Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[O:18]=[C:4]([NH:26][CH2:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)COc1ccc(C(=O)OCC)cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Reaction time: 24 h
Yield: 95.4 %

Procedure:
2.9 g (11 mmole) of ethyl 4-(2-ethoxy-2-oxoethoxy)benzoate, 1.4 g (12 mmole) of 3-picolylamine and 2.1 g (1.3 mmole) of DBU were dissolved in ethanol (12 ml), and reaction was then carried out for 24 hours. After the reaction mixture had been concentrated, partition was carried out between ethyl acetate and water. The organic layer was then treated in an ordinary manner to obtain 3.3 g (yield: 90%) of ethyl 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:27](=[C:28]([F:29])[C:11]=3[O:10][N:9]=2)[N:26]2[CH2:30][C@@H:31]([CH3:35])[O:32][C@@H:33]([CH3:34])[C@@H:25]2[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]2=[O:24])[CH2:15]4)[CH:5]=[N:4][CH:3]=1.[CH3:36][NH:37][CH3:38]>C1COCC1>[CH3:36][N:37]([CH3:38])[C:2]1[N:7]=[C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:27](=[C:28]([F:29])[C:11]=3[O:10][N:9]=2)[N:26]2[CH2:30][C@@H:31]([CH3:35])[O:32][C@@H:33]([CH3:34])[C@@H:25]2[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]2=[O:24])[CH2:15]4)[CH:5]=[N:4][CH:3]=1
Reactant: C[C@@H]1CN2c3c(cc4c(-c5cncc(Cl)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CNC
Solvent: C1CCOC1
Product: C[C@@H]1CN2c3c(cc4c(-c5cncc(N(C)C)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-rel-8-(6-chloropyrazin-2-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 79) and 2N dimethylamine in THF.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[OH:9].[CH:12](OCC)(OCC)OCC>>[CH3:10][N:5]1[CH:6]=[CH:7][C:8]2[O:9][CH:12]=[N:2][C:3]=2[C:4]1=[O:11]
Reactant: CCOC(OCC)OCC
Reactant: Cn1ccc(O)c(N)c1=O
Agent: Cl
Product: Cn1ccc2ocnc2c1=O
Yield: 30 %

Procedure:
The title compound of step 3 (500 mg, 2.8 mmol) in triethyl orthoformate (10 mL) was heated to reflux for 5 h. The mixture was concentrated in vacuo at 55° C. and purified by silica gel chromatography (PE:EA=1:1) to give the title compound (130 mg, yield: 30%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]=[O:20])[N:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH2:19][OH:20])[N:3]=1
Reactant: O=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidine-2-carbaldehyde (70 mg, 0.21 mmol) in MeOH (4 mL) is added sodium borohydride (24 mg, 0.63 mmol). The mixture is stirred for 4 hours at ambient temperature. Water (20 mL) is added and the mixture is extracted thrice with ethyl acatate (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford {4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-methanol (67 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:13][C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:23])[C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 1.00 g (0.0034 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-spiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VI-53) in 40 mL of dimethylformamide was added 1.47 g (0.0104 mole) of iodomethane and 1.68 g (0.00575 mole) of cesium carbonate. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.957 g of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Yield: 41.6 %

Procedure:
170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The mixture was heated at reflux for 24 h and then filtered off through kieselguhr and concentrated under reduced pressure. After standing for a relatively long time (48 h) at RT a solid precipitated out. It was filtered off, stirred three times with a little isopropanol and then filtered off each time and finally washed with diethyl ether. This gave 60.8 g (23.4% of theory) of the title compound. The combined mother liquor of the filtration steps was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase, and this gave a further 46.5 g (18.2% of theory; total yield: 41.6% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][C:13]([CH:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][C:13]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C(C=C1CCCCC1)OCCc1cc(F)c(F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(CC1CCCCC1)OCCc1cc(F)c(F)c(F)c1
Yield: 93.4 %

Procedure:
4-(3',4',5'-Trifluorophenyl)ethoxycarbonylmethylenecyclohexane (18.3 g) was dissolved in ethanol (100 ml), followed by adding Pd/C (5%, 5 g), stirring the mixture, hydrogenating in a hydrogen gas atmosphere until completion of absorption of a hydrogen, filtering off the catalyst after completion of the reaction, and concentrating the solvent under reduced pressure, to obtain 4 -(3',4',5'-trifluorophenyl)ethoxycarbonylmethylcyclohexane (17.2 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]COCC.[N+](=C)=[N-]>O1CCCC1>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(I)cc1
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)cc1
Yield: 99.3 %

Procedure:
Fifty (50) mmol (12.4 g) of commercially available 4-iodobenzoic acid was dissolved in 200 ml of tetrahydrofuran and then added to an ether solution containing freshly prepared diazomethane. The excess diazomethane was subsequently consumed by addition of glacial acetic acid and the resultant solution was concentrated in vacuo. The residue thus obtained was partitioned between ethyl acetate and saturated NaHCO3. The layers were separated and the aqueous phase was extracted with 100 ml of ethyl acetate. The organic extracts were combined, dried over Na2SO4, and concentrated in vacua, yielding 13.01 grams (99.3% yield) of a yellow solid which melted at 111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19]CC)=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[CH:22]=[CH2:23].[OH-].[Li+].C(O)C.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([OH:19])=[O:18])[CH:9]([C:13]([F:15])([F:16])[F:14])[O:10]2)=[CH:5][C:4]=1[CH:22]=[CH2:23]
Reactant: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 80 °C
Yield: 79.6 %

Procedure:
The isolated intermediate from step 1 (150 mg, 0.46 mmol) was dissolved in 3 mL of THF. To the resulting solution was added a solution of lithium hydroxide (2.3 mmol.) in 3 mL of water. To the resulting mixture was added 3 mL of ethanol. The resulting solution was heated to 80° C. for three h. The mixture was concd in vacuo and the residue acidified to pH=1.0 with dilute aqueous hydrochloric acid. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solution was concd in vacuo to afford 110 mg (52%) of the final product: 1H NMR (CDCl3/300 MHz) 7.80(s, 1H), 7.48(s, 1H), 6.98-6.88(dd, J=17.7 Hz, 11.2 Hz, 1H), 6.66(s, 1H), 5.80-5.69(m, 2H), 5.20(d, J=11.4 Hz, 1H), 3.90(s, 3H). MS (ESI+) 301.1 (M+1, 100). MS(ES−) 299.1 (M−H, 100). HRMS (ES−) m/z calcd for (C14H10F3O4) M−H: 299.0526, found 299.0500.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13]C=[CH:11][CH:10]=1.[C:18](=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[CH3:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(-c2ccccc2)cc1
Yield: 55 %

Procedure:
Table 1, Entry 10. In the reaction tube were mixed 4-bromotoluene (0.171 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol), Pd(PPh3)4 (0.0347 g, 0.030 mmol), sodium cabonate (0.212 g, 2.0 mmol), 0.187 ml 95% ethanol, 0.375 ml water and 0.75 ml DME.under nitrogen. The contents of the flask were irradiated for 2.50 min with an effect of 55 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml saline and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane as the eluent. The yield was 55% (white solid).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C(OCC)C>[Cl:19][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCc1cc2ccccc2o1
Reaction time: 1 h

Procedure:
Compound 4 (155.25 g) was dissolved in anhydrous ethyl ether (250 ml) containing dimethylformamide (1 ml). The reaction flask was placed into an ice bath, and when the solution temperature was between 0° C. and 4° C., thionyl chloride (124.3 g, 76.2 ml) was added dropwise, while stirring, over the period of 1 hour. The mixture was then stirred for another hour, washed with water (250 ml), 3% sodium bicarbonate solution (250 ml), and with water again (250 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The product was distilled in vacuo, and the yield was approximately 117 g. The boiling point is about 78° C. at 1.5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([CH3:12])=[CH:7][N:6]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:18](=[O:20])[CH3:19])[C:8]([CH3:12])=[CH:7][N:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(Oc2ccc(F)cc2F)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccc(F)cc2F)ncc1C
Yield: 99 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-5-methylpyridin-4ylamine (3.6 g) in 80 mL of methylene chloride was added 4.7 g of acetic anhydride. The mixture was heated for 24 hours on a steam bath and then poured onto 200 mL of 5% aqueous sodium carbonate. The aqueous solution was extracted with methylene chloride. The organic layers were combined, dried and concentrated to give 4.2 g of N-[2-(2,4-difluorophenoxy)-5-methylpyridin-4-yl]acetamide (99% yield). Mass. Spec. M+H=279.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[N:15]1([CH2:21][CH2:22][NH:23][C:24]2[NH:25][C:26](=O)[C:27]3[N:28]=[CH:29][NH:30][C:31]=3[N:32]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:12][C:26]1[N:25]=[C:24]([NH:23][CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][NH:30]2
Reactant: O=c1[nH]c(NCCN2CCCCC2)nc2[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1nc(NCCN2CCCCC2)nc2[nH]cnc12
Yield: 88.7 %

Procedure:
A mixture of N,N-dimethylaniline (4 ml, 31 mmol) and phosphorus oxychloride (30 ml, 314 mmol) was stirred at ambient temperature for 10 min before Intermediate 37 (5.5 g, 20 mmol) was added portionwise and was then refluxed for 15 min. On cooling the phosphorus oxychloride was evaporated in vacuo, the residue obtained was azeotroped with toluene (3×50 ml). Purification using flash column chromatography with a Biotage column (90 g, SiO2) eluting with 10% methanol/chloroform 1% ammonia gave the title compound as a pale yellow solid (4.980 g). LC/MS SYSTEM C Rt=1.61 min, m/z=281 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][CH2:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][CH2:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(CCCCO)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 200 mg, 0.61 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (305 μL, 0.61 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (145 μL, 1.22 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 0.61 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 45 min. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-butyl)-1H-pyrazol-3-yl]-propionamide (35 mg, 12%) as a white foam: ESI-LRMS m/e calcd for C22H30ClN3O4S [M+] 467.2, found 468.0 [M+H+], 450.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.45-1.99 (m, 12H, 6×CH2), 2.17-2.30 (m, 1H, CH), 2.71 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.8 Hz, 1H, CH), 3.69 (t, J=6.2 Hz, 2H, OCH2), 4.09 (t, J=6.6 Hz, 2H, NCH2), 6.70 (s, 1H, Ar), 7.30 (s, 1H, Ar), 7.49 (d, Jo=8.3 Hz, 1H, Ar), 7.62 (s, 1H, Ar), 8.10 (d, Jo=8.6 Hz, 1H, Ar), 8.47 (brs, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH2:34][CH3:35])[N:12]=[C:11]2[CH3:36])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:37][Mg]Br.C(OCC)(=O)C.O>O1CCCC1>[CH2:32]([C:13]1[N:12]=[C:11]([CH3:36])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([CH3:37])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.5 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 12 hr while allowing to warm to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.54 g, 52%).
Reaction SMILES: [CH:1]1CCCCC=1.[CH2:7]1[CH:11]2[CH:12]3[CH:16]=[CH:15][CH:14]([CH:10]2[CH:9]=[CH:8]1)[CH2:13]3>C(Cl)(Cl)Cl>[CH:12]12[CH2:13][CH:14]([CH:15]=[CH:16]1)[CH:10]1[CH:11]2[CH2:7][CH2:1][CH2:8][CH2:9]1
Reactant: C1=CCCCC1
Reactant: C1=CC2C3C=CC(C3)C2C1
Solvent: ClC(Cl)Cl
Product: C1=CC2CC1C1CCCCC21
Reaction time: 5 h

Procedure:
82 g. (1 mole) of cyclohexene and 66 g. (0.5 mole) of dicyclopentadiene are reacted according to the batch procedure in 300 g. of chloroform. The reaction is carried out for 5 hours at 220° C. to produce a moderate yield of tricyclo [6.2.1.02,7 ] undec-9-ene.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(SSN(C)C(=O)ON=C2SC(C)(C)C(=O)N2C)cc1

Procedure:
2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximino thiazolidin-4-one, 6.64 g (0.028 m) of N-methyl-N-(4-methylphenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from ethylacetate-hexane to yield 8.0 g of solid, m.p. 116°-118° C. It was then recrystallized from ethyl acetate isopropyl ether, to yield a solid, m.p. 123°-125° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[S:42][CH:43]=[C:44]([C:46](O)=[O:47])[N:45]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl.O>[CH:1]1([O:7][C:46]([C:44]2[N:45]=[C:41]([CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[S:42][CH:43]=2)=[O:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (1.21 g), dimethylaminopyridine (113 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.87 g) are added to a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 2.90 g) in dichloromethane (30 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.63 g, 72%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[N:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]1[NH:6][C:7](=[O:9])[CH:8]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[N:4]=1)[CH2:18][CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C#N)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1nc(-c2nnn[nH]2)cc(=O)[nH]1

Procedure:
A stirred solution of 4-cyano-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (325 mg), sodium azide (91 mg) and ammonium chloride (75 mg) in dimethylformamide (15 ml) was heated at 125° C. for 5 hours. Most of the dimethylformamide was removed under reduced pressure and water added to the oily residue which solidified. The mixture was cooled and the solid was collected, acetic acid to yield the title compound, 174 mg, m.p. 219-221° C.
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2C(CC(O)C)=CC=C3C([NH:14][C:15](=O)[C:10]=23)=O)[CH2:5][CH2:4]1)#[N:2].NN.C[OH:33]>>[C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([OH:33])[CH2:15][NH2:14])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(O)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Reactant: CO
Agent: NN
Product: N#CC1(c2ccccc2)CCN(CC(O)CN)CC1
Yield: 94 %

Procedure:
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-hydroxypropyl)phthalimide (10 g, 23.48 mmol) and hydrazine (6.01 g, 188 mmol, 8 eq.) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (5.53 g, 94%).