Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:24][CH3:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 1B, 1.0 g, 2.63 mmol) and DMSO (13.14 mL). Sodium methoxide (0.710 g, 13.14 mmol) was added and the reaction mixture was heated to 80° C. for 2.5 hours. The reaction mixture was cooled to RT and quenched with aqueous, saturated ammonium chloride solution. Water and EtOAc were added, and the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (0-100% EtOAc/hexanes) to afford (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Example 21A; 0.611 g, 1.624 mmol, 61.8% yield) as a yellow solid.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(O[C:16](=[O:18])[CH3:17])(=O)C>>[C:2]([O:4][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[O:10][C:16](=[O:18])[CH3:17])[O:8][C:9](=[O:10])[CH3:11])[O:6][C:5](=[O:6])[CH3:7])[CH:2]=[O:1])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Product: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O

Procedure:
L-Fucose is then acetylated with acetic anhydride to produce fucose tetraacetate. Preferably, the reaction is carried out by suspending the L-fucose in a solvent, such as pyridine, and slowly adding the acetic anhydride. The mixture is stirred, poured into a separating funnel containing ice water, and extracted with chloroform. The organic extracts are washed with water, aqueous sodium bicarbonate, and dried over magnesium sulfate. The mixture is filtered and the solvent removed under reduced pressure. The residue is co-evaporated with toluene to remove any remaining pyridine or acetic acid. The fucose tetraacetate is then brominated to produce 2,3,4-tri-O-acetyl-L-fucopyranosyl bromide having the formula: ##STR13## It is to be noted that in the above formula, and elsewhere herein, the use of "Ac" is understood to represent the acetyl radical, i.e., ##STR14## The fucose tetraacetate is brominated with hydrogen bromide in acetic acid. The mixture is worked up similarly to that just described for preparing fucose tetraacetate, i.e., chloroform extraction from ice water.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]#[N:15])=[N:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:4]3[N:5]=[C:6]([CH2:13][C:14]#[N:15])[C:7]4[C:12]([C:3]3=[N:1][N:2]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N#CCc1nnc(NN)c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(-c2nnc3c4ccccc4c(CC#N)nn23)cc1

Procedure:
A mixture of 4-hydrazino-1-phthalazin-acetonitrile (0.7 g), triethylamine (0.4 g), p-methoxybenzoylchloride (0.68 g), dioxane (10 ml), is heated at reflux for 5 h, then it is cooled, the solvent is evaporated under reduced pressure, the residue is taken up with water, recovered by filtration and crystallized from ethanol/chloroform, yielding 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-acetonitrile. M.p. 252°-254° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:38])[C@@H:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:15][N:14]1C(OC(C)(C)C)=O)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:38])[C@@H:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:15][NH:14]1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@@H]1C[C@@H](Oc2cccc(-c3ccccc3)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCNC(=O)[C@@H]1C[C@@H](Oc2cccc(-c3ccccc3)c2)CN1
Reaction time: 2 h
Yield: 108.9 %

Procedure:
trans-4-(3-Biphenyloxy) N-tert-butoxycarbonyl-L-proline 2-(N-tert-butoxycarbonylamino)ethylamide (C, 175 mg) was dissolved in 4 N hydrogen chloride in 1,4-dioxane (3 mL). After stirring for 2 hr, the reaction mixture was evaporated in vacuo to give a white solid. The solid was washed with ether to afford the titled compound (118 mg): 1H NMR (400 MHz, D2O) δ 2.43 (m, 1H), 2.83 (m, 1H), 3.22 (m, 2H), 3.57 (m, 1H), 3.66 (m, 1H), 4.69-4.84 (m, 3H), 5.44 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.32 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.46-7.58 (m, 4H), and 7.73 (m, 2H).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:32][O:33][CH2:34][C@H:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:37]5[CH2:38][CH2:39][O:40][C@H:35]([CH2:34][O:33][CH3:32])[CH2:36]5)=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: COC[C@@H]1CNCCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[4-Hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:19]([C:20]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OC(F)F)nc(NC(=O)Oc2ccccc2)n1
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 9.0 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine in 30 ml of absolute tetrahydrofuran are added successively 3.9 g of chloroformic acid-phenyl ester and 0.05 g of 4-dimethylamino-pyridine. After the solution has been stirred at 20° to 25° C. for 24 hours, the reaction mixture is diluted with 250 ml of ethyl acetate, and the occurring precipitate is separated. There are thus obtained 3.1 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine hydrochloride, m.p. 204° to 205° C. (decomposition). In order to remove the residual starting material, the filtrate is eluted through an acid with ion-exchanger I®(MERCK), dried over sodium sulfate and concentrated by evaporation to thus obtain as crude product, in the form of a viscous oil, 4.0 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine (compound No. 2.28), which melts at 56° to 58° C. after crystallisation;
Reaction SMILES: Cl[C:2]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)=[O:3].[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:24][N:25]([CH3:26])[C:2](=[O:3])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)Cl)cc2)on1
Reactant: CNC
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)N(C)C)cc2)on1

Procedure:
A solution of 8.0 g of 5-[7-(4-chlorocarbonylphenoxy)heptyl]-3-methylisoxazole in 50 ml of dry toluene was saturated with dimethylamine gas over a 30 minute period. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ether. The ether solution was boiled, treated with petroleum ether until turbid and cooled to produce 6.0 g of N,N-dimethyl-4-[7-(3-methyl-5-isoxazolyl)heptyloxy]benzamide, m.p. 58°-59° C.; MIC vs. polio-2 virus in vitro=2.5 μg/ml.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH2:20]([C:27]1([N:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:30]1([OH:33])[CH2:31][CH2:32][C:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([N:34]([CH3:36])[CH3:35])[CH2:28][CH2:29]1
Reactant: c1ccc2occc2c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of benzo[b]furan (612 mg, 5.12 mmol) in dry THF (40 ml) was cooled to −8° C. under a stream of argon. Thereafter, tert-Butyllithium (6.22 mmol, 4.14 ml of a 1.5 molar pentane solution) was added dropwise such that a reaction temperature of −5° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for two hours at −5° C. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (1.20 g, 5.18 mmol) in dry THF (10 ml) was added dropwise at 0° C. The mixture was stirred for one hour at 0° C. and then for four days at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with 30 ml methylene chloride each time. The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=8:2). 380 mg 1-benzofuran-2-yl-4-benzyl-4-dimethylaminocyclohexanol with a melting point of 121-124° C. were obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:3]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)OC(C)C)s2)n1
Reactant: OCCN1CCNCC1
Product: Cc1nc(Nc2ncc(C(=O)OC(C)C)s2)cc(N2CCN(CCO)CC2)n1
Yield: 77.2 %

Procedure:
Prepared from isopropyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate and Compound 3: isopropyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 77.2%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].[CH3:11]I>CN(C)C=O.C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: CI
Reactant: O=c1cc(I)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 4-iodo-2-pyridone (500 mg), sodium hydride (109 mg) and methyl iodide (482 mg) in dimethylformamide (5.0 mL) was stirred at room temperature for 4 hr. Additional sodium hydride (109 mg) and methyl iodide (482 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-96:4) to afford the title compound (341 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:41]1([CH:47]=[CH:48][CH:49]=[CH:50][CH2:51][OH:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16]([O:52][CH2:51][CH:50]=[CH:49][CH:48]=[CH:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCC=CC=Cc1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 93 %

Procedure:
346 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-3-ethoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 192 mg (1.2 mM) of 5phenyl-2,4-pentadien-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. Thereafter, the reaction mixture was treated in the same manner as Example 48, and 454 mg of ethyl 5-phenyl-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27]C(OC(C)(C)C)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
1-[4′-(4-tert-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.5 g, 3.2 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (4 mL), and the reaction was stirred for 1 hour. The mixture was neutralized and worked up to give the title compound.
Reaction SMILES: [ClH:1].C(O)C.[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]([OH:28])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][N:22](C=O)[CH2:21][CH2:20][N:19]3C=O)[CH:12]=[CH:13][C:6]1=2>CO>[ClH:1].[ClH:1].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]([OH:28])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][NH:22][CH2:21][CH2:20][NH:19]3)[CH:12]=[CH:13][C:6]1=2
Reactant: O=CN1CCN(C=O)C(COCC(O)c2ccc3sccc3c2)C1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: OC(COCC1CNCCN1)c1ccc2sccc2c1
Reaction time: 8 h

Procedure:
In 1.5 ml of methanol was dissolved 270 mg of -(benzo[b]thiophen-5-yl)-2-[(1,4-diformylpiperazin-2-yl)methoxy]ethanol. To the solution was added 1.5. ml. of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with ethanol, and dried to obtain 150 mg of 1-(benzo[b]thiophen-5-yl)-2-[(piperazin-2-yl)methoxy]ethanol dihydrochloride (compound No. 355).
Reaction SMILES: [C:1]1(=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:3][CH2:2]1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH:1]1([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[C:6]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C=C2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCOC(=O)c1c(CC2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1

Procedure:
Ethyl 3-(cyclopropylidenemethyl)-1-[3-(trifluoromethyl)benzyl]-1H-indole-2-carboxylate (Example 182, 140 mg, 0.351 mmol) was stirred over Lindlar catalyst (28 mg) in ethanol (15 mL) under 1 atmosphere of hydrogen for 1 hour. The mixture was filtered through Celite with an excess of ethanol. The filtrate was concentrated, and the resulting crude oil was purified by flash chromatography on silica gel eluted with 20% Et2O/hexane. The title compound was collected as a yellow oil (95 mg, 67%). The product had: 1H NMR (300 MHz, acetone-d6) δ 7.78 (d, 1 H), 7.56-7.45 (m, 4 H), 7.34-7.32 (m, 1 H), 7.28-7.26 (m, 1 H), 7.16-7.13 (m, 1 H), 5.93 (s, 2 H), 4.32 (q, 2 H), 3.08 (d, 2 H), 1.31 (t, 3 H), 1.13-1.15 (m, 1 H), 0.42-0.38 (m, 2 H), 0.29-0.26 (m, 2 H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].CCN(C(C)C)C(C)C.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]=[CH2:27])[C:21]([O:23][CH3:24])=[O:22].Cl>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:19][C@@H:20]([CH2:25][CH:26]=[CH2:27])[C:21]([O:23][CH3:24])=[O:22])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: C=CC[C@H](N)C(=O)OC
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)OCCCC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
Step E (1): Butyl chloroformate (408 mg, 3.0 mmol), followed by DIEA (1.23 mL, 9.0 mmol), was added to a 250-mL single neck round bottom flask charged with a solution of the (S)-methyl 2-aminopent-4-enoate hydrochloride (500 mg, 3.00 mmol) in DCM (50 mL) at 0° C. Warmed the mixture to rt and after 2 h, poured into 1N HCl (200 mL). Extracted with EtOAc. Washed the combined organic extracts with 0.1 N NaOH, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica-gel column chromatography afforded 357 mg (52% yield) of (S)-methyl 2-(butoxycarbonylamino)pent-4-enoate. LC-MS (M+H)+=230.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.91 (t, J=7.48 Hz, 3H) 1.30-1.40 (m, 2H) 1.54-1.61 (m, 2H) 2.43-2.59 (m, 2H) 3.73 (s, 3H) 4.05 (t, J=6.71 Hz, 2H) 4.38-4.46 (m, 1H) 5.08-5.20 (m, 3H) 5.62-5.72 (m, 1H).
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([CH:31]([CH2:34]O)[CH2:32][OH:33])[CH:29]=[CH2:30].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:34][CH:31]([CH2:28][CH:29]=[CH2:30])[CH2:32][OH:33])=[O:26])[CH:22]([CH3:23])[CH3:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: C=CCC(CO)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCC(CO)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Yield: 66.1 %

Procedure:
To a solution of N-trityl-L-valine (5.5 g, 15.2 mmole), 2-allyl-1,3-propandiol (4.4 g, 38 mmol), N,N-dimethylamino pyridine (183 mg, 1.5 mmol) in dichloromethane (120 ml) was added DCC (3.5 g, 16.7 mmol). The reaction was kept under reflux overnight. After filtration through Celite, the organic phase was washed with sodium hydrogen carbonate aqueous solution and dried. Silica gel column chromatography gave 4.6 g intermediate 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH:23]1[CH:28]=[C:27]2[C:29]([CH:32]=O)=[CH:30][NH:31][C:26]2=[CH:25][CH:24]=1>C(O)C>[NH:31]1[C:26]2[C:27](=[CH:28][CH:23]=[CH:24][CH:25]=2)[C:29]([CH:32]=[N:17][NH:16][C:7]2[CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]3[N:6]=2)=[CH:30]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2nc(NN=Cc3c[nH]c4ccccc34)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.5 mg, 0.0988 mM) and then acetic acid (5.0 μL, 0.087 mM) and indole-3-carboxyaldehyde (15.8 mg, 0.109 mM) were added to the solution and the mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and then the resulting solid was washed with methanol to thus give the title compound (26.4 mg, yield: 71%).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14]C)=[O:13]>CO.O>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add NaOH (82.0 mmol) to methyl indole-2-carboxylate 2 (27.0 mmol) as a suspension in MeOH/H2O (3:1, 160 mL). Stir at rt for 16 h, concentrate, and acidify with HCl. Collect the precipitate by filtration, wash with H2O and dry in vacuuo to afford indole-2-carboxylic acid 3.
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[C:42]([O-])([O-])=O.[Cs+].[Cs+]>CO>[Si:30]([O:29][C@@H:28]1[C@@H:27]([CH2:18][O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([O:10][CH3:42])[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Solvent: CO
Product: COc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and methanol (1.0 mL). The reaction mixture was flushed with N2 and stirred at room temperature for 1 h after which the mixture was evaporated to dryness. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 38 mg (77% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.12. 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H, Ar—H), 8.27 (s, 1H, Ar—H), 6.49 (t, 1H, H-1′, J=6.3), 4.62 (m, 1H, H-3′), 4.18 (s, 3H, OCH3), 4.01 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.77 (dd, 1H, H-5′, J=11.2, 2.9), 2.62 (app quint, 1H, H-2′, Japp˜6.3), 2.45 (ddd, 1H, H-2′, J=13.2, 6.4, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 161.1, 152.0, 151.5, 140.6, 122.0, 88.0, 84.5, 71.9, 62.8, 54.0, 41.4, 25.9, 25.7, 18.4, 17.9, −4.7, −4.8, −5.5, −5.6. FAB HRMS calcd for C23H43N4O4Si2 (M++H) 495.2823. found 495.2798.