Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.C(O)(=O)C.Cl>CO.O1CCOCC1.[Zn]>[CH3:18][C:4]1[N:3]=[CH:2][C:7]([NH2:8])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: Cc1cc(Nc2ccccn2)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccccn2)c(N)cn1

Procedure:
To a solution of N-(2-chloro-6-methyl-3-nitropyridin-4-yl)pyridin-2-amine (860 mg, 3.25 mmol) in methanol (30 mL) was added zinc powder (2.12 g, 32.49 mmol) and acetic acid (0.93 mL, 16.25 mmol). The reaction was heated to reflux and stirred for 2 h after which time 4M HCl in dioxane was added (4.0 mL, 16.0 mmol). After stirring at reflux overnight, the zinc was filtered off and the filtrate was concentrated. The residue was dissolved in CH2Cl2 (100 mL) and IPA (10 mL) and 5% Na2CO3 (aq) was added until pH 11 was obtained. The organic layer was separated. Solid NaCl was added to the water layer to saturate it and then it was extracted with 20% IPA/CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to an oil (550 mg, 85%). MS (ESI) mass calcd. C11H12N4, 200.11. m/z found, 201.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(Cc3cc(-c4cccnc4)on3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-benzyloxy-phenyl)-acetohydroximoyl chloride (214 mg, 0.776 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (270 μL, 1.94 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (80 mg, 48%).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][Si](C)(C)C)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C@H](C1C=CC=CC=1)[C@H](OC)C1C=CC=CC=1.[C:36]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(=[O:45])[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl[Si](C)(C)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:6]([NH:13][CH:38]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][C:36]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1
Reactant: C[Si](C)(C)NCc1ccccc1
Agent: CO[C@H](c1ccccc1)[C@H](OC)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CC(NCc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Under an argon atmosphere, n-butyllithium (0.9 mL, 1.6 M in hexane solution, 1.5 mmol) was added to a solution of N-benzyltrimethylsilylamine (0.3 mL, 1.5 mmol) in toluene (4 mL) at −78° C. over 5 min. After stirring for 0.5 hr, a solution of (1R,2R)-1,2-dimethoxy-1,2-diphenylethane (436 mg, 1.8 mmol) in toluene (2 mL) was added, and the mixture was stirred at −78° C. for 0.5 hr. Thereto was added a solution of tert-butyl cinnamate (204 mg, 1.0 mmol) and chlorotrimethylsilane (0.63 mL, 5.0 mmol) in toluene (2 mL) over 5 min. The mixture was stirred at −78° C. for 5 hr, and quenched with saturated aqueous ammonium chloride solution (1.5 mL). After adding a saturated aqueous sodium hydrogen carbonate solution (20 mL), the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, after which it was concentrated and subjected to silica gel column chromatography (ethyl acetate/hexane=1/25) to give the title compound (302 mg, yield 97%) as a colorless oil of [α]25D+32.5 (c 1.35, CHCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[C:24]1([CH2:30][CH2:31][N:32]=[C:33]=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:32]([CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]2=[O:34])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=NCCc1ccccc1
Product: COc1cccc2c1ncc1c(=O)n(CCc3ccccc3)c(=O)n(C3CCCC3)c12
Yield: 48.1 %

Procedure:
1-Cyclopentyl-7-methoxy-3-phenethyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (20 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and (2-phenyl)ethyl isocyanate (0.5 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A reaction mixture comprising 3.0 g of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl, 0.1 g of palladium hydroxide and 30 ml of ethyl acetate was filled with hydrogen gas, and stirred at room temperature for 8 hours. The reaction mixture was filtered, and the solvent of the filtrate was evaporated away. The resulting residue was recrystallized from heptane, and 1.5 g of 4-hydroxy-4′-(trifluoromethoxy)biphenyl was obtained. m.p.: 140-140.5° C.
Reaction SMILES: [NH3:1].[C:2]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[CH:3]1>>[NH3:1].[C:2]([OH:7])(=[O:8])/[CH:3]=[CH:4]\[C:5]([NH2:1])=[O:6]
Reactant: O=C1C=CC(=O)O1
Agent: N
Product: NC(=O)/C=C\C(=O)O
Reaction time: 0.5 h

Procedure:
Into 250 ml of anhydrous liquid ammonia in a beaker, 39.2 g (400 mmol) of maleic anhydride (MA) were carefully added into the solution. The reaction occurred for 30 minutes at −33° C. A white precipitate was formed. After the remaining ammonia was removed by evaporation, the product was dried under vacuum at 40° C. Finally, 52.7 g of maleamic acid ammonia salt (MAA) were obtained. The MAA, in a beaker, was placed in a nitrogen-flowing oven. At about 160° C., the reactant started to melt and turned brown. At approximately the same time, the material started to expand due to the release of ammonia and water vapor. It was then heated at 220° C. for two hours under a nitrogen atmosphere. After cooling down, 38.6 g of brown porous material were obtained.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoic acid in 2.9 ml of DMF are stirred, at RT for 18 h, together with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. The reaction mixture is then poured onto ice water, and this mixture is extracted with 3 portions of ethyl acetate; the combined organic phases are washed with 10% citric acid solution, water and saline, dried with sodium sulfate and evaporated. An oil is obtained. This is followed by hydrolysis of the silyl ester function of the oil, at RT, using 2.2 g of potassium carbonate in 63 ml of methanol/water/THF, 3:1:1, and partial evaporation at RT. The aqueous residue is poured onto 10% citric acid solution and ice, and this mixture is extracted 3 times with ethyl acetate; the organic phases are washed twice with water and saline, dried with sodium sulfate and evaporated. Column chromatography (SiO2, D) of the crude product yields the title compound: TLC Rf (D)=0,17; tRet (I)=33,7 min; FAB-NS (M+H)+ =634.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:18]OC(C)(C)C>C(Cl)Cl>[Cl:18][C:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OCl
Reactant: O=c1cc(N2CCOCC2)oc2ccccc12
Solvent: ClCCl
Product: O=c1c(Cl)c(N2CCOCC2)oc2ccccc12
Yield: 87.5 %

Procedure:
2-(4-Morpholinyl)-4H-benzopyran-4-one (2.0 g, 8.0 mmol) is dissolved in CH2Cl2 (20 mL). t-Butyl hypochlorite (1.0 mL, 8.5 mmol) is added dropwise at 23° C. The reaction mixture is warmed slightly and is finished almost instantaneously. The solvent is removed in vacuo and the residue is taken up in EtOAc (200 mL). The organic layer is washed with water (2×50 mL) and brine (80 mL), then dried (MgSO4). The solution is concentrated in vacuo giving colorless crystals which are recrystallized from EtOAc to give the desired product (1.86 g, 91%) Mp 127°-8° C.; IR (mull) 2962, 2923, 2856, 1635, 1612, 1597, 1562, 1555, 1466, 1457, 1325, 1233, 1119, 872, 762 cm-1 ; 1H NMR (200 Mhz, CDCl3, δ) 8.20 (br d, J=7.5 Hz, 1H), 7.60 (ddd, J=9.1, 6.7, 1.7 Hz, 1H), 7.36 (m, 2 H), 3.88 (m, 4H), 3.74 (m, 4H); MS m/e (rel intensity) 267 (33), 266 (15), 265 (100), 231 (15), 230 (98), 209 (16), 207 (45), 120 (27), 110 (19), 41 (16); UV (EtOH) λ max (ε) 214 (18,900), 238 (18,160), 300 sh (11,530); Anal. calc'd. for C13H12NO3Cl: C, 58.76; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.58; N, 5.37.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[C:15]([Br:22])[N:14]=1>CN(C)C=O>[Br:12][C:13]1[CH:18]=[C:17]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)[CH:16]=[C:15]([Br:22])[N:14]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: FC(F)(F)c1cccc(S)c1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Sc2cc(Br)nc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
1.0 g (0.0056 mol) of 3-trifluoromethylthiophenol was dissolved in 17 ml of dimethylformamide and treated with 0.64 g (0.0056 mol) of potassium tert.-butylate. The mixture was stirred at room temperature for 20 min. and then treated with 1.58 g (0.0056 mol) of 2,6-dibromo-4-nitro-pyridine. The mixture was stirred at room temperature for 3 hrs., the solvent was then removed and the residue was partitioned in water and ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and, after removal of the solvent, the residue was chromatographed on silica gel with ethyl acetate/hexane 1:39. There was obtained 2.08 g (90%) of 2,6-dibromo-4-(3-trifluoromethylphenylsulphanyl)-pyridine as yellow crystals; m.p.: 68-70° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17](OC)=[O:18])[N:16]=2)[N:7]=1)([O-:5])=[O:4].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: COC(=O)c1csc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(Cc2nc(CO)cs2)n1
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole-4-carboxylate (1.10 g, 4.08 mmol) in THF (30 mL) was treated dropwise at 0° C. with DiBAL-H (14.3 mL of a 1.0 M solution in THF, 14.3 mmol) and the resulting solution was stirred for 1 h at 0°. Rochelle's salt solution (100 mL) was added and the mixture was stirred for 1 h at rt. The aq. layer was extracted with EA (2×40 mL) and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.53 min; [M+H]+=241.95.
Reaction SMILES: [C:1]([C@H:6]1[O:10][C@H:9](C(=O)C)[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2].C1C=C(Cl)C=[C:16]([C:21]([O:23]O)=[O:22])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]([C@H:6]1[O:10][C@H:9]([O:23][C:21](=[O:22])[CH3:16])[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1OC[C@@H](C(C)=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1OC[C@@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% mCPBA (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resultant suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-Hexanes) to give the title compound (49% yield) which displayed the following spectral characteristics; 1H NMR (CDCl3):δ 1.29 (t, 3H, J=7.2 Hz), 2.09 (s, 1H), 4.12 (d of d, 1H, J=0.9, 9.1 Hz), 4.19-4.31 (m, 3H), 5.53 (s, 1H), 6.48 (d of d, 1H, J=0.9, 3.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:33]C)(=[O:32])[C@H:29]([CH3:31])O.BrBr>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH3:31])[C:28]([OH:33])=[O:32]
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br)C(=O)O

Procedure:
Prepared from of 2,6-dibromo-4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenol (Example 59) and commercially available (S)-lactic acid, methyl ester. White solid: mp 129-196° C. dec; Opt. rot. [a]25/D=+4.312° (8.812 mg/mL, CHCl3); NMR (DMSO-d6); δ13.12 (broad s, 1 H), 8.12 (d, J=8, 1 Hz, 1 H), 8.06 (d, J =7 Hz, 1 H), 7.82 (q, J=Hz, 2 H), 7.75 (ddd, J=8,7, 1 Hz, 1 H), 7.62-7.49 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.61 (d, J=8 Hz, 1 H), 5.12 (q, J=7 Hz, 1 H), 1.63 (d, J =7 Hz, 3 H); MS (+FAB): [M+], 2 bromine isotope pattern, 680 (45%), 682 (100%), 684 (60%); Anal. Calc. for C25H15Br2IO3S: C, 44.02, H, 2.22, N, 0.00; Found: C, 44.66, H, 2.54, N, 0.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:8][CH2:7]1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 42 h

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (4.15 g) was dissolved in acetone (80 ml). Potassium carbonate (2.42 g), sodium iodide (0.49 g) and then methyl 4-bromobutyrate (1.95 ml) were added and the mixture was stirred for 42 h. The solvent, was evaporated and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phases were dried (MgSO4), filtered and evaporated and the residue was chromatographed eluting with ethyl acetate: triethylamine (99:1) to give the subtitle compound (4.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[C:15]#[N:16])=[CH:4][CH:3]=1.[Br:17]Br.O>O1CCOCC1>[Br:17][C:10]1[C:9]([C:15]#[N:16])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: N#Cc1cc(C#N)c(-c2ccc(Cl)cc2)[nH]1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(C#N)c1Br
Temperature: 25 °C

Procedure:
A sample of 5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile (1.0 g, 0.004 mole) is dissolved in 20 mL of dioxane and a solution of bromine (0.8 g, 0.005 mole) in dioxane (10 mL) is then added thereto. THe solution is stirred several hours at room temperature and then poured into water precipitating a white solid (1.2 g, 100%). The solid has a m.p. >225° C. and a mass spectrum of a sample gives a pattern consistent with the desired structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>C(OCC)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][CH2:13][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 3-bromoaniline (0.50 g, 2.9 mmol) in diethyl ether (Et2O, 5 mL) was added 4 M HCl in dioxane (1 mL), and the mixture was stirred at 25° C. for 1 h. Solvent was removed under reduced pressure, and the resulting HCl salt was dissolved in 2-(2-methoxyethoxy)ethanol (2 mL). 2-Oxazolidinone (0.429 g, 4.93 mmol) was added, and the reaction mixture was heated to 180° C. for 24 h. The collected crude solid was purified by column chromatography (0-10% (1% NH4OH in MeOH)/CH2Cl2) to provide N1-(3-bromo-phenyl)-ethane-1,2-diamine (0.10 g, 16%). 3-(Piperidine-1-carbonyl)-benzaldehyde (Example 1, step D; 0.091 g, 0.42 mmol) was added to a solution of the phenyl-diamine in 1,2-dichloroethane (10 mL), and the reaction mixture was stirred at 25° C. for 15 min. The mixture was treated with NaBH(OAc)3 (0.128 g, 0.604 mmol), and the resulting suspension was stirred at 25° C. for 18 h. The suspension was partitioned with satd NH4Cl (20 mL) and CH2Cl2 (20 mL), and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (2-10% CH3OH/CH2Cl2), and then by preparative TLC (10% CH3OH/CH2Cl2) to provide the desired product (0.060 g, 34%). MS (ESI): mass calculated for C21H26BrN3O, 415.13; m/z found, 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.26 (m, 3H), 7.21-7.16 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74-6.71 (m, 1H), 6.67 (t, J=2.0 Hz, 1H), 6.47-6.44 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 2H), 3.64 (br s, 2H), 3.25 (br s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.83-2.80 (m, 2H), 1.60-1.43 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:24][C:25](C)(CO)[CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:26])[CH2:23][O:22][CH:3]([C:4]2[CH:5]=[C:6]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:8]=2)[O:2][CH2:1]1
Reactant: CC(C)(CO)CO
Reactant: COC(OC)c1cc(-c2ccncc2)n(-c2ccc(F)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(c2cc(-c3ccncc3)n(-c3ccc(F)cc3)n2)OC1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
A solution of 4-[5-dimethoxymethyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-pyridine (3 g, Reference Example 1), 2,2-dimethylpropane-1,3-diol (2.2 g) and p-toluene sulfonic acid (2 g) in dry toluene (50 ml) was refluxed for 1 hour with azeotropic removal of water. The reaction mixture was cooled to room temperature then evaporated. The residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic phase was washed three times with water (50 ml), then dried over magnesium sulphate and then evaporated. The residual oil was triturated twice with diethyl ether then recrystallised from diethyl ether to give the title compound as white needles (1 g), m.p. 150-151° C. [Elemental analysis: C,67.69; H,5.98; N,12.09%. Calculated for C20H20FN3O2: C,67.97; H,5.70; N,11.89%]. MS: 354 [MH]+. RF=0.42 (ethyl acetate, determined by thin layer chromatography on silica).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:22][CH:20]([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)O
Temperature: 31 °C
Reaction time: 20 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (550 mg, 1.83 mmol) in THF (8 mL) was added NaBH4 (139 mg, 3.66 mmol) at 0° C. under N2. The reaction was stirred at 31° C. for 20 hrs. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous NaHCO3. The organic layer was concentrated in vacuo to afford the title compound (520 mg) as a yellow oil which was used directly without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C1COCC1>[CH:17]([O:16][C:13]1[N:12]=[CH:11][C:10]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ccc(C(=O)c2ccc(O)cc2)cn1
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Cc2ccc(O)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(4-Hydroxyphenyl)-(6-isopropoxypyridin-3-yl)methanone (300 mg, 1.17 mmol) was dissolved in 15 ml of THF. Following addition of triethylsilane (678 mg, 5.83 mmol) the mixture was stirred at room temperature for 2 days. Following addition of 116 mg of triethylsilane the mixture was stirred at 60° C. for 8 h, concentrated and admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 52 mg (18%), M+H+: 244.14.