Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[F:40][CH2:39][CH2:38][CH2:37][O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: FCCCBr
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OCCCF)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([C:21]=2[CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(COc2ccc(Cl)cc2)c(C=O)c2ccccc21
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a −20° C. bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (0.50 g, 1.84 mmol) in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55° C. and maintained at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][NH2:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH2:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(CCNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-(3,4-dimethoxyphenyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:23]([F:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10](F)[CH:9]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>CN(C=O)C>[Cl:7][C:8]1[C:23]([F:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10]([O:34][C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[Cl:26])[CH:9]=1
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1Oc1ccc(F)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Cs2CO3 (244.4 mg, 0.75 mmol) was added to a solution of 4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (71.2 mg, 0.25 mmol) and 2-chloro-4-fluorophenol (109.9 mg, 0.75 mmol) in DMF (2 mL) and the reaction was stirred at 100° C. for 1 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (109) (22.8 mg, 27%). ESI-MS m/z calc. 410.00. found 411.2 (M+1)+; Retention time: 1.76 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(Cl)c1Cl
Yield: 87.9 %

Procedure:
A solution of 4.0 grams (0.013 mole) of N-(2,3-dichloro-4-methylphenyl)phthalimide, 2.3 grams (0.013 mole) of N-bromosuccinimide and 0.3 gram of benzoyl peroxide in 200 ml of carbon tetrachloride was heated under reflux for 22 hours. The cooled reaction mixture was poured into 500 ml of ethyl acetate. The solution was washed with three 100 ml portions of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using ethyl acetate:heptane (1:4). The appropriate fractions were combined and concentrated under reduced pressure to yield 4.4 grams of N-(4-bromomethyl-2,3-dichlorophenyl)phthalimide as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:22](=[O:23])[CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCN)cc1C
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Heat a solution of 2-(3-methyl-4-methoxyphenyl)ethylamine (64.4 g) and 3-(4-chlorophenyl)-propionic acid (70.2 g) in xylene (600 mL) at reflux over a Dean-Stark trap for 5.5 h. Pour the hot reaction mixture into water an allow to stand overnight. Filter to collect the solid and recrystallize from ethanol to give N-[2-(3-methyl-4-methoxyphenyl)ehtyl]-3(4-chlorophenyl) propionamide (101.1 g), mp=142°-144° C.
Reaction SMILES: Cl[C:2]1[N:6](COCC[Si](C)(C)C)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.N1CCC1.CCN(C(C)C)C(C)C>C(O)C>[NH:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[N:6]=[CH:2]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: C1CNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]cnc2c1
Temperature: 50 °C

Procedure:
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.5 g) was placed in a flask with azetidine (0.48 mL), Hunig's base (iPr2Net, 1.5 mL) in 1 mL of ethanol. The reaction was heated to 50° C. overnight and then concentrated to dryness to get 0.55 g of crude 2-(azetidin-1-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)(=O)C>O>[C:24]([NH:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(C(=O)O)cc(NC(C)=O)c1C(=O)c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 5-amino-4-benzoyl-3-n-butoxybenzoic acid (0.8 g), acetic anhydride (0.8 ml) and acetic acid (8.0 ml) is heated on a steam-bath for 1 hour. After cooling, the resulting solution is poured into water (about 20 ml) and the mixture is left at room temperature for about 20 hours. The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 5-acetamido-4-benzoyl-3-n-butoxybenzoic acid is obtained with a melting point of 177°-178° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:24]=[C:25]([CH:36]=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[C:17]([O:16][C:15](=[O:21])[N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)[CH2:22][C:23]1[N:24]=[C:25]([CH2:36][OH:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(CO)n1)C1CCN(Cc2ccccc2)CC1
Yield: 99.6 %

Procedure:
To a solution of tert-butyl (1-benzyl-4-piperidinyl)((2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (1.3 g) obtained in Example 83d) in ethanol (10 ml) was added sodium borohydride (95 mg) at 0° C., and mixed at room temperature for 1 hour. Water (1 ml) was added thereto, the solvent was then distilled off under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was collected by separation, washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (1.3 g, 98%).
Reaction SMILES: ClC1C=CC(C2N(CC3C=CC(CCC(O)=O)=CC=3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49](CC3C=C(C=CC=3)C(O)=O)[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=2)=[C:41]([O:66][CH2:67]C2CCCC2)[CH:40]=1.Br[CH2:74][C:75]1[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[C:77]([F:83])[CH:76]=1>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]([CH2:74][C:75]3[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[C:77]([F:83])[CH:76]=3)[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=2)=[C:41]([O:66][CH3:67])[CH:40]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: N#Cc1ccc(CBr)cc1F
Agent: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-2-fluoro-benzonitrile (CAS Reg. No. 222978-03-2). Brown sticky solid (39%). MS (Turbo Spray): m/z=428.2 (M+H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]([C:31]([F:34])([F:33])[F:32])[O:28]2)=[CH:23][CH:22]=1.[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43]O)[CH3:41].N(C(OCC)=O)=NC([O-])=O>C1COCC1>[CH2:40]([CH:42]([CH2:45][CH3:46])[CH2:43][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]([C:31]([F:34])([F:32])[F:33])[O:28]2)=[CH:23][CH:22]=1)[CH3:41]
Reactant: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Reactant: CCC(CC)CO
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(OCC(CC)CC)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The polymer bound PPh3 was suspended in THF for 15 min. Ethyl 7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 1a, Step 1 (2.0 g, 6.94 mmole) and 2-ethyl-1-butanol (1.3 mL, 10.35 mmole) were added to above slurry and the mixture was stirred at r.t. for 15 min. Ethyl azodicarboxylate (1.6 mL, 10.35 mmole) was added to above mixture dropwise and the mixture was stirred at room temperature overnight. LCMS indicated product formation and that there was a trace amount of starting material present. The polymer was filtered off through celite pad and the pad was washed with ether. The filtrate was concentrated and the product mixture was suspended in hexane. The suspension was filtered and the filtrate was evaporated and dried in vacuo to afford yellow oil, (2.37 g, 92%): LCMS m/z 394.95 (M+Na). This ester was of suitable purity to use without further purification.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][NH:20][C:21]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(N)CC1
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Agent: Cl
Product: COC(=O)C1(NCc2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)CC1
Yield: 79 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (Example 12-2c) and methyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 79%. MS 366 (MH+).
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CC#N.O>[C:1]([S:5][S:6][CH2:7][CH:8]([NH:9][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)O
Reaction time: 0.25 h

Procedure:
To S-tert-butylmercapto-L-cysteine (10 g, 47.8 mmol) in CH3CN (40 mL) was added K2CO3 (16.5 g, 119.5 mmol) in H2O (20 mL). After stirring for 15 minutes, iso-butyl chloroformate (9.4 mL, 72 mmol) was injected slowly. The reaction was allowed to run for 3 hours. The white solid was filtered through Celite; the filtrate was concentrated to remove CH3CN. The residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (40 ml×3), brine (40×1), dried over Na2SO4. The title compound was obtained after chromatography (5% MeOH/DCM).
Reaction SMILES: [NH2:1][C:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=2)[C:8]([C:19]2[N:24]=[C:23]3[C:25]([C:47]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[N:21][CH:20]=2)=[N:7]1.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]>ClCCl>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[NH2:1][C:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=2)[C:8]([C:19]2[N:24]=[C:23]3[C:25]([C:47]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:26][NH:27][C:22]3=[N:21][CH:20]=2)=[N:7]1
Reactant: CC(C)(N)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-(1-(4-amino-4-methylpentyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (54 mg, 0.08 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(1-(4-amino-4-methylpentyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (13 mg, 34%) as yellow solid. LCMS: (M+H)+=500; 1H NMR (300 MHz, CD3OD): δ 8.98 (s, 1H), 8.13 (s, 1H), 8.07 (d, 1H, J=2.1 Hz), 7.60 (d, 1H, J=9.3 Hz), 7.29 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.72 (t, 1H, J=74.1 Hz), 4.49-4.47 (m, 2H), 2.03-1.98 (m, 2H), 1.58-1.53 (m, 2H), 1.49 (s, 9H), 1.19 (s, 6H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][OH:22])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41](=[O:45])[CH:42]=[N+]=[N-])[CH3:39].C(O)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:45])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2CCO)O[Si](C)(C)C(C)(C)C)cc1F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)COCCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-{2-[(1R)-1-({(2R)-2-{[Tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}ethanol (545 mg, 1.03 mmol), which had been obtained in Example 180 (180d), was dissolved in methylene chloride (5 mL), added with rhodium diacetate dimer (46 mg, 0.10 mmol) and ethyldiazoacetate (267 μL, 2.58 mmol) at 0° C., and stirred for 1.5 hours. Ethanol was added to the reaction solution to terminate the reaction. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (565 mg, yield 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cn1

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.26 g, 6.31 mmol), and potassium carbonate (2.18 g, 15.77 mmol) was stirred in DMSO (5 mL) at 120° C. overnight. The reaction mixture was concentrated under rotary evaporation and mixed with water (50 mL). The resulting precipitate was filtered, washed with water (3×10 mL) and air-dried to provide the title intermediate.
Reaction SMILES: [N+](C1C=CC(COC(NCCOCC(O)=O)=O)=CC=1)([O-])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+](C1C=CC(COC([N:58]2[CH2:62][C@@H:61]([S:63][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH2:60][C@H:59]2[C:72](N2CCNCC2)=[O:73])=O)=CC=1)([O-])=O>O1CCCC1.C(N(CC)CC)C>[C:72](=[C:59]1[CH2:60][CH:61]([S:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:62][NH:58]1)=[O:73]
Reactant: O=C(S[C@H]1C[C@@H](C(=O)N2CCNCC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)COCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C=C1CC(SC(=O)c2ccccc2)CN1
Reaction time: 1 h

Procedure:
In 10 ml of tetrahydrofuran was dissolved 209 mg of 2-(2-(p-nitrobenzyloxycarbonylamino)ethoxy)acetic acid, followed by stirring on an ice bath. To this were added 161 mg of 1-hydroxybenzotriazole and 433 mg of dicyclohexylcarbodiimide, followed, after 1 hour of stirring at the same temperature, by the addition of 523 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(piperazine-1-yl)carbonyl-4-benzoylthiopyrrolidine and 0.146 m of triethylamine and subsequent 1 hour of stirring. After removing insoluble material by filtration, the resulting filtrate was evaporated under a reduced pressure, and a residue was subjected to a silica gel column chromatography to yield 402 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-(2) -(p-nitrobenzyloxycarbonylamino) ethoxy)acetyl)piperazine-1-yl)carbonyl-4-benzoylthiopyrrolidine as the compound of interest.
Reaction SMILES: [C:1]([OH:19])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].S(Cl)([Cl:22])=O>C1CCCCC1>[C:1]([Cl:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 81.6 %

Procedure:
In a one L (liter) two-necked flask were placed 102.1 g (0.38 mol) of heptadecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 67.3 g (0.57 mol) of thionyl chloride and a reflux tube. Then, the heptadecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction mixture were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant reaction mixture was subjected to vacuum distillation. Thus 88.5 g (0.31 mol) of heptadecanoyl chloride was obtained in a yield of 81.2% based on the fed heptadecanoic acid.