Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[F:20][C:21]([F:35])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl>O1CCOCC1.O>[F:35][C:21]([F:20])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:32])=[O:31]
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reaction time: 3 h
Yield: 86.7 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-phenylcarbamate are added to a solution of 5 g of 2-(3,3,3-trifluoro-1-propen-1-yl)-phenylsulfonamide and 3.3 g of 1,5-diazabicyclo[5,4,0]undec-5-one in 80 ml of dioxan, and the mixture is stirred for 3 hours at 20°-25° C. The clear reaction solution is then taken up in 300 ml of water and the aqueous solution is acidified with 2N hydrochloric acid to pH 4-5. The resinous precipitate is extracted from the aqueous phase with ethyl acetate and the organic extract is dried and concentrated. The oily residue is crystallised from a 1:10 mixture of acetone/ether, affording 7.2 g of the title compound with a melting point of 159°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[C:19](/[CH2:20][OH:21])=[CH:18]\[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 74.7 %

Procedure:
Following the method of example 46a, Suzuki coupling of 4-bromo-benzoic acid methyl ester (1.05 g, 4.88 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.48 g, 5.56 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.35 g, 0.30 mmol) and cesium fluoride (2.1 g, 14 mmol) in dioxane (15 mL) gives the title compound (1.0 g). MS (m/e): 275 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:21]1([CH:20]([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH3:29])[CH2:22][CH2:23]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 269A (0.058 g, 0.14 mmol) in tetrahydrofuran (4 mL) and methanol (0.012 mL, 0.3 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.12 mL, 0.24 mmol). The reaction was stirred at 25° C. for 2 hour, acidified with 1 M hydrochloric acid a pH of approximately 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to dichloromethane/methanol (99:1) to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (m, 8 H) 2.44 (m, 1 H) 5.81 (d, J=2.57 Hz, 1 H) 7.23 (m, 3 H) 7.53 (m, 1 H) 7.64 (d, 1=7.72 Hz, 1 H) 7.74 (s, br, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15][N:16](C)C(=O)C>CO.C(OCC)(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:15]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1)#[N:16]
Reactant: COC(=O)c1cnc2[nH]nc(Br)c2c1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2[nH]nc(C#N)c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.28 g, 5.01 mmol) was combined with N,N-dimethylacetamide (34 mL). To this mixture was added zinc dust (195 mg, 2.90 mmol) and zinc cyanide (1.20 g, 10.2 mmol). Nitrogen was bubbled through the mixture for 30 minutes. Then 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (611 mg, 0.749 mmol) was added and the reaction vessel was sealed. The reaction was heated to 120° C. for 65 hours. The reaction was diluted with 20% methanol/ethyl acetate and filtered through Celite. The filtrate was diluted with water and transferred to a separatory funnel. The phases were separated, and the organics were washed again with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-75% ethyl acetate/heptanes) gave the title compound (390 mg, 39%). +ESI (M+H) 203.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].Cl.CN.[CH2:17]([NH:21]C(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CCC1C(OC)=O)=O)CCC>>[CH3:17][NH:21][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1c2ccccc2CCC1C(=O)OC)NC(=O)OC(C)(C)C
Agent: CN
Agent: Cl
Product: CNC(=O)c1cnc2ccccc2n1

Procedure:
is obtained starting from 0.5 g of 2-quinoxaloyl chloride by reaction with methylamine hydrochloride under customary reaction conditions: Rf (P)=0.69.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=1[C:11]([NH:42][C:41]1[CH:43]=[CH:44][CH:45]=[C:39]([F:38])[CH:40]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(F)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(benzyloxy)-4-(morpholinomethyl)-5-(trifluoromethyl)benzoic acid (270 mg, 0.683 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added DIPEA (0.239 mL, 1.366 mmol), 3-fluoroaniline (0.086 mL, 0.888 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.819 mmol) and EDC (262 mg, 1.366 mmol). The solution was stirred for 3 hours then partitioned between EtOAc (20 ml) and water (15 ml). The organic layer was separated, washed further with water (2×20 ml), dried (MgSO4) and the solvent removed. Purification by column (SiO2, Isolute 3:1-1:1 Cyclohexane/EtOAc) gave the product as a white solid. 133 mg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])([CH3:9])[CH3:8].[S:26](=[O:50])(=[O:49])([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[CH:31][C:30]=1[CH:46]([CH3:48])[CH3:47])[NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][C:32]1[CH:31]=[C:30]([CH:46]([CH3:48])[CH3:47])[C:29]([O:28][S:26](=[O:50])(=[O:49])[NH:27][C:23](=[O:24])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:34]([CH:35]([CH3:37])[CH3:36])[CH:33]=1)([CH3:43])([CH3:45])[CH3:44]
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1OS(N)(=O)=O
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(C)C)c(C(C)C)c1
Reaction time: 6 h
Yield: 72.2 %

Procedure:
Oxalyl chloride (2.45 mL, 28 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (5.66 g, 21.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred for 6 hours and then concentrated in vacuo. The residue was redissolved in 150 mL dichloromethane. 4-(Tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenyl sulfamate (8.36 g, 21.6 mmol) and triethylamine (7.5 mL, 54 mmol) were added, and the resulting mixture was stirred overnight. Washed with 1M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give 9.86 g of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropyl-phenyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[OH-].[Na+].Cl.[CH3:18][C:19]1[C:20]([CH2:26]Cl)=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>CO.O>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:26][C:20]3[C:19]([CH3:18])=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(C)cc2[nH]c(S)nc2c1C
Reactant: Cc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To 4,6-dimethyl-5-methoxy-2-mercapto-1H-benzimidazole (1.04 g, 0.0050 mol) in methanol (50 ml) were added (in the following order) NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) and 3,4-dimethyl-2-chloromethylpyridine hydrochloride (0.96 g, 0.0050 mol). The mixture was heated until reflux. NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) was added dropwise and then the reflux was continued for 3 hours. The mixture was poured on ice-water (200 ml). Filtration and recrystallization from CH3CN gave the desired product (1.1 g, 67%). NMR data for the final product is given below.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][N:24]([CH:22]=[O:23])[CH2:25][CH2:26]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: O=CN1CCNCC1
Solvent: c1ccncc1
Product: O=CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.0 g), 4-formylpiperazine (0.75 g), and pyridine (30 ml) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and extracted with chloroform. The extract was dried, and chloroform was evaporated. Ethanol was added to the residue, and the precipitated crystals were collected by filtration. Recrystallization from chloroform-ethanol gave 1-cyclopropyl-5,6,8-trifluoro-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.58 g), m.p. 290°-297° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[CH2:9])[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[O:17][CH3:18].Cl>C1COCC1>[C:8]([C:6]1[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH2:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: C=C(OCC)c1cc(N)c(OC)c(C(=O)OC)n1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(C)=O)cc(N)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution of methyl 4-amino-6-(1-ethoxyvinyl)-3-methoxypicolinate (1.68 g, 6.66 mmol) in THF (44.4 ml) was added a 2 N solution of hydrochloric acid (6.66 ml, 13.32 mmol). The milky solution was stirred at room temperature overnight. The clear yellow reaction mixture was concentrated. The residue was poured into saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, concentrated and dried in vacuo to afford methyl 6-acetyl-4-amino-3-methoxypicolinate (1.55 g, 6.91 mmol, 104% yield) as an orange solid which was used without further purification in the next step. ESIMS m/z 223 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 4.59 (s, 2H), 4.01 (s, 3H), 3.90 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[OH:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N+:19]([O-])=[C:18]3CC[CH2:28][C:17]=23)[CH2:11][C@H:10]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].[C:37](Cl)(=[O:39])[CH3:38].CCN(C(C)C)C(C)C>>[C:5]([O:4][CH:2]1[C:18]2=[N:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([N:12]3[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][C:37](=[O:39])[CH3:38])[C@H:10]([NH:29][C:30]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:36])[CH2:11]3)=[C:17]2[CH2:28][CH2:1]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Cl
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 79 %

Procedure:
Ac2O (2.0 mL, 21 mmol) was added to tert-butyl [(3R,4R,5S)-4-hydroxy-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (0.090 g, 0.22 mmol) in a tube that was then sealed. The reaction mixture was heated in the sealed tube with stirring in an oil bath at 90° C. oil bath. The reaction mixture was allowed to cool to room temperature and acetyl chloride (0.10 mL) and DIPEA (0.2 mL) were then added. The resulting mixture was stirred at room temperature for 15 min. After removal of the solvents under reduced pressure, the resulting residue was diluted with EtOAc and aq. Na2CO3 and stirred at room temperature for 30 min. The organic layer was separated, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 0-70% EtOAc in hexanes) to give the sub-title compound (86 mg, 79%) as a foamy brown powder. LCMS calc. for C23H33N4O8 (M+1)+: m/z=493.2. Found: 493.2.
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.CCOC(C)=O>[C:20]([O:6][C@H:5]1[C@@H:7]([O:8][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:9]([CH2:11][O:12][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10][C@@H:2]([S:1][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C@@H:3]1[OH:4])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1ccc(S[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A suspended mixture of p-Methylphenyl 1-thio-β-D-galactopyranoside (Vargas-Berenguel, A. et al. J. Chem. Soc. Perkin Trans 1 1994, 3287) (100 mg, 0.350 mmol) and Bu2SnO (266 mg, 1.04 mmol) in toluene-benzene (1:1, 10 mL) was refluxed for 10 min. The mixture was concentrated to a volume of 2 mL by distillation under Ar, then the hot solution (about 100° C.) was treated with benzoyl chloride (130 μL, 1.12 mmol). After being stirred for 1 h at this temperature, the reaction mixture was diluted with EtOAc (20 mL), cooled to room temperature, filtered through Celite and concentrated. Chromatography of the residue (hexane/EtOAc, 4:1 to 2:1 to 1:1) furnished 15 (192 mg, 91.7%) as white white solid: [α]D22 +15° (c, 0.5, CHCl3); 1H-NMR (250 MHz, CDCl3), δ 5.91 (d, 1H, J=3.1 Hz, H-4), 5.43 (dd, 1H, J=3.3, 9.7 Hz, H-3), 4.720 (d, 1H, J=9.6 Hz, H-1), 4.29 (bt, 1H, J=6.5 Hz, H-5), 4.62 (dd, 1H, J=6.6 Hz, H-6) 4.37 (dd, 1H each, J=11.5 Hz, H-6′), 4.03 (t, 1H, J=9.6 Hz, H-2), 2.38 (s, 3H, Me); 13C-NMR (270 MHz, CDCl3) δ 165.98, 165.90, 165.29, 88.26, 74.97, 74.47, 68.59, 67.34, 62.45, 21.28; HRMS for C40H44O8SiCs (M+Cs) calcd 845.1581. found 845.1609.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23]Cl)[N:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.[I-].[K+].[CH3:32][C:33](C)=O>>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23][NH:29][CH:26]2[CH2:33][CH2:32][CH2:27][CH2:28]2)[N:3]=1
Reactant: NC1CC1
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Reactant: CC(C)=O
Agent: [I-]
Agent: [K+]
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CNC3CCCC3)nc2N)cc1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide (1.13 g, 2.37 mmol), cyclopropylamine (0.807 g, 9.48 mmol), and potassium iodide (25 mg) were added to 25 mL acetone. The reaction mixture was stirred under nitrogen at room temperature for 20 hours, then diluted with EtOac. The mixture was washed with water and brine, and the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (8% MeOH/methylene chloride-0.1% NH4OH) to give 15 mg of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-cyclopentylamino-acetamide, m.p.=176.5-178.0° C., MS (M+H)=526.
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([C:26]#[C:27][Si](CC)(CC)CC)[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:26]([C@:10]1([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)#[CH:27]
Reactant: CC[Si](C#C[C@@]1(CO[Si](C)(C)C(C)(C)C)CC[C@H](n2cnc3c(N)nc(F)nc32)O1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#C[C@@]1(CO)CC[C@H](n2cnc3c(N)nc(F)nc32)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 22 (101 mg, 0.200 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of 1-M tetrabutylammonium fluoride in tetrahydrofuran (0.42 ml, 0.42 mmol) was added to the resultant solution, followed by stirring at room temperature for five minutes. After acetic acid (24 μl) was added to the resultant reaction mixture, the resultant mixture was concentrated under reduced pressure. The thus-obtained residue was purified by means of silica gel column chromatography (silica gel 15 ml, chloroform:methanol=40:1 to 20:1), to thereby yield compound 23 (53.0 mg, 0.191 mmol, 95.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)[n+]([O-])c1
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(C)cn1

Procedure:
11.5 g of 2,5-dimethylpyridine-N-oxide in 5 ml of acetic acid were added dropwise to 18 ml of acetic anhydride pre-heated to 120°. The reaction solution was boiled under reflux for a further 45 minutes, concentrated by evaporation on a rotary evaporator, and distilled at 8 mm Hg/115°. 14.0 g of 2-acetoxymethyl-5-methylpyridine was obtained.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>O1CCCC1>[NH:29]1[C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])=[N:2][N:31]=[N:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1nnn[nH]1)C(=O)O
Reaction time: 72 h
Yield: 84.9 %

Procedure:
17.5 g (82 mmol, 1 equiv.) of 3-cyano-2-(1,1-dimethylethoxy) methanamido-propionic acid 26 was dissolved in 125 mL of tetrahydrofuran and 40.5 g (129 mmol, 1.5 equiv.) tributyltin azide was added. The reaction mixture was brought to reflux and held there for 3 days. The reaction mixture was cooled and the volatiles removed in vacuo on a rotary evaporator. The residue was dissolved in 300 mL of 0.5M sodium hydroxide and this aqueous solution was washed with ethyl acetate (4×100 mL). The aqueous layer was passed through a 125 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The volatiles were removed in vacuo on the rotary evaporator to yield 17.9 g of the product as a white solid (85 % yield). 1H-NMR (CD3OD): 4.55 p.p.m (m, 1H); 3.40 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H). This material is suitable for use in solid-phase peptide synthesis.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1[CH:28]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1/[CH:28]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.8 %

Procedure:
A solution 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide (Ex-55A, 830 mg, 2.44 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44 mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Column chromatography (5% MeOH in dichloromethane) gave 772 mg (57%) of the title compound as a brown solid, mp 64–68° C. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76 (quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s, 4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for C29H40N4O5S: 557.2798 [(M+H)+]; Found: 557.2798.