Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[C:29]=3[C:37]([C:39]3[CH:44]=[CH:43][C:42](OCCCCN4CCCC4)=[CH:41][CH:40]=3)=[O:38])=[CH:24][CH:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH2:4].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[C:2]([OH:7])(=[O:6])[C:3]([OH:5])=[O:4].[N:58]1([CH2:57][CH2:56][NH:55][C:42]2[CH:41]=[CH:40][C:39]([C:37]([C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:23][CH:24]=3)=[O:38])=[CH:44][CH:43]=2)[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: NCCN1CCCC1
Reactant: O=C(c1ccc(OCCCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(NCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 130.5 %

Procedure:
4-Fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl)benzo[b]thiophen-3-yl ketone (Example 145, Part A) (1.1 g; 2.5 mmol) was combined with 1.6 mL (12.3 mmol) of 1-(2-aminoethyl)pyrrolidine and 1.0 g (7.4 mmol) of potassium carbonate in 2 mL of dry DMF. The mixture was heated in an oil bath maintained at 130° C. for 18 h. After cooling to room temperature, the mixture was poured into 150 mL of water and stirred for 0.5 h. The product was isolated by filtration and washed with fresh water. The title compound (0.9 g; 68% yield) was purified by flash chromatography on silica gel, eluting with a gradient of hexanes(75-15%)/Et3N(5%)/THF(20-80%). Conversion to the trioxalate was effected as in Example 137, Part E.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH:63]([F:65])[F:64])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([O:62][CH:63]([F:65])[F:64])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(OC(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(OC(F)F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 105 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-difluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 114 mg white solid (68%). MS (ISP) 477.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[O:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc2ccnc(Cl)c2c1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: FC(F)(F)c1ccc2ccnc(Oc3ccccc3)c2c1
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-7-(trifluoromethyl)isoquinoline (1.5 g, 6.5 mmol), from above step C, KOH (0.73 g, 13 mmol) and phenol (6.1 g, 65 mmol) were heated at 100° C. for 72 h. The resulting mixture was cooled to room temperature and taken in Et2O and extracted with 4N NaOH (×3). The organic fraction was washed with water, saturated NaCl, dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1>C(OCC)C>[Br:1][CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)=[O:16]
Reactant: CCCCCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
Bromine (0.02 mol) was added dropwise to a stirred solution of 4'-chlorohexanophenone (0.02 mol) in dry diethyl ether (20 ml) at 10°-20° over one hour. The ether was then removed in vacuo from the reaction mixture to leave a pale-yellow liquid which on distillation gave 2-bromo-4'-chlorohexanophenone, b.p. 124°-126°/0.04 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]COC)=[CH:6][C:5]([O:12]COC)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26].Cl>C(O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([OH:12])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCCCc1c(Br)c(OCOC)cc(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: COCCCc1c(Br)c(O)cc(O)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 1.1 h
Yield: 97.3 %

Procedure:
In the same manner as in the step 2 in Example 25, 4-bromo-1,5-bis(methoxymethoxy)-3-(3-methoxypropyl)-2-phenylbenzene (37.2 mg, 0.0875 mmol) was dissolved in ethanol (4 mL), and concentrated hydrochloric acid (0.1 mL) was added thereto and stirred at 60° C. for 1.1 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (chloroform/methanol=20/1) to obtain Compound 97 (28.7 mg, 97%).
Reaction SMILES: C([C:3]1[C:4](=[O:14])[NH:5][C:6]([CH3:13])=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:8]=1)#N>Cl>[CH2:9]([C:7]1[CH:8]=[CH:3][C:4](=[O:14])[NH:5][C:6]=1[CH3:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Product: CCCCc1ccc(=O)[nH]c1C
Yield: 68.1 %

Procedure:
A suspension of 3-cyano-5-butyl-6-methylpyridin-2(1H)-one (950 mg, 5.0 mmol) in 6N hydrochloric acid (36 mL) was refluxed for 3 days. The reaction was cooled and extracted with methylene chloride to isolate product. It was then dried with methylene chloride solution, filtered and evaporated. The residue was triturated with diethyl ether to yield product (563 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]=NC2C=CC([N+]([O-])=O)=CC=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl>Cl.C(O)C>[NH2:9][C:3]1[C:2]([Br:1])=[CH:7][C:6]([OH:8])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Br)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: Nc1ncc(O)cc1Br
Temperature: 0 °C
Yield: 34 %

Procedure:
The compound from 31b above (5.0 g, 15.8 mmol) and tin chloride (25 g, 111 mmol) were suspended in concentrated HCl and ethanol (150 mL), and the mixture was heated at reflux for 1 hour. The mixture was cooled to 0° C., then filtered. The filtrate was neutralized with sodium bicarbonate (180 g) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; chloroform/methanol/NH4OH, 95:5:0.5-90:10:1) to afford the title compound (3.3 g, 34% yield): MS (CI/NH3) m/z 189, 191 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ7.57 (d, J=2.6 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:21][CH:22]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=1)=[O:26])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:23][CH:22]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][N:35]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:33])=[CH:30][CH:31]=1)=[O:26])[CH3:21]
Reactant: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NC(C)C)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 40.5 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol, synthesized in accordance with WO2004/108683), 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-propylamide (40 mg, 0.18 mmol) prepared in Reference Synthetic Example 3 and p-toluenesulfonic acid (6 mg) were heated with 2-propanol (1.8 mL) for 14 hours with reflux. After cooling, the solvent was evaporated, and the resulting solid was washed with 2-propanol to give 36 mg of the desired product (yield 42%).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=O)[C@H:3]([CH3:5])[OH:4].[NH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:8])[C@H:3]([CH3:5])[OH:4]
Reactant: CC(C)(C)OC(=O)CN
Reactant: C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
In 50 ml of THF are dissolved 5.0 g of Z-(D)-Thr-OH and 3.6 g of H-Gly-OBut. After cooling, 3.9 g of HONB and 4.5 g of DCC are added, and the mixture is stirred overnight. The solvent is distilled off, and the residue is extracted with 100 ml of AcOEt, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt is distilled off, and the residue is treated with petroleum ether. Recrystallization from AcOEt-petroleum ether yields 5.0 g of the desired compound. m.p. 56°-57° C., [α]D23 +13.8° (c=0.5, MeOH), Rf1 =0.69.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([OH:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:48])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:28][C@@H:16]1[CH2:17][CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:48])[CH2:19]2)[C@@H:25]2[C@@H:15]1[C@H:6]1[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]1
Reactant: C[C@]12CCCCC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 89 %

Procedure:
The title compound II-ax was prepared in 89% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxyandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, dmso-d6, ppm from TMS): δ 4.32 (1H, bb), 3.75 (1H, m), 2.40-1.00 (20H, m), 0.96 (3H, s), 0.78 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:36][B-](F)(F)F)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: F[B-](F)(F)CN1CCOCC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester and potassium (morpholin-4-yl)methyltrifluoroborate following a procedure analogous to that described in Step 1 of Intermediate 9.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][N:17]2[CH:26]=1)[C@@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][N:17]2[CH:26]=1)[C@@H:9]([CH3:13])[C:10]([NH2:12])=[O:11]
Reactant: C[C@@H](C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(C(C)(C)C)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(N)=O)[C@H](N)c1cn2cc(C(C)(C)C)ccc2n1
Reaction time: 18 h
Yield: 102.3 %

Procedure:
tert-Butyl((1S,2R)-3-amino-1-(6-(tert-butyl)imidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxopropyl)carbamate (Preparation 37, 311 mg) was dissolved in dichloromethane (ca 4 mL) and excess trifluoroacetic acid (ca 0.5 mL) was added. The reaction mixture was stirred for 18 hours then the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The product stayed in the aqueous phase. The aqueous phase was adjusted to pH=10 with 1N sodium hydroxide, then sodium chloride was added until the solution was saturated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% CMA80 in dichloromethane to afford 233 mg of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](/[Sn](CCCC)(CCCC)CCCC)=[CH:17]\[C:18]([O:20][CH3:21])=[O:19]>Cl[Cu].CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](/[C:16](/[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:17]\[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/C(=O)OC)CCCCCCCCOC1CCCCO1
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(CCCCCCCCOC1CCCCO1)/C(=C/C(=O)OC)CCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a flamed-dried round-bottomed flask was added (E)-methyl 11-((tetrahydro-2H -pyran-2-yl)oxy)-3-(tributylstannyl)undec-2-enoate (1 equiv, 25.5 mmol, 15.0 g), DMF (30 mL), and CuCl (3 equiv, 76.5 mmol, 7.57 g). The reaction was stirred for 3 h at rt, quenched with aq. NH4Cl/NH4OH (pH ˜8) (35 mL), and stirred for 2 h open to the air. The solution was diluted with H2O (50 mL) and Et2O (50 mL). The layers are separated and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine (75 mL), dried with MgSO4, concentrated in vacuo, and purified by flash chromatography (step gradient, 10% EtOAc/Hex to 15% EtOAc/Hex) to afford (2E,4E)-dimethyl 3,4-bis(8-((tetrahydro-2H-pyran-2-yl)oxy)octyl)hexa-2,4-dienedioate (6.27 g, 10.5 mmol, 83%). TLC Rf=0.19 (10% EtOAc/Hex); 1HNMR (500 MHz): δ 5.84 (bs, 2H), 4.55-4.61 (2H), 3.83-3.92 (2H), 3.69-3.77 (s plus ovlp. m, 8H), 3.47-3.55 (m, 2H), 3.38 (dt, 2H, J1=9.6 Hz, J2=6.7 Hz), 2.72-2.84 (4H), 1.78-1.89 (2H), 1.69-1.76 (2H), 1.50-1.63 (12H), 1.28-1.41 (20H); 13CNMR (125 MHz): δ 166.5, 161.8, 117.6, 98.8, 67.7, 62.3, 51.2, 30.8, 29.7, 29.6, 29.4, 29.3, 29.1, 28.7, 26.2, 25.5, 19.7; FTIR: 2927, 2855, 1718, 1628, 1433, 1351, 1193, 1163, 1136, 1078, 1023, 986, 905, 868, 814 cm−1; HRMS-ESI: calc. for C34H58NaO8 (M+Na)+: 617.4029. found: 617.4039.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1.[H-].[Na+].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C)C=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([N:4]3[C:5]([CH3:7])=[CH:6][C:2]([O:1][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3]3)=[CH:9]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2ccc(-n3nc(O)cc3C)cc2c1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(-n3nc(OCCN4CCOCC4)cc3C)cc2c1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
To a solution of 3-hydroxy-5-methyl-1-(7-methoxynaphthalen-2-yl)-1H-pyrazol (1.51 g, 5.96 mmol) in dimethylformamide (40 ml), cooled down to 0° C., a dispersion in mineral oil at 60% of NaH (0.36 g, 8.94 mmol) was added, the cooling bath was removed, and was left to stirring until it recovered the room temperature (1.5 hrs). Subsequently, 2-chloroethylmorpholine (1.02 g, 6.85 mmol) dissolved in DMF (10 ml) was added dropwise, and the resulting mixture was heated at 60° C. during 20 hrs. Water-ice was added and it was evaporated to dryness in a rotavapor. The resulting slurry was divided between water and ethyl ether. The aqueous phase was newly extracted with a solvent, and the collection of organic phases was washed with water, dried over sodium sulfate, filtered, and evaporated yielding 2.19 g of a crude product, which was purified by crystallization of its chlorhydrate (prepared by dissolving in HCl-saturated dioxane) in isopropyl alcohol-ethyl ether. 1.78 g (74%) of the 4-{2-[1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}morpholine chlorhydrate were obtained as a solid with a m.p.=143-147° C.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1-c1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2sccc2-c2ccc3c(c2)OCO3)c1Br
Yield: 60 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]thiophene-2-sulfonamide was prepared in the same manner as described in Example 9 by reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p. 183-186° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=3)[N:16]=2)=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)/C(C)=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.7 %

Procedure:
A flask containing (E)-ethyl 2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C36) (0.96 g, 2.3 mmol) and palladium on carbon (10 wt %, 0.24 g, 0.23 mmol) in ethyl acetate (10 mL) was evacuated under vacuum, filled with nitrogen, evacuated under vacuum, and then placed under hydrogen by balloon (˜1 atm). After stirring at room temperature for 20 hours, the reaction was filtered through a pad of Celite® and concentrated to afford the title compound as a white solid (1.0 g, 100%): mp 73-75° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.14-8.07 (m, 2H), 7.86-7.76 (m, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.22-2.99 (m, 1H), 2.75 (dq, J=13.3, 7.5 Hz, 2H), 1.24-1.15 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 420 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][CH2:53][N:52]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][CH2:53][NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@H](C)C4)c3)c2)c1
Reaction time: 1.5 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (48 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete and the solution stripped to dryness. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as an ivory colored solid [62.1 mg (53%)]. LC-MS m/z 747.3 (M+H)+.