Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)(C)Oc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(Oc1cc([N+](=O)[O-])ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-nitrophenoxy)-2-methylpropionate (compound obtained in Reference Example 62(1); 332 mg) in tetrahydrofuran (1 mL)-ethanol (2 mL) was added an aqueous 5N sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 6N HCl (3 mL) and the mixture was extracted with diethylether. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2-(2-bromo-5-nitrophenoxy)-2-methylpropionic acid (297 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:13])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1c(C)cc(F)cc1C=O
Solvent: CCOCC
Product: COc1c(C)cc(F)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred solution of 5-Fluoro-2-methoxy-3-methylbenzaldehyde (1.2 g, 7.13 mmol) in dry diethyl ether (20 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in ether (6.0 mL, 17.83 mmol). The reaction mixture was brought to room temperature and was stirred for 30 min. then refluxed for 3 h. It was then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanol (1.0 g, 76%): 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, 1H), 6.83 (dd, 1H), 4.72 (m, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 1.47 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][C:63]1[C:64]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[N:65][CH:66]=[CH:67][CH:68]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:61][CH2:62][C:63]2[C:64]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:74])([CH3:76])[CH3:75])=[N:65][CH:66]=[CH:67][CH:68]=2)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CN
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (0.60 g, 1.66 mmol) in DMF (3 mL) was added DIEA (0.329 mL, 2.53 mmol), HBTU (0.756 g, 2.00 mmol), then tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate (0.473 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl (3-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate as a pale yellow solid (545 mg, 57%). LRMS (M+H+) m/z 581.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4cccnc4)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 11, Step 1, using the following starting materials: 3-(1-benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-pyridineboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>N1C=CC=CC=1>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 1.33 h
Yield: 71.1 %

Procedure:
A mixture of methyl 3-[4-(4-chlorophenyl)-2-oxo-4-oxazoline-5-yl]propionate (11.3 g), phosphorus oxychloride (18.6 g) and pyridine (3.2 ml) was stirred at 120 to 180° C. for 80 minutes. The reaction mixture was concentrated, and ice water was added thereto and then stirred at room temperature for 30 minutes. Then, this was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The solvent was evaporated, and the crystals thus precipitated were collected by filtration. These were recrystallized from isopropyl ether to give colorless needles of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.56 g, 71%). m.p. 71-72° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])[C:8]=2[CH:24]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])[C:8]=2[CH:24]=1
Reactant: COC(=O)c1cccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Yield: 50.8 %

Procedure:
A mixture of methyl 3-(6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (0.65 g.) and palladium-on-carbon (10% w/w, 0.025 g.) in ethyl acetate (40 ml.) was hydrogenated at an initial pressure of 2.9 bar. The catalyst was removed by filtration through diatomaceous earth, washing the filter cake with ethyl acetate, and the filtrate was evaporated to give methyl 3-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (X) (0.3 g., 51%) as a gum; partial NMR (80 MHz, CDCl3): 3.3(m,2H, N.CH2CH2.O); 3.9(s,3H, OMe); 4.15(m,2H, N.CH2.CH2.O); 4.5(s,2H, NCH2Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C(O)(=O)C>[O:22]=[C:21]1[CH:20]=[CH:19][C:18](=[O:23])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: CC(C)(c1ccc(O)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A 45.46 gram portion of 4-(1-(4-aminophenyl)-1-methylethyl)phenol (0.20 mole) and 500 milliliters of acetic acid were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was maintained at 25° C., then 19.61 grams of maleic anhydride (0.20 mole) dissolved in 100 milliliters of acetic acid was added to the reactor and heating to a reflux commenced. The 126° C. reflux temperature was maintained for 15 hours (54,000 s), then the product was dried under vacuum by rotary evaporation at 100° C. for 60 minutes (3600 s). The crude product was dissolved in 250 milliliters of o-dichlorobenzene at 120° C. and then cooled to 25° C. The light yellow colored solution was decanted away from a brown colored oil layer and dried under vacuum by rotary evaporation at 100° C. for 60 minutes (3600 s) to provide 31.4 grams of 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl)-1-methylethyl)phenol as a bright yellow colored powder. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=1)[CH:22]=O)([CH3:17])[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]2[CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=[C:19]([O:18][CH:15]([CH3:17])[CH3:16])[CH:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc(OC(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.0 equiv), 3,5-diisopropoxy-benzaldehyde (5.33 g, 24.0 mmol, 1.2 equiv; intermediate D7, vide infra) and acetic acid (4.6 mL, 4.80 g, 80.0 mmol, 4.0 equiv) in ethanol (16 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (2.51 g, 40.0 mmol, 2.0 equiv), dissolved in ethanol (8 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified on a Isolute flash NH2 chromatography column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.23 g (40%) of the title compound. MS (ISP): 407.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17](O)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:45][C:46]1[C:50]([CH:51]([NH2:53])[CH3:52])=[C:49]([CH3:54])[NH:48][N:47]=1>CN(C=O)C>[CH3:45][C:46]1[C:50]([C@@H:51]([NH:53][C:17](=[O:18])[CH2:16][O:15][C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:5]3=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[CH3:52])=[C:49]([CH3:54])[NH:48][N:47]=1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reactant: Cc1n[nH]c(C)c1C(C)N
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1[C@H](C)NC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Reaction time: 8 h
Yield: 9.1 %

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (1.35 g, 3.843 mmol), DIC (727 mg, 5.769 mmol) and HOBt (674 mg, 4.996 mmol) in DMF (15 ml) was stirred at rt for 15 min. 1-(3,5-dimethyl-1H-pyrazole-4-yl)ethanamine (642 mg, 4.612 mmol) was added to the solution at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water was added to the reaction mixture and the mixture was stirred for 10 min. The precipitate was collected by filtration and dried under vacuum. The racemic mixture was subjected to chiral preparative chromatographic separation to yield the enantiomeric pure title compound (165 mg) and the R enantiomer (165 mg, see example 1.62). [1H-NMR (CDCl3, 300 MHz) δ 7.62-7.48 (m, 5H), 6.99 (s, 1H), 6.55 (d, 1H), 5.33-4.92 (m, 3H), 4.1 (s, 3H), 2.25 (s, 6H), 1.55 (d, 3H); HPLC RtE=6.194 min. (98%); LCMS RtA=1.382, [M+H]+=473.1; Mp=145-147° C.]
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]1([C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:4]/[CH:3]=[CH:2]/[C:1]([N:14]1[C@H:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][O:16][C:15]1=[O:18])=[O:5]
Reactant: C/C=C/C(=O)Cl
Reactant: O=C1N[C@H](c2ccccc2)CO1
Product: C/C=C/C(=O)N1C(=O)OC[C@H]1c1ccccc1
Yield: 81.1 %

Procedure:
trans-Crotonoyl chloride (2.67 g, 10.24 mmol, Aldrich) was coupled with (R)-4-phenyl-2-oxazolidinone (1.46 g, 8.9 mmol) according to the procedure of Example 1c to afford the title compound (1.67 g). MS m/z 232 (M+H)+, 249 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4]Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2][CH2:3][CH2:4][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: CSCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSCCOc1ccccc1[N+](=O)[O-]
Yield: 63.1 %

Procedure:
2-methylthioethylchloride (18.0 g, 0.16 mole), o-nitrophenol (20.8 g, 0.15 mole) and potassium carbonate (24.7 g, 0.18 mole) was refluxed in acetonitrile for 24 h. The reaction mixture was filtered and the solvent was evaporated. The residue was dissolved in methylene chloride and washed with water once and thereafter twice with a saturated sodium carbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated giving 20.2 g (63%) of the title compound as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:12])[O:16][C:14](=[O:15])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A suspension of (tert-butoxycarbonyl-carboxymethyl-amino)-acetic acid (5 g, 21.4 mmol) and DCC (4.85 g, 23.6 mmol) in dichloromethane was stirred for 16 hours. The mixture was filtered and the solvent was removed from the filtrate to provide 2,6-dioxo-morpholine-4-carboxylic acid tert-butyl ester (4.86 g, 21.0 mmol, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]([CH3:24])[N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:35][C:36]([O:38]CC)=[O:37])=[O:5])[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]([CH3:24])[N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=2)[C:7]=1[CH2:35][C:36]([OH:38])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3nc(C)ccc3C#N)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3nc(C)ccc3C#N)cc12

Procedure:
2-Ethoxycarbonylmethyl-5-(3-cyano-6-methyl-2-pyridin-yloxy)-1-(4-isopropoxyphenyl)-indole-3-carboxylic acid ethyl ester (275 mg, 0.51 mmol, see step (a) above), 1 M NaOH (aq, 1 M, 1.52 mL) and EtOH (3 mL) was heated at 50° C. for 1 h. The title compound was isolated as described before. Yield 203 mg (77%), mp 179° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1Cc2ccccc2C1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC(N1CCCC1)C2
Reaction time: 8 h

Procedure:
To a solution of 1H-inden-2(3H)-one (6 g, 45.4 mmol) in 100 mL of methanol were added pyrrolidine (7.51 ml, 91 mmol), sodium cyanoborohydride (5.71 g, 91 mmol), and acetic acid (5.20 ml, 91 mmol). The reaction mixture was stirred overnight then concentrated. The crude residue was dissolved in 400 mL of ethyl acetate and washed with aqueous sodium bicarbonate (2×400 mL) and saturated aqueous brine (1×200 mL), dried over magnesium sulfate, filtered and concentrated. Recrystallization in ethyl acetate/hexane afforded the title compound. MS (ESI) m/z 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][CH2:24][OH:25].[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:25][CH2:24][CH3:23])=[CH:8][CH:9]=1
Reactant: CCO
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 9.3 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (0.3 g, 0.89 mmol), EtOH (0.12 g, 2.6 mmol), NaH (60% in mineral oil; 0.1 g, 2.6 mmol) and NMP (2 ml) gave the title compound (30 mg, 9%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH:9]2[CH2:11][CH:3]1[CH:4]1[CH:8]2[CH2:7][CH2:6][CH2:5]1.[CH3:12][O-:13].[Na+].O>C1CCCCC1>[CH:12]([C:9]1[CH:8]=[CH:4][C:3]([CH:11]=[C:10]2[CH:9]3[CH2:11][CH:3]([CH:4]4[CH:8]3[CH2:7][CH2:6][CH2:5]4)[C:2]2=[O:1])=[CH:2][CH:10]=1)=[O:13]
Reactant: O=C1CC2CC1C1CCCC21
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: O=Cc1ccc(C=C2C(=O)C3CC2C2CCCC32)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 40 mmol (6.3 g) of 8-ketotricyclo[5.2.1.02,6 ]decane and 60 mmol of sodium methoxide (11 g of a 30% solution) in 50 ml of cyclohexane are stirred at 50° C. for 30 minutes. 50 mmol (9.0 g) of terephthalaldehyde monodimethyl acetal are then added dropwise and the mixture is refluxed for 1 hour. It is then cooled to room temperature and 100 ml of water are added.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>CN1C(=O)CCC1>[CH2:21]([O:20][C:18]([C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12])=[CH2:19])[CH3:22]
Reactant: Cn1ncc2c(Br)cc(F)cc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: C=C(OCC)c1cc(F)cc2c1cnn2C
Temperature: 110 °C
Yield: 90.1 %

Procedure:
To a mixture of 4-bromo-6-fluoro-1-methyl-1H-indazole (1.42 g, 6.25 mmol) and tributyl(1-ethoxyvinyl)stannane (2.74 mL, 8.13 mmol, 1.3 eq.) in NMP (24 mL) under an argon atmosphere was added Pd(0)(PPh3)4 (1.08 g, 0.94 mmol, 0.2 eq.). After the mixture was heated at 110° C. overnight, it was cooled and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), and evaporated in vacuo. The crude was purified by SiO2 chromatography eluting with hexane:ethyl acetate (3:1) to afford 4-(1-ethoxyvinyl)-6-fluoro-1-methyl-1H-indazole as a yellow oil (1.24 g, 90%). MS (ESI): m/z=221.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:9][C:5]1[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1ccc(F)cc1
Product: Nc1ncc(Br)nc1-c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 19a using 2-amino-3,5-dibromopyrazine, and 4-fluorophenylboronic acid (commercially available) as starting materials to give the title compound as a white solid, MS (ISP) 268.1, 270.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:50]=[N:49][N:48]=3)=[CH:37][CH:36]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([C:5]1[N:6]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[NH:51][N:50]=[N:49][N:48]=3)=[CH:37][CH:36]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C

Procedure:
A methanol (30 mL) suspension of 1-[({[(4R,5R)-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (1.63 g, 1.68 mmol) was heated to 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 3-9% methanol/dichloromethane to give the title compound. 1H NMR (500 MHz, CD3CN) δ 7.71 (dd, J=0.9, 7.8 Hz, 1H), 7.64 (dt, J=1.2, 7.6 Hz, 1H), 7.54 (dt, J=1.1, 7.6 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 6.81 (q, J=5.5 Hz, 1H), 5.53 (d, J=16.7 Hz, 1H), 5.48 (d, J=17.1 Hz, 1H), 5.25-5.35 (m, 2H), 4.11 (t, J=5.8 Hz, 2H) 2.60 (t, J=7.7 Hz, 2H), 1.70-1.84 (m, 4H), 1.58 (quintet, J=7.6 Hz, 2H), 1.49 (d, J=5.5 Hz, 3H), 1.35 (d, J=6.3 Hz, 3H), 1.31 (sextet, J=7.5 Hz, 2H), 0.85 (t, J=7.4 Hz, 3H); LC-MS: m/z 731.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@H:17]([OH:21])[C:18]([OH:20])=[O:19])[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)[CH3:2].CO[C:24](OC)([CH3:26])[CH3:25]>CC(C)=O.[Cu](Cl)Cl>[CH3:25][C:24]1([CH3:26])[O:21][C@@H:17]([C@@H:13]([CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)[C:14]([OH:16])=[O:15])[C:18](=[O:20])[O:19]1
Reactant: COC(C)(C)OC
Reactant: CCOc1ccc(CCC[C@@H](C(=O)O)[C@H](O)C(=O)O)cc1
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CCOc1ccc(CCC[C@@H](C(=O)O)[C@@H]2OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2R,3S)-2-[3-(4-ethoxyphenyl)propyl]-3-hydroxybutanedioic acid (3.06 g; 10.33 mmol; 1.0 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (1.8 g; 17.6 mmol; 1.7 eq.) and copper(II) chloride (135 mg; 1.03 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 14 h at RT. The reaction mixture was evaporated and the residue taken up in Et2O. Filtration on a pad of celite gave the title product as a greenish oil used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.05 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 4.48 d (J=5.0 Hz, 1H), 3.98 (q, J=7.0 Hz, 2H), 3.10-2.81 (m, 1H), 2.74-2.41 (m, 3H), 220-1.15 (m, 4H), 1.61 (s, 3H), 1.50 (s, 3H), 1.35 (t, J=7.0 Hz, 3H).