Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH2:11][CH2:10]/[C:9](=[CH:12]\[CH2:13][O:14]C(=O)C)/[CH2:8][O:7][C:6]1([CH2:19][CH2:20][CH2:21][CH:22]([CH3:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:18])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[OH:4][CH:5]1[CH2:11][CH2:10]/[C:9](=[CH:12]\[CH2:13][OH:14])/[CH2:8][O:7][C:6]1([CH2:19][CH2:20][CH2:21][CH:22]([CH3:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:18]
Reactant: CC(=O)OC/C=C1\CCC(OC(C)=O)C(C)(CCCC(C)COC2CCCCO2)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(CCCC1(C)OC/C(=C/CO)CCC1O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A mixture of 5-[(2RS,3SR)-3-acetoxy-6-[(E)-2-acetoxyethylidene]-2-methyl-2-oxepanyl]-2-methyl-1-(tetrahydropyran-2-yloxy)pentane (1.2 g, 2.73 mM), methanol (10 ml) and saturated potassium carbonate (1 ml) and water (1 ml) is stirred under nitrogen at room temperature for three hours. Most of the solvent is removed in vacuo to give a thick oil. This crude material is filtered through a silica gel column (15 g) and washed with ether (100 ml). The solvent is removed in vacuo to give 5-[(2RS,3SR)-3-hydroxy-6-[(E)-2-hydroxyethylidene]-2-methyl-2-oxepanyl]-2-methyl-1-(tetrahydropyran-2-yloxy)pentane (0.953 g, 87%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:18][CH:17]([S:14]([NH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:16])=[O:15])[CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(N)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-amino-phenyl)-cyclopentyl]-amide (265 mg, 0.94 mmol, prepared in example 23) was dissolved in 10 mL of methylene chloride and cooled to 0° C. under nitrogen. Benzoyl chloride was added (120 uL, 1.03 mmol) and after stirring 15 min the ice bath was removed and stirring continued for 2 hours. The reaction was diluted with methylene chloride and washed with water, then 0.1 N HCl and dried over sodium sulfate. The organic phase was concentrated in vacuo to 360 mg crude oil. The product was purified by radial chromatography eluting first with 70:30 methylene chloride:hexanes then ethyl acetate was added (→20%) until all bands were removed to give 120 mg (33%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[C:12]2[C:16](=O)[O:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13]2)=[CH:6][C:5]=1[CH2:24][O:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29]>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][C:12]([C:16]([NH2:1])=[O:15])=[N:11]2)=[CH:6][C:5]=1[CH2:24][O:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29]
Reactant: [NH4+]
Reactant: O=C1OC(c2ccccc2)=NC1=NNc1ccc(Cl)c(COCC(F)(F)C(F)(F)F)c1
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(-c2ccccc2)n(-c2ccc(Cl)c(COCC(F)(F)C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 100.7 %

Procedure:
A 29% ammonia aqueous solution (3.48 kg, 59.2 mol) was added to 47.8 kg of water. 2-phenyl-4,5-oxazoledione 4-[4-chloro-3-(2,2,3,3,3-pentafluoropropoxy)methylphenyl]hydrazone (14.9 kg, purity: 94.4%, water content: 36.5%, 19.4 mol) was added to the solution and the mixture was heated while stirring. After heating at 80° C. for two hours (after three hours after initiation of the heating), the reaction mixture was cooled to 50° C. and filtered by centrifugation. The residue was washed with hot water dried in a hot air drier to obtain 9.0 kg of the target compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CC(C)=O.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C(N(CC)CC)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 66 %

Procedure:
33.3 g of propionyl chloride were added over 30 minutes at 20°-30° C to a mixture of 480 ml of acetone, 48.3 g of o-trifluoromethyl aniline and 36.42 g of triethylamine and after standing for 12 hours, the mixture was filtered. The acetone was evaporated from the filtrate and the residue was taken up in 500 ml of ethyl acetate. The solution was washed with 10% potassium carbonate solution, then with water until the pH of the wash waters was 6, then with N hydrochloric acid and then with water until the wash water pH was 6. The solution was dried over magnesium sulfate, treated with activated carbon and then evaporated to dryness to obtain 65 g of raw product which was washed with iced essence G to obtain 43 g of N-(2-trifluoromethylphenyl)-propanamide melting at 86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:19][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccccc1CBr
Yield: 80 %

Procedure:
A solution of compound 18b (4.5 g, 30 mmol), NBS (5.9 g, 33 mmol) and AIBN (0.5 g, 3 mmol) in CCl4 (20 mL) was refluxed overnight. The mixture was taken up in H2O (20 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by CC to give the compound 18c (5.5 g, 80% yield).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2([CH2:10][OH:11])[CH2:8][OH:9].[H][H]>C(O)C.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2([CH2:8][OH:9])[CH2:10][OH:11]
Reactant: [H][H]
Reactant: OCC1(CO)CC2C=CC1C2
Agent: [Pd]
Solvent: CCO
Product: OCC1(CO)CC2CCC1C2
Reaction time: 6 h
Yield: 92.7 %

Procedure:
138.18 g of 5-norbornene-2,2-dimethanol (commercially available from Tokyo Kasei Industry Co., Ltd.) was dissolved in 481.63 g of ethanol, and 6.92 g of 5% Pd—C was added, then a hydrogen balloon was attached and the mixture was stirred for 6 hours. The Pd—C was filtered off, then the reaction solution was concentrated and dried to thereby obtain 129.83 g of 2,2-norbornanedimethanol (purity by gas chromatography: 99.1%, yield: 92.9%).
Reaction SMILES: [C:1]1([S:7][C:8](=[N:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:25](=[O:29])[CH2:26][C:27]#[N:28])C.C([O-])(=O)C.[NH4+]>CCO>[C:1]1([S:7][C:8]2[C:9]([CH3:10])=[C:26]([C:27]#[N:28])[C:25](=[O:29])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(NN=C(Sc2ccccc2)C(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(-n2nc(Sc3ccccc3)c(C)c(C#N)c2=O)cc1

Procedure:
The reaction of 429 mg of 1-[(phenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, 375 ul of ethylcyanoacetate and 178 mg of ammonium acetate as in Example 55, yielded 165 mg of 6-[(phenyl)thio]- 2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 179°-180° C. (EtOH).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]2=[CH:13][C:14]=1[Cl:15]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][C:14]=1[Cl:15])[C:8](=[O:9])[O:10][CH2:11]2
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 74.8 %

Procedure:
NaBH4 (5.2 g) was added to a stirred solution of 4,5-dichlorophthalic anhydride (20 g) in anhydrous DMF (100 mL) at 0° C. under nitrogen in small portions over 1 hour. The reaction was warmed to room temperature for a further 2 hours and poured into ice/1M HCl. The resultant white precipitate (4,5-dichloro-2-hydroxymethyl-benzoic acid) was collected by filtration and dried under vacuum. The precipitate was suspended in toluene (200 mL) with catalytic pTSA and heated to reflux under Dean-Stark conditions (precipitate dissolves on heating) for 18 hours. The reaction was cooled to room temperature and the resultant white precipitate collected by filtration to give the sub-title compound as a white solid (14.0 g, 75%); 1H NMR (400 MHz, d6-DMSO) δ 5.40 (2H, s), 8.05 (1H, s), 8.15 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](O)=[O:33])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](=[O:33])[NH:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:13]([Cl:19])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (800 mg), (R) —N-Boc-2-pyrrolidinecarboxylic acid (608 mg) and HBTU (1.46 g) in dry DMF (30 ml) containing N-methylmorpholine (1.26 ml) was stirred at room temp for 18 h. Silica gel (5 g) was then added and the mixture evaporated. The residue was purified by chromatography. Elution with 12:1 petrol:ethyl acetate gave a viscous brown gum (987 mg)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([C@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])[C:4](=[O:15])[O:3]1.[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]>C(Cl)Cl>[F:17][C:18]1[C:23]([O:9][C:8](=[O:10])[C@H:7]([C@@H:5]2[C:4](=[O:15])[O:3][C:2]([CH3:1])([CH3:16])[O:6]2)[CH2:11][CH:12]([CH3:13])[CH3:14])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Solvent: ClCCl
Product: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@H]1OC(C)(C)OC1=O
Yield: 73.4 %

Procedure:
A solution of 2-(S)-(2,2-dimethyl-5-oxo-1.3-dioxolan-4-(R)-yl)-4-methylpentanoic acid (1.1 g, 4.78 mmole), pentafluorophenol (970 mg, 5.27 mmole), and 1-dimethylaminopropyl-3-ethyl carbodiimide methiodide (1.42 g, 4.78 mmole) in CH2Cl2 (25 ml) was stirred at 23° for 24 h. The reaction was washed with H2O, 5% aqueous K2CO3, H2O, dried (K2CO3), and the solvent evaporated, to yield the title compound (1.39 g, 74%).
Reaction SMILES: Cl[C:2]1[CH:31]=[CH:30][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=3[OH:29])[N:8]=[C:4]2[CH:3]=1.[OH-].[K+].[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN1CCCC1=O>[C:34]1([S:40][C:2]2[CH:31]=[CH:30][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:10]=4[OH:29])[N:8]=[C:4]3[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Sc4ccccc4)cc3n2)c1

Procedure:
The tide compound is prepared according to the procedure of Example 4 from 20 g of the compound of Example 8, 20.4 g of 45% aqueous potassium hydroxide, 10.3 g of thiophenol and 100 g of N-methylpyrrolidone. The title compound is an oil purified by chromatography on silica gel using toluene as eluent
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)Cl.CO>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCOCCOCCOC)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: COCCOCCOCCP(=O)(O)O
Temperature: -35 °C
Reaction time: 2 h

Procedure:
{2-[2-(2-Methoxyethoxy)ethoxy]ethyl}phosphonic acid diethyl ester (1.00 g, 3.5 mmol) was dissolved in CH2Cl2 (20 ml) under N2. Bromotrimethylsilane (2.3 ml, 17.5 mmol) was added via syringe and the mixture was stirred for 2 hours. Volatiles were removed in vacuo to give a thick orange oil; this was dissolved in MeOH (100 ml) with fuming to give a give a yellow solution. The mixture was stirred for 2 hours and evaporated to dryness to give a thick yellow oil which was dissolved in CH2Cl2 and extracted with NaOH (3×50 ml, aq., 1M). HCl (conc.) was added to the yellow aqueous layer until the solution was acidic to pH paper. Removal of water in vacuo gave a yellow crystalline solid that was extracted with EtOH and filtered. Cooling the filtrate to −35° C. resulted in precipitation of further white solid which was removed by filtration. Removal of volatiles from the yellow supernatant under vacuum (0.01 torr) afforded the desired product as a thick yellow oil. Yield 0.60 g, 2.6 mmol, 74%. 1H NMR (d6-DMSO, 400 MHz, 298 K): δ 3.55 (ap. q. J=7 Hz, 2H), 3.48 (m, 6H), 3.41 (m, 2H), 3.23 (s, 3H), 1.83 (d of t, JH-P=19 Hz, JH-H=7 Hz, 2H). 13C{1H} NMR (d6-DMSO, 100 MHz, 298 K): δ 71.25, 69.69, 69.58, 69.27, 65.41, 58.05, 28.99 (d, JC-P=132 Hz). 31P{1H} NMR (d6-DMSO, 162 MHz, 298 K): δ 23.15. MS (ESI, m/z): 227 (44−, 100%), 229 ([M+H]+, 10%). Exact mass found (calculated for [M+H]+, m/z): 229.08490 (229.08410).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:26]#[CH:27])[N:7]([N:11]1[C@H:15]([CH3:16])[CH2:14][C@H:13]([NH:17]C(OC(C)(C)C)=O)[C:12]1=[O:25])[C:8](=[O:10])[CH3:9])[CH3:2].[ClH:29]>CCOC(C)=O>[ClH:29].[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:26]#[CH:27])[N:7]([N:11]1[C@H:15]([CH3:16])[CH2:14][C@H:13]([NH2:17])[C:12]1=[O:25])[C:8](=[O:10])[CH3:9])[CH3:2]
Reactant: C#C[C@H](CC(=O)OCC)N(C(C)=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C
Agent: Cl
Solvent: CCOC(C)=O
Product: C#C[C@H](CC(=O)OCC)N(C(C)=O)N1C(=O)[C@@H](N)C[C@H]1C
Reaction time: 0.08 h

Procedure:
To a solution of 13-10 (550 mg, 1.39 mmol) in EtOAc at 0° C. was bubbled HCl gas for 5 minutes. The reaction was stirred an additional 5 minutes, followed by removal of the cooling bath and then purged with Argon for 20 minutes. Evaporative removal of the solvent gave 13-11 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[OH-].[Na+]>CN(C)C=O>[OH:12][CH:10]([CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OC(CNc1ccccc1)CNc1ccccc1
Temperature: 110 °C
Yield: 6.3 %

Procedure:
A mixture of 0.25 ml (2.74 mmol) of aniline, 0.107 ml (1.37 mmol) of epichlorohydrin, and 60.4 mg (1.51 mmol) of sodium hydroxide in 2 ml of dimethylformamide was heated at 110° C. for 20 h. The solvent was removed in vacuo and the residue was purified by flash chromatography using 5% ethyl acetate in chloroform to give 21 mg (6%) of the desired compound (Rf 0.63, 40% ethyl acetate in chloroform). 1H NMR (CDCl3) δ 3.21 (dd, J=13, 8 Hz, 2H), 3.37 (dd, J=13, 4 Hz, 2H), 4.13 (m, 1H), 6.65-6.8 (m, 6H), 7.15-7.3 (m, 6H). Mass spectrum (M+H)+ =243.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1[O:21][C:8]2([CH2:13][CH2:12][C:11](O)([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[O:7][CH2:6]1.[OH-].[Na+]>N1C=CC=CC=1>[CH2:6]1[O:7][C:8]2([CH2:13][CH2:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH2:9]2)[O:21][CH2:5]1
Reactant: OC1(c2cccnc2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2cccnc2)CCC2(C1)OCCO2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (45 mL, 622.5 mmol) was slowly added to a solution of 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene ketal (prepared as in step a, 29.3 g, 124.5 mmol) in pyridine (250 mL) at −10° C. After stirring at 0° C. for 2.5 h, the reaction mixture was poured onto ice and adjusted to pH 8 with 2 N NaOH. The aqueous layer was extracted with CH2Cl2 (100 mL×3) and the combined organic layers were washed with brine (200 mL), dried with MgSO4, and concentrated in vacuo to afford crude 4-(3-pyridyl)cyclohex-3-en-1-one ethylene ketal, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[NH:1]([C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)[C:12]([CH3:13])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Solvent: c1ccncc1
Product: CC(=O)NC1=NC(=O)C2=CC=NC2=N1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
2-Aminopyrrolo(2,3-d)pyrimidin-4-one (3.0 g) and acetic anhydride (10 g) are suspended in pyridine (50 ml) and the reaction is conducted under reflux for 24 hours. The solvent and excess reagent are distilled off under reduced pressure and, on an ice bath, 5% (W/V) alcoholic ammonia (20 ml) is added to the residue. The mixture is stirred for 2 hours. The resulting crystalline precipitate is collected by filtration and washed with dilute hydrochloric acid and water to give the above-identified compound (2.5 g).
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].CO.C(=S)=[S:27]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:27])[N:13]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 97 %

Procedure:
8.0 g of adenosine 1-oxide monohydrate (26.67 mmol) was refluxed in 5 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 9.0 using Amberlite IRC-50 (H+-type) and then concentrated to a small volume to prepare 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime. To this was added 200 ml of an aqueous solution containing 175 ml of methanol. The pH of the resulting solution was 9. 50 ml of carbon disulfide was further added to the solution, and the mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance formed in the autoclave was removed and concentrated to dryness. The residue was dissolved in 63 ml of 2.5N aqueous ammonia, and any impurities were filtered out. A mixture of n-butanol and acetic acid (125 ml:63 ml) was added to the above filtrate to crystallize the product to obtain 8.20 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in a 97% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:32]([NH:31][C:25]1[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:30])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Reactant: Cc1cccc(C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C)cccc2C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-octylphenyl)amine (1.0 g) and 2,6-dimethylphenyl isocyanate (6.4 mL) as starting materials, N-benzyl-N′-(2,6-dimethylphenyl)-N-(4-octylphenyl)urea (0.5 g) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:25]3[CH:24]=[C:23]([CH3:22])[O:27][N:26]=3)=[O:29])[CH3:21])[N:5]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: Cc1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Product: Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile (120 mg, 0.408 mmol) and 5-methylisoxazole-3-carboxylic acid (62 mg, 0.489 mmol). The product was purified with flash-chromatography. Yield 88 mg (53%). 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.43 (s, 3H), 4.32-4.34 (m, 2H), 4.40-4.50 (m, 1H), 6.43 (s, 1H), 7.02 (d, 1H), 7.84 (d, 1H), 8.18 (d, 1H), 8.23-8.25 (m, 1H), 8.29 (s, 1H), 8.71 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:5][CH:4]=1)#[N:2].Cl>C(OCC)(=O)C>[CH:15]12[N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:26][CH:25]=3)[CH:11]([CH2:17][CH2:16]1)[CH2:12][NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2CCOc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCN2C3CCC2CNC3)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
tert-Butyl 8-[2-(4-Cyanophenoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.35 g, 3.8 mmol; from step (b) above) was dissolved in ethyl acetate (30 mL). The solution was cooled to 0° C., ethyl acetate (30 mL) saturated with gaseous HCl was added, and the resulting mixture stirred at r.t for 15 h. The solvent was evaporated before CHCl3 was added. The mixture was extracted with K2CO3 solution, separated, dried and evaporated to give 0.7 g (73%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[CH3:10][C@@H:11](O)[CH2:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:11]([CH3:10])[CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC[C@@H](C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methanesulphonic anhydride (8.33 g, 47.8 mmol) in dichloromethane (30 ml) was added dropwise over 30 minutes to an ice-cooled solution of (R)-2-butanol (4.0 ml, 43.5 mmol) and triethylamine (6.65 ml, 47.8 mmol) in dichloromethane (70 ml). The reaction was then allowed to warm to room temperature and stirred for 18 hours. The mixture was then washed with water, 2N hydrochloric acid, then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a pale yellow oil, 7.0 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[I:16]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([I:16])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1c(N)nc(-c2ccccc2)cc1=O
Solvent: CC(=O)O
Product: Cn1c(N)nc(-c2ccccc2)c(I)c1=O
Temperature: 25 °C

Procedure:
To 1.8 g (8.95 mM) of 2-amino-3-methyl-6-phenyl-4-pyrimidinone was added 75 ml glacial acetic acid and 1.98 g N-iodosuccinimide (8.8 mM). The reaction mixture was heated to 70° for 5 hours. The mixture was allowed to cool to room temperature and evaporated to dryness under vacuum. The residual solid was azeotroped twice from absolute EtOH, heated to reflux with 50 ml absolute EtOH and allowed to cool to room temperature. The solids were filtered, washed well with absolute EtOH, and dried at 80° for 18 hours. Yield of yellow crystals was 1.6 g (56%).