Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O-2].[Ca+2].[CH2:25]([OH:28])[CH2:26]Br.O>CN(C=O)C>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[N:4]([CH2:26][CH2:25][OH:28])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Reactant: OCCBr
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCO)c2cc(C)cc([N+](=O)[O-])c2N)cc1

Procedure:
0.087 mol (28 g) of 2-amino-3-nitro-5-methyl-N-tosylaniline is dissolved in 85 ml of DMF heated beforehand on a boiling water-bath. 9.7 g of quicklime are then added and 0.174 mol (21.75 g) of glycol bromohydrin is then introduced gradually, in the course of 30 minutes and whilst stirring, the heating on the boiling water-bath being maintained. After 11/2 hours, the reaction medium is filtered hot and the filtrate is then poured into 250 ml of iced water. The expected product precipitates. It is filtered off, washed with water and dried in vacuo. After recrystallisation from acetic acid and drying in vacuo, it melts at 201° C.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C:15]3[CH2:16][CH2:17][C:18]4[C@:23]([C:25]=3[CH2:26][CH2:27]2)([CH3:24])[CH2:22][CH2:21][C:20](=[O:30])[CH:19]=4)[CH2:13][CH2:12]1)[CH3:10])[CH3:5].[Cl-].[NH4+]>C(OCC)C>[CH3:1][C@@:18]12[CH2:19][C:20](=[O:30])[CH2:21][CH2:22][C@:23]1([CH3:24])[C:25]1[CH2:26][CH2:27][C@@:28]3([CH3:29])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:4]([CH3:3])[CH3:5])[C:15]=1[CH2:16][CH2:17]2
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@@]1(C)CC3
Reaction time: 0.5 h

Procedure:
0.85 ml of a methyllithium solution (1.6 N, in diethyl ether) are added to a suspension of 130 mg cuprous iodide in diethyl ether at 0° C. The resulting mixture is stirred for one hour before a solution of 130 mg cholesta-4,8-dien-3-one in 1 ml diethyl ether is added. After being stirred for 30 minutes the reaction mixture is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is separated, washed with brine, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with mixture of hexane and ethyl acetate to give 80 mg 5-methyl-5β-cholest-8-en-3-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:12]=[CH:13]/[N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>CCO.C1COCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(CCN2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Yield: 41 %

Procedure:
Pd/C (10% by wt, 0.090 g) was added to a degassed solution of 2-{(E)-2-[3-amino-5-(trifluoromethyl)phenyl]vinyl}-1H-isoindole-1,3(2H)-dione (0.900 g, 2.71 mmol) in EtOH (56 mL) and THF (40 mL). The mixture was hydrogenated (50 psi) at rt until LC/MS indicated reaction was complete. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, 1:1 EtOAc:hexanes) to afford the desired product as a white solid (0.371 g, 40%). LCMS: (FA) ES+ 335.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[F:9][C:10]1[CH:17]=[CH:16][C:15](O)=[CH:14][C:11]=1[CH2:12][OH:13]>>[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:11]=1[CH2:12][OH:13]
Reactant: OCc1cc(O)ccc1F
Reactant: OCCc1cccs1
Product: OCc1cc(OCCc2cccs2)ccc1F

Procedure:
2-Fluoro-5-[2-(2-thienyl)]ethoxybenzyl alcohol was prepared from 2-thiophene-ethanol (0.5 g) and 2-fluoro-5-hydroxybenzyl alcohol according to the procedure described in Example 152 to give the product as a clear oil (0.12 g); δH (400 MHz, CDCl3) 7.16 (1H, dd, J 5, 1.5 Hz), 6.98–6.92 (3H, m), 6.91 (1H, m), 6.78 (1H, dt, J 9, 3.5 Hz), 4.70 (2H, d, J 6 Hz), 4.15 (2H, t, J 6.5 Hz) and 3.28 (2H, dt, J 6.5, 1 Hz); HPLC (XTERRA, 50/80%, 220 nm) 97% (3.49 min).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]5[N:29]([N:31]=[CH:32][C:33]=5[CH2:34][CH3:35])[CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[N:27][C:28]5[N:29]([N:31]=[CH:32][C:33]=5[CH2:34][CH3:35])[CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(CC)cnn5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cnn2cc(-c3cc(-c4nc5cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c6ccc(Cl)cc6)c5s4)ccn3)cnc12
Temperature: 170 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-ethylpyrazolo[1,5-a]pyrimidin-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (31 mg, 0.048 mmol) and lithium iodide (200 mg) in pyridine (0.5 mL) was heated in microwave at 170° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with 5% acetic acid solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2). Lyophilization gave desired product. LCMS-ESI+: calc'd for C33H31ClN5O3S: 612.2 (M+H+); Found: 612.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 9.33 (d, J=2.1 Hz, 1H), 9.02 (d, J=2.1 Hz, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.56-8.49 (m, 2H), 8.29 (s, 1H), 8.02 (s, 1H), 7.85 (tt, J=7.7, 1.8 Hz, 1H), 7.77-7.61 (m, 4H), 7.61-7.49 (m, 3H), 7.43 (ddd, J=7.7, 4.4, 1.5 Hz, 2H), 5.24 (s, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J=7.6 Hz, 3H), 0.96 (d, J=6.8 Hz, 9H).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1
Reactant: CO
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Na]
Product: COc1cc(C#N)ccn1
Yield: 51 %

Procedure:
Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanoldioxan (1:1, 850 ml) was added and the mixture was boiled under reflux for 21/2 hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation in 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%), m.p. 93-95.5°.
Reaction SMILES: [Br:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3](O)=[O:4].S(Cl)([Cl:12])=O>>[Br:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([Cl:12])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Br)C(F)(F)F
Product: O=C(Cl)C(Br)C(F)(F)F

Procedure:
A solution of 2-bromo-3,3,3-trifluoropropanoic acid (5 g.) in thionyl chloride (5 ml.) is refluxed in the steam bath for two hours. The excess thionyl chloride is removed in vacuo, and the residue distilled under reduced pressure to yield 2-bromo-3,3,3-trifluoropropanoic acid chloride.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+:13]([C:16]1[CH:42]=[CH:41][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34](=[O:37])(=[O:36])[NH2:35])=[O:26])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C)C1C=CN=CC=1.O1CCCC1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:35][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:37])=[O:26])=[CH:41][CH:42]=1)([O-:15])=[O:14]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (0.80 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.70 mmol) of 3-(4-nitrobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 5 and 171 mg (1.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 400 mg (yield: 97.9%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]1[CH:16]=[N:17][N:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=1)[N:11]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:10][C@H:9]([CH3:29])[N:8]2[C:30](=[O:32])[CH3:31])(=[O:3])C.[C:33](OC(=O)C)(=[O:35])C>>[C:30]([N:8]1[C:7]2[C:12](=[CH:13][C:14]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:21][CH2:22]4)[CH:19]=3)=[C:5]([NH:4][C:1]([O:35][CH3:33])=[O:3])[CH:6]=2)[N:11]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:10][C@@H:9]1[CH3:29])(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(=O)OC(C)=O
Product: COC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-((methoxycarbonyl)amino)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235), substituting methyl chloroformate for acetic anhydride. MS (ESI, pos. ion) m/z 456 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][CH:8]=[C:7]2[OH:15])[CH3:2].[Br:16]Br>C(O)(=O)C.S(=O)(O)[O-].[Na+]>[Br:16][C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[OH:15])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:13]([CH3:14])[N:12]=2
Reactant: CCOc1cc2c(O)ccnc2nc1C
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc2c(O)c(Br)cnc2nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-ethoxy-7-methyl-1,8-naphthyridin-4-ol, (5.0 g) in glacial acetic acid (60 ml) was stirred at between 15°-20° C. while a solution of bromine (2.4 ml) in glacial acetic acid (10 ml) was added dropwise over 10 minutes. The mixture was stirred at ambient temperature for 1.5 hours and then filtered. The residue was washed with water, ground up in water and the mixture basified with sodium bicarbonate and filtered. The solid obtained was ground in sodium bisulphite solution and filtered to give 3-bromo-6-ethoxy-7-methyl-1,8-naphthyridin-4-ol, m.p. 266°-267° C.
Reaction SMILES: COC[O:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[CH:25]=3)[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:47]=[CH:46][C:8]2[CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[CH:25]=3)[C:10]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[3-(4-(4,4,5,5,5-pentafluoropentylthio)butyloxy)phenyl]-2,3-dihydro-4H-benzopyran (274 mg, 0.4 mmol) and pyridinium p-toluenesulfonate (508 mg, 2.02 mmol) were dissolved in methanol (10 ml) and then refluxed for 14 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 167 mg (yield: 75%) of the title compound as a white foam.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C=O)C>[Si:20]([O:12][C@H:11]1[CH2:10][C@H:9]2[N:13]([CH3:14])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[C:1]([O:3][CH3:4])=[O:2])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2CC[C@H]1N2C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
2β-Carbomethoxy-3β-hydroxytropane (304 mg, 1.43 mmol) was dissolved in 4 mL of dry DMF. Imidazole (208 mg, 3.01 mmol) and tert-butyldimethylsilyl chloride (345 mg, 2.29 mmol) were added, and the reaction mixture was stirred overnight. Water was then added, and the mixture was extracted with ether. The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel half-saturated with ammonia using ethyl acetate as eluent to give 265 mg of the title compound (55% yield): IR (thin film) 2951, 2897, 2857, 1790, 1716, 1497, 1271, 1144, 1107, 837 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 3.91 (dt, 1H, J=11.1, 6.1 Hz), 3.67 (s, 3H), 3.45-3.35 (m, 1H), 3.25-3.17 (m,1H), 2.75-2.68 (m,1H), 2.18 (s, 3H), 2.35- 1.42 (m, 6H), 0.84 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75.46 MHz) δ 171.4, 64.6, 64.4, 61.6, 54.0, 51.1, 41.2, 39.5, 28.2, 25.8, 25.2, 18.1, 6.6, 6.3; mass spectrum m/z 313 (M+), 256, 242, 182, 97, 82; HRMS (FAB) calcd for C16H32NO3Si (MH ) 314.2143, found 314.2145.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:5][C:6]=1[C:7]([O:9]C)=O.[CH:17]([NH2:19])=O>>[N:11]1([C:4]2[S:5][C:6]3[C:7](=[O:9])[N:19]=[CH:17][NH:1][C:2]=3[N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1sc(N2CCOCC2)nc1N
Reactant: NC=O
Product: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Temperature: 150 °C
Yield: 93.2 %

Procedure:
A sealed tube was charged with methyl 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxylate (4 g, 16.44 mmol) and formamide (40 mL, 1004 mmol). The reaction was heated at 150° C. overnight. The reaction mixture was cooled, filtered, and the solid was washed with DCM and MeOH. The solid was collected and dried under vacuum to give 3.65 g (93%) of product. LCMS (ES) m/z=239.0 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δppm 12.4 (br s, 1H, NH), 8.10 (s, 1H) 3.72 (m, 4H). 3.58 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c1ccccc1n2-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Yield: 80.4 %

Procedure:
A mixture of 4-hydroxy-9-phenyl-9H-b-carboline-3-carboxylic acid ethyl ester (399 mg, 1.20 mmol), NBS (227 mg, 1.26 mmol) and BzOOBz (15 mg, 0.06 mmol) in carbontetrachloride (10 mL) was refluxed for 90 min. Then the reaction was cooled, the mixture was then filtered through a Celite plug, followed by the concentration of filtrate to give the desired product (397 mg). The title compound: ESI MS (m/z): 411 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCCCCCCO)OCc1ccccc1

Procedure:
This compound was prepared from 16-hydroxyhexadecanoic acid (2.45 g; 9.0 mmol), benzyl alcohol (4.9 g; 45 mmol), and p-toluenesulphonic acid (100 mg) in toluene (100 mL) using Procedure B. 2.82 g crude product that was a 1:1 mixture of the expected product and the ester between two molecules of 16-hydroxyhexadecanoic acid was obtained. A solution of NaH (ca. 100 mg) (previously washed three times with dry hexane) in benzyl alcohol (10 g) was added to the crude product and the mixture was stirred at 100° C. (bath temperature) under argon for 3 h. After cooling to ambient temperature, the mixture was diluted with dichloromethane (75 mL) and washed with 10% aqueous citric acid solution (1×10 mL) and dried (Na2SO4). After filtration and evaporation, the residue was vacuum dried at 50° C. (bath temperature) and 0.014 mm Hg using a Kugelrohr apparatus. 2.56 g (76%) product was obtained (white solid). Proton NMR indicated that ca. 10% of the dimer ester remained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:12]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:12]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13]1
Reactant: CCc1c(Br)cccc1C=O
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(Br)cccc1CN1CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-2-ethylbenzaldehyde (2.66 g, 12.48 mmol) in Dichloromethane (DCM) (30 mL) were added methyl 3-azetidinecarboxylate (1.987 g, 13.11 mmol) and sodium acetate (1.536 g, 18.73 mmol). The mixture was stirred for 30 min at rt then sodium triacetoxyborohydride (3.97 g, 18.73 mmol) was added to above solution. The obtained mixture was stirred for an hour at rt. The solvent was removed under the reduced pressure, water (30 mL) was added to the above residue and the mixture was adjusted to pH value around 3 with HCl (1.0 N) then extracted with EtOAc (10 mL). Acidic phase was adjusted to pH value around 8 with NaOH (1.0 N) solution then extracted with EtOAc (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under the reduced pressure and dried in vacuum to give methyl 1-(3-bromo-2-ethylbenzyl)azetidine-3-carboxylate (3.04 g) as pale yellow oil
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[C:16]([CH:21]=O)=[N:17][CH:18]=[CH:19][CH:20]=1.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:14][C:15]1[C:16]([C:21]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]3[N:9]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=Cc1ncccc1F
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ncccc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.76 g), 3-fluoropyridin-2-carboaldehyde (0.50 g), sodium hydrogen sulfite (0.50 g) and DMF (3 ml) was stirred at 120° C. for 8 hours. To the cooled reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-fluoropyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.43 g), which is hereinafter referred to as “intermediate compound (M6-2)”.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:21][C:22]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)OCc1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a strirred solution of 0.83 g (4-6 mmol) of 5-fluorotryptamine and 0.48 g (0.55 mL, 5 mmol) of nmethylmorpholine in 10 mL of DMF at 0° C. was added dropwise 0.72 mL (5 mmol) of benzylchloroformate. The reaction mixture was allowed to stir at 0° C. under argon. After 1.5 hours of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash chromatography using hexane:ethyl acetate (2:1) as an eluent to yield 1 g (68%) of N-(Benzyloxycarbonyl)-5-fluorotryptamine as a white solid. mp 104°-105° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:38]=[CH:37][C:19]([CH2:20][O:21][CH2:22][CH:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:24][C@@H]3CCCCO3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl>C(O)C>[C:31]1([C@@H:23]([OH:24])[CH2:22][O:21][CH2:20][C:19]2[CH:37]=[CH:38][C:16](/[CH:15]=[CH:14]/[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=3)=[CH:17][CH:18]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCOc1ccc(C=Cc2ccc(COCC(O[C@@H]3CCCCO3)c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCOc1ccc(/C=C/c2ccc(COC[C@H](O)c3ccccc3)cc2)cc1

Procedure:
1.4 g of (R)-2-(2-{4-[2-(4-Hexyloxy-phenyl)-vinyl]-benzyloxy}-1-phenyl-ethoxy)-tetrahydro-pyran (4) were dissolved in 30 ml of ethanol. Hydrochloric acid was added dropwise to obtain an acidic medium. Then the mixture was refluxed for 30 min. Upon cooling the product crystallized. The solid was filtered, washed with ethanol, and dried in a dessicator.