Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[N:9]1([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1ncc[nH]1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1c[nH]c(CN2CCC2)n1
Yield: 61.4 %

Procedure:
To a mixture of 2-imidazolecarboxaldehyde (3.0 g) and azetidine hydrochloride (3.21 g) in anhydrous tetrahydrofuran (180 ml) was added sodium triacetoxyborohydride (9.99 g) followed by glacial acetic acid (1.72 ml). The resultant mixture was stirred at room temperature for 22 h, after which the insoluble material was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified using silica SPE (eluting with DCM, methanol, methanol:20% aqueous ammonia) to give the title compound (2.63 g) as a beige solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CN1CCN(C(=O)c2cncc(Cl)n2)CC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CN1CCN(C(=O)c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 90 °C

Procedure:
A stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (70 mg, 0.287 mmol, 1 eq) and (6-chloropyrazin-2-yl)(4-methylpiperazin-1-yl)methanone (60) (69 mg, 0.287 mmol, 1.0 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (140 mg, 0.430 mmol, 1.5 eq) followed by addition of Pd(dpp)Cl2 (13.2 mg, 0.0114 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1-2% MeOH/CHCl3 to obtain pale yellow solid compound (6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)(4-methylpiperazin-1-yl)methanone 139 in 20 mg quantity. The compound 139 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.98 (s, 1H), 9.45 (s, 1H), 9.04 (d, J=1.95, 1H), 8.76 (m, J=12.43, 2H), 7.63 (m, J=2.68, 1H), 6.64 (m, J=1.58, 1H), 3.76 (s, 2H), 3.59 (m, J=69.03, 2H), 2.42 (m, 4H), 2.28 (s, 3H); MS m/z 321.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N(OCCC(C)C)=O.[I:20]CI>>[I:20][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: ICI
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: CC(C)CCON=O
Product: Cc1cc(I)ncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 4-methyl-5-nitro-2-pyridinamine (12 g, 78.35 mmol) in diiodomethane (100 mL) was added isoamyl nitrite (22 mL, 160.4 mmol) at rt. After stirring for 30 min, the reaction was kept at 80° C. for 2 hr. The reaction was cooled and concentrated; but most of the diiodomethane remained. The crude mixture was loaded into column directly and eluted with 10% of EtOAc in hexane, and 2-iodo-4-methyl-5-nitropyridine (5.7 g, 28%) was obtained as a yellow solid after the removal of solvents under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:21]1[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]1[O:23]C(=O)C.[NH3:39]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][O:11][C:9]2[N:10]=[C:2]([NH2:39])[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=2)[C@@H:21]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]2[OH:23])=[CH:15][CH:16]=1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 100 °C
Yield: 99 %

Procedure:
A reactor was charged with 6-chloro-2-[2-(4-chlorophenyl)ethoxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (243.8 g, 0.43 mol, Example 2, Step D) in ethanol (3,660 mL). The reactor was chilled to below −33° C., and ammonia (1500 g) is charged into the reactor. The reactor was sealed, then heated to 100° C. and the reaction was monitored by HPLC. Upon completion (approximately 5 hours), the reactor was cooled, vented, and the contents concentrated under reduced pressure. The crude product is purified by column chromatography eluting with dichloromethane/methanol. The pure fractions were concentrated under reduced pressure to about four liters of solvent and the product collected by vacuum filtration. The off-white solid was washed with dichloromethane and dried in vacuo to yield 82 grams of analytically pure (>99%) product as an off-white solid. Additional fractions were combined to provide an additional 73 g of product of lower purity (90-98%). Combined typical yield: 54%.
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25](=[O:31])[CH2:24][CH2:23]1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH3:4])=[O:29])=[CH:26][C:25](=[O:31])[CH2:24][CH2:23]1
Reactant: COc1ccccc1C1CCC(=O)C=C1C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1=CC(=O)CCC1c1ccccc1OC
Temperature: 10 °C
Yield: 94.9 %

Procedure:
235 g (1.66 mol) of methyl iodide and 212 g (1.39 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, dropwise, were successively added to a solution of 288 g (1.17 mol) of (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylic acid in 2.5 dm3 of acetone and then the mixture was brought to reflux for one hour. The acetone was subsequently concentrated and then the residue was stirred with 1 dm3 of water. After cooling to 10° C., the precipitate formed was filtered off, washed with petroleum ether and then dried at 50° C. 289 g (95%) of methyl (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylate were thus obtained in the form of a mustard-coloured powder, the characteristics of which were as follows:
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:24]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=2[O:22][CH3:21])(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: NC1(c2ccccc2)C(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 0.33 h

Procedure:
A solution of 0.3 g of 3-amino-5-chloro-1,3-dihydro-3-phenylindol-2-one in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.037 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 20 minutes, 0.275 g of 2,4-dimethoxybenzenesulfonyl chloride is added and the reaction mixture is stirred overnight, the temperature being allowed to rise to RT. It is poured into water, extracted with AcOEt, washed with water and with a saturated solution of NaCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether/hexane mixture. m=0.31 g. M.p.=108°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[NH:21][CH2:20][CH2:19][C:12]3(C(=O)CCC3=O)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-:25].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:25])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCC(=O)C12CCNC(Cc1ccc(F)c(F)c1)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCNC(Cc2ccc(F)c(F)c2)C1
Temperature: 75 °C

Procedure:
A mixture of intermediate 12 (0.032 mol) in HCl, (6N; 90 ml) was stirred at 75° C., then cooled. CH2Cl2 was added and the mixture was alkalized with NaOH at a temperature below 20° C. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dried, yielding 7.2 g of 2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 13). In a similar way as described in procedure d) were prepared:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:63]([NH2:67])[CH:64]([CH3:66])[CH3:65]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:67][CH2:63][CH:64]([CH3:66])[CH3:65])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and isobutylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (19 mg, 43%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)C>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[C:2]([Cl:1])[CH:9]=1
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 18 ml of nitroethane and 15 g of ammonium acetate in 150 ml of absolute ethanol is refluxed for 2 hours. The mixture is then poured into 1.5 l of water, whereupon the compound separates as a viscous red oil, which crystallizes on scratching. Recrystallization from ethanol yields 18.0 g of the compound, melting at 93°-94°.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].C1N2CN3CN(C2)C[N:17]1C3.C(O)C.Cl>CN(C)C=O>[ClH:1].[NH2:17][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4]
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC(=O)c1ccc2c(c1)CCC(=O)N2
Reaction time: 2 h
Yield: 37.2 %

Procedure:
In to a suspension of 3.0 g of 6-chloroacetyl-3,4-dihydrocarbostyril being suspended in 20 ml of dimethylformamide was added dropwise gradually a solution consisting of 1.9 g of hexamine and 20 ml of dimethylformamide. After the addition was completed the reaction mixture was stirred at 50° to 60° C. for 2 hours. Then the crystals precipitated in the reaction mixture were collected by filtration, and were washed with methanol, dried to obtain 3.5 g of crude crystals of 6-hexaminiumacetyl-3,4-dihydrocarbostyril chloride. Then, 15 ml of ethanol and 6 ml of concentrated hydrochloric acid were added to the 3.5 g of the crude crystals of 6-hexaminiumacetyl-3,4-dihydrocarbostyril chloride and the mixture was stirred at a room temperature for 12 hours. The crystals thus formed were collected by filtration, and recrystallized from methanol-water to obtain 1.2 g of 6-aminoacetyl-3,4-dihydrocarbostyril monohydrochloride in the form of colorless powdery crystals. Melting point: Higher than 300° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([NH2:20])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 8.01 mmol) in Methanol (35 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (10.85 g, 48.1 mmol) and HCl (2.19 mL, 72.1 mmol). The reaction mixture was left to stir at 80° C. for 1 h. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. The brown residue in the round bottomed flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown solid. The water layer was extracted with EtOAc, washed with 1N NaOH, brine, dried (MgSO4) and evaporated to a brown solid. The solids found to be identical by 1 cms and were combined to yield a brown solid 4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-amine (2.33 g, 6.64 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 5.45 (s, 2H) 6.47 (d, J=1.52 Hz, 1H) 6.56 (d, J=7.58 Hz, 1H) 6.86 (d, J=1.52 Hz, 1H) 7.14 (s, 1H) 7.39 (d, J=7.83 Hz, 1H) 8.11 (s, 1H); LC/MS: MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19]>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=C1CCN(C(C)(C)C)CC1
Yield: 84 %

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (1.0 g, 6.5 mmol) in DCM (20 mL) was added MgSO4 (1.5 g, 13 mmol) and tert-butyl hydrazinecarboxylate (0.7 g, 5.3 mmol). The reaction mixture was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:20) to give tert-butyl 2-(1-tert-butylpiperidin-4-ylidene)hydrazinecarboxylate (1.2 g, 84% yield) as a colorless oil. LCMS (ESI) m/z: 270.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1F
Yield: 94.4 %

Procedure:
A mixture of 2,4-difluoro-5-methoxycarbonyloxy-1-nitrobenzene (2.7 g, 0.012 mol) and 10% palladium-on-charcoal catalyst (500 mg) in ethanol (20 ml) and ethyl acetate (10 ml) was stirred under 1 atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation to give 2,4-difluoro-5-methoxycarbonyloxyaniline (2.3 g, 97%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OCC=Cc4ccccc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-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 (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11](Cl)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:19][N:18]=[C:17]2[S:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:11]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:10][CH2:9]3)=[O:12])=[CH:25][CH:26]=2)[CH2:19][N:18]=[C:17]2[S:28][CH:29]=[CH:30][C:16]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2cccc(Cl)c2)CC1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3cccc(Cl)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 469, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine of choice. MS(ES) m/e 421 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)(=O)C>[CH2:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][N:16]1[CH:17]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[C:15]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:29]
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)CCn1cc(-c2ccccc2)cc1C(=O)OCC
Yield: 69 %

Procedure:
Potassium tert-butoxide (100 mg, 0.90 mmol), ethyl 4-phenyl-1H-pyrrole-2-carboxylate (1.0 g, 4.65 mmol) and ethyl acrylate (50 mL) were heated at reflux for 90 min. The reaction mixture was allowed to cool to room temperature and neutralized with acetic acid (1 mL). Excess ethyl acrylate was evaporated in vacuo, the residue diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina using 5% ethyl acetate in petroleum ether as eluent gave ethyl 1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate (1.0 g, 69%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:26]([CH:28]1[CH2:31][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44](Br)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:29]1)#[N:27]>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.[Cu]I>[C:26]([CH:28]1[CH2:29][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([C:4]4[C:5]5[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][C:10]=5[N:2]([CH3:1])[N:3]=4)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:31]1)#[N:27]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCC(C)(C)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 1,6,6-trimethyl-3-tributylstannyl-4,5,6,7-tetrahydro-1H-indazole (110 mg, 0.24 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (95 mg, 0.19 mmol) in DMF (2 mL) were added Pd(PPh3)4 (11 mg, 0.01 mmol) and copper(I) iodide (7 mg, 0.037 mmol). The reaction mixture was heated at 90° C. for 2 h then cooled to room temperature and stirred overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The crude brown oil was purified by silica gel chromatography with 0% to 3% MeOH/CH2Cl2 to afford 43 mg (38%) of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a pale orange foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:19]([O:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CCOC(=O)c1ccccc1)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Using a procedure analogous to that described in Example 3, 5.85 gm (67% of theory) of the ester of the formula ##EQU28## having a boiling point of 181°-185°C at 0.05 mm Hg were obtained by refluxing a mixture consisting of 6.11 gm (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-1-butanol, 6.20 gm (0.051 mol) of benzoic acid, 0.5 gm of p-toluene-sulfonic acid and 40 ml of toluene until no more water separated out.