Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([N:8]([CH2:11][CH3:12])CC)C.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16](Cl)=[O:17]>C1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:17][C:16]([C:15]1[C:14]([F:13])=[CH:22][CH:21]=[CH:20][C:19]=1[F:23])=[C:12]([C:2]1[S:1][CH:5]=[C:4]([C:15]([CH3:19])([CH3:16])[CH3:14])[N:3]=1)[C:11]#[N:8]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: c1cscn1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)c1csc(C(C#N)=C(O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acylation with One Equivalent of Acid Chloride. A mixture of 2.0 g of the thiazole of Embodiment 16, and 2.1 ml of triethylamine in 25 ml of benzene was treated with 2.0 g of 2,6-difluorobenzoyl chloride. After stirring overnight at room temperature with exclusion of ambient atmosphere, a catalytic amount of 4-dimethylaminopyridine, 0.2 g, was added, and stirring was continued for another 24 hours. At this point the mixture was diluted to 100 ml with methylene chloride and washed with water. The organic layer was dried (MgSO4) and concentrated. The resultant brown oil was taken up in 100 ml methanol, treated with 2 drops of concentrated H2SO4, and refluxed for 5 hours. When this solution was cooled and poured into 200 ml of water, the product crystallized. Filtration afforded 2.9 g of the desired product; m.p. 207°-208.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:23](=[O:37])[N:24]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[N:25]=3)[CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:39][OH:40]>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[CH:14]=[CH:13][N:12]3[C:23](=[O:37])[N:24]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=4)[N:25]=[C:11]3[C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:1](=[N:39][OH:40])[CH3:2])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=NO)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reaction time: 108 h

Procedure:
To a stirred solution of 8-(4-acetylphenyl)-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (43.3 mg, 0.083 mmol) in THF (2 mL) and water (2 mL) at room temperature was added hydroxylamine hydrochloride (11.5 mg, 0.17 mmol). After 108 h, the reaction mixture was diluted with water and extracted twice with EtOAc. The organic extracts are combined, dried (MgSO4), filtered and evaporated. Purification by preparative reverse phase HPLC (methanol-water-trifluoroacetic acid), pooling the fractions, evaporating, redissolving the residuum in dichloromethane, washing with saturated aq. NaHCO3 solution, drying (MgSO4), filtering and evaporating provided the title compound as a yellow solid, 38 mg, 85%. HPLC/MS: retention time=3.38 min, [M+H]+=538. 1H NMR (CDCl3): δ 8.79 (d, J=1.8 Hz, 1H), 8.62 (br s, 1H), 7.92 (dd, J=1.8, 8.0 Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.57 (dd, J=2.2, 6.6 Hz, 2H), 7.23 (m, 5H), 7.06 (d, J=6.6 Hz, 2H), 6.65 (d, J=7.1 Hz, 1H), 5.27 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (3 mL) was added benzenesulfonyl chloride (60 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide. LC/MS m/e obsd. (ESI−) [(M−H)−] 459.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[NH2:17]>>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: N[C@@H]1CCCC[C@H]1N
Product: Cc1cscc1NC(=S)N[C@@H]1CCCC[C@H]1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and racemic trans-1,2-diaminocyclohexane. Crystalline solid, m.p. 205-210° C.,
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C.ClCCl>[N:7]1([C@@H:8]([CH3:11])[CH2:9][OH:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C[C@H](N)CO
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H](CO)N1CCCC1
Temperature: 25 °C

Procedure:
Potassium carbonate (41.4 g, 0.30 moles) was added to a solution of (S)-(+)-2-amino-1-propanol (11.27 g, 0.15 moles, Aldrich) in anhydrous acetonitrile (1.5 L) then 1,4-dibromobutane (17.9 mL, 0.15 moles, Aldrich) was added. The resulting mixture was refluxed for 24 hours then cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a straw-colored solid which was dissolved in dichloromethane (150 mL) and again concentrated under vacuum to afford a straw-colored solid. This crude material, believed to be a mixture of the hydrobromide salt and the free base of the product, was again dissolved in dichloromethane (200 mL). Solid potassium carbonate and the mixture was stirred vigorously for 3 hours then filtered and concentrated under vacuum to afford a straw-colored solid. This solid, believed to still be partially the hydrobromide salt, was partitioned between dichloromethane (150 mL) and saturated aqueous potassium carbonate (50 mL). The layers (upper layer organic, lower layer aqueous) were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an amber oil. This crude product was purified by short-path vacuum distillation to afford the title compound as a colorless liquid (bp 53–54.5° C. at 1.5 mm Hg). NMR: (CDCl3, 600 MHz) δ 3.59 & 3.36 (2H, 2 dd, J=4, 10 Hz, H1), 2.64–2.72 (1H, m, H2), 2.54–2.62 (4H, m, H2′ & H5′), 1.72–1.80 (4H, m, H3′ & H4′),1.04 (3H, d, J=7 Hz, H3); MS (electrospray): m/e 130 (M+H), 112 (M−OH). [α]D+0.9°
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].Cl.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26]>C(O)C>[ClH:14].[CH2:2]([CH:1]1[N:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])[C:25]([NH2:26])=[N:27][C:28]([NH2:30])=[N:29]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N=C(N)NC(=N)Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)cc1F

Procedure:
100 ml of ethanol, 6.6 ml (29.9 mmol) of 1-dodecanal and 0.9 ml of concentrated hydrochloric acid were added to 5.0 g (20.0 mmol) of N1-(2,4-difluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 70% aqueous acetonitrile to obtain 3.9 g of colorless crystals having a melting point of 206 to 208° C.
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C1C=CC=CC=1.C(OCC)(=O)C.[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=[N+:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=Cc1ccc[nH]1
Reactant: C1CCNC1
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C(c1ccc[nH]1)=[N+]1CCCC1
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
A suspension of 237.0 g. (1.38 mole) of pyrrolidine perchlorate in 500 ml. of benzene and 500 ml. of ethyl acetate is stirred and refluxed with water separation for 1 hr., then cooled to room temperature. 131.2 g. (1.38 mole) pyrrole-2-carboxaldehyde is added and the reaction mixture is stirred and refluxed with water separation for 6 hrs. After the whole has been cooled in an ice bath, the solvent is decanted from the solid product, and the product is recrystalllized from 1:1 acetonitrile/ether to give 1-(pyrrol- 2-ylmethylene)-pyrrolidinium perchlorate as a yellow solid; m.p. 100°-102° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])[CH3:3].C(N1CCOCC1)C.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])[CH3:25].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([C:13](=[O:15])[C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH:11]=[CH2:12])[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCC)CC1
Reaction time: 1 h

Procedure:
To a solution of 540 mg Boc-L-Allylglycine in 5 ml DMF were added 0.32 ml N-ethylmorpholine, 0.37 ml ethoxycarbonylpiperazine and 0.83 g TOTU at 0° C. The solution was stirred for 1 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) to provide the title compound as colorless powder (2.79 g, 68%). 1 H-NMR (CDCl3) 6: 3.41(3H,s), 3.63(3H,s), 5.59(2H,s), 7.38-7.50(4H,m), 7.65(1H,s), 7.68-7.81(4H,m).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:7])[CH3:3].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20]>CO>[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][S:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:7][C:25](=[O:26])[CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH3:3]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CSCCc1ccccc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CSCCc1ccccc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-phenethyl-L-cysteine ethyl ester hydrochloride (2.85 g) and 3-acetylthio-2-benzylpropionic acid, (2.38 g) in a manner similar to that described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on Prep 500 (2 silica gel cartridges) and elute with CH2Cl2 (4 L) and then CH2Cl2 :ethyl acetate 100:2 to give Isomer A, a white solid (1.32 g), m.p. 63°-64°, [α]D26 =-51.2° (MeOH); overlap Isomer A and Isomer B (0.63 g); and Isomer B, white solid (1.14 g), m.p. 84°-86°, [α]D26 =+5.3° (MeOH).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].N1C=CC=CC=1.[CH3:24][C:25](OC(C)=O)=[O:26]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[C:25]([O:1][CH2:2][C:3]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])=[CH2:17])(=[O:26])[CH3:24]
Reactant: C=C(CO)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(COC(C)=O)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of 2-(2-(hydroxymethyl)allyloxy)-6-nitrobenzonitrile (Example 200d) (0.40 g, 1.73 mmol), 4-dimethylaminopyridine (0.21 g, 1.73 mmol) and pyridine (0.68 g, 8.64 mmol) in CH2Cl2 (10.0 mL) at 0° C., was added Ac2O (0.53 g, 5.19 mmol) under a nitrogen atmosphere. After being stirred at 0° C. for 10 min, the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with 1.5M HCl, saturated aqueous NaHCO3 and brine, and was dried over MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (3:7), to furnish 0.40 g (84%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 7.91 (t, J=8.4 Hz, 1H), 7.74 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 5.43-5.46 (m, 1H), 5.36-5.40 (m, 1H), 4.90 (s, 2H), 4.66 (s, 2H), 2.05 (s, 3H).
Reaction SMILES: [Na].[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[C:21]1([CH3:47])[CH:26]=[CH:25][C:24]([C:27]([O:29][C@@H:30]2[C@@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:38])[O:33][C@H:32](Cl)[CH2:31]2)=[O:28])=[CH:23][CH:22]=1>CC#N.C(Cl)Cl>[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:32]2[O:33][C@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[O:38])[C@@H:30]([O:29][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH3:47])=[CH:26][CH:25]=3)=[O:28])[CH2:31]2)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CCCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1

Procedure:
The sodium salt of 6-(2-butylimidazol-1-yl)-2-chloropurine (0.139 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed traces of α-nucleoside by 1H NMR (500 MHz) (1:24). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→EtOAc) to give the β-anomer (274 mg, 86%) with traces of the α-anomer. Recrystallization (EtOAc/hexanes) gave 6-(2-butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purine: UV (MeOH) max 223, 241, 287 nm (∈ 29 900, 33 400, 13 200), min 230, 265 nm (∈ 28 100, 7500); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J=6.9 Hz, 1H), 5.80 (br s, 1H), 4.78-4.81 (m, 1H), 4.66-4.70 (m, 2H), 3.31 (t, J=7.8 Hz, 2H), 2.97-3.00 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.80 (quint, J=7.4 Hz, 2H), 1.50 (sext, J=7.4 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.98, 154.13, 153.17, 151.43, 147.92, 144.71, 144.39, 142.18, 129.87, 129.53, 129.35, 129.31, 128.91, 126.38, 126.20, 122.70, 120.33, 85.20, 83.57, 74.94, 63.87, 38.61, 30.70, 30.07, 22.64, 21.79, 21.66, 13.91; HRMS 771/z 629.2270 (MH+[C33H34ClN6O5=629.2279]).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:19][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 104 %

Procedure:
To a solution of 10.00 g (41.27 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one in dry tetrahydrofuran (200 mL) under argon at −78° C. was added 82.5 mL (82.5 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 10 min and 25.7 mL of methyl iodide (412.7 mmol) was added. The reaction was stirred at −78° C. for 1 h and then at 0° C. for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1% of methanol) to afford 11.0 g of a white solid (40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C=CC(=O)OC(C)(C)C)cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Yield: 99.7 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.48 g) in ethyl acetate (60 mL) and ethanol (30 mL) was hydrogenated using 1% palladium on carbon at room temperature for overnight to give 2.49 g (100%) of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.12 (br s, 1H, NH), 5.74 (d, J=2.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H, OCH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 2.47 (t, J=7.5 Hz, 2H, CH2), 2.18 (s, 3H, CH3), 1.36 (s, 9H, 3×CH3), 1.28 (t, J=7.1 Hz, 3H, OCH2CH3). MS 282 [M++1].
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15].Cl>CO.C(OCC)(=O)C>[C:3]([CH:2]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CO[C@@H]1CN(C(=O)CCl)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl acetoacetate (510 mg, 4.4 mmol) was dissolved in methanol (15 ml). Sodium methoxide (210 mg, 3.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, benzyl cis(±)-[1-(chloroacetyl)-3-methoxypiperidin-4-yl]carbamate obtained in Example (188a) was dissolved in methanol (10 ml). The solution was added to the reaction solution, and the mixture was stirred at 70° C. overnight. The reaction solution was diluted with ethyl acetate, neutralized with 1 N hydrochloric acid, washed with brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the title compound was obtained. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][SH:8])[C:3]([NH2:5])=[S:4].[Na].Cl.Cl[CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18]>C(O)C>[CH3:1][N:2]([CH2:6][CH2:7][S:8][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])[C:3]([NH2:5])=[S:4]
Reactant: CN(CCS)C(N)=S
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN(C)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
N-Methyl-N1 -(2-mercaptoethyl)thiourea (3.85 g) in dry ethanol (10 ml) was added to a solution of sodium (1.18 g) in dry ethanol (50 ml) and the mixture was stirred at room temperature for one hour. 4-Chloromethyl-5-methylimidazole hydrochloride (4.29 g) was added portionwise over one hour to this stirred mixture at room temperature. The mixture was stirred at room temperature for a further hour and heated under reflux for 1/2 hour, cooled and filtered. The filtrate was evaporated to an oily solid which was recrystallised from water to give N-methyl-N1 -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (3.2 g) m.p. 149°-151° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([CH:28]=O)[CH2:22]2.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:28][CH:23]4[CH2:22][C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[CH2:24]4)[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: Cc1cc2ncn(C3CCNCC3)c2cc1F
Reactant: O=CC1Cc2ccc(F)cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2ncn(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A mixture of 6-fluoro-5-methyl-1-piperidin-4-yl-1H-benzoimidazole (70 mg, 0.300 mmol) and 5-fluoroindane-2-carbaldehyde (49 mg, 0.300 mmol) in CH3OH (4 mL) and acetic acid (0.2 mL) was stirred at rt for 15 minutes. NaCNBH3 (40 mg, 0.635 mmol) was added and then the reaction mixture was stirred for 1 hour. The solvent was removed and the residue was diluted with CH2Cl2. The organic layers were washed with saturated NaHCO3, brine, and dried over Na2SO4. The organic extracts were removed under the reduced pressure and the residue was purified by flash chromatography (5% CH3OH in CH2Cl2) to afford 6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazole (28 mg, 24%) as a white solid.