Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:3]1[CH:2]=[C:1]([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=1)([O-:18])=[O:17]
Reactant: FC(F)(F)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a stirred mixture of benzotrifluoride (80.0 g, 0.55 m) and concentrated sulphuric acid (200 ml) was added fuming nitric acid (95% w/w; 29.3 ml, 44.0 g, 1.2 equivalents) over 30 minutes, maintaining the temperature of the stirred reaction mixture at between 20° and 30° by means of external cooling. After completion of the addition, stirring was continued at room temperature for a further hour and then the reaction mixture was poured onto a mixture of ice (1 kg) and water (100 ml). The resultant mixture was extracted with dichloromethane (2×250 ml) and the combined extracts washed with water (2×100 ml). The organic solution was then dried (over MgSO4) and evaporated under reduced pressure at 30° to give 3-nitrobenzotrifluoride (102 g, 94.0% w/w by GLC assay, 91% yield), as a pale-yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35].[F:49][C:50]([F:61])([F:60])[CH:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1>C(Cl)Cl>[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([O:48][CH2:58][CH2:57][N:54]3[CH2:55][CH2:56][CH:51]([C:50]([F:60])([F:49])[F:61])[CH2:52][CH2:53]3)=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35]
Reactant: OCCN1CCC(C(F)(F)F)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([O:7][Si](C)(C)C)[CH2:3][CH2:2]1.C[Si](C)(C)[O:14][C:15]([CH3:17])=[CH2:16].C(=O)(O)[O-].[Na+].O>C(#N)C>[O:14]=[C:15]([CH3:17])[CH2:16][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1
Reactant: C[Si](C)(C)OC1=CCOCC1
Reactant: C=C(C)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)CC1COCCC1=O
Yield: 46.4 %

Procedure:
(3,6-dihydro-2H-pyran-4-yloxy)trimethylsilane (1.0 g, 5.80 mmol) and trimethyl(prop-1-en-2-yloxy)silane (7.56 g, 58.0 mmol) were added dropwise to a vigorously stirred suspension of ceric ammonium nitrate (6.36 g, 11.61 mmol) and sodium bicarbonate (1.950 g, 23.22 mmol) in dry acetonitrile (40 ml). The resulting mixture was stirred until the orange color disappeared and a thick white precipitate formed. The reaction mixture was then poured into water and extracted with EtOAc. The combined extracts were washed by brine, and dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel, using EtOAc/Hex 10-50% to give the product (0.42 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.30-4.25 (m, 1H), 4.21-4.16 (m, 1H), 3.68-3.62 (m, 1H), 3.37-3.31 (m, 1H), 3.19-3.15 (m, 1H), 2.91-2.85 (m, 1H), 2.75-2.66 (m, 1H), 2.39-2.34 (m, 1H), 2.21-2.15 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH3:11])=[CH:5][C:4]=1[O:12][CH3:13].[H][H]>[Pd].CO>[CH2:9]([C:6]1[CH:5]=[C:4]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][CH3:11]
Reactant: CC=Cc1ccc(OC)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(OC)c(OC)c1
Yield: 97.2 %

Procedure:
An atmospheric pressure hydrogenation equipment was charged with 17.8 g (0.10 M) of 1,2-dimethoxy-4-propenylbenzene, 0.9 g of palladium charcoal and 350 ml of methanol and introduced with hydrogen. The reaction was continued until the absorption of hydrogen was terminated. Palladium charcoal was filtered off from the reaction mixture. The filtrate was distilled off methanol and vacuum distilled to obtain 17.5 g (0.097 M) of 4-propylveratrole as colorless transparent liquid having a boiling point of 106°-108° C./4 mmHg.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[CH3:26].[Li+].[OH-]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:27][CH2:28][CH3:29])[C:3]([OH:30])=[O:2])=[C:7]([CH3:26])[CH:8]=3)[N:15]=2)=[CH:20][CH:21]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid, which was crystalized from hexane/AcOEt to afford colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-OJ), the enantiomeric excess amounts to 98.9%.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([SH:19])[CH2:16][CH2:17][SH:18].B(F)(F)F.CCOCC.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[S:18]1[CH2:17][CH2:16][CH2:15][S:19][CH:2]1[C:10]1[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[C:4]([OH:3])=[O:14]
Reactant: O=C1OC(O)c2ccc([N+](=O)[O-])cc21
Reactant: SCCCS
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of the Compound 3a (5.00 g, 25.6 mmol) and propane-1,3-dithiol (2.92 g, 27 mmol) in chloroform (75 mL) was added boron trifluoride etherate (2 mL). The mixture was stirred and allowed to warm to room temperature. After stirring for 3 hours, most of the solid had dissolved. Magnesium sulfate was added to dry the solution, and stirring was continued overnight. Filtration and evaporation of the solvent afforded a light yellow solid. This material was triturated with butyl chloride to give the Compound 3b; m.p. 192°-194° C.; 1H NMR (CDCl3 +MeSO-d6 +D2O) δ1.8-2.3 (m, 2H, CH2CH2CH2), 2.9-3.2 (m, 4H, --CH2CH2CH2 --), 6.56 (s, 1H, --SCHS--), 7.6-8.8 (m, 3H, ArH).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([S:28](=[O:32])(=[O:31])[NH:29][CH3:30])[CH:19]=2)[N:15]=[C:14]([C:33]#[N:34])[N:13]=1)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].Br([O-])(=O)=O.[Ba+2].Br([O-])(=O)=O>C(#N)C.O>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([S:28](=[O:32])(=[O:31])[NH:29][CH3:30])[CH:19]=2)[N:15]=[C:14]([C:33]#[N:34])[N:13]=1
Reactant: CNS(=O)(=O)c1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Ce+3]
Solvent: O
Solvent: CC#N
Product: CNS(=O)(=O)c1cc(-c2cc(CCCO)nc(C#N)n2)cc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
To a solution of 4-(3-benzyloxy-propyl)-6-(3-methylsulphamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (14.4 mg) in acetonitrile (700 μL) and water (300 μL) was added cerium sulphate (3 mg) and barium bromate (6 mg). The mixture was heated to reflux overnight then filtered through a sinter glass funnel, the residue washed with DCM (10 mL). The filtrate was washed with saturated sodium thiosulphate (10 mL) organics separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield crude product. Purification by preparative-H PLC afforded 4-(3-hydroxy-propyl)-6-(3-methylsulphamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (3.2 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O>[CH:13]1([NH:16][C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: N#Cc1cccnc1Cl
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: N#Cc1cccnc1NC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A reaction flask equipped with a mechanical stirrer, temperature controller, condenser and addition funnel was charged with 2-chloro-3-pyridinecarbonitrile (69.25 g, 0.50 mol), 300 ml of ethanol and 200 ml of water. With agitation, cyclopropylamine ( 114g, 2.0 mol) was added dropwise over 30 minutes at a temperature<30° C. When the addition was completed, the stirred reaction mixture was heated to reflux temperature for 20 hours. The reaction mixture was cooled to 60° C. and then 350 ml of excess cyclopropylamine and ethanol were removed by vacuum distillation using water aspirator vacuum. The remaining aqueous solution was cooled to ambient temperature and allowed to stand overnight. The solid product was collected by filtration and the filter cake rinsed with water. The yield was 81.51 g (theoretical yield is 79.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 58.3 %

Procedure:
Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as an orange solid (150 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:13](O)=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CNC.C=O>O>[CH2:13]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(CCc1ccccc1)C(=O)O
Agent: C=O
Agent: CNC
Solvent: O
Product: C=C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenylethylmalonic acid (1.8 g), 40% aqueous dimethylamine (1.08 ml, 1 eq) and 37% aqueous formaldehyde (0.64 ml, 1 eq) in water (10 ml) was stirred at room temperature overnight. After cooling at 0° C. the solid was filtered off, washed with water and dried. The white solid was heated at 170° C. for 10 minutes and cooled to room temperature. The resulting gum was dissolved in ethyl acetate (20 ml), washed with 10% potassium hydrogen sulphate solution (10 ml), water (2×10 ml), saturated brine (10 ml), dried (MgSO4) and evaporated to give crude 2-methylene4-phenylbutanoic acid. δH (CDCl3) 2.55-2.90 (4 H, m, 2×CH2), 5.65, 6.85 (2 H, 2×s, ##STR8## 7.25 (5 H, m, Ph). The solid was dissolved in thioacetic acid (1 ml) and heated at 100° C. for 1 hour. After evaporation the gum was dissolved in ethyl acetate (10 ml) and extracted with saturated sodium hydrogen carbonate solution (2×10 ml). The combined extracts were washed with ethyl acetate (2×10 ml) and acidified with 10% potassium hydrogen sulphate solution (pH 3). The aqueous layer was extracted with ethyl acetate (2×10 ml) and the combined extracts washed with water (2×10 ml), dried (MgSO4) and evaporated to yield the title compound as a yellow oil (0.52 g, 24%); δH (CDCl3) 2.00 (2 H, m, CH2), 2.71 (3 H, m, CH2, CH), 3.14 (2 H, m, CH2), 7.24 (5 H, m, Ph). EIMS M+ 252 DCIMS MNH4+ 270.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([OH:59])=O)=O)(C)(C)C.[NH2:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73]C(=O)OC(C)(C)C)[CH2:68][CH2:67]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([O:54][CH3:55])[C:48]=2[F:56])=[N:44][C:43]=1[C:57]([NH:60][C:61]1[CH:62]=[N:63][N:64]([CH3:81])[C:65]=1[N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[CH2:68][CH2:67]1)=[O:59]
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1F
Reactant: Cn1ncc(N)c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A solution of PyBOP (211 mg, 0.406 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylic acid (118 mg, 0.31 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (89 mg, 0.29 mmol) and DIPEA (81 μL, 0.46 mmol) in DCM (3 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was re-dissolved in DCM (10 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 354 as a white solid (31 mg, 42%). 1H NMR (400 MHz, d4-MeOD) δ 7.58 (s, 1H), 7.37-6.99 (m, 1H), 7.06 (t, J=10.0 Hz, 1H), 3.93 (s, 3H), 3.73 (s, 3H), 3.29-3.04 (m, 4H), 2.65 (d, J=6.5 Hz, 2H), 1.85 (d, J=12.4 Hz, 2H), 1.70-1.42 (m, 1H), 1.48-1.21 (m, 2H). LCMS (ES+) m/z 478 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
Intermediate 5.64 (218 mg, 0.496 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (303 mg, 0.99 mmol), K3PO4 (420 mg, 2.0 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (18 mg, 0.025 mmol) were taken up in 1,4-dioxane (7 mL) and water (0.72 mL). The stirred reaction mixture was heated to 100° C. Once complete, the reaction mixture was partitioned between EtOAc, water, and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography to provide tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H44N7O5: 666.3; found: 666.3.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:4]=13.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C:4]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:3]2=3)[CH:8]=1)([O-:20])=[O:19]
Reactant: c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 Step 2, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.2 g, 14 mmol), potassium nitrate (1.5 g, 14 mmol) and concentrated sulfuric acid (50 mL) provided 2-nitro-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.0 g). MS (ES) m/z 271.2; HRMS: calcd for C16H18N2O2+H+, 271.14410; found (ESI, [M+H]+), 271.1437.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[CH:32][C:31]([C:34]4[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=4)[C:37](O)=[O:38])=[CH:30][C:24]=3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[CH:32][C:31]([C:34]4[CH:42]=[CH:41][CH:40]=[C:36]([C:37]([N:11]5[CH2:12][CH2:13][CH:9]([C:6]6[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=6)[CH2:10]5)=[O:38])[CH:35]=4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCNC2)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N4CCC(c5ccc(F)cc5)C4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
3-(4-Fluorophenyl)pyrrolidine hydrochloride (25 mg, 0.12 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight, then diluted with MeOH, filtered, and purified by prep HPLC. Concentration afforded the title compound (22 mg, 79% yield) as a pink solid. 1H NMR (˜1:1 ratio of amide rotamers, 500 MHz, DMSO-d6) δ ppm 8.44-8.54 (m, 1 H) 7.98-8.06 (m, 2 H) 7.66-7.91 (m, 5 H) 7.52-7.61 (m, 2 H) 7.36-7.44 (m, 3 H) 7.33 (dd, J=8.55, 5.49 Hz, 1 H) 7.18 (t, J=8.85 Hz, 1 H) 7.12 (t, J=8.85 Hz, 1 H) 4.01 (dd, J=11.14, 7.17 Hz, 0.5 H) 3.72-3.82 (m, 1.5 H) 3.56-3.69 (m, 1.5 H) 3.36-3.55 (m, 1.5 H) 2.87 (d, J=4.58 Hz, 1.5 H) 2.84 (d, J=4.58 Hz, 1.5 H) 2.27-2.34 (m, 0.5 H) 2.24 (dd, J=6.56, 3.51 Hz, 0.5 H) 2.04-2.12 (m, 0.5 H) 2.00 (dd, J=19.84, 10.38 Hz, 0.5 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=537. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.43 min, purity=99%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=13.18 min, purity=99%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carboxylate (0.49 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.06 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.45 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (0.41 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 91-92° C.