Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[C:29]#[CH:30].Cl>C(Cl)Cl.C1N2CCN(CC2)C1>[CH2:1]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:12]([NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[C:13](=[O:19])[O:14][C@@H:15]([CH3:18])[C@@H:16]1[O:17]/[CH:30]=[CH:29]/[C:28]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCc1ccccc1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O/C=C/C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (360 mg, 0.949 mmol, 1.00 equiv) in CH2Cl2 (9.5 mL, 0.1 M) at 0° C. (ice water bath) were added benzyl propiolate (228 mg, 1.42 mmol, 1.5 equiv) and DABCO (5 mg, 0.05 mmol, 0.05 equiv). The resulting solution was stirred at 0° C. for 20 min and then poured into 0.1 N HCl (20 mL). The mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a white crystalline solid. The solid was purified by automated silica gel column chromatography (5-25% acetone in hexanes) to provide (E)-benzyl 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)acrylate (490 mg, 96%) as a white solid: IR (ATR) 3344, 2982, 2941, 1752, 1717, 1690, 1638, 1527, 1454, 1381, 1205, 1079, 833, 751, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=12.2 Hz, 1H), 7.40-7.09 (m, 10H), 5.44 (d, J=12.2 Hz, 1H), 5.16 (s, 2H), 5.09 (d, J=8.2 Hz, 1H), 5.01 (dd, J=9.3, 6.4 Hz, 1H), 4.64 (dd, J=15.3, 7.5 Hz, 1H), 3.91 (dd, J=11.6, 7.5 Hz, 1H), 3.73 (t, J=9.2 Hz, 1H), 3.45 (dt, J=10.6, 8.5 Hz, 2H), 3.28 (dd, J=11.3, 7.5 Hz, 1H), 2.92 (dd, J=13.8, 3.5 Hz, 1H), 2.34 (t, J=12.4 Hz, 1H), 2.05 (s, 1H), 1.51-1.35 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 172.15, 167.40, 163.21, 138.54, 136.22, 129.10, 128.57, 128.25, 128.19, 126.48, 98.54, 89.01, 80.31, 73.94, 72.60, 71.36, 65.87, 52.72, 46.48, 35.21, 28.26, 18.74; HRMS-ESI (m/z) [M+Na]+ calc'd for C30H37NO8Na, 562.2411. found, 562.2427.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(#N)C.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[S:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[S@:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: O=[S@@]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reaction time: 48 h
Yield: 14.1 %

Procedure:
3.5 g of (S)-mandelic acid and 90 cm3 of a mixture of acetonitrile and water (99/1 by volume) are added to 7.15 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide. After stirring, the resulting solution is allowed to stand for 48 hours at room temperature. The crystals obtained are drained, washed with the acetonitrile-water mixture and then dried. The crystals are taken up in 200 cm3 of a boiling acetonitrile-water mixture and after filtering while still hot, the solution obtained is allowed to stand for 5 hours at room temperature. The crystals are drained, washed twice with 10 cm3 of acetonitrile and then dried. 1.5 g of (1R*,4aR*,7aR*)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate are obtained; [α]D 20 =-228°, (c =0 44; acetic acid). The filtrate is allowed to stand for 20 hours at room temperature, the crystals obtained are drained, washed twice with 5 cm3 of acetonitrile and then dried. 0.62 g of (1R*,4aR*,7aR*)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate is obtained; [α]D 20 =-230°, (c =0.45; acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[C:11]3[N:12]=[C:13]([CH3:28])[C:14]([C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[C:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:34]([CH3:37])([CH3:36])[CH3:35])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:34]([O:27][C@@H:22]([C:14]1[C:13]([CH3:28])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:29]=2)[C:15]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:23]([O:25][CH3:26])=[O:24])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.067 g, 0.162 mmol) and tert-butyl acetate (1 ml, 7.40 mmol) in CH2Cl2 (3 mL) was added 70% perchloric acid (0.042 ml, 0.486 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0481 g, 0.102 mmol, 63.2% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.96 (t, J=1.5 Hz, 1H), 7.87 (dt, J=7.6, 1.3 Hz, 1H), 7.41-7.31 (m, 2H), 6.75 (s, 1H), 5.40 (s, 1H), 3.87-3.77 (m, 1H), 3.70 (s, 3H), 2.93-2.79 (m, 2H), 2.73 (s, 3H), 1.96-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.54-1.38 (m, 4H), 1.25 (s, 9H). LCMS (M+H) calcd for C26H33ClN3O3: 470.22. found: 472.4.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:6][CH:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: BrCC1CCCCC1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Product: Cc1nccc2c3ccc(OCC4CCCCC4)cc3n(CC3CCCCC3)c12
Yield: 75 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (0.5 g, 1.587 mmol) in presence of 1-bromomethylcyclohexane (1.240 g, 3.173 mmol) as described here above.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.[H-].[Na+].CCOC(C)=O>O1CCOCC1>[NH:18]1[CH2:22][CH2:21][CH:20]([O:23][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:19]1
Reactant: OC1CCNC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(OCCOc2nccnc2OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
2-Chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) was added to a stirred mixture of 3-pyrrolidinol (260 mg, 2.99 mmol) and NaH (55% dispersion in mineral oil; 110 mg, 2.50 mmol) in dioxane (2 mL), and the reaction was stirred at room temperature for 2 h. EtOAc was added and the mixture was washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using EtOAc/MeOH/HOAc/H2O (50:40:9:1) as eluent to give 38 mg (22%) of the title compound. Anal. (C16H19N3O3) H; C: calcd, 63.77; found, 62.20; N: calcd, 13.94; found, 13.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:49][CH2:48][C:47]3[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=3)=[O:21])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCc3ccc(F)cc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-fluorobenzylamine (13.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-4-fluorobenzylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (38.3 mg).
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH3:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:4]=2[N:3]=1>C(O)C.C(N)(C)C>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:5]2[N:6]([C@@H:7]3[O:13][C@H:12]([CH3:14])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:2]([NH:3][CH:4]([CH3:18])[CH3:5])=[N:3][C:4]=2[CH:18]=1
Reactant: COc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Solvent: CC(C)N
Solvent: CCO
Product: COc1ccc2c(c1)nc(NC(C)C)n2[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 10.2 %

Procedure:
2-Chloro-5-methoxy-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (0.320 g, 1.1 mmol) was dissolved in ethanol (15 mL) and isopropylamine (5 mL). The resulting mixture was heated in a sealed tube for three days, after which time it was concentrated in vacuo. The resulting product was purified by flash chromatography (9:0.5:0.5 CH2Cl2:ethyl acetate:methanol) to yield the title compound (18 mg, 5%) as a 1.5:1 mix of regioisomers by 1H NMR; MS (ES): m/z 322 (M+1); 1H NMR (DMSO-d6) δ: 7.13 (d, J=8.5 Hz, 0.4H), 7.03 (d, J=8.5, 0.6H), 6.85 (d, J=2.4 Hz, 0.6H), 6.76 (d, J=2.4 Hz, 0.4H), 6.62 (dd, 0.4H), 6.50 (dd, 0.6H), 5.67 (t, 1H), 5.28-5.19 (m, 1.5H), 4.37 (m, 1H), 3.73 (s, 3H), 1.40 (m, 3H), 1.23 (d, 6H).
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:7](OC)=[O:8].Cl.O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([C:11]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)ccc1Sc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Br)ccc1Sc1ccccc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A stirred solution of 65 g of lithium borohydride in 1 litre of tetrahydrofuran is treated dropwise under a nitrogen atmosphere over a period of 120 minutes with a solution of 483 g of methyl 3-bromo-6-(phenylthio)-benzoate in 1 litre of tetrahydrofuran. The mixture is stirred for a further 4 hours under reflux. The solution is cooled to 5° C and treated dropwise over a period of 3 hours with 700 ml of 3-N hydrochloric acid. After the addition of approximately 5 litres of water, the mixture is extracted with ether. The organic solution is washed with water and dried over magnesium sulphate. There is obtained crude 3-bromo-6-(phenylthio)-benzyl alcohol as a yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[N+:19]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:1][C:13]=3[CH2:12]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Solvent: CC(=O)O
Product: CC(=O)CCc1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
In 50 ml of acetic acid was suspended 5.90 grams of 4-(2-fluorenyl)-butan-2-one and 6.35 ml of concentrated nitric acid was dropped in during 45 minutes with stirring at room temperature. After stirring for 3 hours and 30 minutes, crystals separated out therefrom were collected by filtration, washed with small amount of acetic acid, and washed with water until the washing became neutral. The resulting crystals were dissolved in 250 ml of chloroform, dried over magnesium sulfate, and chloroform was evaporated therefrom in vacuo. The residue was recrystallized from benzene to give 3.83 grams of 4-(7-nitro-2-fluorenyl)-butan-2-one, yellow crystals, m.p. 159°-161.5° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12](Br)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([NH:8][C:9](=[O:25])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38](=[O:39])[NH:40][CH3:41])[C:36]=3[CH:42]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(NCc1ccccc1)c1nc(Br)ccc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccccc4)n3)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of N-benzyl-3-(benzyloxy)-6-bromopicolinamide (107 mg, 0.27 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (prepared according to previous patents, 117 mg, 0.23 mmol) and K3PO4.3H2O (187 mg, 0.70 mmol) in dioxane/H2O (3 mL) were added Pd2(dba)3 (11 mg, 0.01 mmol) and X-Phos (11 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=50:1) to afford the product of N-benzyl-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (100 mg, yield: 61.7%). 1H-NMR (CD3OD, 400 MHz) δ 7.91˜7.94 (m, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.67˜7.72 (m, 2H), 7.43˜7.45 (m, 2H), 7.29˜7.33 (m, 5H), 7.20˜7.24 (m, 5H), 5.23 (s, 2H), 4.54 (s, 2H), 3.15 (s, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 693.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(OCC)C>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1)(=[O:36])[CH3:35]
Reactant: O=C1CCCCN1c1ccccc1CCN1CCC(C2CCCCN2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N1CCCCC1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 1-(2-{2-[3-(piperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a12-1 (25 mg, 0.070 mmol, 1 eq) in diethylether (2 ml) at 0° C. are added triethylamine and acetic anhydride (7 μl, 0.077 mmol, 1.1 eq). The mixture is stirred for 1 hour at room temperature. The solvent is removed under vacuum. The residue obtained is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 14.5 mg of 1-(2-{2-[3-(1-acetylpiperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 72 as a yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-]>CO.O>[OH:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1OC(C)=O
Yield: 79.7 %

Procedure:
A solution of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (150 mg, 0.36 mmole) in methanol (5 mL) and a saturated solution of ootassium carbonate (3 mL) was stirred at room temperature for 5 minutes. The reaction was poured in water, extracted with methylene chloride, washed with brine, dried (Na2SO4), and concentrated in vacuo to yield 107 mg (79%) of 2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)(C)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: NCCCNc1ccccn1
Reactant: CN=C=S
Solvent: CC(C)O
Product: CNC(=S)NCCCNc1ccccn1
Yield: 60.3 %

Procedure:
A solution of 2-(3-aminopropylamino)pyridine (2.74 g.) and methyl isothiocyanate (1.46 g.) in isopropyl alcohol (50 ml.) was stirred at room temperature for 16 hours Concentration, followed by trituration of the residue under methyl ethyl ketone gave the crude product which, was recrystallised from aqueous ethanol to give N-methyl-N'-[3-(2-pyridylamino)propyl]thiourea (2.45 g.) m.p. 134°-135.5°.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].CC1C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1OC

Procedure:
The title compound was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol), aluminum chloride (4.1 g, 31 mmol) and 4-methylbenzoyl chloride (4.6 mL, 29 mmol) with a reaction time of 6 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the product as a white solid: mp 121.5–122° C.; 1H NMR (CDCl3) δ 7.70–7.67 (d, J=8 Hz, 2H), 7.48–7.26 (m, 4H), 6.91–6.88 (d, J=8.3 Hz, 1H), 6.96 (s, 3H), 3.94 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3) δ 195.1, 152.6, 148.8, 142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8, 21.4; Anal. Calcd for C16H16O3. Theoretical: C, 74.98; H, 6.29. Found: C, 74.84; H, 6.43.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([O:20]C)=[O:19])(=[O:8])=[O:7].Cl>CO.O>[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])(=[O:8])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 50 °C

Procedure:
60.2 g of lithium hydroxide monohydrate are added to a solution of 206.7 g of N,N-dimethyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide in 1500 ml of methanol. The mixture is subsequently stirred at 50° C. until conversion is complete. Following the concentration of the reaction mixture under reduced pressure, the residue is taken up in water and is treated at 0° C. with concentrated hydrochloric acid (pH=1). Filtration with suction followed by drying gives the desired compound. Yield: 162.9 g; m.p.: 160-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:34]([C:38](N)=[NH:39])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:38]([NH2:39])=[NH:34]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Piperazine-1-carboxylic acid benzyl ester (8.00 g; 36.3 mmol), 2-fluoro-4-methyl-1-nitro-benzene (4.70 g; 30.3 mmol) and potassium carbonate (8.5 g; 61.5 mmol) were stirred 3 hours in 50 mL DMSO at 80° C. The reaction mixture was cooled to room temperature and 250 mL Water was added. The mixture was extracted with diethyl ether (2×250 mL). The organic phase was washed with water (100 mL), 1 N HCl (2×100 mL), brine (2×100 mL), dried with MgSO4 and concentrated in vacuo to give 10.5 g (29.5 mmol; 97.6%) 4-(5-methyl-2-nitro-phenyl)-piperazine-1-carboxylic acid benzyl ester.