Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CC(N)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 143, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with bromo acetamide and the crude product subjected flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 155 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.83 (d, J=2.18 Hz, 1H); 7.24 (d, J=2.21 Hz, 1H); 7.18 (d, J=8.31 Hz, 1H); 6.86 (s, 1H); 5.71-5.63 (m, 1H); 5.45 (s, 1H); 4.54 (t, J=5.98 Hz, 2H); 3.87 (t, J=7.28 Hz, 2H); 3.81-3.72 (m, 1H); 3.38 (t, J=6.84 Hz, 2H); 3.22 (s, 2H); 3.16 (t, J=5.99 Hz, 2H); 1.59 (d, J=6.62 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=5.84 min, M+H+=408
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[N:25][OH:26])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C2(C#N)CCC(=NO)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.125 g, 0.4 mmol) in pyridine (2 mL) was added hydroxylamine hydrochloride (0.031 g, 0.44 mmol), the mixture was stirred at room temperature under an argon atmosphere for 4 h and the solvent was evaporated. The mixture was partitioned between water and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/hexanes, followed by trituration of the product with ether/hexanes provided a white solid (0.125 g, 95%): m.p. 50°-53° C.
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:28][CH2:27]1>CO>[F:25][C:2]([F:1])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:36]/[NH:35][C:33](=[O:34])[CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: NNC(=O)CN1CCOCC1
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Solvent: CO
Product: C/C(=N\NC(=O)CN1CCOCC1)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Temperature: 45 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
1-(3-(difluoro(quinolin-6-yl)methyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (25 mg, 0.074 mmol) and 2-morpholinoacetohydrazide (12 mg, 0.075 mmol) were dissolved in MeOH and the pH of the reaction solution was adjusted to 5. The solution was then stirred at 45° C. for 3 hours. Solvent was evaporated and the crude product was purified on HPLC (neutralized to free base) to give the title compound as a white solid (18 mg, 50%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.55 (d, 1H), 8.43 (d, 2H), 8.17 (d, 1H), 8.01 (m, 2H), 7.65 (d, 1H), 3.59 (m, 4H), 2.13 (m, 4H). LCMS (method B): [MH]+=481.1, tR=1.66 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[N+:4]([O-:6])=[O:5].CO[C:13](OC)([CH3:15])[CH3:14]>Cl.C(#N)C>[CH3:14][C:13]1([CH3:15])[O:8][CH2:7][C:3]([CH2:9][OH:10])([N+:4]([O-:6])=[O:5])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: Cl
Solvent: CC#N
Product: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a 250 ml round bottom flask equipped with a stir bar was added 5 g (0.03 mol) tris(hydroxymethyl) nitromethane, 3.75 g (0.36 mol) 2,2-dimethoxypropane, 100 ml acetonitrile and 6 drops concentrated hydrochloric acid. The reaction was heated to 80° C. for 18 hours. After cooling to room temperature tte volatiles were removed in vacuo to give a white solid 2,2-dimethyl-5-hydroxy methyl-5-nitro-1,3-dioxane in 82% yield.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14](Br)[CH2:13]1>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13]1)[C:2]([O:9][CH3:10])=[O:8]
Reactant: CC1CCCC(Br)C1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C1CCCC(C)C1

Procedure:
Sodium metal (7.02 g, 0.30 g atm) was reacted with anhydrous methanol (250 mL). To this was then added dimethyl malonate (70 mL) dropwise while the temperature of the reaction was maintained at 50° C. To this solution was then added dropwise 3-methylcyclohexylbromide (54.0 g, 0.30 mol) and the reaction refluxed overnight. The methanol was removed on a rotovap and the remaining material partitioned between ether and water. The ether layer was separated, dried with MgSO4 and evaporated to give a yellow oil. Distillation of the material at 95-106° C. and 1.2 mm pressure gave a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:16]([OH:18])=[O:17])[C@H:13]([CH3:15])[OH:14].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH3:15])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
2-chloro-4-fluorobenzonitrile (60702-69-4) (2.0 g, 12.86 mmol) was mixed together with H-D-Thr-OH (1.84 g, 15.43 mmol) in DMSO (30 mL). K2CO3 (3.73 g, 27.0 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled down to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane EtOAc and then with EtOAc, 100% to get the pure final product 1.8 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.42 (m, 1H), 4.22 (d, J=6 Hz, 1H), 2.34 (s, 3H), 1.28 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[I:14]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[I:14][C:4]1[CH:5]=[C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(C(C)(C)CO)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(C(C)(C)CO)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-methoxyphenyl)-2-methylpropan-1-ol (661.7 mg, 3.68 mmol) (2-(4-methoxyphenyl)-2-methylpropan-1-ol has been described in the literature. See Helv. Chim. Acta. 1971, 54, p. 868-897.) in EtOH (40 mL) was added Ag2SO4 (1.15 g, 3.68 mmol) followed by I2 (934 mg, 3.68 mmol). The reaction was stirred at room temperature for 2 hours, and then the solids were filtered off through a pad of Celite. The filtrate was concentrated to ˜10 mL and then diluted with EtOAc (50 mL). The organic solution was washed with water, aq. NaHSO3, and brine (15 mL each). The organic layer was then diluted with 50 mL of hexanes and filtered through a short plug of silica gel with (50/50 EtOAc/hexanes). The filtrate was concentrated to afford 2-(3-iodo-4-methoxyphenyl)-2-methylpropan-1-ol. 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J=2.3 Hz, 1H), 7.32 (dd, J=8.7, 2.3 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N+:17]([O-])=O)[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(OC(C)=O)c(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(OC)c(OC(C)=O)c1
Yield: 81.9 %

Procedure:
A solution of methyl 3-(acetyloxy)-4-(methyloxy)-5-nitrobenzoate (27.2 g, 101 mmol.) in ethyl acetate (200 mL) with 10% palladium on carbon (1.0 g) added was hydrogenated at atmospheric pressure until complete reduction to the aniline was observed by TLC (>24 hours). The mixture was then filtered through a bed of celite and the filtrate concentrated to provide methyl 3-(acetyloxy)-5-amino-4-(methyloxy)benzoate (19.8 g, 82% yield) as an oil that slowly crystallized on standing. 1H NMR (400 MHz, CDCl3): 7.30 (d, 1H), 7.14 (d, 1H), 3.97 (br d, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:13][CH:14]4[CH:10]([CH2:9][NH:8][CH2:15]4)[CH2:11]3)=[CH:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC4CNCC4C3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a stirred solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (390 mg; 0.81 mmol) in CH2Cl2 (4 mL) was added TFA (6 mL). The reaction mixture was stirred at RT for 4 h upon which time volatiles were removed in vacuo. Purification by SCX-2 gave the title compound as an off-white solid (273 mg; 89%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C(O)(=O)C>C1COCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (20.0 g) in THF (700 mL) was added dropwise n-butyllithium (2.5 M hexane solution, 58.3 mL) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added triisopropyl borate (52.2 g) at −78° C., and the mixture was stirred at the same temperature for 1 hr, gradually warmed to room temperature, and stirred at room temperature for 20 hr. The reaction mixture was adjusted to pH 5 with acetic acid (20 mL) and concentrated to give the title compound (25.0 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]([NH:26][C:27](=[O:29])[CH3:28])[S:8][C@@H:9]2[C@:16]([NH:22][CH:23]=[O:24])([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+:30].C(OO)(=[O:33])C>>[C:1]([O:4][CH2:5][C:6]1[CH:7]([NH:26][C:27](=[O:29])[CH3:28])[S:8](=[O:33])[C@@H:9]2[C@:16]([NH:22][CH:23]=[O:24])([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+:30]
Reactant: CC(=O)NC1S[C@H]2N(C(=O)[C@@]2(NC=O)c2cccs2)C(C(=O)[O-])=C1COC(N)=O
Reactant: CC(=O)OO
Agent: [Na+]
Product: CC(=O)NC1C(COC(N)=O)=C(C(=O)[O-])N2C(=O)[C@@](NC=O)(c3cccs3)[C@H]2S1=O

Procedure:
Oxidation of sodium 3-carbamoyloxymethyl-7α-formamido-7β-thien-2-yl-acetamido-ceph-3-em-4-carboxylate with peracetic acid in analogous manner to that described in Example 6(d) gives the title compound as a mixture of R- and and S-sulphoxide isomers.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][OH:12].[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:16][C:14]1([C:13]([OH:18])=[O:17])[C:1]2=[C:9]3[C:4]([CH:3]=[C:2]2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH2:8]3
Reactant: OCCC1=Cc2ccccc2C1
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(C(=O)O)OCCC2=CC3=CC=CCC3=C21

Procedure:
Indene-2-ethanol (3.5 g) described in Examples 474 and 476, is treated with ethyl pyruvate (4 g) and boron trifluoride-etherate (2 ml) in benzene (50 ml) according to the procedure of Example 2 to yield the title compound, m.p. 171°-173° C., νmaxnujol 1720 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:34]([CH3:35])[CH:33]=[N:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:34]([CH3:35])[CH:33]=[N:32][N:31]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: Cn1cnnc1CCl
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2nncn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0.334 mmol), 3-(chloromethyl)-4-methyl-4H-1,2,4-triazole (65 mg, 0.5 mmol) and Cs2CO3 (325 mg, 1 mmol) were suspended in DMF. The mixture was stirred overnight at room temperature, then filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford N-(3-(5-cyano-2-methoxyphenyl)-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (23.2 mg, yield: 15%). 1H NMR (CDCl3, 400 MHz) δ: 9.59 (s, 1H), 8.77 (dd, J=2.0, 7.2 Hz, 1H), 8.70 (s, 1H), 8.51 (dd, J=2.0, 4.4 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.99 (q, J=4.4, 6.8 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:15])[CH:13]=O.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[CH3:15])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(C(C)C=O)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(C)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 100 mL round bottom flask, 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanal (100 mg, 0.49 mmol, 1.0 eq) and Boc-piperazine (91 mg, 0.49 mmol, 1.0 eq) was dissolved in DCM (10 mL). To above solution was added sodium triacetoxyborohydride (208 mg, 0.98 mmol, 2.0 eq). The reaction was stirred at r.t. for 16 hr. The reaction was then diluted with DCM (10 mL), washed with aqueous bicarbonate, water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained after purification by flash column chromatography (5% MeOH/DCM). LC-MS (IE, m/z): 375.41 [M+1]+; tR=2.47 min.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][C:3]=1[F:15].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:17])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Into a 20000-mL 4-necked round-bottom flask was placed a solution of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (800 g, 2.96 mol, 1.00 equiv) in toluene (10000 mL), followed by the addition of PCl5 (1540 g, 7.40 mol, 2.50 equiv) in several batches at 25° C. over 1 hour. The resulting solution was heated to reflux for 5 hr, cooled to room temperature and diluted with 5000 mL of ether. The solids were collected by filtration and dissolved in 10000 mL of ether. The resulting mixture was washed with 5000 mL of ammonia (10%), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 700 g (82%) of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47]Cl>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCCl
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
Potassium carbonate (410 mg, 2.97 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature for 30 min. 2-Dimethylaminoethyl chloride hydrochloride (85.6 mg, 0.59 mmol) was then added. The mixture was heated at 80° C. for 1 h. The resulting reaction mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (350 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C31H35N3O5S2 [M+H]+ 594.77, observed 594.2.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3cccc(Cl)c3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (52%) which was obtained as an off-white solid. MS: m/e=359.4 [M+H]+. To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (84%) which was obtained as a white solid. MS: m/e=343.4 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:3]=[C:2]([C:42]2[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=2)[CH:7]=[CH:6][CH:5]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 76.4 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.01 g), 4-trifluoromethylphenylboronic acid (1.70 g), 2M aqueous sodium carbonate solution (22.4 ml) and tetrakis(triphenylphosphine)palladium(0) (323 mg), the title compound (2.58 g) was obtained as colorless needle crystals.