Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COCCCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Product: COCCCn1cnc2ccccc21
Temperature: 0 °C
Yield: 75.7 %

Procedure:
1H-benzo[d]imidazole (12.7 mmoles, 1.5 g) was added to an oven dried 200 mL round-bottomed flask equipped for stirring under nitrogen. DMF (20 mL) was added and the solution was cooled to 0° C. with an ice bath. To this cooled solution was added NaH (60% in mineral oil, 13.3 mmoles, 533 mg) in two portions. The resultant solution was allowed to stir at 0° C. for 30 minutes under nitrogen. 1-bromo-3-methoxypropane (14.0 mmoles, 2.14 g) was added and the solution was allowed to warm to room temperature and stirred for 1 hr. The reaction solution was then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This material was then purified by chromatography on silica gel (5-15% CH3OH/CH2Cl2) to afford 1-(3-methoxypropyl)-1H-benzo[d]imidazole (137A) as a clear oil (9.62 mmoles, 1.83 g, 76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 (dt, J=12.57, 6.22 Hz, 2H) 3.29 (t, J=5.68 Hz, 2H) 3.34 (s, 3H) 4.31 (t, J=6.69 Hz, 2H) 7.23-7.34 (m, 2H) 7.37-7.45 (m, 1H) 7.78-7.83 (m, 1H) 7.89 (s, 1H). ESI-MS: m/z 191.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[I:10][C:11]1[N:12]=[C:13]([CH3:16])[NH:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:10][C:11]1[N:12]=[C:13]([CH3:16])[N:14]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)[CH:15]=1
Reactant: Cc1nc(I)c[nH]1
Reactant: Cn1ncc(Cl)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 160 mg (1.11 mmol) of 5-chloro-2-methyl-2H-pyridazin-3-one (CAS: [14628-34-3]), 230 mg (1.11 mmol) of 4-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]), in 3.5 ml of dry DMF were added 721 mg (2.21 mmol) of cesium carbonate. The suspension was stirred for 30 min at 45° C., then for 3 h at 65° C. and allowed to cool. The cristallised product is filtered off, washed with ethyl acetate and dried in vaccuo to yield 250 mg (0.791 mmol, 71%) of the title compound as a crystalline light yellow solid, MS: m/e=316.9 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:22][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
Boc-D-methionine (34.2 g, 0.137 mole) and L-leucine methylester hydrochloride (25.0 g, 0.137 mole) was dissolved in 450 ml of methylene chloride and triethylamine (19.15 ml, 13.9 g, 0.137 mole) was added. Dicyclohexylcarbodiimide (62 ml of a 0.5 g/ml solution in CH2Cl2, 0.15 mole) was then added followed by stirring at room temperature overnight. The mixture was filtered and the filtrate was extracted with three 150 ml portions of dilute citric acid and three 150 ml portions of 1N sodium biocarbonate. After drying with sodium sulfate, the solution was concentrated in vacuo. Chromatography of the crude material on silica gel eluting with ethyl acetate-hexane (1:1; 2:1) followed by ethyl acetate gave pure product which crystallized from ethyl acetate-hexane to give 28.4 g of product (53%), m.p. 61°-64°. The nmr spectrum was consistent with the expected structure.
Reaction SMILES: COC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=O.O.[Cl-].[NH4+:25]>C(Cl)Cl.[Fe]>[C:17]1([S:14]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([NH2:25])=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Yield: 82.2 %

Procedure:
To the suspension of 2 (1.16 g, 3.84 mmol) in WA (38 mL) and water (9 mL), iron (0.64 g, 11.51 mmol) and ammonium chloride (0.41 g, 7.67 mmol) were added and refluxed overnight. After the reaction was filtrated with celite, the solvent was concentrated under reduced pressure to give a brown residue, which was dissolved in CH2Cl2 and quenched with water, followed by extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a brown residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2:1% NH3(aq)) to afford 27 (0.86 g). 1H NMR (500 MHz, CD3OD): δ 3.60 (s, 2H), 6.48 (d, J=3.6 Hz, 1H), 6.69 (dd, J=8.7, 2.1 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.44 (d, J=3.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.CS(C)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:10]#[N:11]
Reactant: BrCC1CCCCO1
Reactant: COc1ccccc1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C(C#N)CC1CCCCO1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a flask was added 20 g. (0.1346 mole) of (2-methoxyphenyl)acetonitrile, 25 g. (0.1346 mole) of 2-(bromomethyl)tetrahydro-2H-pyran, and 200 ml. of DMSO. The mixture was stirred for five minutes at room temperature and to the resultant solution was added 22 g. (0.2692 mole) of 50% aqueous sodium hydroxide over 30 minutes with the reaction temperature being allowed to exotherm to 60° C. The reaction was stirred an additional two hours, then cooled, water added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried, filtered, and the ether distilled. The organic residue wss fractionally distilled to obtain 27 g. (82% yield) of the 2-(2-methoxyphenyl)-3-(tetrahydropyran-2-yl)propionitrile boiling 145°-160° C. at 5 mm of Hg.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C1C=CN=CC=1)C.COC(C)(C)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([CH3:17])[C:18]2[CH:19]=[N:20][C:21]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 92 %

Procedure:
A mixture of 0.16 g (0.30 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramide, 0.67 ml (6.0 mmol) 1-methylpiperazine and 2 mg (0.02 mmol) 4-(N,N-dimethylamino)pyridine was heated at 140° C. over night. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether and washed with water. The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.16 g (93%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:14]([O:13][C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]3)=[N:7][CH:6]=2)[CH2:10][CH2:9]1)=[O:12])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Product: CCOC(=O)C1(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)CC1
Temperature: 130 °C

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (225.7 mg, 0.001000 mol) and tert-butyl piperazine-1-carboxylate (3.0 eq.) was heated at 130° C. for 6 h. After cooling, the mixture was flash chromatographed on a silica gel column to afford the desired product. LC/MS: 376.5 (M+H+).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:9]=[N:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:15]=2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:38]([CH3:40])[CH3:39].O>CC(C)=O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([C:11]2[N:10]=[CH:9][C:8]([N:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][N:5]4[CH:38]([CH3:40])[CH3:39])=[CH:13][N:12]=2)=[N:15]1
Reactant: Fc1ccccc1Cn1nc(-c2ncc(N3CC4CC3CN4)cn2)c2cccnc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)N1CC2CC1CN2c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.13 mmol) of 3-[5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-pyrimidinyl]-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example 9) are dissolved in 5 ml of absolute acetone, and 92 mg (0.87 mmol) of sodium carbonate are added. 64 mg (0.37 mmol) of 2-iodopropane are added to the suspension, and the mixture is stirred at RT overnight. The reaction solution is mixed with water and extracted with DCM. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried and filtered. The solvent is removed in vacuo, and the residue is purified by preparative HPLC with addition of small portions of aqueous hydrochloric acid. 25 mg (42% of theory) of the product are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=3)[C:14]([NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=5)[C:14]([NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide. 3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide (56 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 24.8 mg of 336. MS (Q1) 515.2 (M)+
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NS(C)(=O)=O)c1ccccc12

Procedure:
A sample of 1'-(1,1-Dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135 Step A, in 3.5 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 270λ of methanesulfonyl chloride (2.2×1.58 mmole) in 3 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, dried with magnesium sulfate and concentrated under reduced pressure to a gum. Preparative TLC on four 8"×8"×1,000 g GF silica gel plates using 1:2 ethyl acetate: hexane afforded the title compound, which crystallized on standing. Yield: 322 mg (54%)
Reaction SMILES: C1(C[B:8]([OH:10])[OH:9])C=CC=CC=1.[C:11]12([OH:22])[CH2:19][CH:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]2([OH:21])[CH3:20].[C:23]([O:27][C:28]([C:30]1[CH:31]=[C:32](CB(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C12(O)CC(C1(C)C)CCC2(O)C>>[C:11]12([OH:22])[CH2:19][CH:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]2([OH:21])[CH3:20].[C:23]([O:27][C:28]([C:30]1[CH:31]=[C:32]([B:8]([O-:10])[O-:9])[CH:33]=[CH:34][CH:35]=1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: OB(O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CB(O)O)c1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Product: CC(C)(C)OC(=O)c1cccc(B([O-])[O-])c1
Yield: 88 %

Procedure:
Following the procedure described for the synthesis of 13a, compound 13b was recovered from 12b as a yellow oil (88% yield). [α]D+8.7 (c 1.4, CHCl3). 1H-NMR (400 MHz, CDCl3): δ 0.87 (3H, s, pinanyl CH3), 1.11 (1H, d, J 11.0, pinanyl Hendo), 1.32 (3H, s, pinanyl CH3), 1.43 (3H, s, pinanyl CH3), 1.63 (9H, s, t-Bu), 1.84-2.39 (5H, m, pinanyl protons), 2.42 (2H, s, BCH2), 4.32 (1H, dd, J 8.8, 2.0, CHOB), 7.33 (1H, t, J 7.7, H5), 7.40 (1H, d, J 7.7, H6), 7.80 (1H, d, J 7.7, H4), 7.86 (1H, s, H2). 13C-NMR (100 MHz, CDCl3): δ 19.3 (CB), 24.0, 26.5, 27.1, 28.2, 28.6, 35.4, 38.2, 39.5, 51.3, 78.0, 80.7, 86.0, 126.2, 128.1, 129.9, 132.0, 133.2, 139.0, 166.0; EI-MS: m/z 370 (M+, 18%), 314 (71), 297 (59), 135 (55), 57 (100). Anal. Calcd. for C22H31BO4: C, 71.36; H, 8.44. Found: C, 71.60; H, 8.27.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.[Si]([O:35][C@@H:36]1[C@H:40]([O:41][Si](C(C)(C)C)(C)C)[C@@H:39]([CH3:49])[O:38][C@H:37]1[N:50]1[CH:57]=[C:56]([F:58])[C:54]([NH2:55])=[N:53][C:51]1=[O:52])(C(C)(C)C)(C)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:58][C:56]1[C:54]([NH:55][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])=[N:53][C:51](=[O:52])[N:50]([CH:57]=1)[C@@H:37]1[O:38][C@H:39]([CH3:49])[C@@H:40]([OH:41])[C@H:36]1[OH:35]
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccoc1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)c3ccoc3)nc2=O)[C@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 76.8 %

Procedure:
3-Furoic acid (0.355 g) and 2,4,6-triisopropyl benzene-sulfonyl chloride (0.96 g) were dissolved in dry pyridine (5 ml). The mixture was stirred for 1 hour. To the mixture were added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (1.0 g) obtained in Reference example (a) and 4-dimethylaminopyridine (0.80 g). After stirring of the mixture for 12 hours at room temperature. pyridine was evaporated under reduced pressure. The residue was then treated as in Example 48 to give 0.55 g of 5'-deoxy-5-fluoro-N4 -(3-furoyl)cytidine, mp 173°~174° C. (ethanol); MS 340 (MH+).
Reaction SMILES: [F:1][C:2]1[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[C:5]([C:7](O)=[O:8])[N:6]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:7]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)=[O:8]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-1-triphenylmethylimidazole-4-carboxylic acid and 3-dimethylaminopropylamine were condensed in THF by the mixed anhydride procedure described for the preparation of starting material for Example 18, to give 4-(3-dimethylaminopropylcarbamoyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.8 (m, 2H); 2.3 (s, 6H); 2.4 (t, 2H); 3.5 (q, 2H); 7.0-7.6 (m, 16H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:27][N:26]=1)[CH3:24]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CCc1cc(CN)on1
Product: CCc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-ethyl-5-isoxazolemethanamine as starting materials; LC-MS (UV peak area/ESI) 100%, 440.0985 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C@H:10]([C@@H:12]1[O:16][C:15](=[O:17])[C@H:14]([O:18][CH3:19])[C@@H:13]1[OH:20])[OH:11].Cl.[NH2:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[O:25][CH2:24]1.C(C(CCCC)C([O-])=O)C.[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C@@H:10]([OH:11])[C@H:12]([OH:16])[C@@H:13]([OH:20])[C@@H:14]([O:18][CH3:19])[C:15]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[O:25][CH2:24]1)=[O:17]
Reactant: CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/c2ccccc2Br)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1COc2ccccc2N(C)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/c1ccccc1Br
Temperature: 25 °C

Procedure:
90 mg of 45 (0.22 mmol), 51 mg of 6 (0.22 mmol) and 93 mg of sodium 2-ethylhexanoate (0.56 mmol) in 2.0 mL of THF are successively introduced into a 10 mL round-bottomed flask, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. 20 mL of CH2Cl2 are added to the reaction medium. The mixture is successively washed with 10 mL of an HCl solution (1N), 10 mL of water saturated with NaCl. The organic phase is dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (9 g, eluent, AcOEt/heptane:85/15). 49 mg of expected product Ex18 (white solid) are recovered.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:26][C@H:27]([CH2:29][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.5 g (8.74 mmol) of cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanol, which is prepared as described in Example 47(b) of WO 97/28161, in 70 ml of dry THF are added under argon 2.75 g (10.5 mmol) of triphenylphosphine and 1.54 g (10.5 mmol) of phthalimide; 1.9 g (1.71 ml; 10.5 mmol) of diethyl azodicarboxylate (96%) are added dropwise thereto. After stirring for 16 h at RT, the solution is concentrated to dryness and the crude compound is purified by flash-chromatography (ethylacetate) to provide cis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}isoindole-1,3-dione. Analytical HPLC: tR=11.96 min (Grad 1); ES-MS: m/eo=529.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Cl)[CH:45]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:50][C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Agent: [B]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (326 mg) and N,N-dimethyl formamide (4.5 ml) was shaken at room temperature for 1 hour. To the mixture was added 3-pyridylmethylchloride hydrochloride (52 mg), and the mixture was further shaken at room temperature for 15 hours. Purification was carried out in a manner similar to Example 222 to obtain 2-(3-methoxyphenyl)-6-phenyl-1-(3-pyridylmethyl)-1H-imidazo[4,5-b]pyridine (67 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].S(=O)(=O)(O)O.II.O.O.[I:26](O)(=O)(=O)=O>C(O)(=O)C.O>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C@H:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:26])=[CH:10][CH:9]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Cc1ccc(I)cc1)NC(=O)C(F)(F)F
Temperature: 70 °C
Yield: 185.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (3.75 g) in acetic acid (32 ml)—water (6.5 ml)—sulfuric acid (0.97 ml) were added iodine (1.65 g) and periodic acid dihydrate (740 mg) at room temperature, and the mixture was heated to 60-80° C. for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide (2.15 g) as a colorless needle.