O.CO>[CH3:17][O:16][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)C(C)(C)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1c([N+](=O)[O-])cc(C(C)(C)CO)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a 0° C. solution of 1.30 g (4.35 mmol) of 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propionic acid methyl ester in 30 mL of THF was added dropwise 17 mL (17 mmol) of 1.0 M DIBAL in CH2Cl2. After stirring an additional 4 h, 2 mL of MeOH and then saturated Na2SO4 (2 mL) were slowly added. The resulting suspension was rapidly stirred for 20 min then 40 mL of EtOAc was added followed by MgSO4. The resulting mixture was then stirred at rt for an additional 30 min. The mixture was filtered through celite, and the filter cake was washed with EtOAc. The filtrate was concentrated to provide 580 mg of 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.Cl.[NH2:25][C@H:26]1[CH2:30][NH:29][CH2:28][C@@H:27]1[OH:31].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[NH2:25][C@@H:26]1[C@@H:27]([OH:31])[CH2:28][N:29]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:30]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Reactant: N[C@H]1CNC[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Temperature: 100 °C
Reaction time: 40 h

Procedure:
3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (240 mg, 0.596 mmol) and TEA (0.332 mL, 2.384 mmol) were added to a vial containing DMSO (0.5 mL). (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride (Stage 245.2, 128 mg, 0.715 mmol) was added. The RM was stirred at 100° C. for 40 h. The RM was treated with sat. aq. Na2CO3 (50 mL) and was extracted with EtOAc. The combined extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (from 100% EtOAc to EtOAc/EtOH/NH3 aq. 90:9:1) to afford the title product as a beige solid. HPLC (Condition 10) tR=6.08 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1/478.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:19][O:18][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][C:6]2=[O:17])[O:4][CH2:3]1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:3][O:4][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[N:7]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:6]2=[O:17])[O:18][CH2:19]1
Reactant: COC(=O)CBr
Reactant: CC1(C)COC2(OC1)C(=O)Nc1ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Crude 5,5-dimethyl-5′-nitrospiro[[1,3]dioxane-2,3′-indolin]-2′-one (obtained as described in Example 17, Step 1) (361 mg) was dissolved in dry DMF (11 ml) and cooled to 0° C.; NaH (60% w/w dispersion in mineral oil, 83 mg, 2.076 mmol) was added; and the mixture was stirred at 0° C. for 10 minutes (the reaction turned dark orange). Methyl 2-bromoacetate (0.144 ml, 1.557 mmol) was then added, the reaction was warmed to room temperature and stirred for 3 hours. The solvent was evaporated, water was added and extracted with EtOAc; the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc from 95:5 to 85:15) affording methyl 2-(5,5-dimethyl-5′-nitro-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (344 mg, 0.982 mmol, 84% yield). MS/ESI+ 351.0 [MH]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:5]1[C:6]([NH:14][C:15](=[O:24])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)/C=C/c2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and cinnamoyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 9H), 6.84 (d, J=14.9 Hz, 1H), 7.02 (dd, J=7.1, 4.1 Hz, 1H), 7.38-7.48 (m, 3H), 7.57-7.64 (m, 3H), 8.51 (dd, J=4.1, 1.7 Hz, 1H), 8.95 (dd, J=7.0, 1.9 Hz, 1H), 9.98 (s, 1H); MS (DCI) m/z 321 (M+H)+; EA calculated for C19H20N4O: C, 71.23; H, 6.29; N, 17.49. Found: C, 70.95; H, 6.06; N, 17.36.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[CH:38]1[C:50]2[CH:49]([CH2:51][NH2:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:52][CH2:51][CH:49]2[C:50]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: NCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
Triethylamine (0.38 ml, 2.7 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (1.0 g, 2.3 mmol) (Preparation 45) and 9H-fluoren-9-ylmethanamine (0.49 g, 2.5 mmol) (J. Org. Chem., 1971, 36(23), 3539) in acetonitrile (30 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was partially redissoved in ethyl acetate (30 ml). The ethyl acetate was washed with water (1 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate (96:4 by volume) increasing in polarity to dichloromethane: ethyl acetate (94:6 by volume). The solvent was removed under reduced pressure to give the title compound (1.23 g) as a foam.
Reaction SMILES: I[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].N1CCC[C@H]1C(O)=O.[CH3:42][S:43]([OH:45])=[O:44].[Na].[OH-].[Na+]>CS(C)=O.[Cu]I>[CH3:14][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[C:5]1[CH:17]=[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:24])[CH3:25])[C:2]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]2=1
Reactant: CS(=O)O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(I)cc21
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(S(C)(=O)=O)cc21
Temperature: 100 °C
Yield: 24 %

Procedure:
(S)-tert-butyl (1-((9-iodo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.177 mmol), L-proline (20.36 mg, 0.177 mmol), methanesulfinic acid, sodium salt (181 mg, 1.769 mmol), NaOH (11.32 mg, 0.283 mmol) and copper(I) iodide (33.7 mg, 0.177 mmol) were taken up in DMSO (5 mL) and purged with nitrogen gas for 5 min. The resultant mixture was sealed in a microwave tube and heated at 100° C. in a microwave for 2.5 h. The reaction mixture was cooled to room temperature, treated with ice-cold water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (S)-tert-butyl 1-(4,6-dimethyl-9-(methylsulfonyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (150 mg, 0.07 mmol, 39% crude yield, 24% purity) as a black gummy solid. The material was taken to the next step with out purification. LC/MS (ESI) m/e 518.2 [(M+H)+, calcd for C26H36N3O6S 518.2] LC/MS retention time (method B): tR=1.51 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][Mg]Cl>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:2]/[CH:3]=[CH:4]/[CH3:5]
Reactant: Cl[Mg]C#CCCCCCCBr
Solvent: C1CCOC1
Product: C/C=C/CC#CCCCCCCBr
Yield: 145 %

Procedure:
The experimental procedure was substantially the same as in Example 1 except that the starting Grignard mixture contained 3 moles of 8-bromo-1-octynyl magnesium chloride in tetrahydrofuran in place of 8-chloro-1-octynyl magnesium chloride to give 529 g of 1-bromo-(E)-10-dodecen-7-yne in a purity of 95%. The yield was 69% of the theoretical value. Partial hydrogenation of 150.5 g of this ene-yne compound in the same manner as in Example 1 gave 145 g of a product boiling at 106° to 110° C. under a pressure of 1 mmHg, which could be identified by analysis to be 1-bromo-(Z,E)-7,10-dodecadiene. The analytical data leading to the identification of this product compound were as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[N+:23]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(O)C.[Zn]>[NH2:23][C:10]1[CH:11]=[C:12]([NH:15][C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4′-benzyloxy-3-nitrophenyl)amino-6-chloro-pyrimidine (4.91 g) and sulfuric acid (8 ml) in ethanol (300 ml) was added zinc dust (4.49 g). The mixture was then heated under reflux for 18 hours, cooled to room temperature then basified with sodium hydrogen carbonate. After evaporation under reduced pressure, the residue was dissolved in ethyl acetate and water. The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was then subjected to column chromatography (SiO2; ethyl acetate:petroleum ether (40/60) 1:1) to give 4-(3′-amino-4′benzyloxyphenyl)amino-6-chloro-pyrimidine, 21% δH (d6 DMSO): 4.84 (2H, s, NH2), 5.00 (2H, s, CH2Ph), 6.50-6.60 (2H, m, ArH), 6.70-6.80 (2H, m, ArH and HetH), 7.20-7.50 (5H, m, ArH), 8.30 (1H, s, HetH), 9.45 (1H, s, NH)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:19].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]([CH3:16])[C:13]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH3:19])=[O:15])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)NC(C)c1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 12 h
Yield: 93.4 %

Procedure:
3-(4-t-Butyl-phenyl)-2-methylacrylic acid (1.1 eq, 0.14 mmol, 31.00 mg) and (R)-N-[4-(1-Amino-ethyl)-2-fluorophenyl]methanesulfonamide (1 eq, 0.13 mmol, 30 mg) were dissolved in DMF. DEPC (1.2 eq, 0.16 mmol, 23.67 μl) and TEA (2 eq, 0.26 mmol, 36.24 μl) were added into the mixture. The reaction mixture was stirred for 12 hrs. DMF was removed in vacuo. The residue was extracted with ethyl acetate and H2O. A combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EtOAc=1:1) to yield the title compound (52.53 mg, 93.5%) as a white solid.