Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[N:12][N:13]([CH3:16])[C:14]=3[NH2:15])=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C1C=CC=CN=1)C.Cl[S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:48])([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[N:12][N:13]([CH3:16])[C:14]=3[NH:15][S:32]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:47])([CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:39][CH:40]=3)(=[O:34])=[O:33])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nc(OCC2CC2)c(-c2ccc3c(c2)OCO3)c1N
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCC3CC3)nn2C)cc1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To 4-(1,3-benzodioxol-5-yl)-3-(cyclopropylmethoxy)-1-methyl-1H-pyrazol-5-ylamine (Preparation 50) (230 mg) in anhydrous pyridine (8 ml) at room temperature under an atmosphere of nitrogen was added dimethylaminopyridine (108 mg) and ethyl 2-[4-(chlorosulfonyl)phenyl]-2-methylpropanoate (512 mg). The mixture was stirred overnight and then concentrated under reduced pressure. HCl 0.01N (100 ml) was poured on the resulting yellow syrup and the resulting mixture was extracted with dichloromethane (3×50 ml). The organic fraction was concentrated under reduced pressure and the residue was dissolved in methanol (8 ml). An aqueous solution of sodium hydroxyde (2M, 2 ml) was added and the reaction was stirred overnight. Water (10 ml) was then added, the mixture was acidified with an aqueous solution of HCl (1N) and extracted with dichloromethane (3×10 ml). The combined organic fractions were dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 35 g) eluted with hexane:ethyl acetate (2:1) to yield the title as a pale yellow oil (281 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N+:33]([O-:35])=[O:34].Cl>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:33]([O-:35])=[O:34])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
NaOH aq. (NaOH (3.64 g, 83 mmol) was added to 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol) in H2O (180 mL), and THF (50 mL) at rt, and the reaction mixture was stirred at rt for 5 min. MeNO2 (16.6 g, 273 mmol) was added dropwise and the mixture was stirred at rt for 16 h. The reaction mixture was acidified with 2 N HCl and extracted with EtOAc. The organic fraction was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. Purification was accomplished by flash chromatography (1:1 hexane/EtOAc) to give 15.9 g of the title compound as a light yellow oil (yield 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:19]O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[O:11])=[CH:17][CH:18]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
Thionyl chloride (2.4 ml, 33 mmol) was added dropwise to a stirred solution of 3-(4-chlorobenzoyl)propionic acid (5.0 g, 24 mmol) in dry methanol (50 ml) at 0° C. The mixture was heated at reflux for 2 h, cooled and the solvent removed under reduced pressure to give methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 97%) as a colourless oil. deltaH (250 MHz, CDCl3) 7.93 (2H, d, J 8.5 Hz), 7.45 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.29 (2H, t, J 6.6 Hz), 2.78 (2H, t, J 6.6 Hz).
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>CCO.O>[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([NH2:17])=[C:11]3[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CN(C)C=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]=[C:33]=[O:34])[CH:25]=1>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH:32][C:33]([NH:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH:9]=[CH:10][C:11]=23)=[O:34])[CH:25]=1
Reactant: COc1ccc(Br)cc1N=C=O
Reactant: Nc1ccnc2c1ccn2Cc1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1NC(=O)Nc1ccnc2c1ccn2Cc1ccncc1

Procedure:
To a solution of Compound 1d (50 mg, 0.2 mmol) in dichloromethane:dimethylformamide (4.0 mL, 3:1) is added 4-bromo-2-isocyanato-1-methoxy-benzene (50 mg, 0.2 mmol, 1 equiv.) and the reaction mixture is heated for 16 hrs, the solvent is then removed and the residue is purified using flash chromatography to afford Compound 1e as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.[Zn](C)[CH3:29]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:23]([CH:22]([CH2:25][CH3:26])[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:29])=[CH:18][C:13]=1[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[N:7]1)[CH3:24]
Reactant: C[Zn]C
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCC(CC)COc1ccc(C)cc1Cn1nc(CCC(=O)O)cc1C
Temperature: 105 °C

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.1363 g, 0.31 mmol), Pd(dppf)Cl2 (0.00506 g, 0.00621 mmol), Zn(CH3)2 (0.31 mlg, 0.62 mmol in 1,4-dioxane (0.93 ml) heated at 105° C. under a N2 atmosphere for 1 h 50 min. The mixture was cooled to RT, quenched with MeOH (0.2 ml) and partitioned between 1 M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([OH:21])=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[ClH:26].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>ClCCl>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([NH:53][CH2:52][CH2:51][O:50][CH3:49])=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=C(O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COCCNC(=O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 22.5 %

Procedure:
A mixture of 33 mg (0.088 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine-1-acetic acid, 30 mg (0.157 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 16 mg (0.105 mmol) of 1-hydroxybenzotriazole hydrate and 14 mg (0.187 mmol) of 2-methoxyethylamine was stirred in 3 ml of dichloromethane for 3 hours. The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed three times on silica gel using dichloromethane/methanol (94:6), dichloromethane/methanol 92:8) and ethyl acetate/methanol (9:1) for the elutions. The product was dissolved in a solution of hydrogen chloride in ethyl acetate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 5 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-N-(2-methoxyethyl)-1H-1,4-benzodiazepin-1-acetamide dihydrochloride as a red solid. MS: m/e 431.9 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:22][C:23]1[N:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:25][CH:24]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]([C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@@H:29]([C:26]1[CH:27]=[N:28][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](CC(=O)OC(C)(C)C)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a solution of (S)—N-benzyl-1-phenylethanamine (3.64 g, 17.26 mmol) in THF (40 mL) at −70° C., was added dropwise n-BuLi (1.6 M, 14.7 mmol) over a period of 30 min and stirred further. After 1 h, a solution of (E)-tert-butyl 3-(6-methylpyridin-3-yl)acrylate (2.7 g, 12.3 mmol) in THF was added slowly to the above mixture and stirred further. After 2 h, sat. NH4Cl solution was added to the reaction mixture and extracted with EtOAc (3×). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue. Purification of the residue by column chromatography (Neutral Al2O3, Et2O/Pet ether 5:95) afforded the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])OC2C=CC=CC=2)=[C:19]([CH3:33])[C:18]=1[CH3:34])(=[O:3])[NH2:2].[CH3:35][NH2:36]>>[CH3:34][C:18]1[C:19]([CH3:33])=[C:20]([NH:23][C:24]([NH:36][CH3:35])=[O:32])[CH:21]=[CH:22][C:17]=1[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3C)c2cc1C(N)=O
Reactant: CN
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)c(C)c1C

Procedure:
The title compound (30 mg) was obtained as colorless crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethyl phenyl)carbamate) (56 mg) and methylamine (2M tetrahydrofuran solution), by the same procedure as in Example 11.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc3ccccc3s2)c1
Yield: 41 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 1-benzothiophene-2-sulfonyl chloride (12.8 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 41% yield (8.9 mg). MS (ESI+) calcd mass for C15H11NO4S2 333.012949, found 333.014269.
Reaction SMILES: [Si]([O:18][C:19]1[CH:52]=[CH:51][C:22]([O:23][CH2:24][C@@H:25]([OH:50])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:49]=[CH:48][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:50][C@H:25]([CH2:24][O:23][C:22]1[CH:51]=[CH:52][C:19]([OH:18])=[CH:20][CH:21]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:49]=[CH:48][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CCCCCC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 71.4 %

Procedure:
1-{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]-amino}ethyl)anilino]-1-piperidinyl}-1-hexanone (0.13 g, 0.168 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.058 g, 0.120 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[N+:11]([O-])[CH:12]=1)[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:12]1[C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:24])=[CH:8][CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)[n+]([O-])c1
Product: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide (9 g, 26.7 mmol) in POCl3 (45 mL) was stirred at 80° C. for 5 h. After completion, reaction mixture was poured into ice water (150 mL), extracted with EtOAc (2×100 mL), combined extracts were treated with NaHCO3 solution, washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography by using (SiO2) EtOAc:Pet ether (2:98) to afford (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 67%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[C:7]([CH:10]=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1.[OH:14][CH2:15][CH2:16]O.O>C1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][O:14][CH:10]1[C:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: OCCO
Reactant: COc1ccc2c(C=O)coc2c1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(C3OCCO3)coc2c1
Yield: 94.7 %

Procedure:
A mixture of 6-methoxybenzofuran-3-carbaldehyde (0.600 g, 3.41 mmol), HOCH2CH2OH (3.17 g, 51 mmol) and p-toluenesulfonic acids (0.001 g) in benzene (20 mL) was refluxed for 8 h using a Dean-Stark water trap. The mixture was concentrated under reduced pressure and then diluted with EtOAc. The organic solution was washed with water, dried over anhydrous MgSO4, and concentrated to give 3-(1,3-dioxolan-2-yl)-6-methoxybenzofuran (0.711 g, 95%)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25].CN1CCOCC1>CO>[CH3:21][O:22][CH2:23][CH2:24][NH:25][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: COCCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: COCCNS(=O)(=O)c1ccc2nc(-c3c(C)n[nH]c3N)sc2c1
Yield: 39 %

Procedure:
the title compound (33 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 2-methoxyethylamine (39 mg, 0.43 mmol) and the polystyrene resin bound base N-3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (0.24 g, 0.45 mmol) in 4 mL of methanol. MS (m/z, ES+): 368.5 (M+1, 100%); 1H NMR (500 MHz, ppm, DMSO-d6): δ 11.8-12.1 (br s, 1H), 8.5 (s, 1H), 7.99 (br d, 1H), 7.83 (d, 1H), 7.73 (t, 1H), 5.9-6.7 (br s, 2H), 3.30 (t, 2H), 3.15 (s, 3H), 2.94 (dt, 2H), 2.41 (br s, 3H). Yield=46%.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[S:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCSc1c(C=O)c(=O)n(C)c(=O)n1C
Reactant: NOCc1ccccc1
Agent: Cl
Product: CCSc1c(C=NOCc2ccccc2)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-(Ethylthio)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 23, Step 1) (0.070 mg, 0.30 mmol) and O-benzyl-hydroxylamine hydrochloride (0.063 mg, 0.40 mmol) were used to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH3:40])[C:19]([NH:21][CH2:22][C:23]1[S:27][CH:26]=[C:25]([N:28]2[C:32]([C:33](O)=[O:34])=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[N:29]2)[CH:24]=1)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:33]([C:32]1[N:28]([C:25]2[CH:24]=[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[CH3:40])[S:27][CH:26]=2)[N:29]=[C:30]([C:36]([F:37])([F:39])[F:38])[CH:31]=1)=[O:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Reactant: Cc1ccccc1CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a solution of 2-methylbenzylamine (0.037 mL, 0.295 mmol) and compound 7 (0.091 g, 0.197 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.075 g, 0.394 mmol) followed by DMAP (9.62 mg, 0.079 mmol). The reaction was left to stir for 16 hours at room temperature. The solvent was then removed on the rotary evaporator and the brown material was purified by silica gel chromatography with a 12M Biotage column and a gradient of 0-5% methanol in dichloromethane to give 61.3 mg of a yellow crust. The sample was further purified by preparative HPLC (C18 Aquasil 20×250 mm; 40-85% methanol in water in 45 minutes at 10 mL/min) to afford compound 15a (34.4 mg, 31%) as a white crust. LRMS (ESI): calc. 565.2; found 466.1 (MH-Boc)+, 588.2 (MNa)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (202.5 mg, 0.67 mmol) in dry N,N-dimethylformamide (3.3 mL) was treated with N,N-diisopropylethylamine (350 μL, 2.00 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (303.8 mg, 0.80 mmol), and 2-aminothiazole (133.7 mg, 1.34 mmol). The reaction mixture was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (150 mL), and the organic phase was washed with a 10% aqueous hydrochloric acid solution (1×75 mL) and a saturated aqueous sodium chloride solution (1×75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (87.5 mg, 34%) as a white solid: mp 244-246° C.; EI-HRMS m/e calcd for C21H27N3O2S (M+) 385.1824, found 385.1832.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11]Br)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20].[CH3:21][NH2:22]>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:22][CH3:21])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[N:20]
Reactant: N#Cc1ccccc1-c1oc2ccc(CBr)cc2c1Br
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc2oc(-c3ccccc3C#N)c(Br)c2c1
Temperature: 25 °C

Procedure:
3.1 g (7.9 mmol) 3-Bromo-5-(bromomethyl)-2-(2-cyanophenyl)benzofuran (prepared according to EP 434 249) were dissolved in 50 ml THF, and 25 ml of a 40% aqueous solution of methylamine was added via a dropping funnel. The mixture was stirred at room temperature over night and warmed for 2 h at 40° C. The solvent was removed in vacuo, the residue stirred with water, filtrated by suction, and washed with water. The title compound was purified by column chromatography (silica gel, dichloromethane/ethanol 99:1 to 90:10) and obtained as a colorless powder after evaporation to dryness, m.p. 114° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](Cl)=[O:26])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2].[N+:29](=[CH2:31])=[N-:30]>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:26])[CH:31]=[N+:29]=[N-:30])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: C=[N+]=[N-]
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 13, compound (19) is reacted with diazomethane at room temperature without being separated from the reaction solution, so that the 4-chlorocarbonyl group of compound (19) is converted into diazoacetyl group, affording 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-4-diazoacetyl-5-(dimethylaminomethyleneamino)imidazole [compound (20)].