Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@@H:19]([O:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[CH:53]=[CH:52][C:48](C(O)=O)=[CH:47][CH:46]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C@H:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:48]3[CH:47]=[CH:46][C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[CH:53][CH:52]=3)=[CH:13][CH:14]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:35][CH:34]=1)([CH3:37])[CH3:38]
Reactant: CC(C)c1ccc(O[C@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(O[C@H](Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 75 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using 2-trimethylsilylethyl (R)-3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (356 mg), 4-pyridine-2-ylbenzoic acid (143 mg), diethyl cyanophosphonate (0.11 ml) and triethylamine (0.10 ml) and the reaction mixture was treated to afford the title compound (307 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](/[N:9]=[C:10]2\[C:11](=[O:19])[NH:12][C:13]3[C:18]\2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:10](=[N:9]/[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)/[C:11]2=[O:19])=[CH:32][CH:31]=1
Reactant: O=C1Nc2ccccc2/C1=N/c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2ccccc2N1c1ccc(Br)cc1
Yield: 42.4 %

Procedure:
A solution of (3Z)-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2H-indol-2-one (100 mg, 0.344 mmol), copper (II) acetate (93 mg, 0.516 mmol), triethylamine (105 mg, 1.03 mmol), and 4-bromobenzene boronic acid (104 mg, 0.516 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine), giving the desired product (65 mg, 42%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38].CO>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (250 mg, 0.440 mmol) and ammonia in MeOH 7M (7 ml, 49.0 mmol) the title compound was obtained as a yellow solid (187 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (br. s., 1H), 7.78 (d, J=5.3 Hz, 1H), 7.55-7.71 (m, 1H), 7.31-7.43 (m, 1H), 7.10-7.30 (m, 4H), 6.52 (s, 2H), 5.59 (d, J=5.2 Hz, 1H), 3.66 (t, J=4.3 Hz, 4H), 3.40 (d, J=4.5 Hz, 4H). MS (ESI): 549.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1>COCCOC.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1nn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1ccc([Sn](C)(C)C)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of methyl 5-bromofuranoate (0.75 g, 3.66 mmol), hexamethylditin (1.0 g, 3.05 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) in DME (50 mL) was heated to reflux overnight. The initial amber coloured solution became black. The solution was allowed to cool and then filtered and concentrated under reduced pressure. The crude stannane was purified by passage through a plug of silica (1:9 EtOAc:cyclohexane) to give methyl 2-trimethylstannyl-5-furanoate (0.17 g, 19%): 1H-NMR (CDCl3); The low yield of the product may be due to its suspected volatility. Pd(PPh3)4 (9 mg, 0.008 mmol) was added to a solution of 1-benzyl-3-iodo-1H-indazole (0.13 g, 0.39 mmol) and methyl 2-trimethylstannyl-5-furanoate (0.17 g, 0.588 mmol) in DME (20 mL).and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool to rt, filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica (3:7 EtOAc:cyclohexane) gave the product as a slightly contaminated yellow solid (88.6 mg, 69%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])[C:14]([NH:16][C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Nc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)C(Nc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of tert-butyl 6-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetyl]amino]pyridine-3-carboxylate (Example A8; 31 mg, 0.057 mmole) in DCM (1 mL) was added TFA at 0° C. Reaction mixture was stirred at rt for 1 hr. TFA was removed invaccuo, residue was neutralised using sat.NaHCO3 solution, extracted with ethyl acetate (3×10 mL) washed with brine, dried over anhydrous sodium sulfate and concentrated. Product was purified using preparative TLC, provided title compound (0.005 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(C(C)=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[O:27][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1SC(F)F
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(Cl)c1SC(F)F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of 2-chloropyrimidine (150 mg), 2-chloro-5-[4-chloro-5-[(difluoromethyl)-thio]-1-methyl-1H-pyrazol-3-yl]-4-fluorophenol (0.3 g) and potassium carbonate (0.18 g) in N,N-dimethylformamide and methyl ethyl ketone (1:4, 20 ml) was heated at reflux overnight. The resulting mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo and the residue purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:3) to give 2-[2-chloro-5-[4-chloro-5-[(difluoromethyl)thio]-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]pyrimidine, (0.29 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)=[O:25]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([C:24](=[O:25])[N:23]([CH3:22])[CH3:35])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CN(C)C(=O)c1ccc2c(c1)CCN2
Product: CN(C)C(=O)c1ccc2c(c1)CCN2c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N,N-dimethylindoline-5-carboxamide (intermediate-13).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][C:31]1[C:45]([O:46][CH3:47])=[CH:44][C:34]2[NH:35][C:36]([C:38]3[C:42]([NH2:43])=[CH:41][NH:40][N:39]=3)=[N:37][C:33]=2[CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CO>[CH3:47][O:46][C:45]1[C:31]([O:30][CH3:29])=[CH:32][C:33]2[NH:37][C:36]([C:38]3[C:42]([NH:43][C:15]([CH:11]4[O:12][CH2:13][CH2:14][N:9]([CH2:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:10]4)=[O:17])=[CH:41][NH:40][N:39]=3)=[N:35][C:34]=2[CH:44]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(Cc4ccccc4)CCO3)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.8 %

Procedure:
To a suspension of rac-4-benzyl-2-morpholinecarboxylic acid hydrochloride (77 mg, 0.30 mmol) in THF (2 ml) was added DMF (2.0 μl, 0.025 mmol) followed by oxalyl chloride (36 ul, 0.41 mmol). After stirring at room temperature for 20 min. the mixture was evaporated to dryness and then re-suspended in THF (2 ml). A solution of 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (60 mg, 0.2 mmol) and diisopropylethylamine (110 μl, 0.9 mmol) in THF (1 ml) was then added and the reaction stirred for at room temperature for 1 h. After 1 h, MeOH (1 ml) was added, the mixture concentrated and the residue purified through preparative LC/MS to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-benzyl-2-morpholinecarboxamide (AT8769) as a white solid (10 mg, 9%). (LC/MS (basic method): Rt 2.86 min, [M+H]+ 463).
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C(OC(=O)C)(=[O:14])C>[Cr].CC#N>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccccc1
Agent: [Cr]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a freshly prepared CH2Cl2 solution of chromyl diacetate (O2Cr(OAc)2, 1 mL, 1 M) was added dropwise a CH3CN solution of H5IO6 (0.33 M, 3 mL) at −40° C. for 10 minutes to give a deep orange solution which is stable at −40° C. for several hours. In a different flask, a CH2Cl2 (0.4 mL) solution of ethyl benzene (212 mg, 2 mmol) and acetic anhydride (0.38 mL, 4 mmol, 2 eq) was cooled to −40° C. The earlier prepared chromium oxidant solution (0.4 mL, 0.25 M. 5 mol %) was added in one portion to the solution of starting material, followed; by the addition of a CH3CN solution of H5IO6 (0.33 M, 18.2 mL, 3 eq) at −40° C. over a period of 30 minutes. The resulting orange colored reaction mixture was gradually warmed up to 0° C. for a period of 1.5 h, quenched by addition of saturated aqueous Na2SO4, extracted with EtOAc, washed with water, brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography to give acetophenone (231 mg, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-])=O.C(N(C(C)C)CC)(C)C>CC(O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccc(O)cc3)ncn2)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4-Chloro-6-(4nitro-phenoxy)pyrimidine (Stage 22.5; 3 g, 11.9 mmol), 4-nitrophenol (1.95 g, 17.9 mmol), and diisopropylethylamine (DIPEA) (3.04 ml, 179 mmol) dissolved in 2-propanol (50 ml) are stirred at 85° C. for 18 h. After concentrating the reaction mixture under reduced pressure, the product precipitates as a colorless fine solid: M+H=245.0; 1H-NMR (400 MHz, DMSO-d6): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5 Hz, 2H, phenyl-NO2), 8.26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H, phenyl-NO2), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H, phenyl-OH), 6.15 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=2:1): 0.48.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21](=[O:43])[N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:24][CH2:23]2)[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:26][CH2:27]2)=[O:43])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (0.003 g, 0.0050 mmol) was placed in DCM (2 mL) at room temperature. TFA (0.4 mL) was then added, and the reaction was stirred for 1 hour. The reaction was concentrated to dryness. The crude residue was dissolved in minimal DCM and added dropwise to a stirring solution of 1M HCl in ether (10 mL). The solid product was then filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.001 g, 40% yield) as the dihydrochloride salt. MS ESI (+) m/z 503 detected.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[N:13]1([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][CH:15]=[N:14]1.[CH2:27]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>O1CCCC1>[O:33]1[C:34]2[CH:35]=[CH:36][C:28]([CH2:27][N:37]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:20](=[O:22])[C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:29][C:30]=2[O:31][CH2:32]1
Reactant: c1ccc(CNCc2ccc3c(c2)OCO3)cc1
Reactant: O=C(O)c1ccccc1-n1cccn1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccccc1-n1cccn1)N(Cc1ccccc1)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperature for 3 h. After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion. After 30 min, the reaction is filtered, diluted with ether and washed with water. The organic layer is dried (Na2SO4) and purified over column chromatography to provide the desired product (390 mg). The proton NMR displays a typically doubled pattern. 1H (CDCl3) 3.83 and 4.32 (two doublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 two doublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14 Hz, 1H), 5.93 and 5.98 (s and doublet, J=2 Hz, 2H, OCH2O), 6.35-6.40 (m, 2H), 6.51 (d, J=4 Hz, 0.5H), 6.4 (m, 1.5H), 7.0-7.88 m, 15H). LC-MS 412.3.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: OCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C

Procedure:
1 mole of butane-1,4-diol, 3 moles of trimethylchlorosilane and 0.002 moles of tetra-n-butyl ammonium bromide were reacted at the reflux temperature (54°-96° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:19]([O:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[CH:18]=[CH2:17]
Reactant: Oc1ccc(F)cc1-c1c(Cl)cccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2′,6′-dichloro-5-fluorobiphenyl-2-ol (11.63 g, 45 mmol) in DMF (150 mL) was added allyl bromide (5.8 mL, 67.5 mmol) and potassium carbonate (18.6 g, 135 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and poured into water. The mixture was extracted with methylene chloride and washed with water. The solvent was removed under vacuum. Chromatography with 0–30% ethyl acetate in hexanes afforded 12.7 g (94%) of 2-allyloxy-2′,6′-dichloro-5-fluorobiphenyl as a light yellow oil. MS (EI) m/z 296 (M+).
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11]
Reactant: CC1(C)CCCNC(=O)C1(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCCNC(=O)C1Cl
Yield: 94.9 %

Procedure:
3.8 g (0.018 moles) of 3,3-dichloro-4,4-dimethyl-2-oxoperhydroazepine were dissolved in 300 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 1.9 g of 10% Pd/C. When the theoretical amount of hydrogen was consumed the catalyst was filtered off and the filtrate evaporated in vacuo to give 3 g of the title compound sufficiently pure for the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:13]([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: C1CCOC1
Product: CN(C)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-chloro-3-nitropyridine (J. Heterocyclic Chem. 2003, 40, 261) (128 mg, 0.54 mmol) was taken into THF (0.25 mL) followed by addition of 40 W % aqueous dimethylamine (0.25 mL) and the resulting solution was stirred for 1 h at room temperature. The mixture was then partitioned with ethyl ether and 1 M aqueous hydrochloric acid. The organic solution was then washed with additional 1 M aqueous hydrochloric acid (3×) then dried over magnesium sulfate, filtered and concentrated to give 5-bromo-N,N-dimethyl-3-nitropyridin-2-amine. MS (EI) for C7H8N3O2Br: 246, 248 (MH+, Br pattern).
Reaction SMILES: [Mg].Br[CH:3]([CH3:5])[CH3:4].C([Mg]Br)(C)C.[C:11]([O:14][C@H:15]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C@H:25]([CH3:31])[CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:16]1)(=[O:13])[CH3:12].Cl>CCOCC.C1C=CC=CC=1.[Br-].[Cd+2].[Br-]>[C:11]([O:14][C@H:15]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C@H:25]([CH3:31])[CH2:26][CH2:27][C:28](=[O:29])[CH:3]([CH3:5])[CH3:4])[CH2:16]1)(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)Cl)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(C)Br
Agent: CC(C)[Mg]Br
Agent: Cl
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
To a mixture of magnesium (24 g, 1.00 mole) in dry ether (500 ml) was added dropwise 2-bromopropane (60 ml, 639 mmole) while stirring. After the addition was completed, the reaction mixture was stirred for thirty minutes. The ethereal solution was transferred to another flask. Then to the resulting isopropyl-magnesium bromide solution was added portionwise cadmium bromide (75 g, 276 mmole) at room temperature. The resulting dark solution was refluxed gently for one hour, followed by the addition of dry benzene (200 ml), then most of the ether was removed. To this mixture, 3β-acetoxy-5-cholenic acid chloride 331 (50 g, 115 mmole) in dry benzene (300 ml) was added dropwise. The reaction mixture was stirred at room temperature for one hour and then poured slowly into a crushed ice and 10% hydrochloric acid mixture. The organic layer was separated. The aqueous layer was extracted with ether (3×300 ml). The combined ethereal solution was washed with 10% HCl, washed with water, dried (MgSO4), filtered, and concentrated in vacuo to give crude product, 3β-acetoxy-24-oxo-5-cholestene 332 (35.6 g, 70% yield), which was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ: 0.69 (3H, s, 18--CH3), 0.95 (3H, d, 21--CH3), 1.04 (3H, s, 19--CH3), 1.25 (6H, 2d, 26--CH3, 27--CH3), 2.04 (3H, s, --OCOCH3), 4.61 (1H, m, 3α-H), 5.38 (1H, m, 6-H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:11]([C:7]2[CH:8]=[N:9][O:10][C:6]=2[CH3:5])=[O:12])=[CH:17][CH:16]=1
Reactant: Cc1oncc1C(=O)Cl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1oncc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of aluminium chloride (16 g) and 5-methylisoxazole-4-carbonyl chloride (5.0 g) in dry chlorobenzene (50 ml) was stirred in an atmosphere of nitrogen for 16 hours. The mixture was heated to 80° C. for 1 hours. The cooled mixture was quenched with excess ice and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ethyl acetate and cyclohexane (1:20) to give 4-(4-chlorobenzoyl)-5-methylisoxazole (compound 9, 5.2 g) as a yellow solid mp 65°-66° C.