Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10 g of 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one are dissolved in 100 ml of dioxane and treated with 3.2 g of sodium borohydride in 5 ml of water. The mixture is subsequently stirred for 20 hours at room temperature. Then the mixture is concentrated under reduced pressure and the residue partitioned between ether and water. The ethereal solution is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There is obtained 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccnc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cccnc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (85 mg, 0.19 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (60 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 8.87-9.04 (m, 1H), 8.21 (d, J=7.1 Hz, 1H), 7.77-7.99 (m, 2H), 7.68 (br. s., 2H), 7.35 (br. s., 2H), 3.91 (d, J=11.6 Hz, 2H), 3.71 (s, 2H), 1.96 (d, J=12.1 Hz, 3H), 1.78 (d, J=11.6 Hz, 3H); MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [CH2:1]([O:17][C:18]1[C@@H:23]([C@H:24]([CH2:26][OH:27])[OH:25])[O:22][C:20](=[O:21])[C:19]=1[OH:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:31](Cl)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[Na+]>CN(C=O)C>[CH2:31]([O:28][C:19]1[C:20]([O:22][C@H:23]([C@H:24]([CH2:26][OH:27])[OH:25])[C:18]=1[O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:21])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCCCCCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC1=C(OCc2ccccc2)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 62 %

Procedure:
A solution of 0.933 g. of 3-O-n-hexadecyl-L-ascorbic acid in 7.5 ml. of anhydrous DMF was added slowly at ambient temperature under a nitrogen atmosphere to a suspension of 2.45 millimoles of NaH in 10 ml. of anhydrous DMF in a 50 ml., 3-neck round-bottom flask equipped with magnetic stirrer, drying tube and dropping funnel. The reaction mixture was stirred for 25 minutes (until H2 evolution stopped) at which time the sodium salt (on the 2-hydroxy) of 3-O-n-hexadecyl-L-ascorbic acid had formed. A solution of 0.295 g. of benzyl chloride in 2 ml. of anhydrous DMF was added. The reaction mixture was stirred at ambient temperature for about 50 minutes. The reaction temperature was then raised to 90° C., at which temperature stirring was continued for an additional 50 minutes. The reaction mixture was cooled and saturated aqueous sodium chloride (brine) added. The resulting aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine and dried. The dried extract was decolorized with charcoal, filtered and the volatile constituents removed in vacuo. The resulting yellow syrup was chromatographed over silica gel 60 using 1:9 ethyl acetate-toluene as the eluant. Fractions shown by TLC to contain the desired product were combined and the solvent removed therefrom. 694 mg. (62% yield) of a yellow waxy solid comprising purified 2-O-benzyl-3-O-n-hexadecyl-L-ascorbic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH2:14][CH:15]2[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]3)[CH2:16]2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+].[CH:33](O)=O.C(OC)(OC)OC.C(O)(C(F)(F)F)=O>CCO.O.[Fe]>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[N:13]([CH2:14][CH:15]3[CH2:30][CH2:29][CH2:28][C:17]4([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH2:18]4)[CH2:16]3)[CH:33]=[N:10][C:8]=2[CH:9]=1
Reactant: O=CO
Reactant: CC(C)(C)CN1CC2(CCCC(CNc3cc(C#N)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: COC(OC)OC
Solvent: CCO
Product: CC(C)(C)CN1CC2(CCCC(Cn3cnc4cc(Cl)c(C#N)cc43)C2)OC1=O
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 55.5 %

Procedure:
A suspension of 2-chloro-5-(((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.236 g, 0.543 mmol), iron (325 mesh) (0.152 g, 2.71 mmol), and ammonium chloride (0.015 g, 0.271 mmol) in EtOH (3 mL) and water (0.5 mL) was stirred at 75° C. for 45 min. The reaction was cooled to rt and filtered through a pad of celite. The celite was washed with EtOAc, and the combined filtrates were partitioned between EtOAc and saturated sodium bicarbonate solution and 1 N NaOH (1:1). The organic layer was dried over Na2SO4, filtered, and concentrated to a purple foam. This residue was dissolved in formic acid (0.060 mL, 1.56 mmol) and trimethyl orthoformate (1.72 mL, 15.6 mmol). The resulting solution was stirred at rt for 18 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic solution was washed with saturated sodium bicarbonate solution and concentrated. The crude product was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 16 minute run; 50 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-70% solvent A) to afford the title compound (0.125 g, 57% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 4.07 (ddd, J=7.53, 14.56, 24.85 Hz, 2H), 3.36 (dd, J=8.53, 24.09 Hz, 2H), 3.00 (dd, J=14.31, 32.37 Hz, 2H), 2.37-2.52 (m, 1H), 2.03 (d, J=16.81 Hz, 1H), 1.94 (dd, J=2.01, 12.80 Hz, 1H), 1.64-1.82 (m, 3H), 1.31-1.44 (m, 1H), 1.22 (t, J=12.80 Hz, 1H), 0.98-1.11 (m, 1H), 0.95 (s, 9H). MS (m/z) 415.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[CH2:13][C:14](OCC)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([OH:15])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=NNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of 382 mg (1.2 mmol) of ethyl trifluoroacetoacetate 4-nitrophenylhydrazone in 10 ml of THF was added 53 mg (60%; 1.32 mmol) of NaH and the resulting mixture was stirred at room temperature for 4 hours and at 50° C. for 16 hours. The reaction mixture was quenched with ammonium chloride solution, the aqueous layer was extracted with ethyl acetate (3×), and the combined organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 50% ethyl acetate in hexane) and recrystallized from methylene chloride/hexane to afford 1-(4-nitrophenyl)-3-trifluoromethyl-5-hydroxypyrazole as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CC(=O)O
Reactant: COc1cc(Br)ccc1N1CCNCC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
Dissolve 1-(4-bromo-2-methoxy-phenyl)-piperazine (7.0 g, 25.8 mmol) and acetic acid (5.9 mL, 103.2 mmol) in methanol (500 mL) and add aqueous formaldehyde (37%, 5.3 mL). After 5 min, add sodium cyanoborohydride (4.05 g, 64.5 mmol) and stir the mixture at room temperature overnight. Concentrate the reaction mixture in vacuo and partition between dichloromethane (200 mL) and 1 N sodium hydroxide (200 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×100 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo to afford 7.1 g (96%) of the title compound. MS/ES m/z (79Br) 285.0 [M+H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:18]([S:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=O)=[O:9])=[O:5])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CC(O)=O>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C@H:7]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:17])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2)=[O:9])[C:18]([S:21][CH:22]([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)(C)SC(C)C
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(C)(C)SC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 1-[2-(R)-ethoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyryl]-pyrrolidine-2-(S)-carboxylic acid (0.160 g), 6-aminomethyl-isoquinolin-1-ylamine (0.078 g), N-methyl morpholine (0.14 mL) and 0.14 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 3 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. 0.100 mL CH3COOH were added, the mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.17 g (66%) of the title compound as a colorless oil. (+)-APCI-MS: 516 (MH+).
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[O:10][CH:11]=1)=[O:6].[OH-].[Na+]>C1COCC1.Cl>[O:18]=[C:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[O:10][CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=1
Reactant: COC(=O)c1coc(CCCCC(C)=O)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CCCCc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5-oxo-hexyl)-oxazole-4-carboxylic acid methyl ester (464 mg, 2.06 mmol) in THF (20 mL) was treated at rt with 1N NaOH (10 mL, 10 mmol) and the reaction mixture was stirred for 1 h at rt. The reaction mixture was poured in 1N HCl (20 mL) and extracted twice with EA (20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.68 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[O:21][CH2:20]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:21])[CH2:20][NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(CCCN2CCN(CC3CO3)CC2)c2ccc(F)cc2)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCc1ccccc1)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 10.1 %

Procedure:
3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:15][C:14]=2[N+:24]([O-])=O)=O)C=C[CH:7]=1.O.O.Cl[Sn]Cl.[CH3:33][CH2:34][OH:35]>>[I:1][C:2]1[CH:7]=[C:9]([C:10]2[CH2:33][C:34](=[O:35])[NH:24][C:14]3[CH:15]=[C:16]([N:19]4[CH:20]=[CH:21][CH:22]=[CH:23]4)[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:8]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(CC(=O)c1cccc(I)c1)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C1CC(c2cccc(I)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from 3-(3-iodo-phenyl)-N-(2-nitro-4-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M8) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as an olive solid (624 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([C:25]([F:28])([F:27])[F:26])[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C(F)(F)F
Temperature: 45 °C

Procedure:
1,1-Dimethylethyl 4-{[5-methyl-2-nitro-4-(trifluoromethyl)phenyl]amino}-1-piperidine-carboxylate (D57) (3.17 mmol, 1.29 g) was dissolved in ethanol (20 ml) and an aqueous suspension of Raney-Nickel (3 ml) was added at room temperature; the mixture was heated to 40-50° C. and hydrazine monohydrate (15 eq., 48 mmol, 1.5 ml) was added over 20-30 min. The reaction mixture was then cooled to room temperature, filtered through celite and the solvent was evaporated to yield the title compound, 1.1 g, 92%, M+-Boc+H=274.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]2[C:14]([CH3:25])=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1cccc(O)c1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3cccc(O)c3)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-hydroxy-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[(R)-1-(3-hydroxy-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[OH:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:31]4[CH2:32][CH2:33][N:28]([OH:27])[CH2:29][CH2:30]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: ON1CCNCC1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCN(O)CC4)c(F)cc3cc2c1=O
Yield: 59.2 %

Procedure:
3-Ethoxycarbonyl-7,9-difluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.9 g), 1-hydroxypiperazine dihydrochloride (1 g) and potassium carbonate (1.6 g). 3-Ethoxycarbonyl-7,9-difluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine (1.4 g) is obtained in the form of a yellow solid, m.p. 255°-258° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([F:23])[F:22])=[C:15]([Cl:24])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[Cl:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH:21]([F:23])[F:22])[CH2:12][N:9]1[C:10](=[O:11])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:7]=2[CH2:8]1
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)F)c(Cl)c1
Reactant: O=COc1ccccc1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1ccc(OCC(F)F)c(Cl)c1)C2=O
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (220 mg, yellow solid) from 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-39) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([C:18]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])([CH3:20])[CH3:19])=[N:12][C:11]=1[C:32]([O:34]C)=O)(=O)C1C=CC=CC=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:42][C:32]([C:11]2[N:12]=[C:13]([C:18]([NH:21][C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([CH3:20])[CH3:19])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[OH:9])=[O:34])=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Product: Cn1c(C(C)(C)NC(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
To a methanolic solution of methyl 5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, p-fluoro benzylamine (3 eq) was added and mixture was refluxed over night. After evaporation of methanol, residue was taken in EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered and evaporated to obtain the title product.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C>[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:21][CH2:22][C:23]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:24]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: Cc1cc(C)cc(OCC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(C)cc(OCC(=O)N[C@@H](CCC(=O)O)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dimethylphenoxyacetic acid (9.0 g, 50 mmole) in benzene (100 mL) was added thionyl chloride (10.89 mL). The resulting mixture was refluxed for 2 hr, then the benzene was removed by distillation. The residual material was dried in vacuo to give 3,5-dimethylphenoxyacetyl chloride, which was dissolved in 20 ml of acetonitrile and used in situ. L-Glutamic acid (8.8 g, 60 mmole) was dissolved in a solution of sodium carbonate (12.72 g, 150 mL, 120 mmole) and the 3,5-dimethylphenoxyacetyl chloride in the acetonitrile solution was slowly added while the pH 8 was adjusted from time-to-time by adding sodium carbonate solution. The reaction mixture was stirred at room temperature for 2 hr, and acidified to pH 2 to give a solid precipitate. The solid precipitate was collected by filtration, treated with hot benzene, filtered, again and washed again with benzene to give Intermediate 31 (9.2 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([Cl:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(O)C>[ClH:19].[CH2:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: ClCC=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C(=Cc1ccccc1)CN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
The process for preparing this compound and its physical properties will be shown below. A mixture of 1.8 grams of isoindoline, 2.5 grams of cinnamyl chloride, 4 milliliters of triethylamine and 40 milliliters of ethanol is stirred for 4 hours at room temperature. After completion of the reaction, the solvent is distilled off, after which water is added to the residue and extracted with ether. The ether layer is collected and dried followed by distilling the ether off. The so obtained oily product is converted to a hydrochloride in a customary manner and then recrystallized from methyl ethyl ketone to obtain 1.4 grams (yield 34.6%) of N-cinnamylisoindoline hydrochloride as crystals having a melting point of 180°-182° C. (decomposition).