Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CBr)CC1.[CH:6]1([CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=2)[CH2:8][CH2:7]1.N1CCCCC1.[O:28]1[CH2:32]C[CH2:30][CH2:29]1>[Pd]>[CH3:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH:6]2[CH2:8][CH2:7]2)[CH:19]=[CH:18][C:17]=1[O:20][CH2:30][CH:29]1[O:28][CH2:32]1
Reactant: C1CCOC1
Reactant: Cc1cc(OCCOCC2CC2)ccc1O
Agent: [Pd]
Agent: BrCC1CC1
Solvent: C1CCNCC1
Product: Cc1cc(OCCOCC2CC2)ccc1OCC1CO1

Procedure:
The epoxide starting material is obtained from reaction of 4-hydroxy-3-methylphenyl benzoate with benzyl bromide to give 4-benzyloxy-3-methylphenyl benzoate (M.P. 120°-121° from methanol/ether), followed by de-esterification with 2M NaOH solution to give 4-benzyloxy-3-methylphenol (M.P. 69°-70° from ether/hexane) and reaction with 2-bromoethanol (light brown oil) to form an alcohol which is reacted with cyclopropylmethyl bromide in tetrahydrofuran. Debenzylation of the cyclopropylmethoxyethoxy derivative (unpurified) with 10% Pd on activated charcoal forms 4-(2-(cyclopropylmethoxy)ethoxy)-2-methylphenol which is then reacted withepichlorhydrin in the presence of a catalytic amount of piperidine to give 2-methyl-1-(2,3-epoxypropoxy)-4-(2-(cyclopropylmethoxy)ethoxy)benzene (light brown oil after chromatography on silica gel with toluene/ethyl-acetate (8:2)).
Reaction SMILES: [OH:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: O=C(O)c1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cnc4ncccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
3-Hydroxy-[1,8]naphthyridine-2-carboxylic acid (15 mg), 4-chloro-6,7-dimethoxyquinoline (47 mg), and 4-dimethylaminopyridine (26 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (6 mg, yield 26%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Into a solution of dibenzo[b,d]thiophene (4.80 g, 26.1 mmol) in ether (70 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C., and the solution was allowed to warm to room temperature and then heated at 35° C. oil bath for 2 h to yield a red solution of dibenzo[b,d]thiophen-4-yl lithium.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:23][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6](=[O:7])[NH:8][C:9]2=[O:10]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])C(=O)NC3=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4-chloro-5-nitrophthalimide (1.05 g, 4.4 mmol), methyl 2-(3-chloro-4-hydroxyphenyl)acetate (821 mg, 4.4 mmol) and potassium carbonate (1.34 g, 9.7 mmol) in 10 mL of DMSO was allowed to stir at 25° C. for 22 h. Upon completion, the mixture was added to 50 mL of water. The resulting mixture was extracted with ethyl acetate (2×30 ml,). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column using 20% EtOAc/hexane as the eluent to give methyl 2-(3-chloro-4-(6-nitro-1,3-dioxoisoindolin-5-yloxy)phenyl)acetate (30.1). MS ESI (pos.) m/e calcd for (M+H)+ 391.0. found 391.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](C(N)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C[O:23][CH:24]([O:28][CH3:29])N(C)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:24]([O:28][CH3:29])=[O:23])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Solvent: CO
Product: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4 hours. After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239–241° C. Anal. Calc'd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:48]([O:56][CH2:57][CH3:58])(=[O:55])[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>>[CH2:57]([O:56][C:48](=[O:55])[CH:49]([C:16](=[O:17])[CH:15]=[CH:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1)[CH3:19])[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH3:58]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Product: CCOC(=O)C(C(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCC
Yield: 87 %

Procedure:
One proceeds in an analogous manner to the process disclosed in Example 4 by reacting 4-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-2-pentenoic acid at first with 12 g of pivaloyl chloride and thereafter with diethyl-ethoxy-magnesium malonate prepared from 17.6 g of diethyl malonate. The reaction mixture is worked up. 43 g of of the viscous oily desired compound are obtained which turns to a faint yellow crystalline product on standing. Mp.: 52°-55° C., yield 87%.
Reaction SMILES: [C@@:1]12(O)[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10].CS(C)=[O:15].N1C=CC=CC=1>C(N(CC)CC)C>[OH:11][C:2]1([CH3:10])[C:3](=[O:15])[CH2:4][CH:5]2[CH2:9][CH:1]1[C:6]2([CH3:8])[CH3:7]
Reactant: CC1(O)CC[C@H]2C[C@]1(O)C2(C)C
Reactant: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(O)C(=O)CC2CC1C2(C)C

Procedure:
oxidizing cis-pinanediol with DMSO activated by pyridine.SO3 and triethylamine in an appropriate solvent to form 2-hydroxy-3-pinanone;
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-])=O)=[CH:7][C:5]=2[N:6]=1>CC(O)=O.CCOC(C)=O.[Fe]>[CH:7]1[C:8]([NH2:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]2[N:3]=[C:2]([Cl:1])[NH:6][C:5]=12
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc2[nH]c(Cl)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
15 A mixture of 1.213 g (5.0 mmol) of 2-chloro-5,6-dinitrobenzimidazole (22) and 1.398 g (25 mmol) of iron powder in 50 mL of AcOH was stirred at room temperature for 4 h. The reaction mixture was diluted with 100 mL of EtOAc, filtered, and the solid was washed with portions of EtOAc (total EtOAc used ~ 100 mL). The filtrate and washings were combined and washed with H2O (100 mL×3). The H2O layer was extracted with 100 mL of EtOAc. The EtOAc solutions were combined, evaporated, coevaporated with toluene (10 mL×3), MeOH (10 mL×2) to give a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2-chloro-phenylamine (6 g, 29.06 mmol), [CAS 38762-41-3], 1,4-cyclohexanedione monoethyleneketal [CAS 4746-97-8], (6.908 g, 43.59 mmol), and sodium triacetoxy-borohydride (9.239 g, 43.59 mmol) in DCE (100 ml) and acetic acid (0.2 ml) was stirred at r.t. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and washed with DCM. The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution), dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/AcOEt 4:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D38 (8.57 g, 85%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:36])([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([CH3:35])=[N:28][NH:29][C:30]=2[Si](C)(C)C)=[CH:22][CH:21]=1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1>O.C(O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:36])([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([CH3:35])=[N:28][NH:29][CH:30]=2)=[CH:22][CH:21]=1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Cc1n[nH]c([Si](C)(C)C)c1-c1ccc([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1n[nH]cc1-c1ccc([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)cc1

Procedure:
A solution of potassium hydroxide (0.26 g, 4.6 mmol) in water (2.8 ml) was added to a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[3-methyl-5-trimethylsilylpyrazol-4-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (0.22 g, 0.45 mmol) in ethanol (12 ml) and the mixture was heated under reflux for 4 hours. The cooled mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and water (25 ml). The aqueous phase was further extracted with ethyl acetate (2×20 ml) and the combined organic layers were washed with brine (20 ml), dried(Na2SO4) and evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=2)=[N:10]1.C1C(=O)N([Br:39])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:39])[NH:12][C:11]([C:21]2[N:25]=[CH:24][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=2)=[N:10]1
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(C)N2)n1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Yield: 69 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.45 g, 0.91 mmol) was reacted with NBS (0.16 g, 0.91 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 69%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8])[CH2:9][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 71 %

Procedure:
Isopropylidineglycerol (solketal, 26.4 g, 0.20 mol) in 60 mL of toluene was added dropwise to a solution of powdered KOH (22.4 g, 0.04 mol) in 150 mL toluene. The resulting mixture was refluxed for 4 hours. 1-Bromodecane (50 g, 0.20 mol) in 40 mL of toluene was then added dropwise, and the solution was refluxed for 10 hours. After cooling, the reaction mixture was diluted with 200 mL of ice-water and extracted with diethyl ether (3×100 mL). The ether layers were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 60 mL of diethyl ether and 260 mL of MeOH. Concentrated HCl (60 mL) was added, and the solution was refluxed for 16 hours. After cooling, ice water (150 mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic fractions were then dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was recrystallized from MeOH to give 37 g (0.14 mol), 71% of a white solid.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Yield: 94.4 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloroquinolin-7-ol (60 mg, 0.196 mmol), K2CO3 (55 mg, 0.392 mmol) and 1-bromo-3-methoxypropane (0.088 ml, 0.785 mmol) in DMF (1 ml) were heated to 70° C. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue was purified via Biotage (SNAP Cartridge KP Sil 10 g, 30-75% EtOAc/Hexane) to yield 6-(tert-butylsulfonyl)-4-chloro-7-(3-methoxypropoxy)quinoline (0.071 g, 0.185 mmol, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.99-2.08 (m, 2H) 3.27 (s, 3H) 3.58 (t, J=6.19 Hz, 2H) 4.32 (t, J=6.19 Hz, 2H) 7.73 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.65 (s, 1H) 8.94 (d, J=4.55 Hz, 1H), MS: m/z: 372.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[C:14]([NH2:20])([NH2:19])=[N:15][C:16]([NH2:18])=[S:17]>>[CH2:1]([O:3][C:4]([CH:6]1[C:7]2[N:18]=[C:16]([NH:15][C:14]([NH2:20])=[NH:19])[S:17][C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: NC(=S)N=C(N)N
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Product: CCOC(=O)C1CCCc2sc(NC(=N)N)nc21

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-2-oxo-cyclohexane carboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to produce the title compound.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[Br:1])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
102.2 g (0.64 mole) of bromine are added dropwise at room temperature, with stirring, to a suspension of 100 g (0.52 mole) of 4-acetamidophenylacetic acid in 1 liter of glacial acetic acid; during this dropwise addition, a solution forms intermittently. Subsequently, heating to 60° C. is effected for 12 hours, followed by cooling to room temperature, diluting with 2 liters of water and extracting three times with diethyl ether. The organic phase is washed with sodium hydrogen sulfite solution and water, dried and concentrated to dryness. The residue is recrystallized from acetonitrile to yield 78 g (55.3% of theory) of 4-acetamido-3-bromophenylacetic acid (m.p. 157° to 159° C.).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH3:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: COc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-methoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.89 (3H, s), 5.22 (2H, s), 5.78 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=2.0 Hz), 6.95-6.98 (1H, m), 7.33-7.35 (1H, m), 7.39 (1H, dd, J=1.2, 5.2 Hz), 7.57-7.58 (1H, m), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O2, 341. Found, 341.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCSC1=O
Reactant: COC(=NC(C)C)NC(C)C
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](/C=C2\CCSC2=O)C1(C)C
Yield: 46 %

Procedure:
Using the procedure of Example 17, 4.5 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 2.2 g of methyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+63.5°±1.5° (c=1.1% in ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]([O:15][CH2:16][O:17][CH3:18])=[N:6][C:5]=2[N:4]([CH3:19])[N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]([O:15][CH2:16][O:17][CH3:18])=[N:6][C:5]=2[N:4]([CH3:19])[N:3]=1
Reactant: COCOc1nc2c(c(C)nn2C)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1nc2c(c(CBr)nn2C)c2ccccc12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1,3-Dimethyl-5-methoxymethoxy-3H-pyrazolo[3,4-c]isoquinoline (1.03 g), N-bromosuccinimide (0.72 g) and benzoyl peroxide (0.05 g) were dissolved in carbon tetrachloride (20 mL), and the mixture was heated under reflux for 4 hrs. After the completion of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was evaporated. The obtained solid was collected by filtration and washed with ether to give 1-bromomethyl-3-methyl-5-methoxymethoxy-3H-pyrazolo[3,4-c]isoquinoline (1.0 g).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:12]
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a mixture of 12.1 g (0.185 g-atom) of zinc powder (−325 mesh) and 160 mL of anhydrous tetrahydrofuran was added 17.6 mL (0.14 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 17.8 mL (0.14 mole) of ethyl bromodifluoroacetate in 20 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 20 g (0.093 mole) of benzotriazol-1-ylmethyl-cyclopentylamine in 80 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was then distilled under vacuum to give 12.4 g of 3-cyclopentylamino-2,2-difluoropropionic acid ethyl ester as a colorless oil. bp 75-82 degrees at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:12]1[CH2:17][CH2:16][N:15]([CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[C:19]([CH3:21])([CH3:20])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)=CN1CCOCC1
Product: CC1(C)C(=O)N(c2ccc(Cl)c(Cl)c2)C1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1.88 g. portion of 3,4-dichlorophenylisocyanate was added to 2.82 g. of 1-morpholino-1-isobutene. The mixture was stirred at room temperature for 48 hours. At the end of that time, the excess enamine was removed under vacuum, and the remaining oil, 3.0 g., was found by nuclear magnetic resonance analysis to be 1-(3,4-dichlorophenyl)-3,3-dimethyl-4-morpholino-2-azetidinone, a liquid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].[C:20](O)(=O)C.C(N)=N.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][CH:20]=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: N=CN
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (0.3 g), formamidine acetate (0.18 g) and anhydrous sodium acetate (0.1 g) was heated in an oil bath at 155°-165° C. for 21/2 hours. The mixture melted and then resolidified. Ethanol (1 ml) was added and the title compound was collected by filtration, 0.31 g, m.p. 256°-258° C.