Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[CH:24][C:23]=2[F:29])[CH:21]=1>>[F:28][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([F:29])[C:22]=1[C:20]1[CH:21]=[C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:17]=[CH:18][C:19]=1[F:30]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: Fc1ccc(Br)cc1-c1c(F)cncc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4c(F)cncc4F)c3)cnc2c1F
Yield: 40 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine as described in Example 6 to give 2-{3-[3-(3,5-difluoropyridin-4-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (80 mg, 40%): δH (360 MHz, d6-DMSO) 1.57 (6H, s), 7.22 (1H, t, J 7), 7.66 (1H, t, J 9), 7.83 (1H, s), 7.94 (2H, dd, J 6 and 2), 8.37 (1H, d, J 7), 8.75 (2H, s); m/z (ES+) 402 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:15]O>>[Br:1][C:2]1[C:3]([C:8]([O:10][CH3:15])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ncccc1Br
Agent: FB(F)F
Product: COC(=O)c1ncccc1Br

Procedure:
3-Bromopicolinic acid (5 g.) is stirred and refluxed under nitrogen with 40 ml. of 14% boron trifluoride in methanol. the solution is cooled and the methanol is evaporated. The residue is dissolved in chloroform. The chloroform extracts are washed with 5% aqueous sodium bicarbonate solution and water, then the organic solution is dried and evaporated. The residue is recrystallized from cyclohexane to give methyl 3-bromopicolinate, m.p. 34°-36°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.N1(CCNC2C3OC=CC=3C=C(N)C=2)CCOCC1>>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: Nc1ccc(-c2cc([N+](=O)[O-])cc3ccoc23)cn1
Agent: Nc1cc(NCCN2CCOCC2)c2occc2c1
Product: Nc1cc(-c2ccc(N)nc2)c2occc2c1

Procedure:
The title compound was prepared from 5-(5-nitro-benzofuran-7-yl)-pyridin-2-ylamine (Intermediate 39) according to the procedure of Intermediate 28. The product was used directly in the subsequent reaction.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=O.[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClC(Cl)C>[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:10](=[O:12])[CH2:9][CH2:8][C:7]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCCCc1ccccc1
Reactant: COC(=O)CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc(CCCCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
45.9 g of oxalyl chloride and 5 drops of dimethylformamide were added to a dichloroethane solution (500 ml) containing 45.5 g of methyl hydrogen succinate, and the mixture was stirred at room temperature for 3 hours. Under ice cooling, a dichloroethane solution (60 ml) containing 31.3 g of [4-(acetylamino)butyl]benzene, and 91.9 g of anhydrous aluminum chloride were added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate to obtain 42.3 g of 4-[4-(acetylamino)butyl]-l-(3-methoxycarbonylpropionyl)benzene.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:15](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:14]=2)=[C:7]([Cl:30])[CH:6]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:6]=[C:7]([Cl:30])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:15](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:14]=1
Reactant: COC(=O)Cc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(/C=C/C(=O)O)c2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)cc1/C=C/C(=O)O
Yield: 35.4 %

Procedure:
Methyl{3,5-dichloro-4-[3-((E)-2-carboxyvinyl)-4-isobutyramidophenoxy]phenyl}acetate(10 mg, 0.02 mmol), LiOH (2 mL, 1N) and THF (1 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into an aqueous solution of hydrochloric acid (1N). The aqueous layer was extracted with ethyl acetate, and the combined organic layers was washed with water, dried over MgSO4, filtered, and concentrated at reduced pressure to give 3.2 mg (35%) of 3,5-dichloro-4-[3-((E)-2-carboxyvinyl)-4-isobutyr-amidophenoxy]phenylacetic acid, m/z 452.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2cc(Cl)ncn2)cc1

Procedure:
4-Chloro-6-(4-trifluoromethoxyphenyl)-pyrimidine was prepared by palladium-catalyzed arylation of 4,6-dichloropyrimidine and 4-trifluoromethoxyphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.14 (d, J=9.8 Hz, 2H), 7.74 (m, 1H), 7.36 (d, J=8.4 Hz, 2H); EIMS m/z 274 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(S(C)(=O)=O)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and methylsulfonyl chloride (343.6 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=20:1) to yield the target product as white solid powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C@@H:7]1[C@@:32]2([CH3:33])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:8]1)=[O:5])[CH3:2].C(OC(O[C@@H]1[C@@]2(C)C(C=C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCCC(O)(C)C)=C[C@@H](OC(OCC)=O)C1)=O)C>CCOCC>[CH2:1]([O:3][C:4]([O:6][CH:7]1[C@@:32]2([CH3:33])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH2:10][CH:9]([O:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Agent: CCOC(=O)O[C@@H]1C=C2C=C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Solvent: CCOCC
Product: CCOC(=O)OC1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C(OC(=O)OCC)C1

Procedure:
The product (482 g) obtained in (1) above was dissolved in ether (10 l). The resulting solution was subjected to the measurement of UV spectrum with a spectrophotometer (cell length; 1 cm, wavelength; 340 nm-200 nm). The UV spectrum showed, as maximum absorbance (λmax), 293, 281, 271, 260 (shoulder), 249.5 (shoulder), 241 and 232. From the ratio of absorbance in λmax ; 281 and 240, the ratio (Δ5,7/Δ4,6) of 1α,3β-diethoxycarbonyloxy-25-hydroxycholesta-5,7-diene to 1α,3β-diethoxycarbonyloxy-25-hydroxycholesta-4,6-diene was 4.36.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21](N(C)C)=[O:22].[NH4+].[Cl-]>CCOCC.O>[C:21]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)N(C)C
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
To a solution of 2,6-dibromopyridine (0.75 mol) in 2000 ml of anhydrous ether, which was cooled to -60° C. under N2, was added a solution of n-butyllithium in hexane (0.75 mol) over 15 minutes. The reaction mixture was cooled to -80° C. and a solution of dimethylacetamide (0.86 mol) in 70 ml anhydrous ether was added slowly over 1 hour. After stirring the mixture for 15 minutes, a solution of NH4Cl (0.93 mol) in 150 ml of water was added slowly over 8 minutes. After stirring an additional 45 minutes at room temperature, the aqueous layer was separated and extracted with 500 ml of ether. The combined organic layer was washed with water (2×800 ml), dried (MgSO4), filtered, and stripped on a rotary evaporator to yield 159 g of the desired product. This material was distilled at 80° C./0.1 mm Hg to give a near colorless oil that crystallized readily on cooling.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C(B(CC)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:3]=3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccnc4)ncnc32)cc1
Yield: 54.9 %

Procedure:
A solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [4 g, Reference Example 3] and diethyl-3-pyridyl-borane (2.1 g) in tetrahydrofuran (180 mL) was treated with palladium tetrakis triphenylphosphine (0.65 g) and potassium carbonate (3.59 g). The solution was stirred at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected twice to flash column chromatography on silica eluting with a mixture of ethyl acetate and methanol (90:10, v/v) and a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (2.5 g) as an amorphous solid. MS: 351 [MH]+. LCMS (Method B) RT=3.05 minutes.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([N+:28]([O-])=O)[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[S:3][C:4]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:16]([NH2:28])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c([N+](=O)[O-])c2)sc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c(N)c2)sc1Br
Yield: 99.4 %

Procedure:
To a solution of 3 (1.37 g, 2.75 mmol) in EtOAc (50 mL) was added stannous chloride dihydrate (2.5 g, 11.08 mmol). The resulting mixture was refluxed for 1 hour under N2. The reaction mixture was poured into a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO3 solution (3×30 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 4:1) of the residue gave the desired intermediate ethyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)-thiophen-3-yl)acetate as a yellow foam (1.28 g, 100%). To a 100 mL flask containing freshly distilled toluene (20 mL) were added ethyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate (1.28 g, 2.70 mmol) and indium tribromide (500 mg, 1.41 mmol) under N2. The resulting mixture was refluxed for 12 hours. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 4 as a yellow amorphous solid (454 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.02 (s, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.70-7.64 (m, 2H), 7.56 (s, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.40 (t, J=7.6 Hz, 1H), 6.90 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.62, 170.13, 144.16, 142.47, 136.69, 135.86, 135.05, 133.38, 131.84, 130.69, 129.31, 128.77, 128.70, 125.92, 121.81, 120.27, 113.73, 100.08, 61.67, 35.43, and 14.44.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[I-].[Na+].[C-:30]#[N:31].[K+].O>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([C:30]#[N:31])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCn1c(C#N)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 58 h
Yield: 60.3 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g, 4.11 mmol) and sodium iodide (123 mg, 0.82 mmol) in anhydrous dimethylsulfoxide (40 ml) was added potassium cyanide (294 mg, 4.52 mmol). After stirring at room temperature for 58 hours, the mixture was treated with water (200 ml) and extracted with ethyl acetate (4×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide (R)-1-(5-Acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (970 mg, 60% yield) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([CH3:31])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:8])[CH3:5].Cl>CO.[OH-].[Na+]>[CH3:31][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:32])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1NCc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 66.4 %

Procedure:
140 mg 2-methyl-2-{[1-(4-trifluoromethyl-benzylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 2 ml methanol and 1 ml 1M aqueous sodium hydroxide solution was refluxed for 0.5 h. The reaction was acidified with 2 M hydrochloric acid, and the precipitated product was collected by filtration, dissolved in ethyl acetate, dried over sodium sulphate, filtrated, concentrated in vacuo, and the resulting crude product was purified by silica gel chromatography to yield 0.09 g 2-methyl-2-{[1-(4-trifluoromethyl-benzylamino)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[NH:26][CH3:27])=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:30].CO>CO>[ClH:30].[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:28]=[CH:29][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[N:26]([CH3:27])[C:19]=2[CH:20]=1
Reactant: CNc1cc(OC)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of 2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy-N-(4-methoxy-2-methylaminophenyl)acetamide (3.0 g) in methanol (46 ml) was added 2 mol/l hydrogen chloride-methanol (14 ml) and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to 40° C. and stirred at the same temperature for 1 hour. At the end of this time the reaction mixture was cooled to 25° C. and the precipitated crystals were filtered to give the title compound (2.9 g, yield 92%). Melting point, IR spectrum and NMR spectrum of this compound are substantially identical with those of the compound obtained in Example 5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:14]1[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=1
Reactant: Cc1ccccc1N
Reactant: O=C1CCNC(=O)C1
Product: Cc1ccccc1NC1=CC(=O)NCC1
Yield: 97.8 %

Procedure:
A mixture of o-toluidine (943 mg) and 2,4-dioxopiperidine (1.0 g) was heated at 120° for 30 min. The oil was cooled, triturated with ether (30 ml) and the solvent was decanted to give the title compound (1.74 g), m.p. 155°-158°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([OH:16])=O)[S:11][C:12]=1[CH3:13])[CH3:2].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[CH2:20][C@@H:19]([NH:18][C:14]([C:10]1[S:11][C:12]([CH3:13])=[C:8]([C:7]2[N:6]([CH3:17])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:16])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:41])([F:40])[F:42]
Reactant: CCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (211 mg, 0.55 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.48 ml, 2.74 mmol) in Dichloromethane (5.47 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (281 mg, 0.60 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (262 mg, 0.45 mmol, 82% yield) as a clear oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C=CC(=O)OC(C)(C)C)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Yield: 99.7 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.48 g) in ethyl acetate (60 mL) and ethanol (30 mL) was hydrogenated using 1% palladium on carbon at room temperature for overnight to give 2.49 g (100%) of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.12 (br s, 1H, NH), 5.74 (d, J=2.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H, OCH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 2.47 (t, J=7.5 Hz, 2H, CH2), 2.18 (s, 3H, CH3), 1.36 (s, 9H, 3×CH3), 1.28 (t, J=7.1 Hz, 3H, OCH2CH3). MS 282 [M++1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CCOC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using ethyl chloroformate (53 μL, 0.55 mmol) to provide ethyl[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate (0.026 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:11](=[O:27])[CH:10]([NH:28]C(OC(C)(C)C)=O)[N:9]=1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:28][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])[C:11]1=[O:27]
Reactant: Cc1cccc2c1N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(CC(=O)C(C)(C)C)C(=O)C(N)N=C2c1ccccc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A mixture of (3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbonylmethyl-3-tert-butoxycarbonylamino-9-methyl-1H-1,4-benzodiazepin-2-one (130 mg) and 4N HCl in ethyl acetate (1 ml) was stirred at 0° C. for 5 hours. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. The separated organic layer was washed with water and brine, and then dried over sodium sulfate. The solvent was evaporated in vacuo to afford (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-tert-butylcarbonylmethyl-9-methyl-1H-1,4-benzodiazepin-2-one (100 mg, 97.1%) as a crystalline powder.