Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cccc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 25.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (200 mg, 0.31 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (123.15 mg, 0.37 mmol) in sodiumcarbonate (98.57 mg, 0.93 mmol), Pd(PPh3)2Cl2 (10.8 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 60 mg (25.4% yield) of titled compound. MS: m/z=760.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Li+].Cl[CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl>COCCOC.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:32][CH:31]=[CH:30][CH2:29]2)=[O:16])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(C(=O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)CC=CC1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (2.0 g), lithium hydride(0.11 g) in 1,2-dimethoxyethane and hexamethylphosphoramide was stirred at 40° C. for 1 hour. cis-1,4-Dichloro-2-butene was then added, and the mixture stirred at 65° C. for 48 hours. The mixture was extracted with ether, washed with brine, dried (magnesium sulphate), evaporated and purified by column chromatography eluting with ethyl acetate/hexane (1:5) to give ethyl 1-[2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionyl]cyclopent-3-enylcarboxylate (Compound 9, 0.62 g), NMR: 1.20(3H, t), 1.52(6H, s), 1.91(3H, s), 3.0-3.25(4H, m), 4.14 (2H, q), 5.17(2H, s), 5.56(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[C:5]([C:19]1[N:15]([CH3:14])[C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a chilled suspension of 9.7 g. (0.07 mole) of aluminum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5° C.). After the addition is complete, the reaction mixture is stirred at 0° C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mμ range contain the desired product. These fractions are combined, the solvent evaporated off, and the oily residue, when triturated with methanol, yields the crystalline product, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (69%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:19])[CH2:17][CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:20]Br>C(O)(=O)C>[Br:20][CH:17]([CH3:18])[C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:19]
Reactant: CCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
This compound is obtained simply by reacting 1-(3,5-ditert-butyl-4-hydroxyphenyl)propan-1-one (prepared from 2,6-ditertbutylphenol according to Russ. J. Org. Chem. (1997), 33, 1409-1416) with bromine in acetic acid or also according to a protocol described in one of the following references: Biorg. Med. Chem. Lett. (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10), 1910-1918; J. Am. Chem. Soc. (1999), 121, 24.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[NH:10][C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1.Cl[CH2:19][O:20][CH3:21]>O>[Br:8][C:9]1[N:10]([CH2:19][O:20][CH3:21])[C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(Br)nc([N+](=O)[O-])c1Br
Reaction time: 5 h
Yield: 84.3 %

Procedure:
Under an ice-cooling condition, sodium hydride (3.56 g) was added to a N,N-dimethylformamide (100 ml) solution of 2,5-dibromo-4-nitroimidazole (20.08 g). 10 minutes later, being added dropwise chloromethylmethyl ether (6.75 ml) thereto at 10 to 15° C., then the reaction mixture was turned back to a room temperature. After being stirred this reaction mixture for 5 hours, under an ice-cooling condition, sodium hydride (0.30 g) and chloromethylmethyl ether (0.56 ml) were added, further stirred at a room temperature for 1 hour. Then the reaction mixture was ice-cooled, water was added and extracted with ethyl acetate. The organic layer was washed with an aqueous solution being saturated with sodium chloride, dried over anhydrous sodium sulfate, then concentrated under a reduced pressure. Thus obtained crude crystals were washed with diisopropyl ether, and dried at 50° C. for 24 hours, there was obtained 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (19.68 g, yield: 84.3%) as yellow powder product.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.Cl.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:38][O:37][C:35](=[O:36])[C@H:24]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:23][C:11](=[O:12])[CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (100 mg), HCl.H-L-Trp-OMe (136 mg) and HOBT (55 mg) in dimethylformamide (6 ml) was added WSCD (64 mg) under ice-bath cooling. After being stirred overnight at room temperature, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophane methyl ester (165 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: OCCc1ccccc1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1ccccc1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 2-(2-bromo-phenyl)-ethanol (5.0 g, 24.9 mmol, 1.0 eq) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (3.4 mL, 37.3 mmol, 1.5 eq.), followed by camphorsulfonic acid (2100 mg). The mixture was stirred at room temperature for 2 h. After adding K2CO3 (300 mg), the mixture was filtered to remove the precipitate, the filtrate was washed with H2O (100 mL), brine (100 mL). The organic phase was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The oily residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 50:50) to give 2-[2-(2-bromo-phenyl)-ethoxy]-tetrahydro-pyran as a colorless oil. 1H NMR (chloroform-d) δ: 7.48-7.54 (m, 1H), 7.25-7.30 (m, 1H), 7.17-7.23 (m, 1H), 7.01-7.09 (m, 1H), 4.56-4.61 (m, 1H), 3.88-3.97 (m, 1H), 3.58-3.67 (m, 1H), 3.04 (t, J=7.2 Hz, 2H), 1.62-1.67 (m, 1H), 1.41-1.60 (m, 5H), 0.85-0.90 (m, 1H). Amount obtained: 6.9 g, 97.1% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:20]=1[CH3:27])=O>>[CH3:27][C:20]1[CH:21]=[C:22]([C:24]([OH:26])=[O:25])[NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](O)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][C:61]=1[O:62][C:63]([F:66])([F:65])[F:64])[CH2:57][NH2:58]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:28])[NH:58][CH2:57][C:56]2[CH:59]=[CH:60][C:61]([O:62][C:63]([F:64])([F:65])[F:66])=[C:54]([F:53])[CH:55]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 95.7 %

Procedure:
To a solution of the compound (1.24 g) obtained in Example 1001, Step 1 in N,N-dimethylformamide (12 ml) were added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.65 g), 1-hydroxybenzotriazole hydrate (0.52 g) and the compound (0.59 g) obtained in Step 3. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96-6:94) to give the title compound (1.70 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNc2ccnc(Nc3cccc(Cl)c3)n2)C1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (500 mg, 2.08 mmol) and tert-butyl (3S)-3-(aminomethyl)pyrrolidine-1-carboxylate (625 mg, 3.12 mmol) in THF (10 mL) is added diisopropylethylamine (0.73 mL, 4.16 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 356 mg (42% yield) of the desired compound: MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([O:5][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)OCc1ccccc1

Procedure:
Boc-DL-Pip-OH (2.29 g, 10 mmol) and benzyl bromide (1.79 ml, 15 mmol) were reacted in DMF (20 ml) in the presence of triethylamine (2.1 ml, 15 mmol) to obtain Boc-DL-Pip-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-DL-Pip-OBzl-HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([Cl:20])[CH:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:2]([N:1]2[C:24](=[O:25])[C:23]3[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]2=[O:26])[CH:3]=[C:4]([Cl:20])[C:5]=1[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:15])[CH3:16])[C:10](=[O:13])[NH:11][N:12]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Temperature: 130 °C
Yield: 60.8 %

Procedure:
A solution of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2H-pyridazin-3-one (910 mg, 2.90 mmol) in glacial acetic acid (12 mL) was treated with phthalic anhydride (430 mg, 2.9 mmol). The reaction was then heated to 130° C. for 3.5 h. At this time, the reaction was poured onto water (200 mL) and extracted into ethyl acetate (300 mL). The organics were then washed with water, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting orange solid was slurried in cold acetonitrile, collected by filtration, washed with cold acetonitrile and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (92) (780 mg, 61%) as a light, tan solid; ES(+)-LRMS for C22H17Cl2N3O3 (M+H)+ at m/z=442. Exact Mass=441.0647; Molecular Weight=442.3051
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>ClCCCl>[CH3:14][N:15]1[C:19]([C:11](=[O:12])[C:9]2[S:10][C:6]([CH3:5])=[CH:7][CH:8]=2)=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22]
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)s1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 25.54 g. (0.019 mole) anhydrous aluminum chloride in 70 ml. of 1,2-dichloroethane is added 30.7 g. (0.019 mole) 5-methyl-2-thenoyl chloride. The resulting solution is added dropwise to a chilled (0°C.) solution of 24 g. (0.02 mole) 1-methylpyrrole-2-acetonitrile. After the addition, the solution is stirred at room temperature for approximately 40 minutes and than heated at reflux for 3 minutes and poured onto ice acidified with dilute hydrochloric acid. The two phases are separated. The organic phase is washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting solid, 1-methyl-5-(5-methyl-2-thenoyl)-pyrrole-2-acetonitrile, is separated by filtration and purified by washing in cold methanol and benzene, m.p. 118°-121°C.
Reaction SMILES: CO.[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.C[O-].[Na+:39]>CCOCC>[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O-:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1.[Na+:39].[Na+:39].[F:3][C:4]1[CH:36]=[CH:35][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O-:29])=[O:28])[N:26]=4)=[CH:18][C:17]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:13])=[O:14])=[C:10]([CH3:11])[C:6]=2[CH:5]=1
Reactant: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(C(=O)[O-])co3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
Into 30 mL of methanol was dissolved 290 mg of Compound 23, followed by addition of 77 mg of sodium methoxide. After 8 hours of stirring at room temperature, ether was added and the precipitated crystals were collected by filtration and washed with ether to obtain 300 mg of the title compound as colorless powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.O1CCOCC1>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:2]([F:1])([F:19])[F:20])[N:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: N#Cc1ccc(-c2ccccc2C(O)C(F)(F)F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccccc3-c3ccc(C#N)nc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 110 °C
Yield: 84 %

Procedure:
A mixture of 5-[2-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-pyridine-2-carbonitrile (46 mg, 0.165 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (59 mg, 0.15 mmol), cesium carbonate (195 mg, 0.6 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, then was poured into 5 ml of water. 1N HCl was added to adjust pH to 4.5, the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated to give 80 mg of crude (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid, yield 84%.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:2][C:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc([N+](=O)[O-])cc2c1OCC2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=CC(=O)c1cc([N+](=O)[O-])cc2c1OCC2
Yield: 80 %

Procedure:
7-Acetyl-5-nitro-2,3-dihydrobenzofuran (D9) (500 mg) was stirred and heated to 80° C. for 1 h with tert-butoxy-bis (dimethylamino) methane (1.08 ml), then the mixture was cooled and partitioned between Na2 CO3 and ethyl acetate. The organic phase was dried (Na2 SO4) and the solvent evaporated under reduced pressure to leave the title compound (0.5 g, 80%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[N:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:25]=[N:24][CH:23]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)n1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cncnc2)n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using 6-bromo-N-(4-(trifluoromethoxy)phenyl)picolinamide (Stage 73.1) and 5-pyrimidine boronic acid to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.08 min, m/z=361.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.43 (d, J=9.38 Hz, 2H) 8.02 (m, J=9.00 Hz, 2H) 8.20-8.28 (m, 2H) 8.42-8.47 (m, 1H) 9.33 (s, 1H) 9.81 (s, 2H) 10.76 (s, 1H).