Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:11][CH2:12][C@@H:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(C(C)C)C(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][CH2:14][C@H:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:12][OH:11])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CO[C@H](CO)CNC(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a 0° C. mixture of (2S)-3-(t-butoxycarbonylamino)-2-(3,4-dimethoxybenzyloxy)propyl triisopropylsilyl ether (1 g, 2.01 mmol) and THF (5 mL) was added 1 M TBAF/THF (2.11 mL, 2.11 mmol). The reaction was stirred for 1 h and satd citric acid (5 mL) and CH2Cl2 were added. The organic layer was partitioned, concentrated, and chromatographed (CH2Cl2 to 50% EtOAc/CH2Cl2) to give the title compound (545 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])[CH:37]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (64.9 uL, 0.48 mmol) (Aldrich), followed by the addition of 3-isocyanato-benzoic acid methyl ester (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 70 mg, 68%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]([C:26]#[C:27][Si](C)(C)C)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:25]1[C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:11]([C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[O:12])=[CH:18][CH:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)#[CH:27]
Reactant: Cn1c(C(=O)c2ccc(Oc3ncccc3C#C[Si](C)(C)C)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccnc1Oc1ccc(C(=O)c2nc3ccccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1-Methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yloxy)phenyl)methanone (0.19 g, 0.44 mmol) and potassium carbonate (0.12 g, 0.88 mmol) was suspended in 1 mL MeOH. The mixture was stirred for 2 h at RT. Purification by prep-plate TLC (10% MeOH/DCM) afforded (4-(3-ethynylpyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone. MS (ESI, pos. ion) m/z: 354.0 (M+1). IC50 (uM) +++.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].O.[OH-].[K+]>C(O)(C)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([O-:20])=[O:19]
Reactant: O=C(O)c1ccccc1S
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-mercapto-benzoic acid (30 g, 0.195 mol) in isopropanol (500 mL) at room temperature were added 1-fluoro-2-nitro-benzene (30.2 g, 0.214 mol), water (100 mL) and potassium hydroxide (31.1 g, 0.555 mol). The reaction mixture was stirred at room temperature overnight, quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×400 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel to give the title compound. ESI-MS (M+1): 276 calc. for C13H9NO4S 275. 1H NMR: (CDCl3, 400 MHz): δ (ppm) 8.12-8.07 (m, 2H), 7.54-7.43 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.12-7.09 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1.O>[N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:25]2[CH:30]=[N:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[CH:27][N:26]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CN=[N+]=[N-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To a solution of the product from Example 174B (98 mg, 0.404 mmol) in tetrahydrofuran (1 mL) was added potassium-t-butoxide (63.5 mg, 0.566 mmol) followed by addition of 2-bromo-5-cyclopropylpyrazine (Combi-Phos Inc; 89 mg, 0.445 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extracts were dried over Na2SO4, filtered, and concentrated under a stream of nitrogen. The residue was purified by flash chromatography on a 12 g silica gel column, eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as a colorless oil (87 mg, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 5.44-5.39 (m, 1H), 4.12-4.04 (m, 1H), 3.71 (dd, J=12.4, 5.3 Hz, 1H), 3.64 (d, J=12.3 Hz, 1H), 3.57 (dd, J=12.4, 4.6 Hz, 1H), 3.39 (dd, J=12.4, 3.2 Hz, 1H), 2.30-2.06 (m, 3H), 1.41 (s, 9H), 0.97-0.90 (m, 2H), 0.87-0.81 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Br[CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)([CH2:28][C:29]#[C:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Cl)cc1)C2
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(Cl)cc1)C2

Procedure:
Reaction of ethyl [6,7-dichloro-1-oxo-2-(p-chlorophenyl)-5-indanyloxy]acetate with 1-bromo-3-(trimethylsilyl)-2-propyne according to the procedure of Example 1, STEP (b), affords the title compound, m.p. 103°-103.5°; purified by chromatography (silica-gel column eluted with chloroform-n-hexane) and crystallization from ether-cyclohexane.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=3[N:10]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (1 ml) was added and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was passed through SCX (Bond Elute SCX500MG), the SCX was washed with methanol, and then elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain N2-[1-(3,4-dichlorobenzyl)-piperidin-4-ylmethyl]-1H-benzimidazole-2,4-diamine. The compound was identified by LC-MS.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([N:9]([CH3:11])[CH3:10])=O.[C:12]([C:14]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:15]=1[NH2:16])#[N:13]>C(Cl)(Cl)Cl>[CH3:10][N:9]([CH3:11])[C:7](=[N:16][C:15]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:14]=1[C:12]#[N:13])[CH3:6]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(N)c(C#N)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)c(N=C(C)N(C)C)cc1OC
Reaction time: 0.08 h

Procedure:
Phosphorous oxychloride (1.0 ml) was added to a stirred solution of dimethylacetamide (2.8 ml) in chloroform (10 ml) at room temperature. The mixture was stirred for 5 minutes, 2-cyano-4,5-dimethoxyaniline (1.78 g) added and the reaction stirred under reflux for 4 hours. The mixture was cooled, poured onto ice and extracted with chloroform and the organic phase discarded. The aqueous layer was basified (solid NaOH) extracted with chloroform, the combined extracts washed with water, dried (Na2SO4) and evaporated in vacuo. A sample of the brown oily residue (2 g) was crystallised from diisopropylether to give N,N-dimethyl-N'-(2-cyano-4,5-dimethoxyphenyl)acetamidine, m.p. 94°-96°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Oc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Yield: 96.6 %

Procedure:
2-Chlorobenzenesulfonic acid 3-benzyloxyphenyl ester (3.75 g, 10 mmol), as prepared in the preceding step, Pd/C (10%) (350 mg) in tetrahydrofuran (80 mL) was hydrogenated (balloon) for 3 h. The catalyst was filtered through Celite and washed with tetrahydrofuran. The combined tetrahydrofuran solution was evaporated in vacuo and the residue was then purified by flash column chromatography (methylene chloride) to give the title compound as a colorless oil (2.75 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([CH2:23]Cl)[NH:22][C:18]=2[CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([CH2:23][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:22][C:18]=2[CH:17]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Reactant: ClCc1nc2ccc(Cl)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
The mixture of ethyl N-(4-chlorophenyl)glycinate (0.43 g), 5-chloro-2-chloromethylbenzimidazole (0.4 g), and sodium bicarbonate (0.17 g) in N,N-dimethylformamide (2 ml) was stirred at 150° C. for 0.5 h. After cooling to rt the mixture was poured into saturated sodium bicarbonate solution (50 ml) and extracted twice with EtOAc (40 ml). The combined organic layers were washed with 10% sodium carbonate solution (40 ml) and water (40 ml) and dried (sodium sulfate). After concentration the crude (0.66 g) was purified by flash chromatography (dichloromethane/1% methanol) on silica gel to provide an orange solid. The solid was further purified by trituration with diethyl ether to give ethyl N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycinate (0.17 g) as a light orange crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[CH:16])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(C)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-((trimethylsilyl)ethynyl)phenyl)picolinate (50 mg, 0.13 mmol) in methanol (0.7 mL) was added potassium carbonate (24 mg, 0.17 mmol). The reaction was stirred at room temperature for 40 min, then diluted with water and extracted with dichloromethane (4×). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a brown oil (34 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21]Br)[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CN3CCOCC3)cc2C1=O
Reaction time: 2 h
Yield: 16.1 %

Procedure:
6-Bromomethyl-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (1.1 g, 2.96 mmol) was dissolved in N,N-dimethylformamide. Pyridine (264 μl, 3.26 mmol) and morpholine (284 μl, 3.26 mmol) were added thereto and the mixture was stirred for 2 hours. After the reaction was completed, the organic layer was extracted with ethyl acetate/ammonium chloride/saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 180 mg of 6-(morpholine-4-yl methyl)-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (180 mg, yield 16.1%) as red oil.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[Si:60]([O:67][CH2:68][C:69](OCC#N)=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>O.O1CCCC1>[Si:60]([O:67][CH2:68][C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (144 mg, 0.227 mmol) in water (1 ml) and a solution of cyanomethyl 2-(tert-butyldimethylsilyloxy)acetate (Compound 21) (104 mg, 0.453 mmol) in tetrahydrofuran (1 ml) were added to buffer A (30 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-(tert-butyldimethylsilyloxy)acetate (Compound 22) (104.5 mg, 57%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6](=[O:12])[CH:5]=1.[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21]Cl)(=[O:15])[CH3:14].[Cl-].[Na+]>CS(C)=O>[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][N:7]1[C:6](=[O:12])[CH:5]=[C:4]([NH2:3])[N:9]([CH3:10])[C:8]1=[O:11])(=[O:15])[CH3:14]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirring suspension of sodium hydride (5.52 g, 230 mmol) in anhydrous dimethylsulfoxide (500 ml) was added 6-amino-1-methyluracil (28.2 g, 200 mmol). After stirring at room temperature under argon for 2 hours, (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol) was added neat and the mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was poured into saturated aqueous sodium chloride solution (1500 ml) and extracted with ethyl acetate (9×200 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting oil was treated with ethyl ether (400 ml). After stirring overnight at room temperature, the precipitate was filtered and rinsed with ether (2×50 ml) to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (44.0 g, 78% yield) as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([F:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C@H:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:25][C:24]1[CH:23]=[C:22]([C@@H:20]([NH:19][C:13]2[N:12]=[C:11]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]4=[N:10][CH:9]=3)[C:16]([F:17])=[CH:15][N:14]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=1
Reactant: Fc1cnc(Cl)nc1-c1cnc2c(Cl)cccn12
Reactant: C[C@H](N)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Nc1ncc(F)c(-c2cnc3c(Cl)cccn23)n1)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 20.5 %

Procedure:
90 mg of the 8-chloro-3-(2-chloro-5-fluoropyrimidin-4-yl)imidazo[1,2-a]pyridine [125-2] was dissolved in 3 mL of dimethylsulfoxide, then 46.6 mg of 3-[(1S)-1-aminoethyl]aniline and 100 mg of potassium carbonate were added thereto, and stirred at 60° C. for 5 hours. The reaction mixture was cooled back to room temperature, and purified by preparative reversed phase liquid chromatography. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 25 mg of N-[(1S)-1-(3-aminophenyl)ethyl]-4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidine-2-amine [125-3] was obtained as a brown oily product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[S:16][C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.O>CN(C=O)C>[C:24]1([C:17]2[S:16][C:15]([S:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:19][C:18]=2[C:20]([O:22][CH3:23])=[O:21])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Sc2ccccc2)sc1-c1ccccc1

Procedure:
A stirred suspension of K2CO3 (4.15 g, 30 mol) in 100 ml of DMF was treated in one portion with thiophenol (1.65 g, 15 mol). The compound of Example 2 (3.8 g, 15 mol) was then added and the mixture heated at 110° C.±5° C. for 2 days. Water was added and the mixture extracted twice with ether. The ether extracts were washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a yellow oil. Bulb to bulb distillation yielded methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, as a yellow oil at 130°-170° C./1 mm. This oil was crystallized from etherpetroleum ether mixtures to yield 1.6 g of white crystals, methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, m.p. 67°-70° C., yield 33%.
Reaction SMILES: [CH2:1]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:2]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[CH2:1][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCCC(=O)CCC(=O)OCC
Reactant: BrC1CCCC1
Product: CCCC(=O)C(CC(=O)OCC)C1CCCC1

Procedure:
The preparation was carried out analogously to Example I from 4.04 g (25.0 mmol) of ethyl hexan-3-onecarboxylate and 2.95 ml (4.10 g, 27.3 mmol) of bromocyclopentane. Purification was carried out chromatographically (silica gel, petroleum ether: ethyl acetate 20:1). MS (EI): 226 [M]+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([OH:15])(=[O:14])[CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].CI>CCCCCC>[CH3:1][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:15])=[O:14]
Reactant: CCCC(CCC)C(=O)O
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Product: CCCC(C)(CCC)C(=O)O

Procedure:
The alkylation of the carboxylic acids at position 2 using alkyl halides is very generally possible with the aid of n-butyllithium at elevated temperature (Pfeffer et al., Alpha-anions of carboxylic acids. II. The formation and alkylation of alpha-metalated aliphatic acids. Journal of Organic Chemistry 37, 451-458 (1972). The methylation of the tertiary carbon atom of valproic acid is possible, for example, by deprotonation of the α-hydrogen atom at C-2 using n-butyllithium in hexane at 50° C. and subsequent methylation with methyl iodide at room temperature in a yield of 32%. The other 2-alkylated carboxylic acids can also be prepared in accordance with this method.