Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH:3]([OH:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=1)[CH2:19][C@H:2]([NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C@H:3]([OH:18])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCC(=O)O1
Reactant: CCc1ccc2c(c1)C(NCC(O)C(N)Cc1cc(F)cc(F)c1)CCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)CCCC(=O)O)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol (0.240 g, 0.64 mmol), triethylamine (0.268 mL, 1.92 mmol), and chloroform (3 mL) was added glutaric anhydride (0.073 g, 0.64 mmol) and reaction was stirred overnight at 60° C. Reaction was washed with 1N HCl, 10% NaHCO3, brine, dried over MgSO4, filtered, concentrated in vacuo to give 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (100 mg). Purified via prep-HPLC. 1H NMR (400 MHz, CD3OD) δ 1.26 (t, J=8 Hz, 3 H), 1.73 (m, 2 H), 1.89 (m, 1 H), 2.01 (m, 1 H), 2.17 (m, 6 H), 2.68 (d, J=8 Hz, 2 H), 2.93 (d, J=6 Hz, 1 H), 3.02 (m, 1 H), 3.30 (m, 2 H), 3.88 (m, 1 H), 4.09 (m, 1 H), 4.57 (m, 1 H), 6.79 (m, 1 H), 6.88 (m, 3 H), 6.93 (d, J=6 Hz, 1 H), 7.20 (m, 2 H), 7.31 (s, 1 H); OAMS: ES+488.9 ES−486.9
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[CH2:31]1[C:39]2[C:34](=[CH:35][C:36](O)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:31]1[C:39]2[C:34](=[CH:35][C:36]([O:19][C:18]([C@H:15]3[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:13][CH2:14]3)=[O:20])=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(N[C@H]1CC[C@@H](C(=O)Oc2ccc3c(c2)CCC3)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a stirred, ice-cold solution of the product from part (a) (1.70 g, 6.13 mmole) in dry methylene chloride (30 ml) were added sequentially, 1-hydroxybenzotriazole (0.92 g, 6.77 mmole), 5-indanol (2.0 g, 15 mmole), N-methylmorpholine (0.80 g, 7.92 mmole) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.53 g, 7.98 mmole). After 10 minutes, the resulting solution was concentrated to an oil which was stirred at room temperature for 18 hours and then dissolved in methylene chloride (150 ml). The latter solution was washed in turn with water (2×50 ml), saturated aqueous sodium bicarbonate solution (2×25 ml), 2N hydrochloric acid (2×25 ml) and saturated brine (2×25 ml), then dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent under vacuum, gave an oil which was purified by chromatography on silica gel eluting with hexane-ethyl acetate (4:1). The appropriate fractions were combined and the solvent evaporated under vacuum to furnish the title compound as a white solid (2.20 g, 91%), which was crystallised from a mixture of diethyl ether and n-pentane, m.p. 68°-69° C. Found: C,73.30; H,7.04; N,3.43. C24H27NO4 requires C,73.26; H,6.92; N,3.56%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:32][C:33]1[CH:50]=[CH:49][C:36]([CH2:37][N:38]2[CH2:42][CH2:41][CH:40]([CH2:43][NH:44][C:45](=[O:48])[CH2:46][NH2:47])[CH2:39]2)=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:47][CH2:46][C:45]([NH:44][CH2:43][CH:40]1[CH2:41][CH2:42][N:38]([CH2:37][C:36]2[CH:49]=[CH:50][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH2:39]1)=[O:48])=[O:6]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
2-Amino-4,5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added to a solution of 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidine (0.050 mmol) in chloro form (1.35 mL) and tert-butanol (0.05 mL). The resulting reaction Mixture was stirred at room temperature for 19 hours, then loaded onto a Varian™ SCX column and washed with methanol/chloroform=1:1 (10 mL) and methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 3-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1506) (22.0 mg, quantitative). The purity was determined by RPLC/MS (92%). ESI/MS m/e 437 (M++H, C21H23ClF2N4O2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCC1CC1
Product: CN(CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CC1CC1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-Methylcyclopropanemethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine, MS: 401 (MH+, 1Cl).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:7][CH:6]=1)=[O:4].[OH-].[Li+].ClCCl>C1COCC1.CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(-c2ccccn2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2-Pyridin-2-yl-thiazol-5-carboxylic acid methyl ester (0.34 g, 1.55 mmol) was dissolved in a THF/methanol (5 ml/1 ml) mixture, cooled to 0° C. and treated with lithium hydroxide (4.7 ml, 1N aqueous solution). The reaction mixture was allowed to warm-up to ambient temperature, stirred at that temperature for 30 min and the pH value was subsequently adjusted to ˜5. The resulting suspension was treated with dichloromethane (50 ml) and filtered. The precipitate was washed with water and dichloromethane, the filtrate was extracted with dichloromethane. The combined organic phases were dried, evaporated and combined with the precipitate to yield the product as light brown solid (0.3 g, 92%). MS: M=161.1 (M-CO2—H)−
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:23][CH2:24]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:32]=1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 110.2 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (88 mg) under a nitrogen atmosphere, 10% palladium-carbon (45 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (90 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24]([NH:34][C:35]([CH3:40])([C:37](O)=[O:38])[CH3:36])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:37](=[O:38])[C:35]([NH:34][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([CH3:40])[CH3:36])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
The amine obtained in Step B of this Example (300 mg; 1.37 mmol) triethylamine (380 ml; 2.73 mmol) and N-carbobenzyloxy-2-methylalanine (278 mg; 1.37 mmol) were dissolved in dry methylene chloride (3 ml) and BOP (605 mg; 1.37 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and the resultant homogenous yellow solution quenched by addition of brine. The two phase system was extracted with methylene chloride (2×25 ml) and the combined methylene chloride layers dried over powdered anhydrous magnesium sulfate. Filtration of the methylene chloride solution to remove the spent drying agent followed by evaporation of solvent afforded an oil which was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate and hexanes (1:1 v/v) as eluant. The desired product (419 mg; 69.7%) was isolated as a white amorphous solid. FAB-MS:- calculated for C25 H30N2O5 438.2; found 439.3 (M+1).
Reaction SMILES: [F:1]/[CH:2]=[C:3]1\[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]\1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:1]/[CH:2]=[C:3]1\[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]\1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C/C(=C\F)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC/C(=C/F)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 70.6 %

Procedure:
1200 mg of (Z)-3-fluoromethylene-4-androsten-17-beta-ol is dissolved in 30 ml of acetone and mixed at 0° C. with 1.5 ml of Jones reagent. Then it is added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate and concentrated. After chromatography on silica gel with hexane/ethyl acetate, 842 mg of (Z)-3-fluoromethylene-4-androsten-17-one is obtained with a melting point of 101°-102° C.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:34]=1[CH:35]=O.COC(=O)C.[Cl:48]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:48].[CH3:31][O:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:34]=1[CH2:35][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: COc1ccc(CN(CC[C@@H](C)Oc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)c(OC)c1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 2,4-dimethoxybenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The free base was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 73 mg (71%). MS (ESI) 554.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][O:13][CH2:26][O:27][CH3:28])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COCCl
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 46 h
Yield: 69.2 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (7.4 g, 31 mmol) was dissolved in methylene chloride (120 ml). N,N-diisopropylethylamine (13.1 ml, 74 mmol) and chloromethylmethyl ether (7.1 ml, 74 mmol) were added to the solution followed by stirring at room temperature for 46 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-2-chloro-1-(2-hydroxy-3-methoxymethoxy-2-methylpropyl)-4-nitroimidazole (6.0 g, yield 69%) as a light yellow oil.
Reaction SMILES: [ClH:1].Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[O-]CC.[Na+:14].[C:15](OC)(=[O:19])[C:16]([CH3:18])=[CH2:17].Cl>>[CH3:17][CH:16]1[CH2:18][N:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:4][C:15]1=[O:19].[Cl-:1].[Na+:14]
Reactant: C=C(C)C(=O)OC
Reactant: NNc1cccnc1
Reactant: Cl
Agent: CC[O-]
Agent: [Na+]
Product: CC1CN(c2cccnc2)NC1=O
Product: [Cl-]
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 730.9 %

Procedure:
To a 250 mL three-neck round bottom flask equipped with a reflux condenser was introduced 3-hydrazinopyridine.dihydrochloride (15.0 g, 82.4 mmol). Sodium ethoxide (21 wt % in ethanol, 92.3 mL, 247 mmol) was added over 5 minutes and the pot temperature increased from 23° C. to 38° C. The resultant light brown-slurry was stirred for 10 minutes. Methyl methacrylate (17.7 mL, 165 mmol) was added slowly over 15 minutes and the pot temperature remained at 38° C. The yellow mixture was stirred at 50° C. under nitrogen for 4 hours. The mixture was then cooled down to 10° C. and hydrochloric acid (4 M in 1,4-dioxane, 20.6 mL) was added slowly to quench excess base leading to a light brown suspension. The mixture was concentrated under reduced pressure to afford the title compound as a brown solid as a mixture with sodium chloride (35.2 g, 241%): EIMS m/z 177 ([M]+). The crude material was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[N:4][N:5]([CH3:7])[CH:6]=1.O[CH:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Br:1][C:2]1[C:3]([N:8]([C:9]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:16])[C@H:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])[CH2:31][CH:32]([CH3:34])[CH3:33])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: COc1ccc(COC(=O)C(O)CC(C)C)cc1
Reactant: Cn1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C)cc2Br)cc1
Reaction time: 48 h

Procedure:
To 2,2,2-trichloroethyl 4-bromo-1-methyl-1H-pyrazol-3-ylcarbamate (2.402 g, 6.83 mmol), 4-methoxybenzyl 2-hydroxy-4-methylpentanoate (3.45 g, 13.67 mmol) and triphenyl phosphine (3.58 g, 13.67 mmol) in dry DMF (50 mL) under dry nitrogen was added dropwise diisopropyl azodicarboxylate (2.7 mL, 13.67 mmol) over 45 minutes and the reaction mixture stirred for 2 days. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[N:8][C:7]=2[N:6]([CH3:34])[C:5]1=[O:35].[CH3:36][NH:37][CH3:38]>C(OCC)(=O)C.O>[ClH:21].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:4]([CH2:3][CH2:2][N:37]([CH3:38])[CH3:36])[C:5](=[O:35])[N:6]([CH3:34])[C:7]=3[N:8]=[C:9]2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)=[CH:16][CH:17]=1
Reactant: Cn1c(=O)n(CCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Product: Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
1-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.0.210 mmol) was dissolved in aqueous dimethylamine (3 mL), then the mixture was heated to 100° C. in a sealed tube with stirring overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by preparative HPLC and lyophilized to give 7-(4-chlorobenzyl)-1-(2-(dimethylamino)ethyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione hydrochloride (29 mg, 25.6% yield) as white solid. 1H-NMR (DMSO-d6) δ 9.67(s, 1H), 7.64-7.60(t, 1H), 7.47-7.41(m, 6H), 7.36-7.34(m, 1H), 5.46(s, 2H), 4.23-4.21(m, 2H), 3.37-3.34(m, 2H), 3.31(s, 3H), 2.87-2.86(d, 6H). LCMS retention time 2.174 min; LCMS MH+ 538.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[OH-].[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO.O.Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])/[CH:11]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)=O)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)/C=C/c2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 1-(2-bromo-4-methoxyphenyl)ethanone (6.2 g, 27.06 mmol) obtained in Step 1 in EtOH (50 mL) at 0° C. was added sequentially aq. NaOH solution (8.12 mL, 81.19 mmol, 3 eq) and benzaldehyde (3.3 mL, 32.48 mmol, 1.2 eq). After being stirred for additional 4 h at room temperature, the mixture was diluted with H2O and neutralized with 3N HCl. The resulting mixture was extracted with EtOAc (20 mL×3). The extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to obtain the desired product (6 g, 70%).
Reaction SMILES: C=CCCC.C([Li])(C)(C)C.[CH3:11][CH:12]([CH:16]([CH3:18])[CH3:17])/[CH:13]=[CH:14]/I.[C:19]([CH:22]1[C:30]2([CH3:31])[CH:25]([C:26](=[CH:32][CH:33]([C:36]34[CH2:41][CH:40]3[CH2:39][CH:38]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:37]4=[CH2:50])[O:34][CH3:35])[CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].Cl[C:52]([O:54][CH3:55])=[O:53].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[CH3:11][CH:12]([CH:16]([CH3:18])[CH3:17])/[CH:13]=[CH:14]/[C@@:19]([CH:22]1[C:30]2([CH3:31])[CH:25]([C:26](=[CH:32][CH:33]([C:36]34[CH2:41][CH:40]3[CH2:39][CH:38]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[C:37]4=[CH2:50])[O:34][CH3:35])[CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23]1)([O:21][C:52]([O:54][CH3:55])=[O:53])[CH3:20]
Reactant: C=C1C(O[Si](C)(C)C(C)(C)C)CC2CC12C(C=C1CCCC2(C)C(C(C)=O)CCC12)OC
Reactant: COC(=O)Cl
Reactant: CC(C)C(C)/C=C/I
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C=CCCC
Product: C=C1C(O[Si](C)(C)C(C)(C)C)CC2CC12C(C=C1CCCC2(C)C1CCC2[C@](C)(/C=C/C(C)C(C)C)OC(=O)OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 ml of 1.5M pentene solution of t-butyllithum was dropwise added, at -78° C., to a solution 416 mg of (E)-3,4-dimethyl-1-iodo-1-pentene dissolved in 5 ml of diethyl ether. The reaction mixture was stirred at room temperature for 2 hours. Thereto was dropwise added a solution of 682 mg of 1-acetyl-4-(2-(3-(t-butyldimethylsilyloxy)-2-methylenebicyclo[3.1.0]hexane-1-yl)-2-methoxyethylidene)-2,3,3a,4,5,6,7,7a-octahydro-7a-methylindene dissolved in 10 ml of tetrahydrofuran. The mixture was stirred for 1 hour. Thereto was dropwise added 0.3 ml of methyl chloroformate. The mixture was stirred at room temperature overnight. The reaction mixture was mixed with an aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and concentrated under reduced pressure to obtain 1.04 g (2S,3E)-5,6-dimethyl-2-(4-(2-(3-(t-butyldimethylsilyloxy)-2-methylenebicyclo[3.1.0]hexane-1-yl)-2-methoxyethylidene)-2,3,3a,4,5,6,7,7a-octahydro-7a-methylinden-1-yl)-2-methoxycarbonyloxy-3-heptene having the follow property.