Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[NH:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.N1C=CC=CC=1CCl>C(Cl)(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: ClCc1ccccn1
Reactant: C1CNCCNCCNCCN1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1ccc(CN2CCNCCNCCNCC2)nc1
Reaction time: 0.5 h

Procedure:
A 2-picolyl chloride solution in chloroform was prepared by basifying 3 mL of an aqueous solution of 1.03 g (6.3 mmol) of 2-picolyl chloride hydrochloride to pH>14 and extracting into chloroform. To a stirred chloroform solution of 2.03 g (11.8 mmol) of 1,4,7,10-tetraazacyclododecane was added 10 mL of the prepared 2-picolyl chloride solution in chloroform in one portion. After stirring at temperature for 30 min, the reaction mixture was concentrated in vacuo to give a residue which was chromatographed on sffica gel (column, 2.5×20 cm), eluting with CHCl3 :CH3OH: NH4OH (10:4:1), Rf =0.29 on SiO2 plate. After concentration of eluent, the monoalkylated product was isolated a as thick pale yellow liquid, which upon standing solidified to give 1.17 g of an off-white powder (72%, based on 2-picolyl chloride), and further characterized by:
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.C(N(CC)CC)C.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.O>C(#N)C.CN(C)C1C=CN=CC=1>[C:26]12([C:36]([O:1][CH:2]3[CH:6]4[O:7][C:8](=[O:18])[CH:9]5[CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:3]3[CH2:4][CH:5]45)=[O:37])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
In 2,000 ml of acetonitrile were dissolved 282 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate (21), 157 g of triethylamine and 13.6 g of 4-dimethylaminopyridine. Below 20° C., 328 g of adamantanecarboxylic chloride (26) was added dropwise to the solution, which was stirred at room temperature for 3 hours. Then 1,000 g of water was added to the solution, followed by standard work-up. Recrystallization from methylene chloride gave 391 g of the target compound (yield 85%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:4][C:3](=[O:5])[CH2:2]1.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>C(OCC)(=O)C>[CH2:7]([NH2+:9][CH2:10][CH3:11])[CH3:8].[OH:6][C:1]1[CH2:4][C:3](=[O:5])[CH:2]=1
Reactant: CCNCC
Reactant: O=C1CC(=O)C1
Solvent: CCOC(C)=O
Product: CC[NH2+]CC
Product: O=C1C=C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
2.1 g of 1,3-cyclobutanedione (23.0 mmol) was suspended in 40 g of ethyl acetate. A solution of 1.84 g of diethylamine (25.0 mmol) in 10 g of ethyl acetate was instilled in this suspension at 20° C. within 15 minutes. After 1 hour of stirring at room temperature, the suspension was filtered and then dried. 3.05 g of the title product with a purity (according to HPLC) of 93.7 percent, corresponding to a yield of 79.2 percent, relative to the cyclobutanedione, was obtained. Data for the title compound was:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13]>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][N:4]4[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: OCCN1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(CCO)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 6 h

Procedure:
2-piperazin-1-yl-ethanol (0.227 g, 1.74 mmol) was added with stirring to a solution of Example 56k (0.5 g, 1.16 mmol) in DMF (10 mL) in an atmosphere of nitrogen. The reaction mixture was stirred at 110° C. for 6 h, concentrated, treated with chilled water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as an off-white solid. Yield: 0.521 g, (85.69%); 1H NMR (DMSO-d6): δ 2.50 (s, 3H, CH3), 3.10 (t, 4H, 2CH2), 3.70 (t, 10H, 5CH2), 3.90 (s, 3H, OCH3), 4.40 (s, 2H, CH2), 5.20 (s, 2H, CH2), 6.10 (s, 1H, Ar), 6.80-6.85 (m, 2H, Ar), 8.10 (m, 2H, Ar); MS: m/e (ES+) 551 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26]CCl>FC(F)(F)C(O)=O>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1.[ClH:26]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Reaction time: 1.5 h

Procedure:
4-(4-Trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (380 mg; 1.06 mmol, prepared in accordance with Example 52) is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (2 mL), and stirred for 90 minutes. The mixture is concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The resulting residue is diluted in ethylacetate (5 mL) and a 4N solution of hydrochloric acid in dioxane (5 mL) is added. A precipitate is obtained which is filtered and dried under high vacuum to afford the desired product as hydrochloride (275 mg; 0.93 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].CO[C:15]1[C:19](OC)=[N:18][S:17](=[O:23])(=[O:22])[N:16]=1.OCC1NC=[N:28][C:27]=1CSCCNC1C(OC)=NSN=1.CN>>[OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:15]1[C:19]([NH:28][CH3:27])=[N:18][S:17](=[O:23])(=[O:22])[N:16]=1
Reactant: COc1nsnc1NCCSCc1nc[nH]c1CO
Reactant: NCCSCc1nc[nH]c1CO
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: CN
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1CO

Procedure:
2-[(5-Hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamine [prepared according to the procedure described in Belgian Pat. No. 843,840] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and the resultant 3-{2-[(5-hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole, 1,1-dioxide is treated with excess methylamine according to the general procedure described in Example 2, and the title compound is thereby produced.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH3:16])N=2)[CH:5]=[CH:4][C:3]=1[OH:17].[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[CH2:36](Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[O:17][C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH3:16])[CH:36]=4)=[CH:7][C:2]=3[N:1]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: ClCCCl
Reactant: CNc1nccc(Oc2ccc(O)c(N)c2)n1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: CC#N
Product: CNc1cc(Oc2ccc3oc(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-4-(2-methylamino-pyrimidin-4-yloxy)-phenol (Step E, 0.143 g, 0.616 mmol) in 30 mL CH3CN was added dropwise over 5 min a solution 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (0.174 g, 0.616 mmol) in 10 mL CH3CN. The reaction was stirred 18 h at RT. The reaction was diluted with 10 mL CH3CN, then EDC (0.118 g, 0.616 mmol) was added. The reaction was heated at 80° C. for 3 h. The reaction was cooled to RT then concentrated in vacuo. The crude mix was dissolved in EtOAc and H2O. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a combination of silica gel column chromatography and silica gel prep plates to obtain the title compound. MS (MH+)=480.2; MW Calc'd 479.97 for C24H26ClN7O2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:16])[C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:16][N:9]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1-n1cccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1-n1cccc1

Procedure:
To a solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid ethyl ester (20 g, 91.2 mmol; available from Butt Park Ltd., Camelford, Cornwall, UK) in methanol (100 mL) and water (100 mL) was added LiOH (2.4 g, 100 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (9 mL), and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:22])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 125.8 %

Procedure:
1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (18 mL) and cooled to 0° C. 2N NaOH (7.03 mL, 14.06 mmol) and 30% peroxide (14.07 mL) were added and the reaction was stirred at room temperature for 45 minutes. The reaction was acidified to pH=2 by addition of 2N HCl and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-benzyl-1H-pyrazol-4-ol (1.54 g) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.25-7.21 (m, 3H), 7.08-7.07 (m, 3H), 6.91 (s, 1H), 5.06 (s, 2H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:11]=2)=[CH:18][CH:17]=1
Reactant: Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 144A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 7.95-7.99 (m, 1H), 7.90-7.95 (m, 1H), 7.84-7.89 (m, 1H), 7.37-7.44 (m, 4H), 7.31-7.38 (m, 4H), 4.32-4.32 (bs, 2H), 3.70 (s, 2H); LC/MS (APCI) M/Z 438 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of n-butyl lithium (2.71 M hexane solution, 3.9 ml) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise a solution of 4-methylthiazole (1.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for one hour and thereto was added dropwise a solution of tri-n-butyltin chloride (3.6 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for 30 minutes, warmed, and further stirred at room temperature overnight. Thereto was added water, and the mixture was extracted with diethyl ether. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (hexane) to give the title compound (1.76 g) as oil. APCI-Mass m/z 386/388 (M+H)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:25])=[C:5]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([Br:23])[CH:14]=1)[C:6]([OH:8])=[O:7].[CH3:26]O>>[Cl:2][C:3]1[C:4]([CH3:25])=[C:5]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([Br:23])[CH:14]=1)[C:6]([O:8][CH3:26])=[O:7]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Agent: Cl
Product: COC(=O)c1cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c(Cl)c1C
Temperature: 20 °C
Reaction time: 22 h

Procedure:
HCl gas was bubbled through a solution of 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (375 mg, 0.86 mmol) in MeOH (20 mL) for 5 min. Upon stirring at 20° C. for 22 hr, HPLC analysis revealed esterification was complete. After removal of the solvent under vacuum and dissolution of the residue in EtOAc, the EtOAc layer was washed 2× with H2O then with brine prior to drying over MgSO4. Removal of the volatiles yielded 391 mg of crude methyl 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoate as a brown solid which was not further purified.
Reaction SMILES: Cl[CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.N[CH2:36][C:37]([NH2:39])=[O:38].C([N:42](CC)CC)C.N1C=CC=NC1=O>CO>[C:37]([NH:39][NH:42][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4])(=[O:38])[CH3:36]
Reactant: CCN(CC)CC
Reactant: NCC(N)=O
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Agent: Cl
Agent: O=c1nccc[nH]1
Solvent: CO
Product: CC(=O)NNC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Temperature: 75 °C
Yield: 85.8 %

Procedure:
A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide, 0.17 g of glycinamide HCl, 0.15 g of triethylamine, 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1M)-pyrimidinone and 1 ml of methyl alcohol is heated at 75° C. for 2 days. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.13 g of tan solid. MS(CI): 494(M+H).
Reaction SMILES: F[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].O>CO>[F:10][C:3]1[CH:2]=[CH:9][CH:8]=[C:7]([O:12][CH3:11])[C:4]=1[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1cccc(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(F)c1C#N
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
640.5 g (4.6 mol) of difluorobenzonitrile were dissolved in 3.5 l of methanol and then cooled to 0-5° C. 828.8 g of 30% strength sodium methoxide solution were added dropwise in this temperature range, and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was added to 20 l of water and the precipitate was filtered off with suction and washed twice with water and twice with heptane. The solid was dried in vacuo at 50° C. Yield: 740 g (99% of theory) of a white solid with a purity of >95% according to GC.
Reaction SMILES: Cl[C:2]1(O)[NH:19][C:18](N)=[N:17][C:16]2[N:6]([C@@H:7]3[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[CH:5]=[N:4][C:3]1=2.C([C@@]1(O)[C@](C(=O)C)(O)[C@@H](C(C(=O)C)O)O[C@H]1N1C2N=C(N)NC(Cl)(O)C=2N=C1)(=O)C.N([O-])=O.[Na+].[ClH:56].[NH3:57]>>[Cl:56][C:18]1[N:19]=[C:2]([NH2:57])[C:3]2[N:4]=[CH:5][N:6]([C:16]=2[N:17]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: N
Reactant: Cl
Reactant: NC1=Nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(O)(Cl)N1
Agent: CC(=O)C(O)[C@H]1O[C@@H](n2cnc3c2N=C(N)NC3(O)Cl)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Agent: O=N[O-]
Agent: [Na+]
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Yield: 60 %

Procedure:
The starting material, 2-chloroadenosine of the formula (II) used in the above Process 1 can be obtained in high yield from 6-chloroguanosine or a 2',3',5'-triacyl-6-chloroguanosine as disclosed in Japanese Patent Application OPI No. 48,496/1973. That is, 6-chloroguanosine or a 2',3',5'-triacyl-6-chloroguanosine, e.g., 2',3',5'-triacetyl-6-chloroguanosine, is first reacted with sodium nitrite and hydrochloric acid in ice-water and thereafter the reaction mixture is neutralized with, for example, aqueous ammonia. The resulting reaction mixture is then extracted with a solvent such as methylene chloride and the extract containing 2,6-dichloropurine riboside is treated without isolation of the riboside, with a methanolic solution saturated with anhydrous ammonia gas and the mixture is allowed to react at a temperature of about 100°C for about 5 hours in a sealed tube to obtain the desired 2-chloroadenosine of the formula (II) in about 60% yield. The preparation of the starting material of the formula (II) will be hereinafter described in greater detail in Reference Example 1.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14].O>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:9][CH2:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 103.7 %

Procedure:
Sodium hydride (60%; 349 mg; 8.7 mmol) was suspended in DMF (3 mL) and cooled to 0° C. under inert atmosphere. Cyclopentylmethanol (0.79 mL; 7.3 mmol) was added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 20 minutes. The solution was then added dropwise to a solution of 2,6-difluorobenzonitrile (1.03 g; 7.4 mmol) in DMF (3 mL) cooled to 0° C. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solution was poured over 50 mL of cooled water and extracted with ethyl acetate and solvent removed. Purification by column chromatography (5% ethyl acetate/hexane) yielded 1.66 grams of 2-fluoro-6-(cyclopentylmethoxy)benzonitrile.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=CC=CC=1S.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Fc1ccccc1S
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:35]=[CH:34][C:15]2[C:16]([CH2:19]CC3CCN(CC4C=CC=CC=4)CC3)=[N:17][O:18][C:14]=2[CH:13]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCl>[CH:6]1[C:1]([S:7]([NH2:11])(=[O:9])=[O:8])=[CH:2][CH:3]=[CH:4][CH:5]=1.[CH3:19][C:16]1[C:15]2[CH:34]=[CH:35][CH:12]=[CH:13][C:14]=2[O:18][N:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Agent: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1noc2ccccc12
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 72.1 %

Procedure:
Benzenesulfonyl chloride (0.528 mL, 4.14 mmol) was added to a cold (0° C.) solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.613 g, 4.14 mmol) and pyridine (0.670 mL, 8.28 mmol) in CH2 Cl2 (30 mL). After 1.3 hours, saturated sodium bicarbonate (NaHCO3) was added and the resulting mixture was stirred overnight at room temperature. The organic layer was separated and washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatograph (5% EtOAc/CH2Cl2) gave the title compound (0.867 g, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[NH:23][C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:39][CH:40]1[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:40]1([CH2:39][N:23]2[C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@H:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:18]([NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:24]2=[O:25])[CH2:42][CH2:41]1
Reactant: COc1ccc2c(c1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)N(CC1CC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N2-[(3,5-difluorophenyl)acetyl]-N1-[(2,3-cis)-7-methoxy-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (68) (95 mg, 0.186 mmol) in DMF (1 mL) under nitrogen was added (bromomethyl)cyclopropane (70 mg, 0.518 mmol) and powdered cesium carbonate (170 mg, 0.521 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate. The residue obtained from the organic extract was purified by flash chromatography on silica gel eluting with diethyl ether to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 62%) as a white solid. TLC Rf=0.26 (diethyl ether). 1H NMR (300 MHz, CDCl3) δ0.23 (m, 1H), 0.37-0.65 (m, 3H), 1.07 (d 1.5H, J=7.0 Hz), 1.21 (d, 1.5H, J=7.0 Hz), 3.43 (s, 1H), 3.47 (s, 1H), 3.83 (s, 3H), 4.09 (m, 1H), 4.25 (m, 1H), 5.05 (m, 1H), 5.61 (m, 1H), 5.89 (br d, 1H), 5.99 (br d, 1H), 6.20 (br t, 1H), 6.66-6.85 (m, 5H) 7.19 (d, 1H, 8.3 Hz), 7.30-7.42 (m, 6H). MS APCI, m/z=564 (M+1). LC/MS: 2.77 min.