Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CCOCC.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19]>CO.CCCCCC>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[NH:19]
Reactant: OCc1ccccc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
0.868 g of 60% sodium hydroxide was measured and placed in a 100 ml flask with a two-way cock, and the gas in the flask was replaced with nitrogen. The sodium hydroxide was twice washed with hexane, and then dried under reduced pressure. The gas in the flask was again replaced with nitrogen, and 20 ml of diethyl ether was then added to form a suspension. The flask was immersed in an ice water bath, and the suspension was stirred for about five minutes. 20 ml of an ether solution containing 7.19 g of benzyl alcohol was added by the use of a cannula, and the reaction solution was stirred at such a temperature for 20 minutes, mixed with 10 ml of trichloroacetonitrile dropwisely added thereto, and stirred for 2 hours, while the temperature of the solution was gradually raised up to room temperature. After the reaction was finished, the reaction solution was mixed with a methanol/hexane solution, and further stirred for 3 hours. The insolubles were filtered off. The filtrate was concentrated under reduced pressure, and then again mixed with hexane. The impurities were filtered off. The solvent was distilled away from the filtrate under reduced pressure to obtain the title compound as a yellow oil (14.84 g, 88%).
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:25]=[CH:24][C:5]3[NH:6][C:7]([N:9]4[CH2:14][CH2:13][C:12]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[C:16](=[O:23])[O:15]5)[CH2:11][CH2:10]4)=[N:8][C:4]=3[CH:3]=2)[CH:27]=1
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1OC2(CCN(c3nc4cc(-c5cccnc5)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Add tetrakistriphenylphosphine palladium(0)(0.01 g, 0.01 mmol) to 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.10 g, 0.22 mmol) in ethylene glycol dimethyl ether (2 mL). To this solution, add pyridine-3-boronic acid (0.06 g, 0.45 mmol) and aqueous sodium carbonate (1M, 1 mL) and heat the reaction at 80° C. for 2 hours. Extract the product with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry over sodium sulfate, and concentrate in vacuo. Purify by flash column chromatography (5% MeOH—CH2Cl2) to obtain 1′-(5-pyridin-3-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:4].I[C@@:21]1([N:30]2[CH:37]=[CH:36][C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24](O)[C@H:22]1O>>[F:1][C:2]([F:18])([F:19])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:36]1[C:34](=[O:35])[NH:33][C:31](=[O:32])[N:30]([CH:37]=1)[C@@H:21]1[O:29][C@H:26]([CH2:27][OH:28])[CH2:24][CH2:22]1)=[O:4]
Reactant: C#CCCCCCCCCCCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O=C(NCCCCCCCCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Protected alkynylamine 63 was coupled for 24 h to 5-iodo-2',3'-dideoxyuridine (47, 676.2 mg, 2.00 mmol, prepared as described in Example 2A) following the general procedure described in Example 1C. Chromatography on silica gel (100 g) eluting with a 0-5% methanol in dichloromethane gradient afforded a dark red foam. The red impurity was removed by chromatography on a reverse phase column (100 g, octadecylsilane on 40 micrometer silica gel, Baker) with 40% water in methanol. The appropriate fractions were combined, concentrated, and co-evaporated twice with absolute ethanol to afford 731 mg of alkynylamino nucleoside 60 as a clear oil. This material was homogeneous by TLC and NMR except for the presence of residual ethanol (25 mole %, corrected yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimlide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N+:16]([O-])=O)[CH:15]=1)[NH:12][C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2>[C].[Pd].O1CCCC1>[NH2:16][C:14]1[CH:15]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc([N+](=O)[O-])c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCCOC)cc(N)c2[nH]1
Yield: 97 %

Procedure:
A mixture of ethyl 5-(3-methoxypropoxy)-7-nitro-1H-indole-2-carboxylate (6.15 g), 10% palladium-carbon (50% containing water, 1.0 g) and tetrahydrofuran (150 mL) was subjected to catalytic reduction at room temperature under hydrogen atmosphere at normal pressure. The catalyst was filtered off, and the filtrate was concentrated. The obtained crystals were washed with diisopropyl ether to give the title compound (5.41 g, yield 97%) as yellow crystals. The crystals were recrystallized from ethyl acetate-diisopropyl ether to give pale-yellow prism crystals. melting point 139-140° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:19])[CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(C)=O)cccc2c1Nc1ccc(O)cc1C
Yield: 24.7 %

Procedure:
A solution of 3-butyryl-4-chloro-8-acetylquinoline (2.0 g) and 4-amino-3-methylphenol (1.23 g, 10 mmol) in 1,4-dioxan (25 ml) was warmed briefly to reflux, then the dioxan evaporated. Chromatography (silica, 4-6% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline (0.65 g), m.p. 183°-185°.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[O:22]=[C:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.[Cl-].[NH4+]>O1CCCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:23]3([OH:22])[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a stirred suspension of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (3.0 g, 14 mmol) in tetrahydrofuran (75 mL) was added chlorotrimethylsilane (4.5 mL, 35 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours and a 2M solution of 2-propylmagnesium chloride in THF (37 mL, 74 mmol) was added dropwise. After 3 hours, tert-butyl 3-oxopiperidine-1-carboxylate (5.6 g, 28 mmol) was added in one portion. The mixture was stirred at room temperature overnight at which time LC/MS indicated the reaction was complete. The reaction was poured over a mixture of ice and saturated aqueous ammonium chloride (500 mL). The mixture was allowed to warm to room temperature and was extracted with ethyl acetate (250 mL) four times. The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The crude solid was triturated with a 2:1 mixture of ethyl acetate:heptane to obtain the title compound (2 g) having the following physical data.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[OH:21])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:31].CC(C)=O>C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[O:21][C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:22])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@@H]12
Reactant: CCCCCCCCCCCCOC(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](CC)C[C@]12C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11β-Ethyl-17β-dodecyloxycarbonyloxyestr-4-en-3-one (9b, CDB-4722) was prepared as follows: Under nitrogen, a solution of 11β-ethylestr-4-en-17β-ol (7b, 0.1 g, 0.33 mmol) in dry CH2Cl2 (5 mL) was cooled to 0° C. in an ice bath. Pyridine (0.1 mL, 97.8 mg, 1.24 mmol) followed by dodecyl chloroformate (0.2 mL, 1.84 mg, 0.74 mmol) were added and the mixture stirred at 0° C. for 15 min and then allowed to warm to room temperature. The reaction was stirred at room temperature overnight, after which time, TLC (2% acetone in CH2Cl2) indicated a complete reaction. The mixture was diluted with additional CH2Cl2 (50 mL) and washed with water (1×), saturated sodium bicarbonate solution (1×), and water (1×). The organic fractions were filtered through anhydrous Na2SO4, combined and concentrated in vacuo to give 0.3 g residue as a clear oil. This crude material was purified by Flash chromatography (2% acetone in CH2Cl2) to give 0.16 g of a clear oil in 94% yield, which resisted crystallization.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=3)[CH2:22][C:21](=[O:33])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCCC4)c(F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-fluoro-5-pyrrolidin-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M47) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (54 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:18])(=[O:3])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36]OC(=N)C(Cl)(Cl)Cl)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:36][CH2:35][C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[C:6]1=[O:18])(=[O:3])[CH3:2]
Reactant: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OCc1ccccc1
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Solvent: ClCCl
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
To a chilled (0° C.) solution of (3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (15.0 g, 58.7 mmol) in anhydrous dichloromethane (100 mL) was added tetrafluoroboric acid diethyl ether complex (3.2 mL). The resultant reaction mixture was stirred at 0° C. for 20 minutes before adding a solution of 2-(3-benzyloxy-4-methoxy-phenyl)ethyl-2,2,2-trichloroacetimidate (24.8 g, 61.6 mmol, 1.05 equiv.) in dichloromethane (100 mL) via an addition funnel over 30 minutes. The reaction mixture was stirred at 0° C. until the reaction was judged complete by HPLC analysis. The reaction mixture was quenched with water (250 mL). The organic layer was separated from the aqueous layer and subsequently washed with dilute NaHCO3 (5% wt solution, 2×100 mL), and water (5×100 mL). The organic layer was dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to −100 mL solution. The solution was cooled at −20° C. for 24 hours and the precipitate (trichloroacetamide) was removed by filtration. The filtrate was further concentrated to a volume of ˜40 mL. This process was repeated three times until the bulk of the by-product (trichloroacetamide) was removed. After the third filtration, the filtrate was concentrated in vacuo to give (1R,2R)-1-{2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate as a pale yellow syrup (25 g, 86% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9](I)=[C:8]([CH3:11])[N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CC(N(C)C)=O.C(OCC)(=O)C.CCCCCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:19]([O:18][C:14](=[O:17])/[CH:15]=[CH:16]/[C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([S:12][CH3:13])=[N:7][C:8]=1[CH3:11])[CH3:20]
Reactant: CCNc1nc(SC)nc(C)c1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: CCNc1nc(SC)nc(C)c1/C=C/C(=O)OCC
Temperature: 100 °C
Yield: 73.3 %

Procedure:
To the solution of N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 81.48 mmol) in DMA (260 mL) were added ethyl acrylate (12.23 g, 122.2 mmol), Pd(OAc)2 (3.65 g, 16.25 mmol), (+)BINAP and triethyl amine (24.68 g, 244.4 mmol). Then the reaction mixture was heated to 100° C. and reacted overnight. After evaporation of solvent, the residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The product (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 73% yield) was isolated by silica gel column chromatography with 6-8% ethyl acetate in hexane as eluent. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J=16.4 Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 5.15 (bs, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.54 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:13]([O:15][CH:16]([O:22]CC)[C:17](OCC)=O)C>C[N+]([O-])=O.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:17]([C:16]([O:15][CH3:13])=[O:22])[O:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)C(OCC)OCC
Reactant: COc1ccc(CCO)cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2cc(Br)c(OC)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled mixture of 2-[3-bromo-4-(methyloxy)phenyl]ethanol (9.5 g, 41 mmol) and ethyl bis(ethyloxy)acetate (8.7 g, 48 mmol) in 60 mL of CH3NO2 was added TiCl4 (31.2 g, 169 mmol) over a period of 20 min. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatography to give methyl 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:26]=[CH:27][C:28]=2[CH3:29])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+]>CO.C1COCC1.O>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[N:14]=[C:13]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)CCc1ccc(C)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COc3cc(CCC(=O)O)ccc3C)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)-4-methylphenyl)propanoate (400 mg) in methanol (5.0 mL) and THF (10 mL) was added a solution of sodium hydroxide (333 mg) in water (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][OH:11])[O:7][C@H:6]1[N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([NH2:42])(=[O:41])=[O:40]>CN(C=O)C.C(#N)C.CCOC(C)=O.O>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][O:11][S:39](=[O:41])(=[O:40])[NH2:42])[O:7][C@H:6]1[N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@H]1C[C@@H](COS(N)(=O)=O)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Yield: 52 %

Procedure:
To a solution of (2R,3R,5S)-5-hydroxymethyl-2-[6-((S)-indan-1-ylamino)-purin-9-yl]tetrahydrofuran-3-yl acetate (0.20 mmol) and triethylamine (56 μL, 0.0.40 mmol) in DMF (3.3 mL) was added dropwise 150 μL of a 2M solution of the chlorosulfonamide in acetonitrile and the cloudy solution was stirred. Identical amounts of triethylamine and the chlorosulfonamide solution were added after 2.5 and 4 hours. The reaction was diluted with EtOAc and water, the layers were separated, and the aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0% to 10% MeOH/CH2Cl2) to afford 51 mg (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].[H-].[Na+].[C:15](Cl)([Cl:17])=[O:16]>O1CCCC1.C(Cl)Cl>[Cl:17][C:15]([O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11])=[O:16]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Cl)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dichloro-4-nitrophenol (5.0 g, 24.0 mmol) in 10 ml of tetrahydrofuran is added dropwise to a suspension of sodium hydride (1.33 g, 50% NaH, 27.6 mmol) in 20 ml of THF. After the addition, stirring is continued for 1 hour at RT and is the mixture is then added dropwise to a solution of phosgene (14.0 g) in 50 ml of methylene chloride at -10°. The mixture is allowed to warm to RT and is purged with N2 to remove excess phosgene. The solvent is stripped and the residue is taken into methylene chloride. The precipitated sodium chloride is filtered and the filtrate is concentrated to give 2,6-dichloro-4-nitrophenyl chloroformate.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1.[Br-:16].[Br-].[Br-].P>C1(C)C=CC=CC=1>[Br:16][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: [Br-]
Reactant: N#Cc1ccccc1-c1ccc(CO)s1
Agent: P
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.1 %

Procedure:
To a solution (50 mL) of 2-[5-(hydroxymethyl)thiophen-2-yl]benzonitrile (2.60 g) in toluene was added phosphine tribromide (2.60 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.20 g, 95%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[OH:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: OCc1cnn(O)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1cc(CO)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-hydroxymethylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, oil).