Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
In a 10 ml flask, hydroxy-acetic acid methyl ester (0.4 ml, 0.53 mmol) was dissolved in tetrahydrofuran (1.5 ml), and then sodium hydride (23 mg, 0.57 mmol) was added thereto. After 40 minutes, 2-chloro-3-nitro-5-trifluoromethyl-pyridine (100 mg, 0.44 mmol) was added and then stirred for 2 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain white solid (84 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[O:13][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1cc(-c2ncco2)ccc1Br
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(-c2ncco2)cc1OCCCc1ccccc1
Reaction time: 15 h
Yield: 51 %

Procedure:
To a solution of the title compound of Step (A) (0.42 g, 1.75 mmol) in 5 mL of DMF at 50° C., anhydrous potassium carbonate (0.29 g, 2.09 mmol) and 1-bromo-3-phenyl propane (0.52 g, 2.63 mmol) were added and stirred for 15 hr. The mixture was then added to 25 mL water and the solution was extracted with 3×25 mL EtOAc. The combined organic extracts were washed with water and dried and evaporated. The residue thus obtained was chromatographed on 25 g of silica gel using 3:1 hexane:EtOAc to afford 0.32 g (51%) of the title compound of this step as a light yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH3:9])=[N:3][CH:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][CH3:9])=[N:3][CH:2]=1
Reactant: CCC(c1ccncn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CCC(N)c1ccncn1
Yield: 84 %

Procedure:
2-[1-(Pyrimidin-4-yl)propyl]isoindoline-1,3-dione (292 mg, 1.09 mmol) in methanol (2 mL) was stirred with hydrazine monohydrate (153 μL, 3.15 mmol) at room temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product (84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:29][CH2:26][CH:27]=[CH2:28])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h

Procedure:
A mixture of 2 g (0.0065 mole) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 0.9 g (0.0065 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated while stirring with 0.35 g (0.0065 mole) of 2-propenylamine. After stirring for 16 h, the reaction mixture was diluted with 100 ml of water whereupon an oil separated. The oil slowly solidified and was collected by filtration (2.3 g wet). The rose colored solid was recrystallized from benzene/ligroin yielding 1.7 g (78.1%) of beige crystals, mp 102°-104°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>S(=O)(=O)(O)O>[CH2:13]([O:16][C:7](=[O:8])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1)[CH2:14][CH3:15]
Reactant: CCCO
Reactant: COc1cc(CCO)ccc1O
Agent: O=S(=O)(O)O
Product: CCCOC(=O)Cc1ccc(O)c(OC)c1
Temperature: 100 °C

Procedure:
4-Hydroxy-3-methoxyphenethyl alcohol (Sigma-Aldrich) was dissolved in anhydrous 1-propanol. To this solution ˜5 drops of concentrated sulphuric acid were added and the solution was heated at 100° C. for 3-5 hours in a pressure tube. When the reaction was complete, the 1-propanol was removed under reduced pressure, the resulting oil was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, distilled water, and then brine. The solution was dried over magnesium sulfate and filtered and the solvent was removed under reduced pressure, giving 15-A as a red oil in almost quantitative yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[C:4]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:5][C:6]2[C:11]([CH:2]=1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1nc2cccnc2cc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
The preparation of 4-chloro-3-nitro[1,5]naphthyridine is described in Part A of Example 1. Ethyl 4-aminobutyrate hydrochloride (9.6 g, 57.3 mmol, 1.2 eq) was added to a suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol, 1.0 eq) in dichloromethane (200 mL) and stirred at 5° C. Triethylamine (16.6 mL, 119.3 mmol, 2.5 eq) was added and the reaction mixture was stirred for 2 hours and allowed to warm to ambient temperature. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The phases were separated and the combined aqueous layers were extracted with chloroform (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.5 g of ethyl 4-[(3-nitro[1,5]naphthyridinyl)amino]butyrate as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[OH-].[Na+].[CH2:30]1[O:32][C@H:31]1[CH2:33]Cl>C(O)(C)C.CCOC(C)=O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:33][C@@H:31]4[CH2:30][O:32]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 109.6 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (700 mg, 1.90 mmol) in isopropanol (12 mL), are added 3M aq. NaOH (4 mL) and R-epichlorohydrine (1.49 mL, 19.0 mmol). The reaction mixture is stirred at rt for 15 h, then is diluted with EtOAc and washed with 1M aq. NaOH followed by brine. The org. phase is dried over Na2SO4, filtered, evaporated and purified by CC (eluting with Heptane/EtOAc 4:1) to give the title compound as a yellow oil (882 mg); LC-MS: tR=1.23; [M+H]+=424.04. 1H NMR (CDCl3) δ 1.25 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.79 (m, 3H), 2.94 (t, J=4.5 Hz, 1H), 3.42 (m, 1H), 3.76 (q, J=7.0 Hz, 4H), 3.83 (dd, J=11.0, 5.8 Hz, 1H), 4.13 (dd, J=11.0, 3.0 Hz, 1H), 7.23 (s, 1H), 7.89 (d, J=5.5 Hz, 2H).
Reaction SMILES: O[Li].O.[Si]([O:11][C@H:12]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[CH:18]=2)[C@@H:14]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[CH2:13]1)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.O>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[C@H:14]1[CH2:13][C@@H:12]([OH:11])[CH2:16][N:15]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3F)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 8 h

Procedure:
1M aq. solution of LiOH.H2O (0.4 mL) was added to a stirred solution of ethyl 5-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Isomer-I) (Int-60) (0.07 g, 0.14 mmol) in EtOH (5 mL) and the stirring was continued at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with citric acid solution, filtered the solid precipitated to afford 5-((2R,4R)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (Int-62) as yellow solid. MS (ESI): m/z 360 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[N:7][CH:8]=1.Cl[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[NH2:9][C:6]1[C:5]([NH:10][C:14](=[O:15])[O:16][CH3:17])=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=1
Reactant: Nc1cc(C(F)(F)F)cnc1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-trifluoromethylpyridin-2,3-diamine (1.2 g) and pyridine (20 ml), methyl chloroformate (0.63 ml) was added under ice-cooling. The mixture was heated to room temperature, stirred for 8 hours, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 628 mg of methyl (2-amino-5-trifluoromethylpyridin-3-yl)-carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[S:40]([CH3:43])(=[O:42])=[O:41])[N:27]2[N:26]=1)=O>>[CH3:43][S:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:33]1[N:27]2[C:28]([CH:29]=[N:30][C:25]([NH:21][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][CH:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[N:26]2)=[CH:31][CH:32]=1)(=[O:41])=[O:42]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Temperature: 190 °C

Procedure:
Following the procedure of example 532 (c), 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (0.095 g, 0.33 mmol) and 2-Methanesulfinyl-7-(2-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.17 g, 0.51 mmol) were heated in the microwave at 190° C. for 3 hours. Purification by Gilson chromatography gave [7-(2-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[2-methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a tan solid; MP: 111-112° C.; LCMS (m/e) 563 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 8.16-8.14 (d, 1H, J=8.04 Hz), 7.887.85 (t, 1H, J=7.25 Hz), 7.807.60 (t, 1H, J=7.48 Hz), 7.707.68 (d, 1H, J=7.58 Hz), 7.60 (s, 1H), 7.43-7.41 (d, 1H, J=8.45 Hz), 6.94-6.92 (q, 2H, J=5.45 Hz), 6.56 (s, 1H), 6.21-6.19 (d, 1H, J=8.80 Hz), 5.75 (s, 1H), 3.76 (s, 3H), 3.62-3.58 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H), 2.61-2.55 (t, 1H), 2.23 (t, 1H), 1.86-1.83 (d, 2H, J=11.77 Hz), 1.48-1.45 (q, 2H, J=11.36).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C:10]([CH:12]1[CH:16]([CH:17]=[C:18]([F:20])[F:19])[CH2:15][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]1=[O:32])=[O:11])C>O.CO>[F:20][C:18]([F:19])=[CH:17][CH:16]1[CH2:15][N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13](=[O:32])[CH:12]1[C:10]([OH:11])=[O:9]
Reactant: CCOC(=O)C1C(=O)N(Cc2ccc(OC)cc2OC)CC1C=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2CC(C=C(F)F)C(C(=O)O)C2=O)c(OC)c1
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of potassium carbonate (581 g, 4.20 mol) in water (4 L) is added to a stirred refluxed solution of (H) in methanol (1 L). The mixture is stirred for 18 h, washed with toluene (2×5 L) and acidified to a pH<2 with concentrated HCl (750 mL). The aqueous layer is extracted with ethyl acetate. This organic layer is washed with water, dried over anhydrous MgSO4 and concentrated to give 615 g of (K) (yield=89%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(N2CC[C@H](O)C2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3S)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (4.1 g, 16.9 mmol) (obtained as described in Reference Example 20(3)) in dimethylformamide (120 ml) were added t-butyldiphenylsilyl chloride (8.8 ml, 33.8 mmol) and imidazole (2.3 g, 33.8 mmol) in an ice bath, and then the reaction mixture was brought to room temperature in 10 minutes, and stirred for overnight. After checking the completion of the reaction, ethanol (1.18 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3S)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (7.60 g, yield 94%) as a pale brown solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12]C2CCCCO2)[O:9][CH:10]=1.O.N>CO.Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][OH:12])[O:9][CH:10]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCl
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: O=c1cc(CO)occ1OCCCl
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.9 %

Procedure:
To a solution of 314 g of 5-(2-chloroethoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 630 mL of methanol, 6.3 mL of concentrated hydrochloric acid was added and the mixture was stirred for 6 hours at room temperature. To the reaction mixture, 13 mL of 28% ammonia water was added and the solvent was evaporated under reduced pressure to give 240 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one (crude product) as a brown oily substance.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[F:22]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])=[CH:16][C:15]=1[F:22]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Br)c(F)c1)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-butyllithium (2.5 M/hexane, 0.98 mL, 2.46 mmol) in THF (7 mL) at −78° C. was added 2-bromopyridine (0.235 mL, 2.46 mmol) dropwise. The mixture was stirred at −78° C. for 1 hr. This solution was added via cannula to a solution of 4-bromo-3-fluorobenzaldehyde (as described in Example 20, Step A) (0.5 g, 2.46 mmol) in THF (5 mL) at −78° C. The resulting solution was stirred at −78° C. for 15 min. and at 25° C. for 2 hr. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was partitioned with EtOAc and the organic layer was washed with water, brine and dried over MgSO4. The solvents were removed in vacuo to obtain the title compound after chromatography (silica gel, CH2Cl2:MeOH 99:1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)#[CH:17]>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.C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 354.1 %

Procedure:
1,4-Diiodobenzene (4.95 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.07 g, 0.10 mmol), copper(I) iodide (0.019 g, 0.10 mmol), triethylamine (5 mL), THF (10 mL) and 4-ethynylaniline 0.585 g, 5.00 mmol) were used following the general procedure for couplings. For the synthesis of 4-ethynylaniline, please see Tour et al. Chem. Eur. J. 2001, vol. 7, pp. 5118-5134 incorporated herein by reference. The tube was capped and stirred room temperature for 12 h. Flash column chromatography (CH2Cl2—hexanes as eluent) afforded the desired product as light yellow needles (1.13 g, 71% yield). IR (KBr) 3441, 3356, 2210, 1612, 1515, 1281, 1135, 1003, 842, 811, 512 cm−1. 1H NMR (400 MHz, CDCl3)δ7.650 (m, AA′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.324 (m, XX′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.208 (m, AA′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 6.630 (m, XX′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 3.833 (s, 2H). 13C NMR (100 MHz, CDCl3) δ147.05, 137.60, 133.20, 133.07, 123.67, 114.95, 112.39, 93.45, 91.83, 86.69.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])=[CH:37][CH:36]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)Cc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 51.8 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added 4-chlorophenylacetyl chloride (267 mg, 1.41 mmol) and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a orange foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a yellow syrup that was triturated with diethyl ether to afford the title compound 0.230 g, 52%) as a yellow solid, m.p. 83° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[N:39]1([CH2:45][CH2:46][NH2:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[N:39]1([CH2:45][CH2:46][NH:47][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCN6CCOCC6)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and 2-(morpholin-4-yl)ethylamine in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ 8.57 (1H, d, J=5.1 Hz), 8.06 (1H,s), 7.97 (1H, bs), 7.83 (1H, d, J=8.6 Hz), 7.66 (1H, s), 7.27 (1H, d, J=8.3 Hz), 6.71 (1H, d, J=5.3 Hz), 4.20–3.95 (4H, m), 3.70–3.35 (10H, m), 3.25 (3H, d, J=12.6 Hz), 2.64 (3H, s), 2.41 (3H, s), 2.06 (2H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: c1ccc2ccccc2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Yield: 59.3 %

Procedure:
To 900 ml of dichloromethane contained in a 3 liter, 3-neck flask equipped with a mechanical stirrer, drying tube and thermometer and surrounded by an ice water bath was added 290.0 g (2.26 moles) naphthalene. To the stirred suspension was added 145.2 g (1.44 moles) of succinic anhydride. A total of 400 g of aluminum chloride was then added in small increments over the next 41/2 hours while stirring and cooling in an ice water bath. The resulting amber brown-yellow reaction mixture was stirred at room temperature overnight. Next morning it was poured on crushed ice and acidified with conc. hydrochloric acid. The aqueous portion was decanted and the organic layer was filtered to collect white solids. The solids were washed with dichloromethane containing 20% hexanes and slurried in 700 ml of boiling ethyl acetate. After cooling in a cold water bath, the solids were collected by filtration and washed with fresh ethyl acetate. Then the solids were recrystallized from 500 ml of glacial acetic acid and dried under vacuum to give 195.0 g (59.4% yield) of 4-(2-naphthyl)4-oxobutyric acid as an off-white solid. M.P. 171°-175° C.; M/e 229; λmax 282 nm (7,260) in ethanol.