Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][O:34][C:35]([C:37]1([NH:40][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH2:39][CH2:38]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-amino-cyclopropanecarboxylic acid methyl ester hydrochloride (100 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-1-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropanecarboxylic acid methyl ester as a white powder (120 mg, 49.6%). HRMS (ES+) m/z Calcd for C28H29Cl2F2N3O3+H [(M+H)+]: 564.1627. found: 564.1627.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(N2CCC(O)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 10.1 g (42.9 mmol) 4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 8.0 g (52 mmol) tert-butyldimethylchlorosilane and 6.5 g (94 mmol) imidazole in 90 ml N,N-dimethylformamide was stirred at room temperature over night. The reaction was quenched with water. The resulting suspension was extracted with ethyl acetate. The organic extract was washed with 3 portions of water. The combined aqueous layers were extracted with 3 portions of dichloromethane. The combined organic extracts were dried with sodium sulfate, concentrated and dried in vacuo (0.5 mbar) at 80° C. Flash column chromatography afforded 14.6 g (97.3%) of the title compound as a light yellow solid. MS m/e (%): 349 (M+, 21).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Br[Mg]c1cccc(Br)c1
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.502 g, 2.80 mmol) and (3-bromophenyl)magnesium bromide (synthesized in situ) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (3-Bromophenyl)magnesium bromide was synthesized as follows: Activated magnesium (0.306 g, 12.6 mmol) was placed in a flask and anhydrous THF (50 mL) was added. 1,3-dibromobenzene (1.6 mL, 13.2 mmol) and a catalytic amount of 12 was added. The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). Methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording a 1:1 mixture of the title compound and dehalogenated product as a slightly yellow solid: 0.315 g (67% yield). LCMS (ESI−) 318.0 (M−H).
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].C([Al+]CC(C)C)C(C)C.[O:32]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:32])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-1-(2-chloro-phenyl) methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 mL) was cooled to -78° C. under argon, and a solution of diisobutyl aluminum hydride in toluene (30 mL of 1 M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; m.p. 98-101° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Cl-].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]#[N:25])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[CH2:1]([N:4]([CH2:11][CH2:12][OH:13])[C:5]1[CH:10]=[CH:9][C:8]([N:25]=[N:24][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CCO)c1ccccc1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Product: C=CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
N-allyl-N-(2-hydroxyethyl)benzenamine (7.1 g, 0.04 mol) is treated with a solution of p-nitrobenzenediazonium chloride, as discussed in Example 5, to provide N-allyl-N-(2-hydroxyethyl)-4-(4'-nitrophenylazo)benzenamine.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=O)[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[C:6]([Cl:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c[nH]cc(C(=O)OCC)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1cncc(C(=O)OCC)c1Cl

Procedure:
Ethyl 5-n-butyl-4-oxo-1,4-dihydropyridine-3-carboxylate (prepared as described by M. Balogh, et al. in J. Heterocyclic Chem., 17, 359-368 (1980)) is refluxed in phosphorous oxychloride to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[OH2:14].[OH-].[K+]>CS(C)=O>[CH3:13][N:11]1[CH:12]=[C:8]([C:7]2[C:2](=[O:14])[NH:3][CH:4]=[CH:5][N:6]=2)[CH:9]=[N:10]1
Reactant: O
Reactant: Cn1cc(-c2nccnc2Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1cc(-c2ncc[nH]c2=O)cn1
Temperature: 80 °C

Procedure:
To 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (200 mg, 1.03 mmol) from Step 1 of this Example in DMSO (1.5 mL) and water (1.5 mL) was added KOH (890 mg, 15.4 mmol) and the mixture was heated at 80° C. for 3 h. The mixture was cooled and partitioned between EtOAc and 4 N HCl. The aqueous layer was concentrated under reduced pressure and then a mixture of MeOH and EtOH was added and the suspension was filtered through Celite. The filtrate was concentrated under reduced pressure and then Et2O was added and the mixture again concentrated under reduced pressure. The residue was triturated with DCM and filtered to afford crude 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one (300 mg, quantitative) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.24-7.39 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17]OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[Na+].[I-:26]>CC(=O)CC>[I:26][CH2:17][C:13]1([CH2:12][C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: [I-]
Reactant: CS(=O)(=O)OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1
Agent: [Na+]
Solvent: CCC(C)=O
Product: FC(F)(F)Oc1ccc(C#CCC2(CI)CCC2)cc1
Temperature: 90 °C
Yield: 87.3 %

Procedure:
To a solution of 0.78 g (2.15 mmol) methanesulfonic acid 1-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-cyclobutylmethyl ester in 30 ml 2-butanone was added 0.65 g (4.30 mmol) NaI. The mixture was heated for 9 h at 90° C. The solvent was evaporated and the residue suspended in dichloromethane, ether was added and the suspension was filtrated. Evaporation of the organic phase gave 0.74 g of the title compound as dark brown oil.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]1[C:21]2([CH2:24][C:23](=O)[CH2:22]2)[CH2:20][O:19]1>C1COCC1>[CH2:18]1[C:21]2([CH2:24][C:23](=[CH:3][C:1]#[N:2])[CH2:22]2)[CH2:20][O:19]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CC2(COC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC2(COC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (82 mg; 0.464 mmol) in THF (2 mL) at 0° C. under nitrogen was added potassium t-butoxide (0.51 mmol; 1M solution in THF) and the mixture was stirred at 0° C. for 1 hour. A solution of 2-oxaspiro[3.3]heptan-6-one (52 mg; 0.464 mmol) in THF (1 mL) was added. A precipitate formed and further THF (1 mL) was added to enhance the stirring. The reaction mixture was allowed to stir for 4 hours at ambient temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride (10 mL) and ethyl acetate (10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The extracts were combined, dried (sodium sulfate), filtered and evaporated under reduced pressure. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:2) to give the product as a colorless oil (20 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:27])=[CH:5][C:6]([Cl:26])=[C:7]([C:9]2[NH:10][C:11](=[O:25])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:26][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:25])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:4]([F:27])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(F)c(C(F)(F)F)c3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(F)c(C(F)(F)F)c3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-81, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.065 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.12 (s, 9H), 4.30 (m, 2H), 7.61-7.69 (m, 3H), 8.16 (br s, 1H), 8.25 (br s, 2H), 12.73 (s, 1H); MS (m/z): 489.47 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[I:13]I>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([I:13])[C:7]=1[OH:8]
Reactant: II
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cc(Cl)c(O)c(I)c1

Procedure:
To a solution of 3-chloro-4-hydroxyphenylacetic acid (1.25 g) in glacial acetic acid (20 mL) was added 2.0 g of iodine crystals while stirring. The mixture was stirred in dark at ambient temperature for 2 days. The resulting mixture was diluted with water, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-chloro-5-iodo-4-hydroxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (2 mL) carefully, stirred at reflux for 20 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with water, extracted with dichloromethane. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-chloro-5-iodo-4-hydroxyphenylacetic acid methyl ester (90 mg, 4%).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.012 g, 14%). MP: 93-104° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.49 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 2H), 6.57 (s, 1H), 6.20-6.10 (m, 1H), 5.90 (tt, 1H, J=56.0 Hz and 3.9 Hz), 3.81 (s, 3H), 3.37 (p, 2H, J=6.7 Hz), 2.90 (dt, 2H, J=15.0 Hz and 4.1 Hz), 2.84-2.73 (m, 4H), 2.72-2.66 (m, 2H), 2.60-2.52 (m, 2H), 1.10 (t, 3H, J=7.3 Hz). MS: 549 (MH)+.
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=S)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[N:28]([CH2:31][C:32](=[O:34])[CH3:33])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[O:34][C:32]([CH3:33])=[CH:31][N:28]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Reactant: CC(=O)CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)o3)nc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 25 %

Procedure:
To a solution of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 45.7 mg, 0.120 mmol) in dioxane (343 μL) was added 1-azidopropan-2-one (14.28 mg, 0.144 mmol) and triphenylphosphine (37.8 mg, 0.144 mmol). The contents of the flask were immersed into a preheated oil bath for 35 min and cooled to room temperature. The residue was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on an Isco 12 g column eluting with 1-10% MeOH/CH2Cl2. The pale yellow solid was taken up in MeOH and further purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(5-methyloxazol-2-ylamino)-1,6-dihydro imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated (10 mg, 25% yield) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>O>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: COc1ccc(N2CCC(N)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(NC(=O)CCc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A mixture of 3-phenyl propionic acid (360 mg, 2.4 mmol), CDI (410 mg, 2.5 mmol) and DMF (20 ml) was stirred at 50° for 1 h. After cooling to 0°, 1-(4-methoxy-phenyl)-piperidin-4-ylamine (500 mg, 2.4 mmol) was added and stirring continued for 1 h. After the addition of H2O (60 ml) the white precipitate was collected to give N-[1-(4-methoxy-phenyl)-piperidin-4-yl]-3-phenyl-propionamide (618 mg, 76%, MS: m/e=339.3 (M+H+)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[N+:19]([C:11]1[CH:10]=[C:9]([CH2:8][O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])([O-:21])=[O:20]
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 10 h
Yield: 101.1 %

Procedure:
0.50 g of potassium carbonate and 0.50 g of methyl 4-(bromomethyl)-2-nitrobenzoate were added to 5 mL of N,N-dimethylformamide solution containing 0.18 g of phenol at room temperature and stirred at the same temperature for 10 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=6:1] to obtain 0.53 g of methyl 2-nitro-4-(phenoxymethyl)benzoate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)(/C=C/B1O[C:40](C)([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:42]=[CH:40]/[C:39]([OH:38])([CH3:45])[CH3:44])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: CC(C)(O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
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: CN(C)C=O
Product: CC(C)(O)/C=C/c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-[(2,6-dichloro-4-iodophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 156, Step 1) (30 mg, 0.06 mmol) in DMF (1.5 mL) were added sodium carbonate (2 M, 0.5 mL), tetrakis(triphenylphosphine)palladium (0) (14.3 mg, 0.12 mmol), and (3E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (13.2 mg, 0.06 mmol). The solution was degassed by bubbling nitrogen gas and heated to 80° C. overnight. After cooling to room temperature, the mixture was extracted with 3:1 CHCl3/iPrOH. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27](O)[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si](C(C)(C)C)(C)C)[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([O:63][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].C(N(S(F)(F)[F:78])CC)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:78])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a stirred solution of 17-Ethyl-1,20-di-hydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in methylene chloride cooled to -78° C. was added diethylaminosulfur trifluoride. After 3 min., saturated sodium bicarbonate solution was added followed by ethyl acetate and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 1:2+1% methanol. To a solution of this material (10 mg) in THF (0.6 ml) in a polypropylene vial was added 40 μL of HF-pyridine solution in THF. After stirring for 28 hours at rt, the mixture was added to a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 2:1+1% methanol) to give the title compound. Mass Spectrum (FAB): 832 (M+Na)