Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([C:5]1[N:6]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[NH:12][CH:13]=[N:14]3)[CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[C:19]1([CH3:45])[CH:24]=[CH:23][C:22]([C:25]([O:27][C@@H:28]2[C@@H:32]([CH2:33][O:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[O:36])[O:31][C@H:30](Cl)[CH2:29]2)=[O:26])=[CH:21][CH:20]=1>CC#N.C1(C)C=CC=CC=1>[C:19]1([CH3:45])[CH:20]=[CH:21][C:22]([C:25]([O:27][C@@H:28]2[C@@H:32]([CH2:33][O:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)=[O:36])[O:31][C@@H:30]([N:14]3[CH:13]=[N:12][C:11]4[C:15]3=[N:16][CH:17]=[N:18][C:10]=4[N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:2][CH2:3][CH3:4])[CH2:29]2)=[O:26])=[CH:23][CH:24]=1
Reactant: CCCc1nccn1-c1ncnc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCc1nccn1-c1ncnc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 49.3 %

Procedure:
The sodium salt of 6-(2-propylimidazol-1-yl)purine (55 mg, 0.24 mmol) in dried CH3CN (5 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.15 g, 0.39 mmol) in toluene (5 mL) by general method 1. The residue was chromatographed (25 g silica gel, MeOH/CH2Cl2, 1:12) to give the two diastereomers [quantitative, containing traces of α-anomer (α/β ˜1:34)]. Recrystallization (EtOAc) gave 9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (68.7 mg, 53%): mp 197-197.5° C.; UV (MeOH) max 242, 276 nm (∈ 31200, 12 500), min 223, 263 nm (∈ 16 400, 9700); 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.12 (s, 1H) 6.65 (dd, J=6.2, 8.1 Hz, 1H), 5.85-5.87 (m, 1H), 4.68-4.83 (m, 3H), 3.30 (t, J=7.3 Hz, 2H), 3.17-3.23 (m, 1H), 2.91-2.95 (m, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 1.85 (sext, J=7.5 Hz, 2H), 1.03 (t, J=7.3 Hz, 3H); NOE difference: irradiation at H1′ gave enhancement of the H4′ (small), H8 and H2′,2″ signals; 13C NMR (125 MHz, CDCl3) δ 166.4, 166.2, 153.1, 152.1, 151.0, 148.1, 144.9, 144.6, 142.4, 130.1, 129.8, 129.6, 129.5, 128.8, 126.8, 126.5, 124.6, 120.8, 85.5, 83.6, 75.2, 64.1, 38.3, 32.8, 22.0, 21.9, 21.5, 14.3; HRMS m/z 603.2347 (MNa+ [C32H32N6O5Na]=603.2332); Anal. Calcd for C32H32N6O5: C, 66.20; H, 5.56; N, 14.47. Found: C, 66.59; H, 5.67; N, 14.62.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH3:25][C:24]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ncccc4C)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(3-Methyl-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 14.1c from 100 mg (0.24 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1b) and 138 mg (0.97 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]2([OH:38])[CH2:37][CH2:36][CH2:35]2)[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]2([OH:38])[CH2:35][CH2:36][CH2:37]2)[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(C2(O)CCC2)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(C3(O)CCC3)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 60 mg (0.276 mmol) of the compound of Example 73A gave 115 mg (82% of theory, 96% pure) of the title compound. In this case, the reaction time was 1 h. Final trituration of the product was carried out using a mixture of 10 ml of pentane and 2 ml of diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN>C(O)C>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: Cc1ccc2c(c1)C(=O)c1c-2csc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)C(=O)c1c-2csc1N
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 11, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
1-(3-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 14, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: C=CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Allylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-allylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21](S(C)(=O)=O)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Fc1cnccc1-c1cc2nc(N3CCOCC3)[nH]c2nc1-c1cccnc1
Yield: 43 %

Procedure:
A solution of 6-(3-fluoropyridin-4-yl)-2-(methylsulfonyl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridine (0.025 g, 0.068 mmol), morpholine (0.024 mL, 0.268 mmol) in dioxane (0.5 mL) was heated in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.011 g, 44% of yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2>CS(C)=O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:15]2[C:16]([CH3:35])=[N:17][C:18]3[C:23](=[C:22]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:24]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 28.9 %

Procedure:
Prepared according to Example 131, using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (189 mg, 1.012 mmol, CNH Technologies, Inc., Woburn, Mass.) and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 100 mg, 0.337 mmol) in DMSO (1.5 mL) and heating at 85° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (R)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (45 mg, 28.8%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.90-7.96 (1H, m) 7.63-7.69 (1H, m) 7.42 (1H, t, J=1.00 Hz) 7.11 (1H, s) 4.65-4.80 (1H, m) 3.87-4.03 (1H, m) 3.57-3.68 (3H, m) 3.49-3.55 (1H, m) 3.40-3.49 (1H, m) 2.94-3.03 (1H, m) 2.61 (3H, s) 2.35-2.49 (2H, m) 2.19-2.34 (1H, m) 1.45-1.54 (9H, m). m/z (ESI, +ve) 463.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[NH:5]1>CS(C)=O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:5]1[CH2:22][CH2:6][CH2:7][OH:21]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C(=O)N(CCCO)C3(CCOCC3)C2=O)cc1C(F)(F)F
Temperature: 50 °C
Yield: 147.7 %

Procedure:
Using the procedure of Example 4, 109 mg of 50% sodium hydride, 510 mg of the product of Example 2 and 4 ml of dimethylsulfoxide were reacted and rinsing was carried out with 0.5 ml of dimethylsulfoxide. Then, 20 minutes after the release of hydrogen had stopped, 1.004 g of 3-bromopropoxydiphenyl-tert-butyl-silane were added and the solution was heated to about 50° C. Proceeding as in Example 4, the solution was taken up in 30 ml of methanol, 10 ml of 2N hydrochloric acid, 10 ml of chloroform and refluxed. After purification on silica with methylene chloride-acetone: 8-2 as eluant, 441 mg of the expected product (white crystals) melting at 155-156° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Temperature: 25 °C

Procedure:
Under argon, 105 g (270 mmol) of ethyl 8-(benzyloxy)-6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 85A were suspended in 4.2 l of 1,4-dioxane, 135.4 g (539 mmol, purity 50%) of trimethylboroxine, 31.2 g (27 mmol) of tetrakis(triphenylphosphine)palladium(0) and 78.3 g (566 mmol) of potassium carbonate were added in succession and the mixture was stirred under reflux for 8 h. The reaction mixture was cooled to RT, the precipitate was filtered off over silica gel and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (dichloromethane:ethyl acetate=9:1). This gave 74 g (84.6% of theory; purity 100%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 5-Bromo-2-hydroxy-benzoic acid methyl ester (29.8 g, 129 mmol) and dimethylthiocarbamoyl chloride (17.54 g, 142 mmol) in DMF at room temperature was added DABCO (21.7 g, 193.5 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH˜4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide crude 5-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid in 91% yield. The product was used directly in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:24]
Reactant: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 76.9 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (49) (250 mg, 0.8 mmol) in dichloromethane (10 mL) was added pyridine (633 mg, 8.0 mmol, 0.6 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (367 mg, 3.2 mmol, 0.2 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×20 mL) and water (2×20 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 10 g, 34 CV, 30 mL/min) then triturated with diethyl ether to afford 250 mg (80%) of methanesulfonic acid 2-(4-diethylcarbamoyl-2-methyl-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δ 12.9, 13.0, 15.2, 22.0, 29.7, 30.2, 36.7, 36.8, 40.8, 41.6, 42.0, 67.8, 108.6, 109.5, 118.6, 119.6, 121.2, 126.4, 136.2, 136.4, 173.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccncc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyridine-4-boronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 1): tR=1.31 min; Mass spectrum (ESI+): m/z=380 [M+H]+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1)NO
Reaction time: 72 h
Yield: 70 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to II (2.5 mg, 0.006 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:6) to furnish III as a colourless oil (1.63 mg, 70%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Zn+2].[Cl-].CS(C)=O>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CS(C)=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and zinc chloride (81.6 g, 0.6 mol) were added to 200 mL dimethyl sulfoxide. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (37.2 g, 0.4 mol) was then added and reacted at 120° C. for 8 hours. The mixture was filtered and water was added to the filtrate. The filtrate was extracted with ethyl acetate for 3 times, and then the organic phases were combined, the solvent was evaporated to provide 53 g of colorless oil with 92% yield. HPLC: 99.0%.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH2:40]([O:47][C:48]1[CH:49]=[CH:50][C:51]([Br:55])=[C:52](O)[CH:53]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:24][O:25][C:50]1[CH:49]=[C:48]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:53]=[CH:52][C:51]=1[Br:55])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1cc(OCc2ccccc2)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
Diisopropylazodicarboxylate (0.10 ml, 0.603 mmol) was added to (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (161 mg, 0.469 mmol), 5-benzyloxy-2-bromophenol (131 mg, 0.469 mmol) and triphenylphosphine (160 mg, 0.610 mmol) in tetrahydrofuran (3 ml) under a nitrogen stream, followed by stirring for 5 hours at room temperature. Diisopropylazodicarboxylate (0.05 ml, 0.302 mmol) was added to the reaction mixture followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4, v/v) to give (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1(4-benzyloxyphenyl)ethylamine (214 mg, Yield 75%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH2:23]=O>C(O)=O>[CH3:23][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CCCn1nc(C(=O)NC2CCN(C)CC2)c2ccccc21
Yield: 18 %

Procedure:
To N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.32 g) obtained in Example 20 were added formic acid (0.7 ml) and a 36% aqueous solution of formaldehyde (0.3 ml), and the mixture was stirred at room temperature for 5 hours. Then formic acid (4 ml) and a 36% aqueous solution of formaldehyde (1.6 ml) were further added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was distilled off under reduced pressure, and to the residue were added chloroform and aqueous ammonia. After extraction with chloroform, the chloroform layer was washed with-saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol:aqueous ammonia=90:10:2) to give the title compound (0.06 g). Yield=18%.