Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.C[Si]([C:33]#[CH:34])(C)C.C(N(CC)CC)C>C1COCC1.[Cu](I)I>[OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]#[CH:34])=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(Nc2c(C)c(=O)n(C)c3ncn(C[C@@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
(R)-3-(2,3 Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (200 mg, 0.4 mmol, Example 8), trimethylsilyl acetylene (66 μL, 0.6 mmol), triethylamine (84 μL, 0.6 mmol), copper iodide (14 mg, cat) and dichlorobis(triphenylphoshine) palladium(II) (14 mg, 0.02 mmol) were mixed in THF (2 mL). The mixture was subjected to microwave irradiation at 120° C. for 20 minutes. The solvent was removed in vacuo and the residue dissolved in methanol. Potassium carbonate (50 mg) was added and the solution stirred at RT for 1 hour. After filtration and evaporation the residue was purified by HPLC to give 119 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.79 (s, 3 H) 3.11 (s, 1 H) 3.54-3.66 (m, 3 H) 3.82-3.90 (m, 1 H) 3.94-4.02 (m, 1 H) 4.30 (dd, J=14.15, 3.79 Hz, 1 H) 6.67 (t, J=8.46 Hz, 1 H) 7.19 (dd, J=8.21, 0.88 Hz, 1 H) 7.21-7.25 (m, 1 H) 8.27 (s, 1 H) [M+H] calc'd for C20H19FN4O4, 399; found, 399.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16](=O)[CH3:17])[N:10]=1>CO>[CH3:6][O:5][C:1]([NH:2][N:3]=[C:16]([CH3:17])[CH2:15][N:11]1[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]1=[O:14])=[O:4]
Reactant: COc1nn(CC(C)=O)c(=O)s1
Reactant: COC(=O)NN
Solvent: CO
Product: COC(=O)NN=C(C)Cn1nc(OC)sc1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.8 %

Procedure:
9.1 g of methyl carbazate are added to a solution of 18.8 g of 5-methoxy-3-(2-oxo-propyl)-3H-[1,3,4]thiadiazol-2-one (Comp. 7.001) in 150 ml of methanol and the mixture is then stirred at room temperature for 36 hours. The reaction mixture is concentrated by evaporation and the residue is stirred with isopropanol and filtered with suction to yield 20.5 g of crystals of the title compound having a melting point of 142°-143°.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[CH:9][C:10]2[C:11]3[C:16]([N:17]=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[CH:9][C:10]2[C:23]3[C:18]([N:17]=[C:16]4[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Reaction time: 5 h

Procedure:
The 9-(4-nitrostyryl)acridine product (2.86 g, 10.0 mmol) is dissolved in ethyl acetate (250 ml) and then brought to reflux. A solution of tin(II) chloride dehydrate (9.0 g, 40 mmol) in hot ethanol (150 ml) is cooled and added to the solution of 9-(4-nitrostyryl)acridine. The mixture is reacted under reflux and with stirring for 5 hours. After cooling, the 9-(4-aminostyryl)acridine precipitates and is isolated by filtration under vacuum. The filtrate is dried by evaporation and taken up in water (500 ml) with stirring. The solution is basified (pH 13–14) with a sodium hydroxide solution. The 9-(4-aminostyryl)acridine fraction previously isolated, which contains a high proportion of tin salt, is also basified. The 9-(4-aminostyryl)acridine is separated by filtration, washed with water and dried. It is sufficiently pure for the following step.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].N1C=CC=CC=1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C>[O:8]([CH2:7][C@H:6]1[O:5][C@@H:4]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@@H:3]1[CH2:2][OH:1])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a round-bottom flask were placed 10 g of 9-((2R,3R,4S)-3,4-bis-hyroxymethyl-oxetan-2-yl)adenine and 100 mL of pyridine. To the system was added 6.4 g of tert-butylchlorodimethylsilane, and the reaction mixture was stirred under nitrogen at room temperature for 1 day. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated with a rotary evaporator. The residue was purified by column chromatography to afford 9-((2R, 3R, 4S)-4-t-butyldimethylsiloxymethyl-3-hydroxymethyl -oxetan-2-yl)adenine.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N:20]([CH3:22])[CH3:21])=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=1.CN(C)[CH:29]=[O:30]>>[C:23]([C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([Cl:19])[C:16]=1[N:20]([CH3:22])[CH3:21])[CH:29]=[O:30])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)C=O
Reactant: CN(C)c1c(Cl)cc(Br)cc1C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)c1c(Cl)cc(C=O)cc1C(C)(C)C
Yield: 98.7 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 2.25 ml (5.6 mmol) of 2.5M n-butyllithium/hexane with 1.5 g (5.2 mmol) of (4-bromo-2-tert-butyl-6-chlorophenyl)dimethylamine and 450 μl (5.8 mmol) of dimethylformamide. 1.23 g of 3-tert-butyl-5-chloro-4-dimethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH2:17][C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH2:14][CH:13]=2)=[N:5][C:4]([NH2:24])=[N:3]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH2:17][C:16]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH2:14][CH:13]=2)=[N:5][C:4]([N:24]=[CH:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[N:3]1
Reactant: O=Cc1ccncc1
Reactant: Cn1nc(N)nc1NCCCOC1=CCC=C(CN2CCCC2)C1
Solvent: c1ccccc1
Product: Cn1nc(N=Cc2ccncc2)nc1NCCCOC1=CCC=C(CN2CCCC2)C1
Yield: 29.1 %

Procedure:
A stirred solution of 1-methyl-N5 -[3-[[5-(1-pyrrolidinylmethyl)-1,4-cyclohexadien-1-yl]oxy]propyl]-1H-1,2,4-triazole-3,5-diamine (0.95 g) and 4-pyridinecarboxaldehyde (0.35 g) in benzene (30 ml) was heated under reflux in a Dean-Stark separator for 30 h. The solution was evaporated in vacuo to give a solid which was recrystallised from ethyl acetate (10 ml) to afford the title compound as a yellow solid (0.35 g). m.p. 166°-167° C.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[N:22]=1>C1(C)C=CC=CC=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>[CH:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:22]=1)=[O:28]
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2cccc3ccccc23)n1
Temperature: 70 °C
Yield: 87 %

Procedure:
Inside of a dry box, naphthylboronic acid (9.12 g, 53.0 mmol) and Na2CO3 (11.64 g, 110 mmol) are dissolved in 290 mL of degassed 4:1H2O/MeOH. This solution is added to a solution of 8 g (43 mmol) of 2-bromo-6-formylpyridine and 810 mg (0.7 mmol) of Pd(PPh3)4 in 290 mL of degassed toluene. The charged reactor is removed from the dry box, while under a blanket of N2 and is connected to the house N2 line. The biphasic solution is vigorously stirred and heated to 70° C. for 4 h. On cooling to RT, the organic phase is separated. The aqueous layer is washed with 3×75 mL of Et2O. The combined organic extracts are washed with 3×100 mL of H2O and 1×100 mL of brine and dried over Na2SO4. After removing the volatiles in vacuo, the resultant light yellow oil is purified via trituration with hexanes. The isolated material is recrystallized from a hot hexane solution and ultimately yielded 8.75 g, 87% yield. mp 65-66° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].C(O)(=[O:15])C>>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10].[C:11]([OH:12])(=[O:15])[CH:9]([CH3:7])[OH:10]
Reactant: CC(=O)O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
intermedius NRRL B-30560 was grown essentially as described in Example 2 in simplified MRS medium under anaerobic conditions using 2% fructose as the carbon source. The product patterns were analyzed by HPLC. The bacterium produced mannitol, lactic acid and acetic acid in product ratios similar to those obtained under aerobic conditions.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7](=[O:20])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>O.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>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:27]=[CH2:28])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:20]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc2c(ccc(=O)n2COCC[Si](C)(C)C)c1
Temperature: 110 °C
Yield: 94 %

Procedure:
To a solution of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (1 g, 2.82 mmol) in toluene (20 mL) and water (20.00 mL) were added trivinylboraxin (0.684 g, 4.23 mmol), K2CO3 (0.780 g, 5.64 mmol). The reaction mixture was purged with N2 for 15 min, then Tetrakis (0.652 g, 0.564 mmol) was added and the reaction mixture was heated to 110° C. for 12 h. The reaction mixture was concentrated and dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and concentrated to get the 1-((2-(trimethylsilyl)ethoxy)methyl)-6-vinylquinolin-2(1H)-one (0.8 g, 94%), used without further purification. LCMS (ES-API), RT: 2.17 m/z 302.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>C(#N)C.C(Cl)Cl>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:22])=[O:21]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Reaction time: 1 h

Procedure:
Piperazine (24.46 g) is dissolved in acetonitrile (200 ml) and anhydrous potassium carbonate (10.47 g) is added. Then 2-chloronitrobenzene (10.0 g) is added dropwise. After stirring 1 hr at 20°, the reaction mixture is diluted with methylene chloride, washed with water, and saturated aqueous potassium carbonate. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.75, 7.49, 7.14, 7.04, 3.03 and 1.93δ.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[O:13][C@@H:12]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[N:44]1[C:48](=O)C[CH2:46][C:45]1=[O:50].[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl.O1CCCC1>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([CH2:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[O:13][C@@H:12]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:46]3[C:45](=[O:50])[NH:44][C:48]4[C:56]([N:51]=3)=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:29]2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](n2ccc3ccccc32)C1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](n2cc(-c3nc4ccccc4[nH]c3=O)c3ccccc32)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 31 %

Procedure:
1(3-O-Benzoyl-6-phthalimido-2,4,6-trideoxy-β-D-threo-hexopyranosyl)-1H-indole (0.30 g, 0.62 mmol) was dissolved in dichloromethane (3 ml) and cooled to 0° C. Oxalyichloride (65 μl, 0.74 mmol) was added and the reaction mixture kept at 0° C. for 15 ml and then stirred at room temperature for another 45 minutes. N-hydroxysuccinimid (0.08 g 0.70 mmol) was added followed by careful addition of pyridine (0.10 ml, 1.23 mmol). The reaction mixture was stirred at room temperature for 16 hours and then washed twice with water. The organic layer was evaporated and the crude mixed with tetrahydrofuran (10 ml) and 1,2-diphenylenediamine (0.09 g, 0.80 mmol) and stirred at room temperature for 16 hours. The resulting percipitate was collected by centrifugation, washed twice with ether and dried to give 0.12 g (32%) of the subtitle product.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)(Cl)(Cl)Cl>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:17])[CH:15]=[CH2:16]
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 62 %

Procedure:
In 200 ml of carbon tetrachloride, 19.1 g (0.100 mol) of 4-cyano-2,3, 5,6-tetrafluorophenol and 11.3 g (0.125 mol) of acrylic acid chloride were dissolved. To the resultant solution, 20 g of molecular sieve 3 Å in diameter was added. The mixture was stirred under reflux for 38 hours. The resultant reaction mixture was cooled off and filtered to separate the molecular sieve. The filtrate was dried with magnesium sulfate and evaporated to dryness with a rotary evaporator. Consequently, there was obtained 15.2 g of 4-cyano-2,3,5,6-tetrafluorophenyl acrylate (yield 62.0% based on 4-cyano-2,3,5,6-tetrafluorophenol, purity 96.4%) having a melting point below determined.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][CH2:13][C:14](Cl)=[O:15].CCOCC>O1CCCC1>[Cl:12][CH2:13][C:14]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])=[O:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride (30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1 hour. The solution is cooled and concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL) is added and the yellow solid is collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:24]=1[CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]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.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][C:24]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:23]=4[F:22])[CH:30]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cc(F)ccc3F)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Yield: 42.63 %

Procedure:
Using similar reaction conditions as described in step-i of example 1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (1 g, 2.37 mmol) was coupled with 1-(2,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 6) (688 mg, 3.3 mmol) in sodium carbonate (749 mg, 7.07 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (83 mg, 0.11 mmol) and toluene/ethanol/water (10/10/5 ml) to afford 550 mg (42.63% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.59-8.51 (m, 3H), 8.29 (s, 1H), 8.13 (s, 1H), 7.98-7.95 (d, 2H), 7.42-7.40 (d, 2H), 7.35-7.10 (m, 4H), 5.52 (s, 2H), 2.33 (s, 3H). MS: m/z=542.6 (M−1).
Reaction SMILES: C(=O)([O-])[O:2][C:3](Cl)(Cl)[Cl:4].Cl.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH3:18])=[O:16].C(N(C(C)C)CC)(C)C.ClC1C=CC(O)=C(C=1)C(NC1C=CC([N+]([O-])=O)=CC=1Cl)=O>C(Cl)(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:4][C:3]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH3:18])=[O:16])=[O:2]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C([O-])OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)ccc1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Methyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was prepared following the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenlee et al with minor modification. A solution of 5.63 g (19.0 mmol) bis(trichloromethyl carbonate in chloroform (15 mL) was added dropwise to a solution of (S)-Methyl pyrrolidine-2-carboxylate hydrochloride (2.62 g., 15.82 mmol) and diisopropylethylamine (11.0 mL, 63.28 mmol) in chloroform (15 mL) at ice-bath temperature. After one hour, the solution was washed with 1 N aqueous HCl and water, and dried over magnesium sulfate. The dried solution was concentrated and placed on a 85 mm i.d.×35 mm column of silica gel. The product was eluted in 20 percent ethyl acetate in hexanes and concentrated to a colorless oil. This was dissolved in chloroform (10 mL) and added to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (645 mg, 1.97 mmol) in pyridine (15 mL) containing 20 mg of 4-dimethylaminopyridine. After stirring for 120 hours at room temperature, the reaction solution was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate phase was washed with water, then brine, and dried over magnesium sulfate. Concentration afforded an off-white solid which was recrystallized from ethyl acetate/hexanes. The 1H NMR spectrum is complex and reveals the existence of rotational isomers due to restricted rotation about the pyrrolidine-1-carboxylate bond. 1HNMR (300 MHz, DMSO-d6): δ 1.823-2.003 (m, 3H, pyrrolidine C4 methylene and pyrrolidine C3 syn-H), 2.213 (m, 1H, pyrrolidine C3 anti-H), 3.450 (m, 1H, pyrrolidine C5), 3.599 (m, 1H, pyrrolidine C5), 3.600 (s, 1.5H, methyl ester), 3.621 (s, 1.5H, methyl ester), 4.252 (m, 0.5H, pyrrolidine methine), 4.541 (m, 0.5H, pyrrolidine methine), 7.108 (d, J=8.5 Hz, 0.33H, H3), 7.216 (d, J=8.5 Hz, 0.33H, H3), 7.361 (d, J=9 Hz, 0.33H, H3), 7.545 (m, 0.33H, H4), 7.665 (m, 0.66H, H4), 7.763 (m, 0.66H, H6), 7.974 (m, 0.33H, H6), 8.133 (m, 0.66H, H6′), 8.287 (m, 1H, H5′), 8.302 (m, 0.33H, H3′), 8.539 (m, 0.33H, H3′), 8.446 (m, 0.33H, H3′), 8.822 (d, J=9.5 Hz, 0.33H, H6′), 10.313 (s, 0.33H, NH), 10.385 (s, 0.33H, NH), 11.367 (br s, 0.17H, NH), 12.519 (br s, 0.17H, NH).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]1[CH2:56][CH2:55][CH2:54][C@H:9]1[C:10]([N:12]1[CH2:53][CH2:52][CH2:51][C@H:13]1[C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH2:50])=[O:49])[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].CO.CC(O)C.O(C(C)C)C(C)C.C(Cl)[Cl:78]>>[NH2:1][C@H:2]([C:6]([N:8]1[CH2:56][CH2:55][CH2:54][C@H:9]1[C:10]([N:12]1[CH2:53][CH2:52][CH2:51][C@H:13]1[C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([NH2:50])=[O:49])[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:78]
Reactant: ClCCl
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)C(N)=O
Product: Cl
Yield: 68 %

Procedure:
Starting from 2.45 g (2.73 mmol) of BOC-Val-Pro-Pro-Leu-Gly-Trp-Met-NH2 (XV) and operating as described in Example 1, Step 6, but using as eluant systems CH2Cl2 :MeOH:H2O=85:15:1 by volume and CH2Cl2 :MeOH:H2O=80:20:1 by volume during the chromatographic purification, 1.55 g (68% yield) of compound XVI were obtained from MeOH/iPrOH/iPr2O after desalting on Sephadex G-10 (Trade Mark): m.p. 150°-158° C.; [α]D24 =-74.8° (c=1, MeOH); RFD 0.36; E1.2 0.55 Glu.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(Cl)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-chloropyridin-3-yl)boronic acid and to afford an off-white solid. UPLC-MS (condition 1) tR=2.51 min, m/z=493.0-495.0 [M+H]+, m/z=494.1-493.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.78-1.92 (m, 1H) 2.23 (ddd, J=13.63, 7.09, 6.91 Hz, 1H) 2.98 (dd, J=10.88, 6.97 Hz, 1H) 3.12-3.22 (m, 2H) 3.21-3.31 (m, 3H, in HDO) 4.62 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.61 (d, J=8.31 Hz, 1H) 7.85 (d, J=9.29 Hz, 2H) 7.89 (dd, J=8.31, 2.45 Hz, 1H) 8.03 (d, J=2.44 Hz, 1H) 8.49 (d, J=2.45 Hz, 1H) 8.77 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).