Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C([S+]1CCCC1)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CSCC[C@H](N)C(=O)[O-]
Agent: CCCC[S+]1CCCC1
Agent: Cl
Solvent: CC#N
Product: CSCC[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. A solution prepared by dissolving 633 mg (mL) of butyltetrahydrothiophenium methionine salt in 15 mL of acetonitrile was dropped to the solution, and then the mixture was stirred for 20 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-methionine was obtained. An isolation amount and an isolation yield were 428.8 mg and 80%, respectively.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH:40]1[C:45](N=C=S)=[CH:44][C:43]2[C:49]([O:51][C:52]3([C:62]4[CH:63]=[CH:64][C:65]([OH:67])=[CH:66][C:61]=4[O:60][C:54]4[CH:55]=[C:56]([OH:59])[CH:57]=[CH:58][C:53]3=4)[C:42]=2[CH:41]=1)=[O:50]>C(=O)([O-])[O-].[Na+].[Na+].[Al]>[CH:40]1[CH:45]=[CH:44][C:43]([C:49]([OH:51])=[O:50])=[C:42]([C:52]2[C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=3[O:60][C:61]3[C:62]=2[CH:63]=[CH:64][C:65]([CH:66]=3)=[O:67])[CH:41]=1.[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: O=C([O-])[O-]
Agent: [Al]
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
An aliquot of 120 mg of desferrioxamine and 233.64 mg of fluorescein isothiocyanate (FITC) are mixed in 50 mL of 0.1 M sodium carbonate pH 9.5. A molar ratio of 3:1 of FITC: desferrioxamine is used as described in Hentz et al. (1997) Anal. Chem. 69:4994-5000. The reaction mixture is wrapped in aluminum foil to avoid light exposure and allowed to react for at least 24 hours at room temperature. To separate fluorescently labeled desferrioxamine from free fluorescein and free desferrioxamine, the mixture is separated using a P-2 column (Bio-Rad) equilibrated in saline and samples are eluted in 2 mL fractions. The fluorescein-desferrioxamine is eluted in the void volume of the column. The first peak is collected and used for preparing fluorescein-desferrioxamine, desferrioxamine, and rhodamine liposomes.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8](N=C=S)=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13]>O.CN(C)C=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]([C:15]2[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[O:23][C:24]3[C:25]=2[CH:26]=[CH:27][C:28]([CH:29]=3)=[O:30])[CH:4]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 24 h

Procedure:
Bovine serum albumin (100 mg) was dissolved in distilled water (2.0 ml) and the mixture was adjusted to a pH of 9 with 1N NaOH. Fluorescein isothiocyanate (FITC, 100 mg) in dimethylformamide (1.0 ml) was added by drops with stirring while maintaining the pH at 9 by addition of 1N NaOH. After all of the FITC was added, the mixture was stirred at room temperature for two hours. The solution was then dialysed in a cellulose dialyzing tube (MW 12,000-14,000) against 10 mM phosphate buffer (1.0 liter, pH 7) for two hours. The dialyzing tube was then dialysed against two changes of 0.9% aqueous sodium chloride (4.0 liters), for 19 hours each time, and then against three changes of 10% dimethylsulfoxide in 0.9% aqueous sodium chloride, for 24 hours each time. The final solution showed no sign of fluorescein in the dialysis solution. The resulting immunogen solution was then removed from the dialyzing tube and lyophilized to yield an orange solid. The immunogen was used according to standard procedures to produce a rabbit anti-fluorescein antibody capture reagent. The antibody was purified according to the procedure described in Example 1.c. above.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
The amine (11.3 mg, 23 μmol) was combined with fluorescein isothiocyanate (10.4 mg, 35 μmol) and DIEA (12 μL, 69 μmol) in DMF (400 μL). The solution was stirred 1.5 h and concentrated. The product was purified using HPLC (gradient 50-70% ACN/H2O) to yield 11 as an orange solid (16.2 mg, 18.5 μmol) in 80% yield. 1H (300 MHz, CD3OD): δ 8.11 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.51 (d, 2H, J=7.8 Hz), 7.20 (s, 4H), 7.15 (d, 2H, J=8.5 Hz), 7.08 (d, 1H, J=8.2 Hz), 6.71 (d, 2H, J=8.5 Hz), 6.68 (d, 2H, J=2.1 Hz), 6.54 (dd, 2H, J=8.8, 2.4 Hz), 4.66 (dd, 1H, J=8.4, 5.0 Hz), 3.53 (m, 2H), 3.30 (dd, 1H, J=14.4, 5.0 Hz), 3.05 (dd, 1H, J=14.0, 8.2 Hz), 2.56 (t, 2H, J=7.8 Hz), 1.60-1.57 (m, 4H), 1.31 (br s, 8H); 13C (75 mHz, CD3OD): δ 182.5, 173.4, 170.4, 170.1, 154.6, 136.5, 133.6, 131.8, 130.5, 129.6, 129.3, 126.9, 126.0, 114.1, 144.0, 103.2, 60.4, 60.3, 37.7, 36.3, 32.1, 30.1, 30.0, 29.8, 29.6, 27.6; LC/MS (ESI) (m/z) [M+H]+ calcd 875.3. found 875.3.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Cl:14])=[N:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-3-nitro-5-bromopyridine (10 g) was combined with 25 mL of phosphorus oxychloride and 5 g of phosphorus pentachloride. The mixture was heated to 110° C. for 2 h, then cooled to room temperature and poured into ice-water and stirred 30 min. The mixture was extracted with CHCl3, then the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by chromatography through a short plug of SiO2, eluting with 4:1 hexanes:EtOAc afforded 6.72 g of 5-bromo-2-chloro-3-nitro-pyridine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]#[N:17])[CH:11]=[CH:12][C:13]=1[Cl:14].[OH-].[Na+].CCOCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:16]#[N:17])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,4-Dibromobutane (106 ml) was added dropwise over 1 hour at 70°-80° C. under nitrogen to a stirred mixture of 3,4-dichlorophenylacetonitrile (150 g) , benzyltriethylammonium chloride (2 g) and 50% aqueous sodium hydroxide solution (300 ml). When the addition was complete the mixture was stirred at 70°-80° C. for 2 hours, then cooled to ambient temperature. Ether (400 ml) and water (200 ml) were added and the layers were separated. The aqueous layer was washed with ether (2×200 ml), then the combined organic solutions were dried over magnesium sulphate and the solvent removed in vacuo. The residue was distilled to give 1-(3,4-dichlorophenyl)cyclopentanecarbonitrile as a pale yellow oil (135 g), b.p. 132°-140° C./0.4 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>[Zn].Cl[Hg]Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1OC
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCC(=O)O)cc1OC

Procedure:
A mixture containing 37.6 g of the product obtained in Example 38 and 64 g of zinc turnings (treated with a solution of HgCl2), 55 ml of toluene and 220 ml of conc. hydrochloric acid was refluxed for 1 h. Toluene phase was separated and evaporated in vacuo. The residue was crystallized from toluene-petroleum ether, yield 11.5 g (32%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:20]1([C:19](=[N:32][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(N=C(c3ccccc3)c3ccccc3)nc2)C1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 117a (2.00 g, 7.46 mmol), benzophenoneimine (1.62 g, 8.96 mmol), sodium tert-butoxide (1.00 g, 10.4 mmol), (dibenzylideneacetone)-dipalladium(0) (340 mg, 0.373 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (700 mg, 1.12 mmol), and the reaction was heated at 100° C. for 3 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting oil was purified by column chromatography to afford a 79% yield (2.44 g) of 117b as a brown solid: mp 104-105° C.; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, 1H, J=2.0 Hz), 7.85 (br s, 2H), 7.52 (br s, 1H), 7.44 (br s, 2H), 7.47 (dd, 1H, J=8.5, 2.0 Hz), 7.17 (br s, 5H), 6.61 (d, 1H, J=8.5 Hz), 4.30 (t, 2H, J=8.5 Hz), 3.86 (dd, 2H, J=8.5, 4.5 Hz), 3.62 (m, 1H), 1.45 (s, 9H); MS (ESI+) m/z 413.8 (M+H).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@H:19]([O:20]C(=O)C)[C@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]1([S:7][C@@H:8]2[O:25][C@H:24]([CH2:26][OH:27])[C@H:19]([OH:20])[C@H:14]([OH:15])[C@H:9]2[OH:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of thioglycoside 39 (1.10 g, 2.5 mmol) in 50 mL of MeOH is added K2CO3 in small portions, until the reaction mixture tested basic to pH paper (pH 11). The reaction mixture is stirred at room temperature for 15 min and then neutralized with Amberlite resin (acid form). The resin is removed by filtration and washed with MeOH (2×50 mL). The filtrates are concentrated and azeotroped from toluene to remove the residue MeOH to afford 1-deoxy-1-(phenylthio)-β-D-galactopyranose which is taken on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([O:32]C)=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[C@@H:8]1[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][C@@H:10]([CH3:21])[N:9]1[CH2:22][C:23]([F:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=[CH:17][CH:16]=3.C(O)(C)C.[OH-].[Na+].Cl>O>[F:27][C:6]1[CH:5]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:3]=[C:2]([F:1])[C:7]=1[C@@H:8]1[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][C@@H:10]([CH3:21])[N:9]1[CH2:22][C:23]([F:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)N1CC(C)(C)F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
(E)-Methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (350 g, 766.69 mmol) was charged a 5 L fixed vessel. Isopropyl alcohol (2.80 L) was added to the vessel. Sodium hydroxide (5M, 460 ml, 2.30 mol) was added in one portion and the mixture was stirred at 21 C for 16 hrs. The dark solution was screened through a filter to remove particulates. The filtrate was returned to the reactor vessel. The filter and filtrate collection vessel were washed with isopropanol (700 ml) and the washings were added to the reactor vessel. The reaction mixture was agitated and water (1.75 L) was added. Concentrated hydrochloric acid (37% w/w, 165 ml, 1.92 mol) was charged to the vessel. Further hydrochloric acid (21.5 ml) was added to the vessel to adjust the pH between 4.0 and 4.5. The solution was heated to 50° C. Water (1.92 L) added to the vessel over 1 hour maintaining the internal temperature between 50-53° C. The jacket temperature was raised to 70° C. to maintain the reactor temperature in this range during the addition. Within 10 minutes of completion of the water addition, the mixture self seeded and started to crystallise. The mixture was held at 50-52° C. for 1.5 hours (jacket set temperature 58° C.). The resulting yellow suspension was cooled to 5° C. (jacket temperature) over 6 hours. The slurry was held at 5° C. (jacket temperature) for 11 hrs. The resultant yellow solid was isolated by filtration. The cake was pasted with a spatula to prevent cracking of the cake. The vessel was washed with water (1.05 L). The washings were used to wash the cake. The cake was pulled dry in air then dried in vacuo to constant weight over 4 days (oven temperature=30° C.). (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid was thus isolated as a yellow crystalline solid, “Form B” (319.45 g, 94%). 1H NMR (500 MHz, DMSO, 27° C.) 1.05 (3H, d), 1.08-1.28 (6H, m), 2.35 (1H, dd), 2.58 (1H, dd), 2.8-2.97 (2H, n), 3.47-3.57 (1H, m), 5.22 (1H, s), 6.67 (1H, d), 6.91-7.06 (2H, m), 7.19 (1H, d), 7.41 (1H, d), 7.46 (2H, d), 7.54 (1H, d), 10.58 (1H, s), 12.62 (1H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN1CCCC1=O.C(OCC)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: O=Cc1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCOC(COc1ccc(C=O)cc1)OCC
Yield: 96.6 %

Procedure:
Bromoacetaldehyde-diethyl-acetal (98.5 g, 0.5 m) and p-hydroxybenzaldehyde (76.4 g, 0.63 m) were dissolved in N-methylpyrrolidone (250 cm3) and heated at 120° for 12 hours. The reaction mixture was cooled, diluted with diethyl ether and the ether layer was extracted four times with 5% sodium hydroxide solution to remove excess of p-hydroxybenzaldehyde. The ether was removed and the product distilled under reduced pressure to give 115 g (97%) of p-formylphenoxy-acetaldehyde-diethyl-acetal, b. 139°-140°/1.5 mbs. Acetylbenzene-sulphonic acid (sodium salt, 40 g, 0.18 m) was dispersed in a mixture of methanol (400 cm3) and 10% aqueous sodium hydroxide (150 cm3).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13][C:14](=[O:16])[CH3:15])/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6].[NH4+].[Cl-].[Na+].[Cl-].[CH3:21][O:22][C:23](=O)[O:24]C>C1(C)C=CC=CC=1.CN1CCCC1=O>[O:16]=[C:14]([CH2:13][CH2:3][CH:4]=[C:5]([CH3:6])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:15][C:23]([O:22][CH3:21])=[O:24]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: COC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
24 g (0.55M) of sodium hydride (55% dispersion in mineral oil) were added at 20° under nitrogen to a solution of 135 g (1.5M) of dimethylcarbonate in 500 ml of a mixture of toluene/N-methylpyrrolidone (9:1). The obtained mixture was heated to reflux (bath temperature 100°) then, during 1 h, there was added a solution of 0.5M of geranylacetone in 135 g (1.5M) of dimethylcarbonate, where upon the resulting reaction mixture was kept refluxing during 10 min. It was finally poured into a 10% aqueous solution of NH4Cl saturated with NaCl. An ether extraction, followed by the usual work up of the combined organic extracts and fractional distillation gave methyl 3-oxo-7,11-dimethyl-dodeca-6,10-dienoate.
Reaction SMILES: [H-].[Na+].[S:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:5]=[CH:4]1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[CH:20][C:13]([Cl:12])=[C:14]([CH2:15][N:8]2[CH2:7][C:6]3[CH:5]=[CH:4][S:3][C:11]=3[CH2:10][CH2:9]2)[CH:17]=1
Reactant: ClCc1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example A-2, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3×40 ml). The methylene chloride extracts are washed (1×50 ml water) and 1×50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N#N.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O.CCCCCC.O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc21
Reactant: Clc1ncccn1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(Oc3ncccn3)ccc21
Temperature: 100 °C

Procedure:
5-Hydroxyindanone (3.2 g, 21.6 mmol) was dissolved in dry DMF (20 mL) in a 3-neck flask fitted with an N2 inlet and reflux condenser. The system was blanketed with N2, and 60% NaH in mineral oil (860 mg) was added slowly and in portions at 0° C. Then 2-chloropyrimidine (2.5 g) was added, the ice bath was replaced with an oil bath, and the solution was heated at 100° C. for 3 hours. This was then cooled to room temperature before removal of DMF in vacuo. To the residue was added water (50 mL), the mixture was extracted with CH2Cl2 (50 mL), and the aqueous layer extracted twice more with CH2Cl2. The organic layer was extracted with 1N NaOH (50 mL) to remove unreacted phenol and then dried with Na2SO4 and evaporated to a dark brown solid (3.6 g). The solid was extracted with EtOAc; filtration removed an insoluble precipitate. The filtrate was dried as before and evaporated to yield the product which was pure by NMR and TLC (1:1 hexane:EtOAc).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1.ClCCl.O>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2n1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
4 ml (36.4 mmol) of titanium(IV) chloride are added to a solution of 4 ml (36 mmol) of ethyl chlorooxoacetate in 100 ml of 1,2-dichloroethane. The reaction mixture is stirred for 30 min at room temperature, 7.8 g (32.8 mmol) of ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate are then added and the reaction mixture is stirred for 4 hours at room temperature. The mixture is cooled and 200 ml of dichloromethane and 100 ml of water are added. The organic phase is separated by settling, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 9.4 g (27.7 mmol) of product are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 4-bromoaniline (1.0 eq) in dichloromethane, triethylamine (2.2 eq) was added at 0° C. and stirred for 15 min. To this mixture was added acetic anhydride (1.0 eq) in dichloromethane at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-bromophenyl)acetamide. (Yield=65%)
Reaction SMILES: N1C=CC=CC=1.C(O[C:11](=[O:13])[CH3:12])(=O)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:11](=[O:13])[CH3:12])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)cc1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Pyridine (551 mg, 5.8 mmol) and acetic anhydride (650 mg, 0.6 mL, 6.4 mmol) were added to a cold solution (at 0° C.) of 4-bromo-phenylamine (1 g, 5.8 mmol) in DCM (10 mL) and stirring was continued at ambient temperature for 2 hrs. The reaction mixture was diluted with DCM and washed the organic layer with water followed by brine solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure to afford 900 mg (69.5% yield) of N-(4-bromo-phenyl)-acetamide.