Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([CH2:8][OH:9])=[N:6][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])[N+:3]=1[O-:22].C(#N)C.N(OCCC(C)C)=O.[ClH:34]>C(OCC)C>[CH2:11]([O:10][C:5]1[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])=[N+:3]([O-:22])[C:2]([Cl:34])=[C:7]([CH2:8][OH:9])[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Reactant: Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(Cl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
There were mixed 2.17 g of 2-amino-5-benzyloxy-3-hydroxymethyl-6-isobutylpyrazine 1-oxide, 2.89 g of cuprous chloride, 1.42 g of cupric chloride and 22 ml of acetonitrile, and the mixture was stirred for 10 minutes at room temperature. Thereto was added 2.88 ml of isoamyl nitrite at room temperature. The mixture was stirred for 30 minutes, whereby an exothermic reaction of 40°-45° C. was taken place. (No cooling was made.) To the reaction mixture were added 60 ml of 2% hydrochloric acid and 50 ml of diethyl ether to cause phase separation. The aqueous layer was extracted with 50 ml of diethyl ether twice. The extract was combined with the above diethyl ether layer. The combined mixture was dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization by diethyl ether-n-hexane to obtain 1.73 g of 3-benzyloxy-6-chloro- 5-hydroxymethyl-2-isobutylpyrazine 1-oxide (Compound B-12) as pale yellow plate-like crystals having a melting point of 85.0°-88.0° C.
Reaction SMILES: CO[C:3](=[O:34])[CH2:4][NH:5][C:6](=[O:33])[C@H:7]([CH3:32])[NH:8][C:9](=[O:31])[CH2:10][NH:11][C:12](=[O:30])[CH2:13][NH:14][C:15](=[O:29])[C@H:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O.[NH2:36][NH2:37]>CO>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([NH:36][NH2:37])=[O:34])=[O:33])[CH3:32])=[O:31])=[O:30])=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)NN

Procedure:
A solution of Boc-Leu-Gly-Gly-Ala-Gly-OMe (2.0 g, 4 mmole, described in Example 10) and hydrazine hydrate (4.12 ml, 80 mmole) in methanol (50 ml) is stirred at 0° C for 4 hr. The solution is concentrated to 4 ml and added to diethyl ether (200 ml). The precipitate is collected, dissolved in methanol (4 ml) and added to diethyl ether (200 ml). The precipitate is collected and dried to give the title compound; mp 174° - 176.5° C; [α]D24 = -12.0° (c = 1, dimethylformamide).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7]([OH:9])=O)=[O:3].FC(F)(F)C(O)=O.N[C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49](F)[CH:48]=[C:47](F)[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1>>[CH2:44]([C@H:30]([NH:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
Following the procedure of CHART P and Example 739 and making non-critical variations but using 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoic acid (IX) and (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII), the title compound is obtained, HRMS (FAB)=615.3571.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.43 ml) and dimethylformamide (2 drops) were added to a solution of (R)-(+)-4-(1-benzyloxycarbonylaminoethyl)-benzoic acid (2 g) in dichloromethane (20 ml), and the mixture was refluxed under heating for 1 hour. Afterthe reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml) and the solution was dropwise added to a solution of 4-aminopyridine (525 mg) and diisopropylethylamine (1.17 ml) in acetonitrile (20 ml) under ice-cooling, which was followed by stirring at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate-hexane to give 1.87 g of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.Cl.C(OCC)(=O)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[C:10]2[CH:11]=[C:2]([C:26](=[O:28])[CH3:27])[CH:3]=[CH:4][C:5]=2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:7][CH2:8]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of 7-bromo-1,1-dimethyl-4-p-tolyl-1,2-dihydro-naphthalene (Compound 4, 295 mg, 0.90 mmol) in 5 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (650 mg, 1.80 mmol) and PdCl2(PPh3)2 (63 mg, 0.09 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10% HCl was added. The mixture was then stirred for another 30 min before extraction with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (80:20 hexane/ethyl acetate) afforded the title compound (248 mg, 95% yield) as a colorless oil:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15](Br)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12.[C:26](=[O:33])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([NH:27][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12
Reactant: CC(C)(C)OC(N)=O
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(OC)c3)c2c1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2sc(NC(=O)OC(C)(C)C)c(-c3cccc(OC)c3)c2c1N
Temperature: 110 °C
Yield: 93.2 %

Procedure:
A mixture of ethyl 4-amino-2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (Description 15) (1.52 g, 3.61 mmol), tert-butyl carbamate (0.845 g, 7.22 mmol), Pd2(dba)3 (0.066 g, 0.072 mmol), xantphos (0.084 g, 0.144 mmol) and Cs2CO3 (3.53 g, 10.82 mmol) in 1,4-dioxane (25 mL) was heated at 110° C. for ca. 6 h. After cooling to RT, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by chromatography, eluting with a gradient of 30-60% ethyl acetate in cyclohexane, to give the title compound (1.54 g). LCMS (A) m/z: 458 [M+1]+, Rt 1.44 min (acidic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([OH:19])[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:13]=2[CH2:12][CH2:11][N:10]([CH3:20])[CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2ccc(O)cc2C(c2ccccc2F)C1
Solvent: CC(=O)O
Product: CN1CCc2cc([N+](=O)[O-])c(O)cc2C(c2ccccc2F)C1
Temperature: 0 °C

Procedure:
5.0 g 5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 90 ml of a mixture of acetic acid and cooled in ice-water bath 0° C. Under stirring was added 1.7 ml fuming nitric acid and the mixture was stirred in the cold for 1 h. The reaction mixture was neutralized (pH 7.9) and the precipitate was extracted with ethyl acetate, dried and evaporated. After column chromatography (kieselgel/CH2Cl2: CH3OH 95:5) was isolated yellow crystals. M.p. 90-94° C. (dec). NMR: C5H 4.61 d; C6H g 41% 6 s and C9H 7.88 s ppm. respectively.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][C@@H:7]1[CH2:8][C@H:6]1[CH:4]=[O:3])([CH3:15])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CNC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Trans-2-(tert-Butoxycarbonylamino-methyl)-cyclopropanecarboxylic acid ethyl ester (0.320 g, 1.3 mmol), in toluene (5 mL) at −78° C. a 1.2M solution of DIBAL-H (1.86 mL, 2.2 mmol) in toluene was added. The mixture was stirred at −78° C. until TLC after 0.5 h indicated completion of the reaction. A saturated solution of sodium tartrate was added and the water was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was used without purification on the next step. MS (m/e): 200.3 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:8](=O)[C:7]=2[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:33]=1
Reactant: COC(=O)/C=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 75 °C
Yield: 58.1 %

Procedure:
To a 30 mL vial containing (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (200 mg, 0.43 mmol) was added THF (5 mL), triphenylphosphine (420 mg, 1.60 mmol) and TMS-C1 (0.553 mL, 4.32 mmol). The reaction was heated to 75° C. for 18 h after which time the mixture was cooled to room temperature, quenched with sat. aq. NaHCO3 and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-60% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (110 mg, 0.25 mmol, 57% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=7.58-7.73 (m, 3 H), 7.38-7.50 (m, J=8.59 Hz, 2 H), 7.28 (t, J=2.27 Hz, 2 H), 6.96-7.05 (m, J=8.59 Hz, 2 H), 6.85-6.96 (m, 3H), 6.32 (d, J=15.66 Hz, 1 H), 3.90 (s, 3 H), 3.81 (s, 3 H), 3.82 (s, 3 H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([CH:35]5[CH2:36][O:33][CH2:34]5)[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1COC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4COC4)C3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 530 and 3-oxetanone were reacted to give 529. LCMS m/z: 489.2 (MH+)
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([NH:22][CH3:23])[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:34][C:35](=[O:37])[CH3:36].[OH-].[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([N:22]([CH3:23])[CH2:34][C:35](=[O:37])[CH3:36])[N:5]=1)[CH3:2]
Reactant: CCSc1nc(NC)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCSc1nc(N(C)CC(C)=O)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 140 °C
Yield: 31.1 %

Procedure:
To a solution of 150 mg (0.45 mmol) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 123) in NMP (1 ml) were added 229 μl (1.35 mmol) DIPEA and 39 μl (0.50 mmol) chloroacetone. The mixture was heated in the MW to 140° C. for 40 min and subsequently partiotionated between a 1M aq. NaOH sol and EtOAc. The organic layer was separated, washed with a 1M aq. NaOH sol, water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 13:7) provided 53 mg (0.14 mmol, 30%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(2-oxo-propyl)-amino]-pyridine-3-carboxylic acid amide (example 253). [M+H]+ 390.2
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[K+].[Cl:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]3[CH:19]=[CH:18]C(C([O-])=O)=[CH:16][C:14]=3[S:15][C:11]=2[CH:10]=1>C1C=CC=CC=1>[Cl:4][C:2]([C:1]1[CH:18]=[CH:19][C:13]2[C:12]3[CH:23]=[CH:24][C:9]([Cl:8])=[CH:10][C:11]=3[S:15][C:14]=2[CH:16]=1)=[O:3]
Reactant: O=C([O-])c1ccc2c(c1)sc1cc(Cl)ccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)sc1cc(Cl)ccc12

Procedure:
A solution of 10.5 g. of oxalyl chloride in 100 ml. of benzene was added, with stirring, to a suspension of 16.53 g. of 7-chlorodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of benzene. The mixture was stirred and refluxed for two hours and then filtered. On distillation to dryness on the steam bath in vacuo 9 g. of crude 3-chlorocarbonyl-7-chlorodibenzothiophene was obtained as a residue.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>O1CCCC1.O>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][N:14]([C:21]([NH:20][CH3:19])=[O:22])[CH2:13]1
Reactant: Fc1cccc(OC2CNC2)c1
Reactant: CN=C=O
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(F)c2)C1
Reaction time: 3 h
Yield: 66.9 %

Procedure:
A stirred mixture of 5.4 g (0.02 mole) of 3-(3-fluorophenoxy)-azetidine oxalate and 1.7 g (0.022 mole) of methyl isocyanate in 20 ml of tetrahydrofuran was treated with 5 ml of triethylamine then stirring was continued for 3 hr. The reaction was diluted with water and the fine crystalline precipitate obtained was collected by filtration and dried at 60° C. under vacuum to yield 3 g (66.9%) of product, m.p. 155°-156° C.
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[NH2:7][C:8]([O:10][CH2:11][CH3:12])=O.S(=O)(=O)(O)O.C(O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][CH:8]=[N:7][C:1]([O:2][CH2:3][CH3:4])=[O:6])[CH3:12]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(N)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC=NC(=O)OCC
Reaction time: 2 h
Yield: 32.4 %

Procedure:
In 40 ml toluene was dissolved 44.4 g (0.3 mol) of ethyl orthoformate, and while keeping the temperature at 110°-120° C., 18 g (0.2 ml) of urethane and 200 ml of a mixture of sulfuric acid with toluene were dropped thereto spending about 2 hours, during which produced ethanol was distilled out of the reaction vessel. After the dropping had been finished, toluene was removed by distillation. The intended product (9.5 g) was obtained by distillation of the residue; b.p. 72.4° C. (15 mmHg), yield 38.8%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH2:25])[CH2:19][CH2:18]1.[N:26]([C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31](OCC)=[O:32])=[C:27]=[S:28]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:31](=[O:32])[C:30]3[C:29](=[CH:39][CH:38]=[CH:37][CH:36]=3)[NH:26][C:27]2=[S:28])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccccc1N=C=S
Reactant: NCCN1CCC(Cc2nc3cccnc3n2Cc2ccco2)CC1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Cc2nc3cccnc3n2Cc2ccco2)CC1
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a stirred mixture of 5.1 parts of 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineethanamine and 270 parts of tetrahydrofuran was added dropwise a solution of 3.8 parts of ethyl 2-isothiocyanatobenzoate in tetrahydrofuran. Upon completion, stirring was continued for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.4 parts (18.6%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; mp. 192.0° C. (492).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Product: CCc1cc(OCc2ccc(C(=O)OC)cc2)c2c(n1)CCCC2
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 1, but starting from 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone and methyl 4-(bromomethyl)benzoate and purifying the product by flash chromatography eluting with methane/dichloromethane (1:49 v/v), there was obtained in 67% yield methyl 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy)methyl]benzoate (B), m.p. 79°-80° C.; NMR (CDCl3): 1.3(t,3H), 1.75-1.95(m,4H), 2.65-2.8(m,4H), 2.85-2.95(m,4H), 3.9(s,3H), 5.2(s,2H), 6.5(s,1H), 7.5(d,2H), 8.1(d,2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cn1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 6.9 mmol) and potassium carbonate (1.308 g, 9.46 mmol) in DMSO (20 mL) was heated at 100° C. overnight. The reaction mixture was cooled to RT, and filtered through a pad of silica gel, eluted with EtOAc (150 mL). The filtrate was washed with water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a brownish oil which was purified by silica gel chromatography (80 g silica gel, 0-60% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title intermediate as a yellowish solid. (m/z): [M+H]+ calcd for C15H22N4O4 323.16 found 323.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[NH2:12][CH:13]([CH:15]1[CH2:19][N:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](=O)[CH2:16]1)[CH3:14].[OH-].[Na+]>O>[NH2:12][CH:13]([CH:15]1[CH2:16][CH2:17][N:18]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19]1)[CH3:14]
Reactant: CC(N)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(N)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (0.55 g, 0.014 mole) was added to tetrahydrofuran (45 mL) with stirring under nitrogen. 4-(1-Aminoethyl)-1-benzyl-2-oxopyrrolidine (1.60 g, 0.0073 mole) was added in several portions over 30 minutes and the reaction was brought to reflux over 75 minutes. The reaction was refluxed 16 hours and cooled to room temperature. The reaction was treated with water (0.55 mL), 10% NaOH (0.55 mL), and water (1.65 mL) slowly dropwise and the solid filtered off and washed with dichloromethane. The combined filtrates were evaporated under reduced pressure to give 3-(1-aminoethyl)-1-benzylpyrrolidine isomer A (1.05 g, 70%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].[C:14]1(I)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:14]1([C:4]#[C:3][C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)([CH3:1])[CH3:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1ccccc1
Reactant: C#CC(C)(C)c1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a stirred solution of Compound 21 (299 mg, 1.72 mmol), PhI (385 mg, 1.89 mmol), and (PPh3)2PdCl2 (60 mg, 0.086 mmol) in Et2NH (10 ml) was added CuI (33 mg, 0.17 mmol) at r.t. under N2, and stirred for 18 h. The mixture was quenched by the addition of H2O, and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 67 (360 mg, 84%) as a colorless oil.