Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[O:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH2:29][O:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=4[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CNCCO3)cc2)ncc1C(F)(F)F
Yield: 89.8 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate (I91) (23 mg, 0.039 mmol) was stirred with DCM (3 mL) and TFA (0.3 mL). After 18 hours the mixture was concentrated and the residue suspended in 10% aqueous NaOH (1 mL) and brine (1 mL). The mixture was extracted with ethyl acetate (5×3 mL), and the combined ethyl acetate phases washed with brine (20 mL), dried over sodium sulfate and evaporated to give the title compound (22) (17 mg, 89%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.67 (s, 1H), 7.74-7.67 (m, 2H), 7.42 (s, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.25-7.21 (m, 1H), 7.19-7.14 (m, 3H), 6.91 (s, 1H), 4.32 (dd, J=10.1, 2.1 Hz, 1H), 3.86 (d, J=10.9 Hz, 1H), 3.58 (dt, J=11.2, 7.2 Hz, 1H), 3.50 (s, 2H), 3.15-2.98 (m, 4H), 2.89 (dd, J=12.3, 2.2 Hz, 1H), 2.72 (d, J=5.2 Hz, 2H). LCMS Method C: rt 4.75 min; m/z 486.1 [M+H]+, 508.0 [M+Na]+; m/z 484.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].Cl.C1(C(O)=O)CCCCC=1>C(O)CC(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([C:12]([OH:14])=[O:13])[CH2:15][CH2:16]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(Cc2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C(O)C1=CCCCC1
Agent: [Na]
Solvent: CC(C)CCO
Product: COc1ccc(CC2CCC(C(=O)O)CC2)cc1

Procedure:
A solution of 49.5 g. of 4-(4-methoxybenzyl)benzoic acid (Example 1c) in 1000 ml. of isoamyl alcohol was heated at reflux and 109 g. of sodium was added in pieces over a 40 minute period. The reaction mixture was heated under reflux for three hours, then cooled and steam distilled until 2.5 liters of distillate was obtained. The resulting aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate and the solvent removed to give 34 g. of a crystalline residue comprising a mixture of the desired compound with the corresponding cyclohex-1-enecarboxylic acid. The latter mixture was dissolved in 170 ml. of ethanol and hydrogenated in the presence of 3 g. of 10% palladium-on-carbon catalyst. The catalyst was filtered off and the solvent removed to give 34 g. of 4-(4-methoxybenzyl)cyclohexanecarboxylic acid, used directly in the next reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:26])[C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[OH:26][CH:15]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Yield: 36.2 %

Procedure:
As in Example 19, a stirred solution of rac-4-[4-hydroxy-4-(2-naphthalenyl)butoxy]-alpha-oxobenzeneacetic acid methyl ester (0.172 g) in warm methanol (2.5 mL) was treated with 1N sodium hydroxide (1 mL) and then water (25 mL) was added. After the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (1.2 mL) and extracted with dichloromethane (1×50 mL, 1×10 mL). The dried (MgSO4) extracts were concentrated and the residual gummy solid (~0.17 g) was crystallized from acetone-hexane to give 0.06 g of rac-4-[4-hydroxy-4-(2-naphthalenyl) butoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 108°-110° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH3:14])[CH:20]=[CH:19][C:18](/[C:21](/[CH3:22])=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(=C\C#N)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (13.2 g, 74.6 mmol) in 50 mL of THF was added sodium hydride (60% content, 2.98 g, 74.6 mmol). The mixture was stirred at room temperature for 2 hours. 1-(4-methylphenyl)ethanone (5 g, 37.3 mmol) was added and the mixture was stirred for 2 hours. After evaporation of THF, the residue was taken up in ethyl acetate (50 mL) and quenched with water (50 mL). The organic phase was washed with water (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was used in the next step without further purification. LC-MS: m/z 158 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1.[I:14]I.Cl>C1COCC1>[I:14][C:6]1[N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccn2ncc(C(=O)O)c2c1
Reactant: II
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(I)n2ncc(C(=O)O)c2c1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.11 g) in THF (40 mL) was added 1M lithiumhexadisilazide THF solution (35.9 mL) at 0° C., the mixture was stirred for 30 min, and iodine (3.65 g) was added thereto. The reaction mixture was stirred overnight at room temperature under nitrogen gas atmosphere, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium thiosulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane/IPE to give the title compound (3.42 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C.BrN1C(=O)CCC1=O>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOCCN(CC)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCN(CC)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of N-ethyl-N-(2-propoxyethyl)aniline (10.18 g) in DMF (50 ml) was added at room temperature a solution of N-bromosuccinimide (7.45 g) in DMF (50 ml) for 40 minutes, and the mixture was stirred for 3 hours. To the mixture was added a solution of N-bromosuccinimide (0.2 g) in DMF (10 ml), and the mixture was stirred for 15 hours. The reaction mixture was added to water, and the mixture was extracted with diethylether. The organic layer was washed with water (twice) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (0.7 mmHg, 134° C.) to give pale yellow oil of 4-bromo-N-ethyl-N-(2-propoxyethyl)aniline (9.49 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C@H:11]([CH3:22])[NH:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)=[O:14])[CH3:2].C(O)C(O)C.[S:30]([O-])([O-])(=O)=S.[Na+].[Na+]>O>[CH2:1]([O:3][C:4](=[O:24])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C@H:11]([CH3:22])[NH:12][C:13]([C:15]1[CH:20]=[CH:19][NH:18][C:17](=[S:30])[CH:16]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccnc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(O)CO
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1cc[nH]c(=S)c1
Yield: 85 %

Procedure:
To a solution of 4.5 g (0.013 mol) of N-[(2-Chloro-4-pyridinyl)carbonyl]-L-alanyl-L-proline ethyl ester (Compound No. 3) in 45 ml of a 10:1 mixture of 1,2-propyleneglycol:water, 15.2 g of sodium thiosulfate are added, and the mixture is heated under reflux for 15 hours. The resulting reaction mixture is diluted with 100 ml of water and extracted with four 100 ml portions of methylene chloride. The organic layer is washed three times with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off at reduced pressure. The residue obtained is purified by crystallisation from a mixture of acetone:petroleum ether, to give the title product as a yellow solid (yield: 85%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[BrH:10].O>C1C=CC=CC=1>[Br:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: Br
Reactant: OCCCCCCCO
Solvent: c1ccccc1
Solvent: O
Product: OCCCCCCCBr
Reaction time: 16 h
Yield: 62 %

Procedure:
Heptane-1,7-diol (36.0 g, 272 mmol; Alfa Aesar) and aq. 48% HBr (38 mL, 0.9 equiv.) were heated under reflux in benzene (400 mL) with water removal using a Dean-Stark apparatus. After 16 h, all volatiles were removed in vacuo and the residue was purified by SiO2 column chromatography using a gradient of 10-30% EtOAc/hexanes as eluent to give 7-bromoheptan-1-ol (26.22 g, 62%) as a colorless oil. TLC: 50% EtOAc/hexanes, Rf˜0.40; 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H, J=7.1 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.80-1.88 (m, 2H), 1.52-1.58 (m, 2H), 1.30-1.46 (m, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 0 °C

Procedure:
95.7 g of finely pulverised aluminium chloride are suspended in 180 ml of absolute methylene chloride. While stirring and cooling, 35 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester, dissolved in a small amount of methylene chloride, are added dropwise in such a manner that the temperature remains below 30°. At the same temperature, 50.5 g of benzoyl chloride are added dropwise thereto and the whole is subsequently heated at reflux for 4 hours. After cooling, the reaction mixture is poured onto 600 g of ice. The organic phase is separated off and the aqueous phase is extracted 3 times with 150 ml of methylene chloride each time. The combined organic phases are washed once with 250 ml of water, dried over magnesium sulphate and concentrated by evaporation. The excess benzoyl chloride is distilled off under a high vacuum and the residue is crystallised from ether/petroleum ether. 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of yellow crystals having a melting point of 75°-76°.
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])C>C1COCC1.CO.O>[N+:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:7]([OH:8])=[O:6])=[CH:17]2)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiOH.H2O (1.06 g, 46.2 mmol, 2.1 eq.) was added to a suspension of 5-nitro-1H-indole-2-carboxylic acid ethyl ester (II) (5.15 g, 22 mmol, 1 eq.) in THF/MeOH/H2O 1:1:2 (180 ml). The final suspension turned to dark yellow and was stirred at 25° C. After 30 min the solubilization was complete and total conversion was achieved after 6 hours. The reaction mixture was cooled to 0° C. and quenched with HCl 2N until the solution reached pH 5. Organic volatiles were removed under reduced pressure and the white precipitate was filtered and dried to give the compound of formula (III). Yield=4.53 g (quantitative).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1)=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([O:8][CH2:9][CH:10]([C:12]1[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(COCc1ccccc1)c1cnc(N)cn1
Agent: [Pd]
Solvent: CO
Product: CC(COCc1ccccc1)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-(benzyloxy)prop-1-en-2-yl)pyrazin-2-amine (91 mg, 0.377 mmol) in methanol (3771 μL) was added Pd/C (40.1 mg, 0.377 mmol) at room temperature. The reaction mixture was stirred at room temperature under hydrogen balloon for overnight. The reaction mixture was filtered through Celite, washed with methanol and EtOAc. The crude material was used in next step reaction without purification. LCMS (m/z): 244.2 (MH+), 0.62 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][NH:10][C:9]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>O1CCCC1.CN1CCCC1=O.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:9]1=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CN(CC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled 0° C. solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (0.59 g, 1.93 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (2.29 mL, 2.29 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.33 mL, 2.29 mmol) was added and the resulting mixture was stirred at 0° C. for 4 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→100% ethyl acetate/hexane) was followed by separation of the cis/trans diastereoisomers using normal-phase HPLC using a ChiralPak® AD column, eluting with 60% ethanol in hexanes to afford the title compound as the second diastereomer to elute. MS: m/z=391.2 (M+1).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][NH:25]2.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26][N:25]2[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: O=C1CNc2cc(Cl)ccc2N1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.55 mmol) (from example 1c supra), 6-Chloro-3,4-dihydro-1H-quinoxalin-2-one (100 mg, 0.55 mmol) and K2CO3 (150 mg, 1.09 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hour. The mixture was concentrated in vacuo and purified by flash column chromatography to give 110 mg 6-Chloro-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-1H-quinoxalin-2-one. MS: [M+H]+=472.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCc2ccc(Br)cc2F)c1
Yield: 71.5 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 716.7 μl (5.181 mmol) of 2-fluoro-4-bromobenzylbromide, there was added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 1 hour at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, water and aequeous sodium bicarbonate, water and aqueous sodium cholride solution in this sequene and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 50 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 212.4 mg (0.3706 mmol, 72%) of 2-(2-fluoro-4-bromobenzyloxy)-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[CH:31]=3)[CH:13]=[C:8]2[N:7]=1)=[O:4].C(#N)C.[ClH:36]>O1CCOCC1>[ClH:36].[O:23]1[C:17]2[CH:16]=[CH:15][C:14]([C:12]3[CH:13]=[C:8]4[NH:7][C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])=[N:32][C:9]4=[N:10][CH:11]=3)=[CH:31][C:18]=2[CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: COC(=O)Nc1nc2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cnc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-3H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.52 g, 1.2 mmol) was taken into acetonitrile (5 mL) followed by addition of 4M hydrogen chloride in 1,4-dioxane (5 mL) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give a white solid. It was washed with ether then dried to give methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride salt (0.40 g, 100% yield), MS (EI) for C17H17N5O3: 340 (MH+).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11](C2(O)CCCCCCC2)[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.Cl.Cl.C1(C([C:51]2([OH:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)CN2CCNCC2)C2C(=CC=CC=2)C=CC=1>>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH:11]([CH:52]2[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH:51]2[OH:59])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9]1
Reactant: OC1(C(CN2CCNCC2)c2cccc3ccccc23)CCCCCCC1
Reactant: CN1CCN(CC(c2cccc3ccccc23)C2(O)CCCCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2cccc3ccccc23)C2CCCCCCC2O)CC1

Procedure:
In an analogous manner to Example 24, 1-[2-(4-methylpiperazin-1-yl)-1-(1-naphthyl)ethyl]cyclooctanol dihydrochloride was prepared from 1-[1-(1-naphthyl)-2-piperazin-1-ylethyl]cyclooctanol dihydrochloride (See Example 269). MS (ESI) m/z 381; HRMS: calcd for C25H36N2O+H, 381.29059; found (ESI, [M+H]+), 381.2893.
Reaction SMILES: Cl.N[C:3]1[O:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1.C([OH:15])CC>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[C:3]([OH:15])[O:7][N:6]=1
Reactant: Nc1cc(C(F)(F)F)no1
Reactant: CCCO
Agent: Cl
Product: Oc1cc(C(F)(F)F)no1
Yield: 0.7 %

Procedure:
A solution of 36% HCl (9.12 g, 15 eq.) and n-propanol (9.0 ml) was added to 5-amino-3-trifluoromethylisoxazole (0.91 g, 6.0 mmole) from Preparation 1 and heated at reflux for 23 hours. The reaction mixture was cooled, extracted with methylene chloride and distilled under reduced pressure to give 0.006 g (0.7%) of the titled compound as a colorless liquid, b.p. 35°-37° C./1.4 mmHg. This product was thought to be the keto form or a mixture of the keto and enol form by NMR and IR.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:11])[CH3:10].CN1CCOCC1>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:11])[CH3:10]
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: CC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in chloroform (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (350 mg, 74%) as a colorless clear syrup.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[N:3]1.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl.[OH-].[K+]>C(O)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[C:20]2[CH2:21][CH2:22][NH:17][CH2:18][CH:19]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc3[nH]ccc3c2)n1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nnc(-c2ccc3[nH]cc(C4=CCNCC4)c3c2)n1
Temperature: 25 °C

Procedure:
A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification.