Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[N:33]=2)[C:22]=1[CH3:40]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[NH:33][C:34](=[O:38])[CH:35]=[CH:36][CH:37]=4)[C:22]=3[CH3:40])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(=O)[nH]2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (108 mg, 0.48 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (100 μL, 0.40 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (120 mg, 0.40 mmol) (described herein), and NMP (660 μL). The reaction mixture was stirred and heated in a microwave at 150° C. for 180 min. Purification afforded 6-(4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one as a yellow solid. Mass Spectrum (ESI) m/e=479 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].[ClH:12].[C:13]1(C)[CH:18]=CC=C[CH:14]=1>C(O)(C)C>[ClH:12].[NH2:1][C@@H:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]([OH:7])[C:4]([O:6][CH:13]([CH3:18])[CH3:14])=[O:5]
Reactant: Cc1ccccc1
Reactant: CC(C)CC(N)C(O)C(=O)O
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Temperature: 25 °C

Procedure:
3-Amino-2-hydroxy-5-methylhexanoic acid (Example A), 26.5 g (0.164 mol), is dissolved in isopropyl alcohol, treated with hydrochloric acid (anhydrous) for five minutes, treated with toluene (250 ml) and 3A molecular seives and warmed to reflux for 15 minutes. The solution is cooled to room temperature, filtered, and the solvents evaporated in vacuo to give the title compound as an extremely hygroscopic foam, 40 g. The foam is used without further purification.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.N1CCCCC1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:35][C@:31]([C:28]1[CH:27]=[C:26]([CH3:25])[O:30][N:29]=1)([CH3:32])[C:33]#[C:34][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)no1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
To a pressure tube was added 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (99 mg, 0.28 mmol) followed by piperidine (2.0 mL), tetrakis(triphenylphosphine)palladium (0) (32 mg, 0.03 mmol), copper(I) iodide (5 mg, 0.03 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (63 mg, 0.42 mmol). The reaction vessel was sealed and heated at 60° C. for 30 minutes. The reaction mixture was cooled and concentrated in vacuo. and then co-evaporated with dichloromethane (2×10 ml). The crude material was purified by FCC (silica, 2-8% methanol in dichloromethane) to provide 59 mg (56%) of the title compound as a pale brown solid. 1H NMR (DMSO, 500 MHz) δ 1.80 (3H, s), 2.41 (3H, s), 3.17 (2H, t, J=5.8 Hz), 4.49 (2H, t, J=5.8 Hz), 6.32-6.39 (1H, m), 6.52 (1H, s), 6.72 (1H, s), 7.21 (1H, d, J=8.4 Hz), 7.34 (1H, s), 7.37 (1H, dd, J=8.4, 2.1 Hz), 7.79 (1H, s), 8.02 (1H, d, J=2.1 Hz); M+23=401.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CO.[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
4-(2-Propenyloxy)benzoic acid was synthesized by Apfel's method (Apfel et al, Anal. Chem., 1985, 57, 651-658). A 1 L three-neck round-bottom flask was equipped with a condenser, 150 mL additional funnel, heating bath, and magnetic stirrer. 90 g (0.65 mol) of 4-hydroxybenzoic acid and 400 mL of methanol were added at 25° C. and stirred. After the acid was dissolved, 105 g (1.9 mol) of potassium hydroxide in 125 mL of distilled water was added dropwise. The reaction mixture was heated to reflux, and 90 g (0.74 mol) of allyl bromide was then added over a 2 hour period. The reaction mixture was allowed to reflux for 8 hours. As the reaction proceeded, potassium bromide precipitated. From this mixture, 250 mL of methanol was removed by evaporation. The remainder of the reaction mixture was cooled to 25° C. and then added to 2.5 L of distilled water. Hexane (250 mL) was added to extract organic impurities. After discarding the organic phase, the aqueous phase was heated to 40° C. and neutralized with 300 mL of 20% HCl. The crude product precipitated during the neutralization, was subsequently collected by filtration and purified by recrystallization from ethanol. Yield: 46 g (40.2%), mp 165° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([Br:13])[CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Br:13])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(N)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)c(C(=O)O)cc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A solution of the intermediate methyl 4-amino-2-bromo-5-fluorobenzoate (5.24 mmol, 1.3 g) in tetrahydrofuran (15 mL) was treated with a solution of lithium hydroxide (15.72 mmol, 0.66 g) in water (15 mL) and stirred at 60° C. for 4 hours. The reaction mixture was then cooled to room temperature, taken to ˜pH 5 with dilute hydrochloric acid and concentrated under vacuum. The residue was dissolved in tetrahydrofuran and purified by column chromatography (9:1 dichloromethane/methanol) to give the title compound (1.1 g). 1H NMR ((CD3)2SO, 400 MHz): δ6.11 (2H, s), 7.02 (1H, d), 7.52 (1H, d)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N:11]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:15]=2)[CH3:12])[CH:5]=1.Cl.O1CCOCC1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:15]=3)[N:11]([CH3:12])[C:6]=2[CH:5]=1)=[O:29]
Reactant: CCCN(CCC)Cc1cccc(C(=O)N(C)c2cc(C(=O)OC)ccc2N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(CCC)Cc1cccc(-c2nc3ccc(C(=O)OC)cc3n2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
The compound (83.0 mg) obtained in Example 18-4 was dissolved in methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol to generate a free compound therefrom through an anion-exchange resin (Amberlite IRA-410). The resin was separated by filtration and the filtrate subjected to distillation of the solvent under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (44.0 mg) as a brown solid.
Reaction SMILES: C([O:8][C:9](=[O:27])[CH2:10][N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14](CC2C=CC=CC=2)[CH2:13][C@@H:12]1[CH2:25][CH3:26])C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH2:25]([C@H:12]1[CH2:13][NH:14][C@H:15]([CH3:17])[CH2:16][N:11]1[CH2:10][C:9]([OH:27])=[O:8])[CH3:26]
Reactant: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H]1CN[C@H](C)CN1CC(=O)O
Reaction time: 8 h
Yield: 108 %

Procedure:
A solution of ((2S,5R)-4-benzyl-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid benzyl ester (3.4 g, 9.3 mmol) in MeOH (93 mL) containing Pd/C (10%, 985 mg) and acetic acid (1.57 mL) was stirred overnight under H2 (3.5 bar). The mixture was filtered through Celite and the solvent was removed in vacuo to give ((2S,5R)-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid, (1.87 g) as a white solid. The compound was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[OH:10][CH2:11][C:12](O)=[O:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(#N)C>[OH:13][CH2:12][C:11]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyacetic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile, and hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were then added to the solution in an ice-water bath. The ice-water bath was then removed, and the reaction mixture was stirred overnight at 25° C. The solvent was evaporated, and 20 mL of ethyl acetate was then added to the residue. The mixture was filtered and the filtrate was washed with 20 mL of water. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH2:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(Cl)cc1
Temperature: 35 °C
Yield: 86.2 %

Procedure:
A solution of 4-chlorobenzaldehyde (23.4 g) in dry dimethylformamide (DMF: 100 ml) was added over 10 minutes to a stirred mixture of sodium cyanide (4.0 g) and dry DMF (200 ml). After 5 minutes a solution of methyl acrylate (10.75 g) in dry DMF (100 ml) was added to the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at 35° C. throughout both additions and then for a further 3 hours before it was poured into water and extracted with diethyl ether. The extracts were washed successively with water (several times), dilute sulphuric acid, aqueous sodium bicarbonate, and water, before drying over magnesium sulphate and concentration under reduced pressure to give methyl 3-(4-chlorobenzoyl)propanoate (24.4 g, 86%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 25.8 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at 40° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 22 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (d, 1 H), 6.64 (s, 1 H), 5.65 (s, 2 H), 3.66 (d, 2 H), 3.19-3.30 (m, 1 H), 2.85-2.95 (m, 5 H), 2.11 (d, 2 H), 1.69-1.80 (m, 2 H); ES-MS m/z 502.31 [M+H]+, HPLC RT (min) 2.73.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>CO>[CH2:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:1][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: F[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyl-4-fluoropyrrolidine (186 mg) was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (80.0 mg) and benzaldehyde (90.8 μL) were sequentially added and the mixture was stirred at room temperature for 1 hour. Subsequently, a borane-pyridine complex (90.2 μL) was added and the mixture was further stirred at room temperature for 3 hours. This was followed by addition of 6 mol/L hydrochloric acid (1.5 mL) and stirring for 1 hour. Subsequently, a 6 mol/L aqueous solution of sodium hydroxide was added to make the mixture basic and the mixture was extracted with diethyl ether (3×10 mL). The diethyl ether extracts were combined and the combined diethyl ether layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=4:1) to give 179 mg of (3S,4S)-1-benzyl-3-benzylaminomethyl-4-fluoropyrrolidine as a pale brown oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:31]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH3:30]>>[CH2:28]([N:31]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H35N3O5
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[CH2:22][NH:21][C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2ccc(F)cc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(F)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 195-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:12]3(N3CCCC3)[O:11][N:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCCC2C(c3ccc(OC)cc3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2noc3c2CCCC(C(=O)O)C3)cc1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
2.32 g (0.006 mol) of methyl 3a,5,6,7,8,8a-hexahydro-3-(4-methoxyphenyl)-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate were dissolved in a mixture of 6 ml of glacial acetic acid, 6 ml of water and 6 ml of concentrated sulfuric acid. The mixture was held at 100° C. for 1 hour, cooled and diluted with 20 ml of water to give a white precipitate which was filtered off, washed and dried. Crystallization from ethyl acetate gave 1.04 g of 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 194°-196° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCC(N)C(=O)O
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of 2,5-difluoronitrobenzene (119 ml, 1.10 mol), 2-aminobutanoic acid (114 g, 1.10 mol), and potassium carbonate (152.2 g, 1.10 mol) in dimethyl sulfoxide (410 ml, 1.10 mol) was stirred at 80° C. for 23 h. ([Note 1]: The mixture had a deep orange red color. The internal temperature of the mixture went up to ˜110° C. for 1 h and then went down to 80° C.). After 23 h, the reaction was cooled to rt and carefully poured into water (2 L+1 L). The aqueous mixture was washed with diethyl ether (1 L×2) to remove organic impurities. The aqueous layer was then acidified to ˜pH 1.5 with concentrated HCl (300 mL) to generate a yellow solid. The yellow solid was collected by filtration, washed with water (3 L), and air-dried to give the desired product, a wet orange solid. The wet orange solid was recrystallized from 3 L toluene and stood at rt overnight to afford the desired product as an orange crystalline solid. The orange crystalline solid was filtered, washed with toluene (2 L), and dried under high vacuum at 80° C. for 4 h and then on lyophilizer overnight to afford 2-(4-fluoro-2-nitrophenylamino)-butanoic acid (203.6 g, 76.4% yield) as an orange crystalline solid. The orange crystalline solid was carried on without further purification to the next step.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@H:38]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[N:39]1[CH2:45][CH2:46][CH2:47][C:48]1[S:52][C:51]([C:53]([O:55][CH3:56])=[O:54])=[CH:50][CH:49]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:36][CH2:37][C@H:38]1[CH2:42][CH2:41][S:40](=[O:43])(=[O:44])[N:39]1[CH2:45][CH2:46][CH2:47][C:48]1[S:52][C:51]([C:53]([O:55][CH3:56])=[O:54])=[CH:50][CH:49]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCS2(=O)=O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2[C@@H](CO)CCS2(=O)=O)s1
Reaction time: 16 h
Yield: 73.7 %

Procedure:
Tetrabutylammonium fluoride (1.95 mL of a 1.0M solution in THF, 1.95 mmol) was added to a solution of the silyl ether 9 (751 mg, 1.29 mmol) in THF (3.0 mL). After stirring for 16 h the reaction was diluted with EtOAc and washed with water followed by brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 20% EtOAc/hex followed by 40% EtOAc/hex) afforded 317 mg (73%) of alcohol 10.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)=[O:4].[OH-].[K+].O>C(O)C>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]([OH:4])=[O:2])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccsc1COc1ccc(CCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccsc1COc1ccc(CCCCO)cc1
Yield: 87 %

Procedure:
A stirred solution of 7.96 g of 2-[4-(4-hydroxybutyl)phenoxymethyl]-3-thiophenecarboxylic acid methyl ester, 14.41 g of potassium hydroxide, 15 ml of water and 100 ml of 95% ethanol was refluxed for one hour. The solution was concentrated. The residue was diluted with 200 ml of water and the solution was extracted once with ether. The aqueous phase was acidified with concentrated hydrochloric acid, with cooling, and the precipitate was collected, washed with water and dried in vacuo at 40° C. overnight over sodium hydroxide pellets. Recrystallization from 20 ml of 95% ethanol gave 6.62 g (88%) of product, m.p. 139.5°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([F:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)ccc1CBr
Yield: 94.3 %

Procedure:
1-Bromo-3-fluoro-4-methylbenzene (28.37 g, 0.15 mol, 1 eq), N-bromosuccinimide (26.72 g, 0.15 mol, 1 eq), azobisisobutyronitrile (1.44 g) and carbon tetrachloride (500 mL) were mixed and refluxed overnight. The mixture was filtered and washed with water (3×300 mL). The organic layer was dried (MgSO4), and the solvent removed in vacuo to yield 37.88 g of an oil (75% product by NMR). NMR (CDCl3) δ 4.45 (s, 2H). This material was used in the subsequent step without further purification. ##STR47##
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F-:15].[K+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)F)cc1
Yield: 28.7 %

Procedure:
60 gm (.257 mole) of p-acetamidobenzenesulfonyl chloride was added to 15 ml water and stirred to form a thick paste. 20 gm (.416 mole) of potassium fluoride dissolved in 25 ml water was added and the resulting slurry was heated for one hour in an oil bath at reflux. After one hour the slurry was cooled, filtered, washed with ice water and dried by suction. The crude product was recrystallized from 95% ethanol to give 16 gm of p-acetamidobenzenesulfonyl fluoride mp 169°-171° C; literature value 171° C.