Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[CH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.B(F)(F)F.CC[O:29]CC.C1O[C@H]1CO.[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]2C=CC(F)=[CH:47][CH:46]=2)=[CH:40][CH:39]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:47][C@H:46]([OH:29])[CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOCc1ccccc1
Reactant: Fc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 59.5 %

Procedure:
To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued for 20 min. at −78° C. A THF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 82.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-fluorophenyl 4-hydroxyphenyl ketone (324 mg) were mixed and stirred at 170° C. for 20 minutes. The reaction mixture was then purified in the same manner as described in Example 41 to obtain 114 mg of the title compound (yield: 57%).
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1Cl)CCC.[CH:16]1([Mg]Br)[CH2:18][CH2:17]1.[O:21]1CCCC1>CCOCC.[Cl-].[Mn+2].[Cl-]>[CH:16]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=2[CH:6]=[O:21])[CH2:18][CH2:17]1
Reactant: C1CCOC1
Reactant: CCCC/N=C/c1c(Cl)cccc1CC
Reactant: Br[Mg]C1CC1
Agent: [Mn+2]
Agent: [Cl-]
Solvent: CCOCC
Product: CCc1cccc(C2CC2)c1C=O

Procedure:
Prepared in analogy to Example 57(c) from butyl-[1-(2-chloro-6-ethyl-phenyl)-meth-(E)-ylidene]-amine, cyclopropylmagnesium bromide and manganese(II) chloride in tetrahydrofuran and ether followed by chromatography on silical gel. Yellow oil. 1H-NMR (CDCl3): 0.74 (2H, m, CH2), 1.02 (2H, m, CH2), 1.25 (3H, t, CH3), 2.40 (1H, m, CH), 2.98 (2H, q, CH2), 7.04 (1H, d, ArH), 7.12 (1H, d, ArH), 7.36 (1H, dd, ArH), 10.9 (1H, s, CHO).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:21]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Cn2cnc3c(N)nc(Cl)nc32)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
2-Chloroadenine (1.70 g, 10.0 mmol) and potassium carbonate (9.67 g, 70.0 mmol) were added to DMF (35 ml) and the mixture was stirred at 60° C. for 1.5 hours. After cooling to room temperature, methyl 3-bromomethylphenylacetate (3.16 g, 13.0 mmol) was added thereto and the mixture was stirred at room temperature for 1.5 hours. After removing the solvent, thereto was added chloroform (50 ml) and the resulting solid was washed with water to give the captioned compound (2.13 g, 6.41 mmol, yield: 64%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: OC1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: OC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
943 mg of 3-hydroxypiperidine was dissolved in 15 mL of toluene, to which, under ice cooling, 1.13 mL of benzaldehyde, 2.97 g of sodium triacetoxyborohydride and 0.3 mL of acetic acid were sequentially added, and stirred at room temperature for 24 hours. To the reaction mixture, saturated sodium bicarbonate was added, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform to chloroform:methanol-ammonia=60:1) to obtain 866.3 mg (49%) of 1-benzyl-3-hydroxypiperidine crude product as a colorless oil.
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=O)C.[OH-].[K+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CO>[CH2:19]([O:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:26][CH3:27])[C:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[N:6][CH:15]=[C:14]2[CH:16]=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(Cc2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 42.7 %

Procedure:
To a solution of 6-benzyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (85 mg, 0.17 mmol) in methanol (3 mL) was added powdered potassium hydroxide (97.7 mg, 1.75 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs. The solvent was evaporated and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane, 75% ethyl acetate/hexane, ethyl acetate) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde as a colorless oil (30 mg, 42% yield).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[C:6]([CH2:14][C:15]([O:17]CC)=O)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.C(O)C>[C:7]1([C:6]2[O:13][N:4]=[C:15]([OH:17])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of sodium hydroxide was dissolved in 200 ml of water and 300 ml of ethanol. 69.5 g of hydroxylamine hydrochloride was added to the solution. A mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water was added to the solution so that the pH thereof was adjusted to 10.0. 192 g of ethyl benzoylacetate and a mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water were added dropwise to the solution at the same time under cooling with ice in such a manner that the pH thereof was 10±0.3. After the dropwise addition was finished, the solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture of 500 g of conc. hydrochloric acid and 500 g of ice. 2.5 l of ethanol was added to the reaction mixture. The reaction mixture was heated under reflux for 3 hours. 2 l of water was added to cool the solution. The resulting crystals were filtered off, washed with water, and dried. (Yield: 98 g (61%); m.p.: 150°-151° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15](=[O:17])[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15](=[O:17])[NH2:16])[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(carbamoylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde 0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) 6: 1.50 (9H, s), 1.60-1.80 (2H, m), 2.10 (1H, m), 3.10-3.60 (8H, m), 5.65 (1H, br, s), 6.90 (1H, br, s) 7.20-7.40 (4H, m). ESI-MS m/z: 367 (M+1), UV retention time: 1.94 min.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>CC(C)=O>[CH3:15][N:16]([C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=1)[C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(N(C)c2nc(=O)c3cccnc3s2)cc1
Yield: 49.7 %

Procedure:
The reaction procedure of Example 102 was followed except that 1.256 g of 2-chloronicotinoyl chloride, 543 mg of ammonium thiocyanate, 1.379 g of ethyl [4-(methylamino)phenyl]acetate and 24 ml of acetone were used. The product was then recrystallized from ethanol to obtain 1.26 g of ethyl [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]phenyl]acetate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: OCCOCCOCCOCCOCCOCCOCC(F)(F)F
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
To a stirred solution of the product of step (d) (1.5 g) in toluene (30 mL) was added potassium tert-butoxide (0.69 g) and the resulting mixture was stirred at room temperature for 3 hours. Ethyl bromoacetate (1.38 g) was added and the reaction was stirred at 130° C. for 48 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (500 mL) and washed with water (2×400 mL). The organic layer was washed with brine (300 mL), dried and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (Biotage), eluting with 65–75% ethyl acetate in cyclohexane to give the title compound as a brown oil (0.40 g). LC retention time 2.77 min. Mass spectrum m/z 468 [MNH4+]
Reaction SMILES: N1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[CH3:12][O:13][C:14](=[O:26])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([Cl:25])[CH:18]=1)[CH3:16].Cl.[O:28]1CCOCC1>>[CH3:12][O:13][C:14](=[O:26])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2=[O:28])=[C:19]([Cl:25])[CH:18]=1)[CH3:16]
Reactant: C1COCCO1
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: COC(=O)C(C)c1ccc(CBr)c(Cl)c1
Agent: Cl
Product: COC(=O)C(C)c1ccc(CC2CCCCC2=O)c(Cl)c1
Yield: 73 %

Procedure:
4.4 g of 1-pyrrolidino-1-cyclohexene, 6 g of methyl-2-(4-bromomethyl-3-chlorophenyl)propionate and 20 ml of dioxane were mixed together to obtain a mixed liquid which was refluxed under agitation for 4 hours. After the end of the reaction, the reaction mixture obtained was incorporated with diluted hydrochloric acid and then extracted with 100 ml of ethyl acetate. The extract obtained was washed with water, dried, freed of the solvent and then distilled at a reduced pressure thereby to obtain 4.6 g (in a yield of 73%) of oily methyl-2-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]propionate.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[Br:12]N1C(=O)CCC1=O.CCOCC>ClC(Cl)C>[Br:12][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)Cc2ccccc2O1
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CC1(C)Cc2cc(Br)ccc2O1
Temperature: 25 °C
Yield: 79 %

Procedure:
2,2-Dimethyl-2,3-dihydrobenzo[b]furan (prepared according to the method of Baker and Shulgin, J. Org. Chem., 28, 1963, 2468) (500 mg, 3.38 mmol) was taken up in dichloroethane (5.5 ml) and stirred at room temperature under nitrogen, and N-bromosuccinimide (661 mg, 3.72 mmol) added in one portion. The reaction was then refluxed for 2 h, ether was added (10 ml) and a white precipitate of succinimide filtered off. The filtrate was evaporated to dryness, and then purified by column chromatography using 5% ether in pentane as eluant to give the title product (604 mg, 79%); 1HNMR (400 MHz, CDCl3) δ: 1.43 (s, 6H), 2.92 (s, 2H), 6.54 (d, 1H), 7.16 (d, 1H), 7.19 (s, 1H); LRMS: M+H, 227. (TS+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=Cc1ccccc1
Solvent: CI
Solvent: CCO
Product: CNCCc1ccc(OC)c(OC)c1
Yield: 74.3 %

Procedure:
3,4-Dimethoxybenzeneethanamine (100 g) was mixed with benzaldehyde (59 g), and rotoevaporated to give an oil. Methyl iodide (69 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (500 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (80 g) as an oil that was distilled under reduced pressure, b.p. 0.1 mm; 92°-95°.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:20](=[O:22])[CH3:21])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(OC2CNC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-(4-bromophenoxy)azetidine (207 mg, 0.91 mmol) in CH2Cl2 (10 mL) was added triethylamine (276 mg, 2.73 mmol) and acetic anhydride (186 mg, 1.82 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a yellow oil. The crude product was diluted with ethyl acetate (20 mL), washed with 1N HCl and saturated NaHCO3, dried over sodium sulfate, and concentrated in vacuo to give 1-[3-(4-bromophenoxy)azetidin-1-yl]ethanone (245 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 2H), 6.61 (d, 2H), 4.89 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.17 (m, 1H), 4.03 (m, 1H), 1.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (200 mg, 0.73 mmol, 1.0 eq) and K2CO3 (204 mg 1.47 mmol 2.0 eq) in DMF (5 mL), was added methyl iodide (210 mg, 1.47 mmol 2.0 eq) at RT and the mixture was stirred at RT for 6 h. K2CO3 was filtered out and the filtrate concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with EtOAc (20 mL). The organic layer was separated washed with brine solution, dried over anhydrous Na2SO4 and the solvent evaporated to get dimethyl 2-(2-fluoro-4-nitrophenyl)-2-methylmalonate (150 mg, 71%; TLC system: EtOAc/PE (1:9), Rf: 0.4).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:28]([OH:33])[C:29]([O:31][CH3:32])=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:28]([O:33][C:2]([CH3:7])([CH3:3])[CH3:1])[C:29]([O:31][CH3:32])=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 103.7 %

Procedure:
A solution of 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetonitrile (1.8 g, 3.09 mmol) in Ethanol (50 mL) was treated with NaOH (25 mL, 144 mmol) and the mixture was heated at 140° C. in a sealed tube overnight. HCl (conc.) was added until pH<2 and then the mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in Methanol (30 mL), cooled to 0° C. and then treated with TMS-diazomethane (6.19 mL, 12.38 mmol). The mixture was stirred for 2 hours and then concentrated. The resulting residue was dissolved in t-Butyl acetate (10 mL), treated with perchloric acid (0.186 mL, 3.09 mmol) and then stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1M NaOH, then brine. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford the title compound (280 mg) as well as methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (500 mg). An ice cold solution of methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (500 mg) in t-Butyl acetate (5 mL) was treated with perchloric acid (1 eq.) then kept at 0° C. for 2 days without stirring. The mixture was diluted with ethyl acetate, washed with 1M NaOH, then brine. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford the title compound (290 mg). The material from each purification was combined to give the title compound (570 mg, 34% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.37-7.29 (m, 5H), 7.15 (m, 1H), 7.02-6.91 (m, 1H), 6.74 (m, 1H), 5.99-5.67 (m, 3H), 5.28 (s, 0.7H), 5.10 (s, 0.3H), 4.27-4.15 (m, 2H), 3.77 (s, 2H), 3.73 (s, 1H), 3.67 (s, 3H), 2.77-2.58 (m, 2H), 2.17-2.03 (m, 2H), 1.92 (s, 3H), 1.12 (s, 3H), 0.97 (s, 6H); LC/MS (m/z) ES+=529 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[C:36]([NH:39][CH2:40][CH2:41][NH2:42])(=[O:38])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:42][CH2:41][CH2:40][NH:39][C:36](=[O:38])[CH3:37])=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CC(=O)NCCN
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NCCNC(C)=O)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (52 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 5 hr. Next, 2-acetamidoethylamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (6 mg, yield 8%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[F:25].[OH-].[Na+]>CO.O1CCCC1.O>[F:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1F
Yield: 88.4 %

Procedure:
A solution of 2-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.425 g of purified 2-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 155°-156° C.