Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1O[C:14]([CH2:16][CH2:17][CH2:18][CH2:19]Br)([CH3:15])[O:13]C1.[BH4-].[Na+]>C(#N)C>[CH2:19]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:18][CH2:17][CH2:16][C:14](=[O:13])[CH3:15]
Reactant: c1cnc2ccncc2c1
Reactant: CC1(CCCCBr)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)CCCCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (13.0 g, 0.1 mol) and 6-bromohexan-2-one ethylene ketal (26.8 g, 0.12 mol) in acetonitrile (100 ml) was refluxed for 10 hours. The reaction mixture was evaporated in vacuo, dissolved in methanol (600 ml) and water (200 ml). To the mixture, sodium borohydride (19.5 g, 0.5 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with ethyl acetate. The organic layer was dried over anhydrous potassium carbonate, evaporated in vacuo. The resulting residue was dissolved in 1 N-HCl and stirred overnight, neutralized with 33% NaOH solution and extracted with chloroform. The organic layer was dried over anhydrous potassium carbonate, evaporated in vacuo. The residue was purified by alumina column chromatography (eluted with chloroform-methanol (10:1)) and distilled, bp. 157°-158° C./0.6 mmHg, to afford the Compound No. 29 (9.3 g, 40.1%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]2=[O:16])=[C:12]([F:17])[CH:11]=[CH:10][CH:9]=3)[C:5]2[CH:18]=[CH:19][N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:4]=2[N:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([N:40]([CH3:47])[C:41](=[O:46])[CH2:42][N:43]([CH3:45])[CH3:44])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>O1CCCC1>[F:17][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14](=[O:16])[N:15]1[C:2]([NH:31][C:32]3[CH:33]=[C:34]([N:40]([CH3:47])[C:41](=[O:46])[CH2:42][N:43]([CH3:45])[CH3:44])[CH:35]=[CH:36][C:37]=3[O:38][CH3:39])=[N:3][C:4]3[N:20]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:19]=[CH:18][C:5]=3[C:6]1=[N:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1ccc(N(C)C(=O)CN(C)C)cc1N
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)CN(C)C)cc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Temperature: 65 °C
Yield: 95 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (2.00 g, 4.17 mmol) and N1-[3-amino-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (1.040 g, 4.38 mmol) in tetrahydrofuran (75 ml) was maintained at 65° C. for 16 hours in a sealed pressure tube. The reaction was cooled, taken to a residue under reduced pressure, and partitioned between dichloromethane/saturated sodium bicarbonate with 2,2,2-trifluoroethanol added until all solids had dissolved. The organic layer was separated, taken to a residue under reduced pressure, and triturated with diethyl ether to afford analytically pure N1-[3-({8-fluoro-3-[(4-methylphenyl)sulfonyl]-7-oxo-3,7-dihydropyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-5-yl}amino)-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (2.55 g, 3.96 mmol, 95% yield) as a pale yellow solid. ESIMS (M+H)+=644.
Reaction SMILES: [Cl-].C[NH3+].CN.[C:6]([BH3-])#[N:7].[Na+].[CH:10]([C:13]1[C:18]([CH:19]=O)=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:15]([CH:33]([CH3:35])[CH3:34])[N:14]=1)([CH3:12])[CH3:11]>CO>[CH:10]([C:13]1[C:18]([CH2:19][NH:7][CH3:6])=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:15]([CH:33]([CH3:34])[CH3:35])[N:14]=1)([CH3:11])[CH3:12]
Reactant: [BH3-]C#N
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: CN
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CO
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CNC)c1-c1ccc(F)cc1
Yield: 33.7 %

Procedure:
Methylammonium chloride (37.99 mg, 0.563 mmol) was added to a stirred solution of methylamine in methanol (2M, 0.28 mL) under argon in an oven-dried round bottom flask equipped with a stir bar. Then sodium cyanoborohydride (4 eq., 10.60 mg, 0.169 mmol) was added and 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) (100 mg, 0.281 mmol) was added as a solution in methanol (2 mL). The reaction was refluxed for 18 hours and then quenched with water. Concentration and addition of CH2Cl2 (25 mL) allowed washings with water (2×15 mL), brine (1×25 mL), following which the solution was dried with MgSO4, filtered, and concentrated to afford a clear oil. Flash chromatography using silica gel (40% ether/CH2Cl2) yielded the title compound as a white solid (21 mg, 0.057 mmol, 20%). 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 3.26 (m, 4 H), 2.24 (m, 5 H), 1.20 (m, 19 H), 0.783 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C24H35FN2) 370, found 371 (M+H). mp 77-79° C. Rf=0.2 (20% ether/CH2Cl2).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C1C=CC=CC=1>[S:19]1[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:18]1
Reactant: C1CSCCN1
Reactant: COC(=O)CCCI
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCSCC1

Procedure:
A mixture of 64.0 g. (0.28 mole) of methyl γ-iodobutyrate, 28.0 g. (0.28 mole) of triethylamine, 28.7 g. (0.28 mole) of thiomorpholine (J. Am. Chem. Soc. 76, 1187 (1954)) and 1 liter of benzene was stirred and heated at 60°-70°C. for 18 hours. After cooling the reaction mixture, the precipitated amine hydroiodide was removed by suction filtration. The benzene solution was evaporated to give a orange-red residue which was vacuum distilled (b.p. 84°-85°C. at 0.1 mm) to give 28.38 g. (50%) of the product as a colorless liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C:42](O)=[O:43])=[O:36])[N:30]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CC[N:54]([CH:58]([CH3:60])[CH3:59])C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C:42](=[O:43])[NH:54][CH:58]3[CH2:60][CH2:59]3)=[O:36])[N:30]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 300 mg 4-[(S)-4-tert-butoxycarbonyl-2-({5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 5 ml DMF were added 66 μl DIPEA and 160 mg HATU. After 20 minutes 29 μl cyclopropylamine were added. After stirring for 12 h saturated NaHCO3 solution was added and the mixture loaded on a Chem Elut® cartridge, the crude product being eluted with dichloromethane. The solution was concentrated to a volume of 5 ml and stirred in the presence of 476 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])([OH:5])=[O:3]
Reactant: CCOC(=O)COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1C(OCC(=O)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of 6-ethoxycarbonylmethoxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]-octane (17 mg) and 1N aqueous sodium hydroxide solution (0.09 ml) in ethanol (0.2 ml) was stirred for one hour at ambient temperature. The solution was neutralized with 1N hydrochloric acid and the separated oil was extracted with diethyl ether. The solvent was dried and concentrated in vacuo to yield 6-carboxymethoxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro-[2,5]octane (14.4 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[C:47]([O:49][C:50]2[CH:69]=[CH:68][C:53]3[N:54]([CH3:67])[C:55]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([CH:64]([CH3:66])[CH3:65])[CH:59]=4)=[N:56][C:52]=3[CH:51]=2)[CH:46]=[CH:45][N:44]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:64]([C:60]1[CH:59]=[C:58]([NH:57][C:55]2[N:54]([CH3:67])[C:53]3[CH:68]=[CH:69][C:50]([O:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]5)=[O:17])[CH:48]=4)=[CH:51][C:52]=3[N:56]=2)[CH:63]=[CH:62][CH:61]=1)([CH3:66])[CH3:65]
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(N)c4)ccc3n2C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(NC(=O)CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3n2C)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (1 eq) in N,N-dimethyl formamide and N,N,disopropylethylamine (4 eq) was added HATU (2 eq) and the mixture was stirred at ambient temperature until it becomes homogeneous. To it was added 5-(2-aminopyridin-4-yloxy)-N-(3-isopropylphenyl)-1-methyl-1H-benzo[d]-imidazol-2-amine (1 eq) and 4-(dimethylamino)pyridine (0.05 eq) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting tert-butyl 4-((4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-1-carboxylate was purified by HPLC. HPLC=4.63 min; MS: MH+=599.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([OH:23])(=[S:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([S:22][CH:14]([CH2:13][C:11](=[S:12])[C:10]1[CH:18]=[CH:19][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:15]([OH:17])=[O:16])(=[O:23])[CH3:21]
Reactant: O=C(O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Reactant: CC(O)=S
Solvent: ClC(Cl)Cl
Product: CC(=O)SC(CC(=S)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.84 g of 3-(4-phenylthiobenzoyl)acrylic acid in 30 ml of chloroform was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred for 5 hours at room temperature. The chloroform was removed from the mixture by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) and then recrystallized from a mixture of hexane and ethyl acetate to give 3.24 g of 2-acetylthio-3-(4-phenylthiobenzoyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:4]1[CH:3]=[C:2]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:16])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Reactant: CC1(C)OB(C=Cc2ccccc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 4-bromo-2-methylbenzoate (2 g, 7 mmol) in dioxane/water (50 mL, 4:1) was added styrylboronic acid pinacol ester (1.64 g, 7 mmol), tetrakis(triphenylphosphine)palladium (0.7 mmol, 0.904 g), sodium carbonate (21 mmol, 2.3 g). The mixture was stirred at 90° C. under nitrogen gas atmosphere for 18 hours. LC-MS showed the start material has been consumed. Then evaporated the solvent and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 2-methyl-4-(1-phenylvinyl)benzoate (1.8 g, 91%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][N:25]=1.Cl>CC#N>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][N:25]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: O=[N+]([O-])c1nnc(Br)s1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask were placed a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (800 mg, 2.73 mmol, 1.00 equiv, 90%) in CH3CN (30 mL), KHCO3 (1.5 g, 15.00 mmol, 5.00 equiv) and 2-bromo-5-nitro-1,3,4-thiadiazole (890 mg, 3.80 mmol, 1.40 equiv, 90%). The resulting mixture was stirred overnight at room temperature. The pH value of the solution was adjusted to 4 with HCl (2 mol/L), then extracted with 4×50 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 0.4 g (22%) of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate as a brown oil.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:27]([F:28])=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)c(F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)c(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 99.8 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.740 mmol), 3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 270 mg of the product 195. 1H NMR (CDCl3) δ 8.60 (s, 1H), 7.40-7.10 (m, 3H), 5.15-4.90 (m, 2H), 4.30-4.10 (m, 2H), 2.70-2.55 (m, 1H), 2.20-2.05 (m, 1H), 1.85-1.10 (m, 15H); MS: m/z 366 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.[ClH:19].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][CH:44]1[CH2:51][CH:50]2[N:52]([CH3:53])[CH:46]([CH2:47][CH2:48][CH2:49]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[ClH:19].[CH3:53][N:52]1[CH:46]2[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:51][CH:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[S:5][CH:4]=[N:3][C:2]=4[CH3:1])=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: Cc1ncsc1-c1nc2c(C(=O)O)cccc2o1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncsc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A mixture of 2-(4-methylthiazol-5-yl)benzoxazole-4-carboxylic acid (60 mg, 0.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (65 mg, 0.29 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.29 mL, 2.11 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (57 mg, 63%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.92 (br s, 1H), 8.90 (s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd, J=8.1, 1.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 4.70-4.57 (m, 1H), 3.25-3.10 (m, 2H), 3.10 (s, 3H), 2.75-2.60 (m, 2H), 2.57 (s, 3H), 2.15-1.95 (m, 3H), 1.65-1.45 (m, 3H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 397 (M+H).
Reaction SMILES: Cl.C(OC([N:9]1[C:13]2=[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)=O)(C)(C)C.CO>C1COCC1.C(Cl)(Cl)Cl>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]2[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:34][CH2:35]3)(=[O:32])=[O:31])=[C:13]3[NH:9][CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]=2[CH3:19])=[C:22]([F:28])[CH:23]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2
Temperature: 45 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
Concentrated HCl (3 mL) was added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-8-[1-(2,3-dihydroxy-propyl)-cyclopropanesulfonylamino]-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (75 mg) in THF (10 mL). The resulting mixture was stirred at 45° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 25 mg of the product (39.58% yield).
Reaction SMILES: [CH2:1]([C@H:4]1[C:8](=[O:9])[N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:6]([C:17](OCC)=[O:18])[CH2:5]1)[CH:2]=[CH2:3].[BH4-].[Na+]>CO.O>[OH:18][CH2:17][C@@H:6]([NH:7][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][C@H:4]([CH2:8][OH:9])[CH2:1][CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of (2S,4R)-1-tert-butyl 2-ethyl 4-allyl-5-oxopyrrolidine-1,2-dicarboxylate (30 g, 0.1 mol) in MeOH/H2O (700/70 mL) was added NaBH4 (25 g, 0.66 mol), the result mixture was stirred 1 hr at rt and quenched with sat. aq. NH4Cl (300 mL). The organic solvent was removed under vacuum and extracted with EtOAc (3×250 mL). The combined organic phases were washed with brine (250 mL) and dried over anhydrous Na2SO4, filtered and evaporated to afford crude tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (22 g, 85%). It was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][NH2:24].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][N:24]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: COc1ccccc1OCCN
Reactant: NC(=O)c1ccnc(N2CCC(=O)CC2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccccc1OCCN=C1CCN(c2nccc(C(N)=O)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 g (0.0118 mol) of 2-(4-oxopiperidin-yl)pyrimidine-4-carboxamide, 1.97 g (0.0188 mol) of 2-(2-methoxyphenoxy)ethylamine, 4.26 g (0.0354 mol) of magnesium sulphate and 152 ml of dichloromethane are introduced into a 500 ml flask and the mixture is stirred at room temperature for 24 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@@H:28]1OC(=N)C(Cl)(Cl)Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>ClCCl>[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@H:28]1[O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=1)(=[O:25])[CH3:24]
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 5-methoxy-2-(4-[2-(methoxymethyloxy)ethyl]benzyl)phenol (0.19 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.40 g) in dichloromethane (15 mL) was added boron trifluoride diethyl ether complex (0.088 mL), and the mixture was stirred for 20 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]-benzyl}phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.33 g).