Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]([CH:13]1[CH2:17][NH:16][C:15](=[O:18])[CH2:14]1)[CH2:11][CH3:12].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O.C(N(CC)C(=O)OCN1CC(CCC)CC1=O)C>C(#N)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[N:16]1[CH2:17][CH:13]([CH2:10][CH2:11][CH3:12])[CH2:14][C:15]1=[O:18]
Reactant: CCCC1CNC(=O)C1
Reactant: O=Cc1ccco1
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(C(c2ccco2)c2c[nH]c3ccccc23)C1
Temperature: 25 °C

Procedure:
A solution of indole x4 (117 mg, 1 eq, 1 mmol), 4-propylpyrrolidin-2-one 1 (127 mg, 1 eq, 1 mmol), 2-furaldehyde x5 (0.33 ml, 4 eq, 4 mmol) and (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (25 mg, 0.1 eq, 0.1 mmol) in acetonitrile (3 ml) is heated 30 minutes in a microwave apparatus (Biotage, 150 W, 130° C.). After cooling to room temperature, the solvent is removed under reduced pressure, and the crude mixture is purified by preparative chromatography on silicagel (CH2Cl2) leading to 1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 153 as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C: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)=[C:9]([CH2:11][S:12]([CH2:15][C:16]([O:18]CC)=[O:17])(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:32])[F:33])[CH:24]=3)=[C:9]([CH2:11][S:12]([CH2:15][C:16]([OH:18])=[O:17])(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)CS(=O)(=O)Cc1nc2ccc(Cl)cn2c1C#Cc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CS(=O)(=O)Cc1nc2ccc(Cl)cn2c1C#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
100 mg (0.200 mmol) of ethyl 2-((6-chloro-3-((3-(trifluoromethoxy)phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylsulfonyl)acetate were dissolved in 2 ml of ethanol before adding 0.060 ml (0.599 mmol) of a 32% sodium hydroxide aqueous solution. The mixture was stirred at r.t. for 16 h. The solution was poured into 10 ml of water, acidified to an acid pH with acetic acid, extracted with 2×5 ml of dichloromethane, the combined organic phases were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. 76 mg (yield=80%) of 2-((6-chloro-3-((3-(trifluoromethoxy)phenyl)ethynyl)-imidazo[1,2-a]pyridin-2-yl)methylsulfonyl)acetic acid were obtained as a yellow solid. LC-MS: m/z=473 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 14.72-12.20 (m, 1H), 9.00 (d, J=1.2 Hz, 1H), 7.88-7.76 (m, 3H), 7.62-7.45 (m, 3H), 4.96 (s, 2H), 4.42 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:47][C:48](=O)[CH2:49][C:50]([F:53])([F:52])[F:51].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:48](=[O:47])[CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: O=C(CC(F)(F)F)ON1C(=O)CCC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
The compound (66 mg, 0.15 mmol) prepared in Example 117 was dissolved in dichloromethane (10 ml). Diisopropylethylamine (0.08 ml, 0.44 mmol) and 3,3,3-trifluoropropionic acid 2,5-dioxo-pyrrolidin-1-yl ester (29 mg, 0.13 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (6 mg, Yield 9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: O=C1CC2(CCCC2)c2ccc(O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)C(=O)CC21CCCC1

Procedure:
A mixture of 5'-hydroxy-spiro(cyclopentane-1,1'-indan)-3'-one (20.2 g; 0.1 mole), acetone (1000 ml), anhydrous potassium carbonate (37.5 g) and methyl iodide (50 ml) is refluxed for 5-6 hours. The mixture is evaporated to dryness, after which the residue is taken up in water and trichloroethylene. The trichloroetylene solution is extracted with 2×150 ml of 2 N sodium hydroxide and dried with anhydrous magnesium sulphate. The solvent is distilled off and a yellow oil is obtained, which soon crystallizes, yield 16 g (74%). After recrystallization from n-hexane the substance melts at 80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:29]=[N:28][C:27]([O:26][CH2:24][CH3:25])=[CH:32][CH:31]=3)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4′-bromo-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.Cl.[CH3:24][O:25][NH2:26]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[N:26][O:25][CH3:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CON
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C(C)c2nc(N)no2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 105.2 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.60 g, 2.0 mmol) in pyridine (10 ml) was added methoxyamine hydrochloride (0.224 g, 2.7 mol). After reflux with stirring for 18 h, the mixture was poured upon ice water, extracted with ethylacetate. The extracts were washed with water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(α-methoxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.678 g, quantitive yield) as oily substance: NMR(CDCl3)δ 1.70(d, 3H), 3.97(s, 3H), 4.24(q, 1H), 4.48(broad singlet, 2H), 7.21-7.58(m, 9H) ppm; IR(neat) 3310, 3220, 1625, 1585, 1410, 1050 cm-1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.OC1C2N=NNC=2C=CC=1.[NH:50]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:51]([C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH:52]([CH3:54])[CH3:53].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[C:65]([O:64][C:62](=[O:63])[NH:50][CH:51]([C:55](=[O:56])[NH:57][CH2:58][C:59](=[O:60])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])[N:20]([CH2:35][CH2:36][O:37][CH3:38])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:52]([CH3:53])[CH3:54])([CH3:66])([CH3:68])[CH3:67]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)C(NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(C(=O)N3CCOCC3)cccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indol-3-yl]-methanone hydrochloride (100 mg, 0.18 mmol) was dissolved in DMF (2.6 mL) under nitrogen and stirred at 0° C. for 5 min. To this was added sequentially hydroxybenzotriazole (77 mg, 0.57 mmol), BOC-Val-Gly-OH (59 mg, 0.21 mmol), triethylamine (0.05 mL, 0.36 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg, 0.21 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL). The brine was back extracted with ethyl acetate (2×30 mL) and the organic fractions were combined and washed with 10% citric acid (2×30 mL), sat sodium bicarbonate solution (2×30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by SiO2 column chromatography using 5% MeOH/CH2Cl2 as the eluent to afford (1-{[(4-fluoro-3-{1-[1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-methyl]-carbamoyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (100 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.40-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.18-7.10 (m, 1H), 7.08-7.00 (m, 1H), 6.98-6.85 (m, 1H), 5.00-4.90 (br s, 1H), 4.30 (t, 2H), 3.85-3.70 (br m, 2H), 3.73 (t, 2H), 3.47 (s, 2H), 3.33 (s, 3H), 3.20-2.90 (br m, 2H), 1.90-1.60 (br m, 6H), 1.30-1.24 (m, 10H), 1.80-1.70 (br m, 6H); 19F NMR (282 MHz, CDCl3) δ −57.60 (s, 1F); MS m/z: [M+H]+=779.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38].CCN(C(C)C)C(C)C.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:38])([F:39])[F:40])[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Reactant: FC(F)(F)c1ccccc1CCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCc2cn(Cc3ccccc3C(F)(F)F)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (35 mg, 0.030 mmol) and morpholine (174 μl, 2.0 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (50 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:20][CH3:21].[CH2:22]1COC[CH2:23]1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:20][CH3:21])[CH:3]=[N:4][CH:5]=1.[Br:8][C:6]1[CH:7]=[C:2]([N:1]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:3]=[N:4][CH:5]=1
Reactant: C1CCOC1
Reactant: CCI
Reactant: Nc1cncc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCN(CC)c1cncc(Br)c1
Product: CCNc1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-amino-5-bromopyridine (CAS#13535-01-8, 520 mg, 3.0 mmol) in THF (12 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 6.9 mL, 3.45 mmol). The reaction was stirred for 20 minutes at −78° C. and was then charged with iodoethane (0.25 mL, 3.15 mmol). The reaction was stiffed for an additional 30 minutes, at which time mixture was charged with additional potassium bis(trimethylsilyl)amide (0.5 M in toluene, 6.9 mL, 3.45 mmol) and iodoethane (0.25 mL, 3.15 mmol). The reaction was then permitted to warm to −20° C. over 2 h at which time it was quenched with aqueous ammonium hydroxide (5 mL) and was stirred for 30 minutes at room temperature. The reaction was then diluted with brine and ethyl acetate. The layers were separated and the aqueous layer was extracted two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford both (5-bromo-pyridin-3-yl)-ethyl-amine and (5-bromo-pyridin-3-yl)-diethyl-amine separately.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:31][C:27]3[S:28][CH:29]=[CH:30][C:26]=3[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cc2ccsc2s1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccsc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example D4 above), the title compound was prepared as a solid. The product was purified by titruation from Et2O/hexanes.
Reaction SMILES: C(OC(=O)NCC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1C#N)=O)(C)(C)C.F[C:20](F)(F)[C:21]([OH:23])=O.Cl[CH2:27]Cl>>[CH2:15]1[CH:14]2[CH2:27][C:21](=[O:23])[CH2:20][CH:13]2[CH2:12][NH:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C#N
Product: O=C1CC2CNCC2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 1e (0.32 g, 1.42 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (3.27 mL, 42.7 mmol) was then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 30 minutes, then the solvent was evaporated to dryness to obtain the title compound hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f which was directly used in the further reaction.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[CH2:22]([SH:25])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[S:25][CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1
Reactant: CCCS
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 125.9 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg, 0.27 mmol, intermediate 8) in DMF (5 mL) was added propane-1-thiol (24.7 mg, 0.32 mmol) followed by potassium carbonate (112.2 mg, 0.81 mmol). The reaction was stirred at 60° C. for 4 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude white solid product (124 mg, 99.9% yield). LCMS MH+ 365.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][C@@H:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][C:33](=[O:42])[NH:32]1.[Cl-].[Li+]>C1COCC1>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:32]2[C@H:31]([CH3:30])[C@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: C[C@@H](CCC(=O)O)CCC1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4.17 g (19.6 mmol) of (R)-6-cyclohexyl-4-methyl-hexanoic acid, 40 mL of THF, and 8.56 mL (61.4 mmol) of triethylamine. The mixture was cooled in a 0° C. bath, and 2.41 mL (19.6 mmol) of pivaloyl chloride was added. The mixture was stirred for 1 h at 0° C. Then 2.79 g (16.4 mmol) of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.823 g (19.6 mmol) of lithium chloride were added as solids. The mixture was allowed to warm to room temperature and stirred overnight. The resulting solids were filtered off. The solvent was stripped under reduce pressure, and the residue was purified by column chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g (quant.) of a clear oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (m, 8 H) 1.16 (m, 6 H) 1.68 (m, 9 H) 2.87 (m, 1 H) 2.99 (m, 1 H) 4.76 (qd, J=6.83, 6.59 Hz, 1 H) 5.66 (d, J=7.32 Hz, 1 H) 7.30 (m, 2 H) 7.40 (m, 3 H). MS (APCl) m+1/z=372.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=O)[CH:3]([CH2:4]2)[CH2:2]1.[CH3:9][O-].[Na+].CO.[CH:14]1[CH2:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.O>[C:3]12([C:15]3[C:14](=[CH2:9])[CH:18]=[CH:17][CH:16]=3)[CH2:4][CH:5]([CH2:6][CH2:7]1)[CH2:1][CH2:2]2
Reactant: C[O-]
Reactant: C1=CCC=C1
Reactant: O=C1CC2CCC1C2
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: C=C1C=CC=C1C12CCC(CC1)C2
Reaction time: 68 h

Procedure:
Norcamphor (10.00 g, 90.8 mmol) and sodium methoxide (12.0 g, 222 mmol) and 100 mL methanol were added to a 250 mL flask. The solids were dissolved before addition of cyclopentadiene (12.0 g, 182 mmol). After stirring for 68 hours, 200 mL water and 100 mL diethyl ether were added to the deep red solution. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered and rotavapped to yield the crude product in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([O:26][CH:27]([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=1[O:8][CH3:9].[C-:30]#[N:31].[Na+].C(OCC)(=O)C>C(#N)CC.[Cu](I)I>[C:30]([C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([O:26][CH:27]([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=1[O:8][CH3:9])#[N:31]
Reactant: CCOC(=O)C(Cc1cc(Br)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: [C-]#N
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(C#N)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Yield: 75.5 %

Procedure:
876 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml propionitrile, and 182 mg of sodium cyanide, 214 mg of tetrakistriphenylphosphine palladium and 70 mg of copper iodide were added, followed by heating under reflux overnight in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added thereto and filtered through Celite. The filtrate was evapoarated and the residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (4:1), 586 mg of ethyl 3-(3-cyano-5-[(tertiary butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH:42][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-CCl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.