Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:27])[NH:15][C:16](=[O:26])[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg]>CO.C(OCC)(=O)C>[C:1]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:16](=[O:26])[NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1cccc(C2=C(c3cn4c5c(cccc35)CCC4)C(=O)NC2=O)c1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc([C@@H]2C(=O)NC(=O)[C@H]2c2cn3c4c(cccc24)CCC3)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)-1H-pyrrole-2,5-dione (0.73 g, 2.04 mmol), magnesium (0.89 g, 36.7 mmol) in anhydrous methanol was heated to reflux for 1.5 h. After cooling to room temperature, the light yellow solution was diluted with ethyl acetate (200 mL), washed with 1.0 M hydrochloric acid (2×50 mL), water (100 mL), dried over sodium sulfate and concentrated to provide a light brown solid. The residue was purified by column chromatography on silica gel eluting with 40-50% ethyl acetate in hexane to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)pyrrolidine-2,5-dione as a light yellow solid. Mp 87-91° C.; 1H NMR (CDCl3) 400 MHz δ: 8.73 (s. 1 H), 7.25-7.30 (m, 1 H), 7.14 (d, J=7.6 Hz, 1 H), 6.93-7.01 (m, 3 H), 6.77-6.86 (m, 3 H), 4.36 (d, J=6.4 Hz, 1 H), 4.24 (d, J=6.4 Hz, 1 H), 4.18 (t J=5.5 Hz, 2 H), 3.78 (s, 3 H), 2.97 (t, J=5.6 Hz, 2 H), 2.19-2.24 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1>>[Cl:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Clc1cccc(OCCCCBr)c1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4cccc(Cl)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.065 g of 1-(4-bromobutoxy)-3-chlorobenzene are used to prepare the title compound. Rf=0.29 (2:1 EtOAc-heptane); Rt=6.16.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)=[O:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C(OCC)(=O)C.[Pt]=O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[C:16](=[O:17])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1cc2ccccc2o1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1cc2ccccc2o1
Yield: 39.3 %

Procedure:
A solution of benzofuran-2-yl 2-[1-(phenylmethyl)-4-piperidinyl]vinyl ketone (410 mg) in a mixture of ethanol (70 ml) and ethyl acetate (40 ml) was treated with platinum oxide (80 mg) and hydrogenated at 45 psi for 1 hour. The mixture was filtered through Celite® and the filtrate was concentrated to dryness to give an off-white solid which was recrystallized from ethyl acetate to give 162 mg of white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9](Cl)=[O:10].[CH2:13]([C:20]1[S:21][C:22]([CH2:25][OH:26])=[CH:23][N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:26][CH2:25][C:22]1[S:21][C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:24][CH:23]=1)=[O:10]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Reactant: OCc1cnc(Cc2ccccc2)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Cc3ccccc3)s2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
A solution of 1.26 g of (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-carboxylic acid chloride in 8 ml of benzene was added with stirring at 5° C. to a solution of 0.8 g of (2-benzyl-5-thiazolyl)-methanol in 8 ml of benzene and 0.8 ml of pyridine and the mixture was stirred at 20° C. for 17 hours and was poured into aqueous 2N hydrochloric acid solution with stirring. The decanted organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 hexane-ethyl acetate mixture to obtain 1.41 g of (2-benzyl-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylate melting at 66° C. and having a specific rotation of [α]D20 =+9°±1° (c=1% in benzene).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([C:18]([NH2:20])=[O:19])[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([C:18]([NH2:20])=[O:19])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-Acetylphenyl)-2-nitrothiophene-3-carboxamide (0.21 g, 0.723 mmol) was taken up in MeOH (4 mL), followed by the addition of sodium borohydride (0.027 g, 0.723 mmol). The reaction mixture stirred at room temperature for 3 hours. Water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[NH:7][C:8]([C:10]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:11]=3[N:12]=[C:13]([NH:21][C:22]3([CH3:25])[CH2:24][CH2:23]3)[C:14]([CH3:20])=[N:15]4)=[CH:9][C:5]=2[C:4](=[O:26])[NH:3]1.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[C:5]2[C:4](=[O:26])[NH:3][C@H:2]([CH3:1])[C:6]=2[NH:7][C:8]=1[C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([NH:21][C:22]1([CH3:25])[CH2:23][CH2:24]1)[C:14]([CH3:20])=[N:15]2
Reactant: ClC(Cl)Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1NC1(C)CC1
Product: Cc1nc2cccc(-c3[nH]c4c(c3Cl)C(=O)N[C@@H]4C)c2nc1NC1(C)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a suspension of (R)-6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)-amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (333) (160 mg, 0.46 mmol) in 5 mL of CHCl3 at RT was added n-chlorosuccinimide (73.8 mg, 0.55 mmol) and the mixture was stirred in an oil bath at 50° C. for 1.5 h. LCMS indicated 80% conversion. Additional n-chlorosuccinimide (21 mg, 1.55 mmol) was added and heating at 50° C. was continued for another 30 min. It was cooled to RT, treated with 5 mL of ice cold 0.5 N NaOH, and extracted with 25 mL of DCM followed by 25 mL of EtOAc. The combined organic extracts were concentrated and the residue was purified on a silica gel column (50% EtOAc in DCM followed by 5% MeOH in EtOAc) to give (R)-3-chloro-6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (454) (145 mg, 82% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.97 (1H, br.), 8.26 (1H, dd, J=7.6, 1.2 Hz), 7.84 (1H, s), 7.72 (1H, dd, J=8.0, 1.2 Hz), 7.64 (1H, s), 7.43 (1H, t, J=7.8 Hz), 4.61 (1H, q, J=6.7 Hz), 2.45 (3H, s), 1.45 (3H, s), 1.37 (3H, d, J=6.7 Hz), 0.89 (2H, m), 0.75 (2H, m). m/z (ESI, +ve) 382.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]#[CH:22]>C1COCC1.CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:22][C:21]#[CH:20])[C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CCBr
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium hydride (0.82 g, 23.0 mmol, 60% mineral oil dispersion) is added to a solution of 4-benzyloxycarbonylpiperazin-2-one (5.13 g, 21.9 mmol) in THF/DMF (75 mL, 3/1 v/v) at 0° C. The mixture is stirred for 5 minutes, then propargyl bromide (3.7 mL, 41.5 mmol) is added dropwise. The resulting solution is stirred for 1 hour then brought to room temperature and stirred for 2 hours. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (4×) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (5.96 g, 21.9 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.3 (m, 5H), 5.12 (s, 2H), 4.25 (s,2H), 4.16 (s, 2H), 3.75 (m, 2H), 3.47 (m, 2H), 2.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:21]COC)[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCO[C@@H](CCOCc1ccccc1)COCc1ccccc1
Agent: Cl
Solvent: CO
Product: O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85 %

Procedure:
To a solution of (S)-1,4-dibenzyloxy-2-(methoxymethoxy)butane (2 g, 6 mmol) in methanol (14 ml) was added a 2% solution of methanolic hydrogen chloride (6 ml, 2.5 mmol). The solution was stirred at room temperature for 7 hours, the solvent removed and the residue chromatographed on silica eluting with ethyl acetate hexane 1:1 to give (S)-1,4-dibenzyloxy-2-hydroxybutane (1.46 g, 84%), [α]D25 -7.3° (c 1.1 in ethanol); IR: υmax (film) 3450, 3080, 3060, 3015, 2920, 2860, 2800, 1950, 1870, 1810, 1605, 1585, 1495, 1450, 1365, 1310, 1260, 1205, 1100, 1030, 1000, 950, 915, 820, 805, 760, 700, 610 cm-1 ; 1H NMR: δH (CDCl3) 1.79 (2H, d, t J=6 Hz and 6 Hz, CH2), 2.86 (1H, d, J=3 Hz, D2O exchangeable, OH), 3.45 (2H, m, CH2), 3.65 (2H, m, CH2), 4.05 (1H, m, CH), 4.51 (2H, s, CH2), 4.55 (2H, s, CH2), 7.3 (10H, m, 2×C6H5). Found: C, 75.64; H, 7.87%. C18H22O3 requires: C, 75.50; H, 7.74%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:54])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:37](C(OC(C)(C)C)=O)[CH2:38][CH:39]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH3:40])[C:25](=[O:36])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)(C)(C)C>Cl.CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:54])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:25](=[O:36])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:34])[CH3:35])=[CH:29][CH:28]=2)[NH:37][CH2:38][CH:39]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH3:40])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NC(=O)C(c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)N(CC(C)N2CCOCC2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CC(C)c1ccc(NC(=O)C(NCC(C)N2CCOCC2)c2ccc(/C=C/C(=O)Nc3ccccc3N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
(E)-[2-(3-{4-[[tert-Butoxycarbonyl-(2-morpholin-4-yl-propyl)-amino]-(4-isopropyl-phenylcarbamoyl)-methyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (crude product from Example 3) was dissolved in 1.25M HCl/MeOH (2.9 mL) and stirred at room temperature overnight. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain 150 mg desired product (56% over two steps). MS: calc'd 556 (MH+), exp 556 (MH+).
Reaction SMILES: [C:1]1([CH3:46])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:33]=[C:34]([C:42]([O:44]C)=[O:43])[CH:35]=[C:36]([CH:41]=4)[C:37]([O:39]C)=[O:38])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH3:46])[CH:2]=[CH:3][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][O:31][C:32]4[CH:41]=[C:36]([C:37]([OH:39])=[O:38])[CH:35]=[C:34]([CH:33]=4)[C:42]([OH:44])=[O:43])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(OCCC2(CCN3CCC(N(C(=O)c4ccco4)c4ccc(C)cc4)CC3)CCCCC2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCOc4cc(C(=O)O)cc(C(=O)O)c4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
To a solution of dimethyl 5-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethoxy]isophthalate (synthesized in Example 28) (255 mg) dissolved in methanol (5 mL) was added a 2N aqueous sodium hydroxide solution (2.0 mL). The solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure. Water was then added to the solution, and it was neutralized with acetic acid (0.23 mL) and extracted with chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (243 mg).
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.[H][H]>[Pt].CO>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:33][CH:32]=2)[CH2:12][CH2:13]1)=[O:31]
Reactant: [H][H]
Reactant: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
To 1 part of a solution of 2 parts of thophene in 40 parts of ethanol are added 18 parts of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 7.5 parts (45%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp. 113.2° C. The mother liquor is evaporated, yielding a second fraction of 6 parts (36%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide as an oily residue.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of N-(piperidin-4-yl)acetamide (341 mg, 2.4 mmol) in DMF (15 mL) was added K2CO3 (331 mg, 2.4 mmol) and 1-fluoro-4-nitrobenzene (282 mg, 2 mmol) at room temperature. The reaction was stirred at 80° C. for 24 hours. After that, the reaction was poured into 50 mL of water and extracted with EA (3×25 mL), washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 264 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccccc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(Sc2ccccc2CO)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A mixture of a 60% solution of Na bis-(2-methoxyethoxy)aluminum hydride (85.0 g) and toluene (120 ml) was added dropwise during 1 h to a stirred suspension of 2-(4-methoxyphenylsulfanyl)benzoic acid (33.4 g, 0.128 mol) in toluene (270 ml) under nitrogen atmosphere. Temperature of the reaction mixture was allowed to reach 50° C., then the mixture was cooled down to 20° C. and the mixture was stirred for 5 h. Then a 10% solution of sodium hydroxide (50 ml) was added, the toluene layer was separated and successively washed with a 5% solution of sulfuric acid (50 ml) and water (2×50 ml). An oily residue after evaporation of toluene (31.2 g, 99.2%) was used for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][N:19]([O:23]CC3C=CC=CC=3)[C:20](=[O:22])[CH3:21])=[CH:16][C:3]1=2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][N:19]([OH:23])[C:20](=[O:22])[CH3:21])=[CH:16][C:3]1=2
Reactant: CC(=O)N(CCc1ccc2c(c1)C(=O)c1ccccc1CO2)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
A solution of N-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-N-(phenylmethoxy)acetamide (4.07 g) in absolute ethanol was treated with ammonium formate (3.2 g) and 700 mg 5% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours then filtered through a short pad of celite. The filtrate was evaporated and the residue purified by flash chromatography (silica gel, 2:1 ethyl acetate-hexane) to give an oil. This oil crystallized from ethyl acetate-hexane to give 1.3 g of N-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-N-hydroxyacetamide, as crystals, m.p. 113-115° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:34][CH2:35]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Reactant: CC(C)(C)OC(=O)N1CCOCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.58 h
Yield: 50.7 %

Procedure:
3-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 250 mg, 0.76 mmol) in THF (5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 138 mg, 3.45 mmol) in anhydrous THF (5 mL) at 0° C. and stirred under nitrogen for 35 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 501 mg, 1.38 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. and the solvents removed in vacuo. The residue was suspended between aq Na2CO3 (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with aq Na2CO3 (20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]3[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]3[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(C)Nc2c(cnn2CC)C1c1cccc(Cl)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a stirred solution of ethyl 4-(3-chlorophenyl)-1-ethyl-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (135 mg) in THF (3 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (97.5 mg) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:5) to give ethyl 4-(3-chlorophenyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (47 mg) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17]C)[N:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]([C:4]2[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH:15]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A 250 mL 2-neck flask fitted with a rubber septum, temperature probe, and addition funnel was charged with 2,4,5-trichloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidine (5.97 g, 18.54 mmol) and CH2Cl2 (90 mL) and kept under a N2 atmosphere. BBr3 (1 M in CH2Cl2; 37.1 mL, 37.1 mmol, 2 equiv.) was added slowly via addition funnel so that the temperature never exceeded 25° C. After 1 h, water (90 mL) was added and the mixture was stirred for approximately 30 min. The organic layer was washed with satd. aq. NaHCO3, dried, and concentrated to give a yellow powder (5.6 g, 98%). MS (ESI+): mass calcd. for C10H5Cl4N2O, 308.9; m/z found, 308.9 [M+H]+. 1H NMR (CDCl3): 9.76 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.39 (dd, J=8.9, 2.6 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H).