Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C([CH2:18][C:19]([O-])=[O:20])=C.C(OCC)(=O)C.CO>CN(C=O)C>[C:19]([O:15][CH2:14][C@H:9]1[O:8][CH:6]([OH:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:11]([OH:12])[C@@H:10]1[OH:13])(=[O:20])[CH3:18]
Reactant: C=CCC(=O)[O-]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1C(O)O[C@H](COC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
In 2 mL of DMF were suspended 500 mg (2.2 mmol) of N-acetylmannosamine. Vinylacetate (1 mL, 5 equivalent) and 160 mg of subtilisin mutant 8399 [Zhong et al., J. Am. Chem. Soc., 113:683 (1991)] were then added and the suspension was stirred vigorously at room temperature. The reaction progress was monitored by TLC with ethyl acetate/methanol (2/1). After 5 hours when the formation of the di-acetylated derivatives began, the reaction was stopped by evaporating the vinylacetate and DMF. Methanol was then added to dissolve the sugar. After the enzyme and salt were filtered off, the filtrate was concentrated. The residual syrup was chromatographed on a silica gel, with ethyl acetate/methanol (10/1) to give 6-O-Acetyl N-acetylmannosamine (92 percent) as α/β mixture (3:1) based on the NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:22])[N:8]2[CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([N:23]3[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]3)=[O:22])[N:8]2[CH2:11][CH2:12][OH:13])=[CH:4][C:3]=1[O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCO[Si](C)(C)C(C)(C)C)c3cc2Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CCO)c3cc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A mixture of [6-bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (130 mg, 1.0 eq.) and trifluoroacetic acid in dichloromethane was stirred for 1 h at room temperature and concentrated in vacuo. The crude mixture was partitioned between an aqueous solution of sodium hydroxide and dichloromethane. The aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo, to yield 106 mg (99%) of the desired product as white foam. MS (m/e): 542.1 (M+H, 100%).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)#N.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.C1C=CC2N(O)N=[N:38][C:36]=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[C:36]([CH:15]1[CH2:14][O:13][CH:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[CH:11][CH:10]=3)[C:6]([C:18]3[CH:19]=[C:20]([C:21]([NH:31][CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[N:7]2)[CH2:17][CH2:16]1)#[N:38]
Reactant: NC1CCC1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(C(=O)O)c1)nn2C1CCCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1CCC(n2nc(-c3cccc(C(=O)NC4CCC4)c3)c3ccccc32)OC1
Yield: 90.1 %

Procedure:
The title compound was prepared in a similar fashion to that of Example 367 A using the following amounts of reagents: 3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)benzoic acid (800 mg, 2.29 mmol), cyclobutyl amine (738 μL, 8.64 mmol), HOBT (1.17 g, 8.70 mmol), EDAC.HCl (1.67 g, 8.70 mmol) in anhydrous THF (25.0 mL) and anhydrous DMF (7.0 mL). Precipitation from methanol and ethyl acetate with hexanes afforded the desired compound (826 mg, 72% yield) as an off-white powder. ES-MS (m/z) 401 [M+H]+.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[OH:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[O:8]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2-:1][C:2]([CH3:4])=[O:3].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:5][CH2:6][C@@H:7]1[C@H:11]([OH:12])[C@H:10]([OH:13])[C@H:9]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[O:8]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCOC4)ncnc32)[C@@H](O)[C@H]1O
Reactant: Oc1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [CH2-]C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O[C@@H]1[C@H](O)[C@H](n2cnc3c(NC4CCOC4)ncnc32)O[C@@H]1COc1ccccc1F
Temperature: 25 °C

Procedure:
To a solution of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide (500 mg, 1.33 mmol), 2-fluorophenol (179.4 mg, 1.6 mmol), and triphenylphospine (418.3 mg, 1.6 mmol) in anhydrous tetrahydrofuran (20 mL), DIAD (diisopropylazodicarboxylate, 320 μL, 1.6 mmol) was added and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was purified by column chromatography (eluting with ethyl acetate: hexane 50:50) to give (4S,2R,3R,5R)-2-(2-fluorophenoxy)methyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol acetonide as a pure white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[C:3]=1[F:19].[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=3)=[C:4]([F:18])[C:3]=2[F:19])=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2F)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 12 h
Yield: 33.1 %

Procedure:
To a suspension of 4-(4-amino-2,3-difluorophenoxy)picolinamide (180 mg, 0.68 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (161 mg, 0.69 mmol) in DCM (4 mL) was added EDCI (157 mg, 0.82 mmol) and HOAT (19 mg, 0.14 mmol). The mixture was stirred at 45° C. for 12 hours, then more 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (87 mg, 0.37 mmol) was added and the reaction was continued to stir at 45° C. for 5 hours. The mixture was cooled to rt, quenched with 5 mL of water, and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL×3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc 100%) to give the title compound as an orange solid (108 mg, 33.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(=O)O
Reactant: COc1cccc(/C=C/C(C)=O)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(/C=C/C(=O)/C=C/C(=O)O)c1

Procedure:
A solution of 14.7 g (83.4 mmol) of (E)-4-(3-methoxyphenyl)but-3-en-2-one and 7.67 g (83.4 mmol) of glyoxylic acid monohydrate in 21.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/ethyl acetate yielded (E,E)-6-(3-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 158°-160°.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.F[C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C(O)C.[OH-].[Na+]>Cl.C(O)(=O)C.O>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(NCCC[C@H](N)C(=O)O)c1
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 474 mg (2 mmol) of Noc-BOC-L-ornithine (supplier BAChem) and 314 mg (2 mmol) of 3-fluoro-4-nitrotoluene (Aldrich Chemical Co.)in 2 mL of ethanol and 2 mL of 1N NaOH was heated at reflux for 12 hours. Another 2 mmol each of NaOH and 3-fluoro-4-nitrotoluene was added and the reaction was continued another two hours. The solution was poured into 50 mL of water and extracted with dichloromethane (2×80 mL). The organic phase was dried and concentrated to give a solid residue, which was stirred in 20 mL of 4N HCl in 33% acetic acid for four hours, filtered and concentrated to leave a yellow solid, which was recrystallized from ethanol/water to afford 296 mg (56% yield) of the title product as an amorphous orange powder. mp 263°-264° (decomp.); MS M/Z 268 [M+H], 285 [M+NH4 ]; 1H NMR (300 MHz, D2O/NaOD) δ: 1.64 (m, 4H)2.18 (s, 3H), 3.12 (m, 2H), 3.30 (t, J=4.5 Hz, 1H), 6.22 (d, J=8.1 Hz, 1H), 6.43 (s, 1H), 7.58 (d, J=8.1 Hz, 1H); 13C NMR (75.5 MHz, D2O/NaOD) δ: 185.88, 158.28, 148.71, 130.81,128.71,120.22, 116.11, 58.73, 45.24, 35.40, 27.73, 24.24; Analysis calc'd for C12H17N3O4.0.4 HCl: C, 50.81; H, 6.25; N, 14.81; found: C, 50.79; H, 6.27; N, 14.73.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])C.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[C:26]3[C:27]=2[C:22](=[CH:23][CH:24]=[CH:25]3)[C:21]1=[O:34]>>[O:34]=[C:21]1[C:22]2[C:27]3[C:26](=[CH:33][CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:20]1[CH2:19][CH2:18][CH2:17][NH:12][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:3])=[O:15])(=[O:13])=[O:14])[CH:25]=[CH:24][CH:23]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCBr
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Product: O=C(O)c1ccccc1S(=O)(=O)NCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
The compound was prepared according to GP-2 using 2-sulfamoylbenzoic acid ethyl ester 4 and compound 3a. The crude product was purified by flash column chromatography using MeOH—CHCl3 to obtain 5a. 1H NMR (500 MHz, DMSO-d6) δ 9.43 (bs, 2H), 8.49-8.46 (m, 4H), 7.87 (t, J=8.0 Hz, 2H), 7.68 (d, J=7.5 Hz 1H), 7.64 (d, J=8.0 Hz 1H), 7.49 (t, J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 4.02 (t, J=7.5, 2H), 2.76 (q, J=7.0 Hz, 2H), 1.90-1.60 (m, 2H). MS (ES−) m/z 437 (M−H)−.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)[N:5]=1)[CH3:3].C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32]([NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][N:6]2[C:7]([CH2:9][CH3:10])=[CH:8][C:4]([CH2:2][CH3:3])=[N:5]2)[CH2:17][CH2:16]1)=[O:33]
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(CC)n(C[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-4-(3,5-diethyl-pyrazol-1-ylmethyl)-cyclohexylamine hydrochloride (Intermediate B) (65 mg, 0.238 mmol) was placed in a flask with DCM (5 ml) and triethylamine (72 mg, 0.714 mmol). 5-Chloro-2-methylnicotinoyl chloride (Intermediate C) (54 mg, 0.238 mmol) was added portionwise. After addition of the acid chloride, the reaction mixture was stirred at RT for 1 hour and partitioned between DCM and sat. NaHCO3. The organic phase was passed through a phase separator and the solvent was removed in vacuo. The crude product was triturated in EtOAc:iso-hexane—1:1, filtered and dried to afford the title compound; 1H NMR (d6-DMSO, 400 MHz) δ 8.52 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 5.82 (1H, s), 3.76 (2H, d), 3.67 (1H, m), 2.57 (2H, q), 2.47 (5H, m), 1.89 (2H, m), 1.72 (1H, m), 1.57 (2H, m), 1.23 (10H, m); LC-MS Rt 2.35 mins, [M+H]+ 389; Method LowpH_v002.
Reaction SMILES: Cl.[C:2]([C:5]1CNCCC=1)(=[O:4])[NH2:3].Cl[C:12]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]2[C:13]=1[N:14]([CH2:34][C:35]([NH2:37])=[O:36])[C:15](=[O:33])[N:16]2[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:23]=1[S:31][CH3:32].C([N:41]([CH:44]([CH3:46])C)[CH2:42][CH3:43])(C)C>C(O)C.O>[C:2]([C:5]1[CH2:46][CH2:44][N:41]([C:12]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]3[C:13]=2[N:14]([CH2:34][C:35]([NH2:37])=[O:36])[C:15](=[O:33])[N:16]3[C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:23]=2[S:31][CH3:32])[CH2:42][CH:43]=1)(=[O:4])[NH2:3]
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(Cl)nc(C)nc21
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)C1=CCCNC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(N3CC=C(C(N)=O)CC3)nc(C)nc21
Yield: 45.1 %

Procedure:
In 4 ml of ethanol, 0.16 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine hydrochloride, 0.40 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide, and 0.38 g of diisopropylethylamine were dissolved. Several drops of water were added thereto, and the reaction mixture was heated under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=7:1), followed by crystallization from ethyl acetate to yield 0.22 g of 2-[6-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide.
Reaction SMILES: [Cl:1]C1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=NC=1.Br[C:13]1[C:14]2[N:15]([C:19]([Cl:22])=[CH:20][N:21]=2)[CH:16]=[CH:17][N:18]=1.N1CCNCC1>C(#N)C>[ClH:1].[Cl:22][C:19]1[N:15]2[CH:16]=[CH:17][N:18]=[C:13]([N:6]3[CH2:7][CH2:8][NH:9][CH2:10][CH2:5]3)[C:14]2=[N:21][CH:20]=1
Reactant: Clc1nccn2c(Cl)cnc12
Reactant: Clc1cnc2c(Br)nccn12
Agent: C1CNCCN1
Solvent: CC#N
Product: Cl
Product: Clc1cnc2c(N3CCNCC3)nccn12

Procedure:
To a solution of the mixture of 3,8-dichloroimidazo[1,2-a]pyrazine and 8-bromo-3-chloroimidazo[1,2-a]pyrazine obtained above in 25 ml of acetonitrile is added an excess amount of piperazine (5 g). After refluxing and isolation in essentially the same manner as Example 1, Step B, 3-chloro-8-(1-piperazinyl)-imidazo[1,2-a]pyrazine hydrochloride salt is obtained with m.p. >300° C. dec.
Reaction SMILES: Cl.[F:2][CH:3]([F:25])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49](Cl)=[O:50])[CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:25][CH:3]([F:2])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:49]([N:43]4[CH2:44][CH2:45][C:46](=[O:48])[CH2:47][CH:42]4[C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=4)=[O:50])[CH2:18][C:17]=3[CH:23]=2)=[CH:11][CH:12]=1
Reactant: O=C(NCC(F)F)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc(C(=O)NCC(F)F)cc4)cc3C2)C(c2cccc(F)c2)C1
Temperature: 50 °C
Yield: 13.2 %

Procedure:
To a slurry of N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride (0.19 g, 0.51 mmol), DIPEA (0.45 mL, 2.6 mL) and tetrahydrofuran (3 mL) was added 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.13 g, 0.51 mmol). The reaction mixture was heated (50° C.) for 3 h and then concentrated. Purification by preparative reverse phase HPLC provided N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide (37 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 7.82 (d, 2H), 7.55 (d, 2H), 7.47 (dd, 1H), 7.20-7.34 (m, 3H), 7.13 (d, 1H), 6.93-7.06 (m, 3H), 6.43 (t, 1H), 5.99 (tt, 1H), 5.34-5.40 (m, 1H), 4.54 (s, 2H), 4.20-4.30 (m, 2H), 3.73-3.93 (m, 5H), 3.20-3.30 (m, 1H), 2.84-3.06 (m, 2H), 2.54-2.64 (m, 1H), 2.32 (d, 1H); MS (EI) for C30H28F3N3O4: 552 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: CC(/C=C/CO)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of (E)-4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane: ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[C:32]([CH3:34])[C:5]([O:6][C:7]2[C:8]3[NH:31][CH:30]=[CH:29][C:9]=3[N:10]=[C:11]([N:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=2)=[C:4]([CH3:35])[CH:3]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:35])[C:5]([O:6][C:7]2[C:8]3[N:31]([CH3:37])[CH:30]=[CH:29][C:9]=3[N:10]=[C:11]([N:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=2)=[C:32]([CH3:34])[CH:33]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a cold mixture of tert-butyl 4-(4-bromo-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (0.81 g, 1.5 mmol) in THF (5 ml) at −78° C. was added a solution of LiHMDS (1M, 2 ml, 2 mmol). The mixture was warmed to 0° C. over 2 hours and then was cooled to −78° C. Idomethane (0.37 ml, 6 mmol) was added and the mixture was warmed to room temperature over 2 hours and then stirred at this temperature for an additional 2 hours. The mixture was washed with brine, extracted with ethyl acetate (×3). The organic layers were combined dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography on silica to obtain the title compound (0.782 g, 1.42 mmol, 95%). 1H NMR (CDCl3, 400 MHz) δ 1.32 (s, 9H), 2.07 (s, 6H), 4.18 (s, 3H), 6.65 (d, J=3.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.21 (s, 2H), 7.37 (d, J=3.8 Hz, 1H), 7.49 (d, J=8.8, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[C:11]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[C:12]2[CH:18]=[N:17][N:16](CC3C=CC(OC)=CC=3)[C:13]2=[N:14][CH:15]=1)#[N:9].C(Cl)[Cl:42]>>[ClH:42].[ClH:42].[N:28]1([C:11]2[C:10]([C:8]#[N:9])=[CH:15][N:14]=[C:13]3[NH:16][N:17]=[CH:18][C:12]=23)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#Cc1cnc2[nH]ncc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
TFA (1 mL) was added to tert-butyl 4-(5-cyano-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.158 g, 0.352 mmol) in DCM (5 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness and dried under vacuum for 3 hours. TFA (1.1 mL, 14.7 mmol) was added, and the mixture was heated at 65° C. for 2 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in DCM (3 mL), and HCl in ether (2 mL, 2M) and ether (5 mL) were added. The resulting solid was collected by filtration to give 4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.091 g, 70%). MS APCI (+) m/z 229.1 detected.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C(N(CC)CC)C.C1COCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CO>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][NH:20][C:18](=[O:19])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1)NOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
Under nitrogen a microwave vial is charged with (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (5.00 mmol), Trimethylsilylacetylene (6.00 mmol), CuI (0.50 mmol), bis(triphenylphosphine)palladium(II)chloride (0.25 mmol), triethylamine (10.0 mmol) and THF (8 ml). The reaction mixture is heated in a Personal Chemistry Microwave oven at 100° C. for 3600 seconds. Methanol is added to the reaction mixture and the solution is filtered over alumina (10 g, neutral, activity II-III) using MeOH as eluent. After evaporation of the solvent the crude product is purified by prep. HPLC yielding the title compound as yellow powder (2.29 mmol). Deprotection