Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:16])[CH2:12][CH:13]3[CH2:15][O:14]3)[CH2:9][CH2:8][CH:7]1[CH:6]([OH:17])[CH2:5][CH2:4][CH2:3]2.C(OCC)(=O)C.[CH3:24][Si:25](C1NC=CN=1)([CH3:27])[CH3:26]>O>[CH3:24][Si:25]([O:17][CH:6]1[CH2:5][CH2:4][CH2:3][C:2]2([CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]2[CH:11]([CH3:16])[CH2:12][CH:13]1[CH2:15][O:14]1)([CH3:27])[CH3:26]
Reactant: CC(CC1CO1)C1CCC2C(O)CCCC12C
Reactant: C[Si](C)(C)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CC1CO1)C1CCC2C(O[Si](C)(C)C)CCCC12C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.4 g of [1R-[1alpha(R*,S*), 3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol and 40 mL of ethyl acetate is added 1.64 g of trimethylsilylimidazole. The mixture was stirred under a dry argon atmosphere at room temperature for 20 minutes then poured into 100 mL of cold water and extracted 3×25 mL of heptane/ethyl acetate (1:1). The extracts were washed with 3×50 Ml of water and dried over anhydrous sodium sulfate. The mixture was filtered and solvent removed in vacuo. Chromatography on silica gel (2.5×100 cm Altex column, 40-60μ silica gel) eluting with hexane/ethyl acetate (6:1) gave 1.81 g (99%) of [1R-[1alpha(R*,S*),3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol trimethylsilyl ether. This material which contained traces of starting material and slowly reverted to starting material on standing was used with no further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=O)[NH:9]2.Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:14]([C:8]3[NH:9][C:10]4[C:6]([CH:7]=3)=[C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH:13]=[CH:12][CH:11]=4)=[O:16])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 85 (preparation see below) and amine 5.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.CC(C)=[O:27]>[OH-].[Na+]>[C:17]([O:16][C:14]([NH:9][C@@H:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:22][CH:21]=1)[CH2:12][CH2:11][C:10]([OH:13])=[O:27])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
(R)-tert-Butyl 2-(4-(trifluoromethyl)benzyl)-5-oxopyrrolidine-1-carboxylate (4.0 g, 12 mmol) was dissolved in 25 mL acetone and 40 mL of 1.0 M aqueous sodium hydroxide. The resulting mixture was stirred for 30 minutes. The acetone was removed and the mixture was acidified with 5.0 M HCl. The resulting solid was filtered and washed with water twice. The crude product was recrystallized from hexane/EtOAc solvent (10:1 ratio, total volume hexane: 100 mL). After the solution was cooled, the crystals slowly appeared and the solution was put in the freezer for 2 hours. Filtration of the solid afforded the desired compound as a white crystalline solid (3.9 g, 93%). MS (API-ES) m/z (%): 384.1 (100%, M++Na).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14].[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14]
Reactant: Cc1cc2ccccc2c(O)c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C#N)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
The suspension of 1-hydroxy-3-methyl-2-naphthonitrile (47.23 g), potassium carbonate (71.3 g), iodomethane (100 ml), and DMF (250 ml) was-stirred overnight at ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from water/methanol to give the titled compound (50 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1.[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[C:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a reactivial containing ethyl [2-methyl-4-({[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (100 mg, 0.225 mmol) was added pyridine (0.321 mL, 3.97 mmol) and 1-propanesulfonyl chloride (25.3 μL, 0.225 mmol). The resulting mixture was stirred in a sealed reactivial at 80° C. for 16 h. The reaction mixture was allowed to cool to room temperature and was partitioned between CH2Cl2 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (12 g Silica column) eluted with 1:9 EtOAc:cyclohexane afforded the title compound as a yellow oil (20 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[CH2:23]([O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[CH3:24]
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Product: CCOC(=O)Nc1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.0 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (100 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (50 mg) and triethylamine (0.14 g) were added, the mixture was cooled to 0° C. and a solution of ethylchloroformate (0.44 g) in ethyl acetate (70 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-ethoxycarbonylamino-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.6 g). The oxalate salt was prepared by dissolving the free base in ether (200 ml) and a minimum amount of MeOH (20 ml) and adding a solution of oxalic acid in ether.
Reaction SMILES: C(OC(=O)[CH2:7][CH2:8][C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[OH:22]CCC1C=CC(C#N)=CC=1>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][OH:22])=[CH:10][CH:11]=1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CCO)cc1
Product: N=C(NO)c1ccc(CCO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-(2-hydroxy-ethyl)-benzonitrile; LC-MS: tR=0.50*min, [M+1]+=181.27.
Reaction SMILES: [CH:1]1([CH2:4][C:5](N(OC)C)=[O:6])[CH2:3][CH2:2]1.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>O1CCCC1>[CH:1]1([CH2:4][C:5](=[O:6])[CH2:13][CH:12]=[CH2:11])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)CC1CC1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(=O)CC1CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (C63) (48 g, 0.3 mol) in tetrahydrofuran (900 mL) was added a solution of allylmagnesium bromide (1.0 M in diethyl ether, 1.5 L, 1.5 mol) drop-wise at −60° C. The mixture was stirred at −60° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (120 mL). The reaction was extracted with dichloromethane (2×500 mL), and the organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried and concentrated in vacuo to give the product as a yellow oil, which was used directly in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>CS(C)=O.C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=4)=[O:41])=[CH:28][CH:27]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)c1
Temperature: 85 °C
Yield: 100 %

Procedure:
After dissolving 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (919 mg, 2.5 mmol) in dimethylsulfoxide (10 ml), phenyl N-(3-(methylsulfonyl)phenyl)carbamate (801 mg, 2.75 mmol) was added and the mixture was heated at 85° C. for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with 1N aqueous sodium hydroxide (10 ml), water (20 ml×2) and saturated saline (10 ml) and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the residue was suspended in ethyl acetate (30 ml), after which hexane (30 ml) was added, sonication was performed and the precipitated crystals were filtered out and dried under reduced pressure to obtain the title compound (1.43 g, 2.5 mmol) as light brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) and triethylamine (70 ml; 0.5 mol) in dichloromethane (1.5 l) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 0.75 mol) is added dropwise and the reaction mixture is then agitated for 1 hour at ambient temperature. The mixture obtained is then washed successively with water, a 10% solution of sodium bicarbonate and saturated salt water. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the product in the title (78 g; 91% yield) in the form of a whitish solid (M.p. 126-127.5° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.Cl[CH2:27][CH2:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][C:10]1[CH:11]=[C:3]([CH2:2][N:1]2[CH2:32][CH2:31][N:29]([CH3:30])[CH2:28][CH2:27]2)[CH:4]=[C:5]2[C:9]=1[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: CN(CCCl)CCCl
Reactant: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 110 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
In sealed vial, a mixture of 5-aminomethyl-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.104 g, 0.3 mmol), bis(2-chloro-ethyl)-methyl-amine (0.077 g, 0.4 mmol), and K2CO3 (0.083 g, 0.6 mmol) in DMF (3 mL) was stirred at 110° C. for 16 h. After this time, the GC-MS of the reaction mixture indicated the completion of reaction. The reaction was cooled to ambient temperature and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography of the resulting material using 5:1 CHCl3-MeOH afforded 7-methyl-5-(4-methyl-piperazin-1-ylmethyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.040 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.24 (s, 3H), 2.34-2.52 (m, 8H), 2.74 (s, 3H), 3.49 (s, 2H), 4.20 (s, 2H), 4.76 (s, 2H), 7.15-7.37 (m, 6H). GC-MS: m/z 433 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]=2[F:24])=[C:7]([F:14])[C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[F:24])=[C:7]([F:14])[C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: C=Cc1ccc(Nc2c(C(=O)OC)cn3ccnc3c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)OC)cn3ccnc3c2F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
8-Fluoro-7-(2-fluoro-4-vinyl-phenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (165 mg, 0.50 mmol) was suspended in ethanol (5 mL), added 10% Pd/C (267 mg, 0.25 mmol) and placed under an atmosphere of H2. The reaction mixture was stirred vigorously at room temperature for 16 hours. The reaction mixture was filtered through celite, washed with ethanol and tetrahydrofuran and the filtrate concentrated to a yellow oil. Purification of the crude product by flash column chromatography (gradient of dichloromethane to 20:1 dichloromethane/methanol) provided the desired product (110 mg, 66%) as a dark yellow solid. MS ESI (+) in/z 332 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CS(C)=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5]
Reactant: BrCc1ccccn1
Reactant: Cc1cc(O)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cc(OCc2ccccn2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-difluoro-N-{1-[(4-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Example 48)(103 mg, 0.30 mmol) in dimethyl sulfoxide (1 ml) was added cesium carbonate (195 mg, 0.60 mmol) and then 2-(bromomethyl)pyridine hydrobromide (107 mg, 0.423 mmol, Aldrich). The resulting red solution was stirred at ambient temperature under nitrogen overnight. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as an orange gum (28.3 mg); LCMS: (System 4) MH+=435, tRET=2.27 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nc(N)c3nc(O)n(Cc4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-methoxybenzyl chloride (0.098 ml, 0.72 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (80 mg, yield 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]([O-])=[O:32].[NH4+].CC([O:39]C)(C)C.CC(OC)(C)C.CO>CO.[OH-].[OH-].[Pd+2]>[CH3:2][C:1]([O:5][CH3:6])([CH3:4])[CH3:3].[CH3:31][OH:32].[NH4+:8].[OH-:39].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Reactant: O=C[O-]
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 87 %

Procedure:
Pd(OH)2/C (1.2 g, 1.71 mmol) was flushed with argon, (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (10.95 g, 26.7 mmol) dissolved in methanol (25 mL) was added followed by the addition of ammonium formate (1.68 g, 26.7 mmol). The reaction mixture was refluxed for 1 h, cooled down to room temperature, filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2 then TBME then TBME/MeOH 100/0 to 90/10 then TBME/MeOH/NH4OH 85/15/5) gave (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.39 g, 87% yield) as a yellow sticky oil. 1H NMR (400 MHz, methanol-d4, 298K) δ ppm 1.46-1.46 (m, 9 H) 2.10-2.30 (m, 2 H) 2.78-2.83 (m, 2 H) 3.11-3.14 (m, 2 H) 3.41-3.60 (m, 3 H) 3.65-3.72 (m, 1 H) 3.78 (s, 2 H) 5.68 (m, 1 H) 8.52 (s, 1 H). LCMS: [M+H]+=321.2, Rt(2)=0.87 min
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Si:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(Cl)[CH2:26][Cl:27])=[CH:21][CH:20]=1>O1CCCC1>[Cl:27][CH2:26][Si:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)([C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=1)[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: Fc1ccc([Si](Cl)(CCl)c2ccc(F)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC#C[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.9 ml (0.024 mol) of 1-hexyne in 50 ml of tetrahydrofuran under nitrogen was cooled to -5° C. A solution of n-butyllithium in hexane (15 ml of 1.6 molar, 0.024 mol) was added dropwise, and the resulting solution was warmed to room temperature and stirred for 1.5 hours. The solution was then cooled to -65° C., and a solution of 6.0 g (0.0198 mol) of bis(4-fluorophenyl)chlorochloromethylsilane in 10 ml of THF was added dropwise. The reaction was warmed to room temperature and quenched by addition of saturated aqueous ammonium chloride. The solution was partitioned between water and ether, and the organic layer was separated, washed with brine and dried over magnesium sulfate. Removal of solvent gave the title compound as a clear colorless oil: nmr (CDCl3) 1.0 (3H, m), 1.5 (4H, m), 2.4 (2H, m), 3.2 (2H, s), 7.2 (4H, t, J= 9 Hz), 7.7 (4H, d of d, J=9, 6 Hz); ir (neat) 2180 cm-1.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:33])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(CCO)n1)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide (66 mg, 0.13 mmol) was added ethanol (3 mL) and concentrated hydrochloric acid (three drops) and was stirred at 25° C. for 2 h. It was then diluted with ethyl acetate (30 mL) and washed with water (1×10 mL) and saturated aqueous brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (26 mg, 51%) as a colorless gum: [α]26589=−22.5° (c=0.16, methanol); ES-HRMS m/e calcd for C20H24N3O2F3 (M+H)+ 396.1894, observed 396.1892; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.20 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.07-2.19 (m, 1H, CH), 3.67 (q, J=5.6 Hz, 2H, OCH2), 3.89 (dd, J=9.0, 5.5 Hz, 1H, ArCH), 3.99 (t, J=5.6 Hz, 2H, NCH2), 4.83 (t, J=5.6 Hz, 1H, OH), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.54-7.73 (m, 4H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[CH:31]([NH:34][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: CC(C)Nc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 266 mg (4.50 mmol) of isopropylamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 266 mg (4.50 mmol) of isopropylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 69.0 mg (66% of theory)