Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[CH3:26]>O1CCCC1.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:12][C:5]3[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=3[C:3]=2[C:13]([NH2:15])=[O:14])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(N=C=O)ccc1Cl
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)c(C)c3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of compound F4 (450 mg, 2.00 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature under nitrogen was added a solution of compound F2 (402 mg, 2.40 mmol) in anhydrous methylene chloride (6 mL) dropwise over 3 min. Then the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered. The filter cake was washed with methylene chloride (5 mL) and then dried under reduced pressure to provide compound F5 as a white solid (301 mg, 38%): 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.12 (s, 1H), 7.48-6.75 (m, 5H), 3.45 (s, 2H), 2.77 (d, J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.55-2.45 (m, 2H), 2.30 (s, 3H), 1.07 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)OCC[O:27]1.[Mg]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:26](=[O:27])[CH3:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC1(CCCCCCCBr)OCCO1
Agent: [Mg]
Product: CC(=O)CCCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 18.5 %

Procedure:
By following the procedure as in Reference Example 25 using a Grignard reagent prepared from 3 g of 3,4-dibenzyloxybenzaldehyde, 2.5 g of 2-methyl-(7-bromoheptyl)-1,3-dioxolane, and 0.3 g of magnesium, 0.8 g of 1-(3,4-dibenzyloxyphenyl)-1,9-decanedione was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:15]>>[ClH:15].[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: Cl
Product: COC(=O)c1cccc(N)c1C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 185.6 g of stannous chloride dihydrate in concentrated hydrochloric acid (450 ml) at 15° was added 48.8 g of 2-methyl-3-nitrobenzoic acid, methyl ester. The temperature of the reaction mixture rose steadily to 63° before a cooling bath was applied. After the addition was complete, the solution was stirred at 40° to room temperature for 1.5 hours. The desired product was obtained by filtration of the reaction mixture at 7°, washing with ethyl acetate and n-butyl chloride, and drying. The yield of 3-amino-2-methylbenzoic acid, methyl ester, hydrochloride m.p. 220°-228°(dec.), was 60.8 g as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]([O:16][CH3:15])=[O:26])=[CH:19][CH:20]=2)[N:7]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: COC(=O)CCc1nc(I)ccc1O
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Yield: 59 %

Procedure:
Under the conditions of example 5 A, 6.3 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 3.28 g of 4-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 4.1 g of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 173°-177° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:22])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: NC1(C(=O)O)CC1
Reactant: Cc1cc(C#N)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc2c1NC(c1cccc(NC3(C(=O)O)CC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (355.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyano-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (79.8 mg, 21.3%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 376.2.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[C:11]=1[Cl:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1cc(NC(=O)C2CC2)no1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1onc(NC(=O)C2CC2)c1Cl
Yield: 84.4 %

Procedure:
Methylene chloride (20 ml) and sulfuryl chloride (5.40 g) are added to N-(5-t-butyl-3-isoxazolyl)cyclopropanecarboxamide (4.17 g) and refluxed with heating for 1.5 hours. The methylene chloride and the unreacted sulfuryl chloride are evaporated under reduced pressure. The residue is chromatographed on a column of silica gel and recrystallized from benzene to give N-(5-t-butyl-4-chloro-3-isoxazolyl)cyclopropanecarboxamide (4.10 g) as colorless needles melting at 129.5° to 131.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:11]#[N:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (1.0 g, 6.3 mmol) was added to a solution of ethyl 2-cyanoacetate (0.71 g, 6.3 mmol) and piperidine (0.081 ml, 0.82 mmol) in toluene (10 mL) at room temperature. The mixture was heated at 100° C. for 7 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and rinsed with hexane to give ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanoacrylate (1.4 g, 88%). LCMS (APCI+) [M+H]+253.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=1)[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:15]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(CO)cc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
A 2.00 g (5.68 mmol) portion of 3,5-di-(tert-butoxycarbonylamino)benzoic acid was dissolved in 15 ml of THF, 3.77 ml (39.7 mmol) of borane-methyl sulfide complex dissolved in 10 ml of THF was added dropwise to the thus prepared solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was cooled to 0° C., mixed with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 1.08 g (yield, 56%) of 1,3-di-tert-butoxycarbonylamino-5-hydroxymethylbenzene.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
10.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester are dissolved in 150 ml of chloroform and treated with 8.2 ml of diisopropylethylamine at 0°. 2.4 ml of ethyl chloroformate are added and the mixture is heated to reflux for 3 hours. The reaction mixture is washed with 0.1M hydrochloric acid and brine, dried and concentrated. Amorphous product. TLC (system N3) Rf : 0.45.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)[CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(C2CCCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixed solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added cyclohexanecarbonyl chloride (0.18 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide. To 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL)) was added, and the precipitate was collected by filtration to give the title compound (252 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:19])[N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:19])[N:13]=[C:14]([O:25][CH2:24][CH2:23][O:22][CH3:21])[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Reactant: COCCO
Agent: Cl
Product: COCCOc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of Na (2.0 mg, 0.07 mmol) in 2-methoxyethanol (1 ml) was added 2-(4-fluorophenyl)-7-methylthio-thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.14 mmol). The reaction mixture was heated at 80° C. for 20 hours. After cooling, the mixture was neutralized with 1N HCl and the solvent was removed under reduced pressure. The crude residue was extracted by ethyl acetate, brine and dried over Na2SO4. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (35 mg, 80%).
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[C:19]12([C:17]3[N:8]4[C:9]([C:10](=[O:12])[NH:11][C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:7]4)=[C:13]([CH2:14][CH3:15])[N:16]=3)[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2
Reactant: CCC(NC(=O)C12CC3CC(CC(C3)C1)C2)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C23CC4CC(CC(C4)C2)C3)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.52 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-1-adamantanecarboxamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[C:10]2=[O:25])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:10]2=[O:25])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.543 mmol) in DCM (10 ml) cooled to 0° C., TFA (0.418 ml, 5.43 mmol) was added drop wise, and the solution stirred at room temperature for 24 hours. The solvent was removed under vacuum and dried to give 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetic acid as a yellow solid (0.170 g, 0.544 mmol, yield considered to be quantitative, MS/ESI+ 312.9 [MH]+). This product was used without any further purification.
Reaction SMILES: C([O:20][NH:21][C:22](=[O:55])[C@H:23]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:20][NH:21][C:22](=[O:55])[C@H:23]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])[CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37]
Reactant: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
A solution of the title A compound, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide (288 mg, 0.374 mmol) in 3 mL of dichloromethane is treated sequentially with triethylsilane (0.119 mL, 0.745 mmol) and trifluoroacetic acid (0.225 mL, 2.92 mmol) at 0° C. After 10 min, the solution is concentrated at 0° C. in a stream of nitrogen, and the residue is triturated from 5 mL of diethyl ether. The product is collected by vacuum filtration and dried to give 162.3 mg (82%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid hydroxyamide as a white solid: m.p. 204-206° C. (dec); NMR(DMSO-d6) 1.24-1.33 (br m, 1H), 1.37-1.50 (br m, 3H), 3.39-3.47 (m, 2H), 3.52-3.62 (m, 1H), 7.53 (d, 2H, J=8.3), 7.70 (d, 2H, J=8.3), 7.80 (br s, 8H), 8.12 (d, 1H, J=8.5), 8.82 (br s, 1H), 10.56 (s, 1H); IR 1772, 1341, 1159; ESI-MS 528 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:15]=[C:14]([CH3:16])[NH:13][CH:12]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[C:11]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])C(OC)=O.Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:26]([O:28][CH3:29])=[O:27])=[C:14]([CH3:16])[NH:13][C:12]([CH2:17][O:18][CH2:19][CH2:20][O:21][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1(C(=O)OC)C(COCCO)NC(C)=CC1c1ccccc1Cl
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCOc2ncccn2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.3 %

Procedure:
Sodium hydride (90 mg. of an 80% by weight dispersion in oil) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-3-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.60 g) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for 45 minutes and then treated with 2-chloropyrimidine (0.17 g). The mixture was stirred at room temperature for 3 days and evaporated. The residue was dissolved in ethyl acetate and the solution washed successively with 2M hydrochloric acid, 5% aqueous sodium carbonate solution and brine, dried over MgSO4 and evaporated. The residue was crystallised from ether to give the title compound (90 mg), m.p. 101°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Reactant: Nc1ccnnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Pyridazinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hrs. The N,N-dimethylformamide was evaporated under reduced pressure on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 mins. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification. No further purification carried out. 0.98 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=1)=[O:9]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ncc(C(=O)O)c(O)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
The compound 20 (138 g, 0.596 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 g, 0.775 mol), and 1-hydroxybenzotriazole (100 g, 0.656 mol) were dissolved in dimethylformamide (970 ml), and 4-fluorobenzylamine (79 ml, 0.715 mol) was added. After the reaction solution was stirred at room temperature for 9 hours, water (2000 ml) was added, and crystals were collected by filtration, followed by washing with ether. 5-Bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 21 (156 g, 77%) was obtained as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[CH3:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:37][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:42][C:39]2([C:36]3[N:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)[CH2:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.023 g (44%). 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 2H), 8.14 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.66 (bs, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.21-7.15 (m, 3H), 6.18 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.92 (m, 2H), 1.67 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ −76.71 (TFA), −110.50, −120.06. LCMS: (ES+) m/z=553.2 (M+H)+