Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: Cc1ccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1

Procedure:
50 mg (0.11 mmol) of the compound of Example 41A is reacted analogously to the synthesis of the compound of Example 1 with 15 mg (0.13 mmol) of 4-imidazolinone-hydrochloride. 47 mg (81% of theory) of the title compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH2:27])[CH:21]=1>CCO>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][CH2:2][C:3]([C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]=2[CH3:10])=[O:4])[CH:21]=1
Reactant: Cc1c(C(=O)CBr)cnn1-c1ccccc1
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: CCO
Product: COC(=O)c1ccc(C)c(NCC(=O)c2cnn(-c3ccccc3)c2C)c1
Yield: 52 %

Procedure:
A solution of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (829 mg; 2.97 mmol) and 3-amino-4-methyl benzoic acid methyl ester in 6 mL of EtOH was stirred at 75° C. for 6 h. The mixture was cooled, and the resulting precipitate was filtered and washed with cold EtOH to provide 564 mg (1.55 mmol; 52%) of 4-methyl-3-[2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-benzoic acid methyl ester as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[Si:63]([O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH2:78])=[N:74]1)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64]>>[C:66]([Si:63]([CH3:65])([CH3:64])[O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH:78][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:74]1)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine (WO2009127544) (0.16 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as a off white foam (Yield 0.1 g, 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(C3(c4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)CCCCC3)cc2)cc1
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(C3(c4ccc(Cc5ccc(N)cc5)cc4)CCCCC3)cc2)cc1
Yield: 82.2 %

Procedure:
1,1-bis[4-(4-nitrobenzyl)phenyl]cyclohexane 98.93 g was dissolved in 1100 ml of tetrahydrofuran, a Pd--C catalyst (5% purity, water content 55.9%) 9.8 g was added, and the mixture was cooled with water at atmospheric pressure and contacted with hydrogen gas with stirring. After the absorption of hydrogen stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was recrystallized with toluene solvent to obtain 71.71 g of 1,1-bis[4-(4aminobenzyl)phenyl]cyclohexane which is a diamino compound of the present invention. The melting point was 154.4°-155.5° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[C:26]([Br:27])=[CH:25][N:24]([CH3:28])[N:23]=2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:27][C:26]1[C:22]([C:18]2[CH:17]=[C:16]([NH:15][C:8]([C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:9])[CH:21]=[CH:20][CH:19]=2)=[N:23][N:24]([CH3:28])[CH:25]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(OC(F)(F)F)cc3)c2)n1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To 4-(trifluoromethoxy)benzoyl chloride (19 μL, 0.12 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (40 mg, 76%), m.p. 138.6-139.6° C. (EtOAc/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([F:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCCl
Product: Nc1cc(F)c(C(=O)Cl)cc1[N+](=O)[O-]
Yield: 99 %

Procedure:
Prepared analogously to example 53a from 4-amino-5-nitro-2-fluoro-benzoic acid and thionyl chloride in 1,2-dichloroethane. Yield: 99%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
4-Morpholinoaniline (0.286 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.077 g, 0.144 mmol, 27%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=[NH:30])OCC>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: Cc1ccccc1COc1cccnc1N
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1C
Yield: 14.8 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 2-methylphenylacetimidate hydrochloride (5.7 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.37 g), m.p. 147°-154° C.
Reaction SMILES: [C:1]1([S:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C(O)(C)C.[OH-].[Cu+2:29].[OH-]>O>[CH2:11]([O:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cu:29]
Reactant: [Cu+2]
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: [Cu]

Procedure:
Into a fritted column was added: 12 g (12 meq H+) ion exchange resin (Amberlite® IR 120 brand). Resin beads were washed with 100 ml deionized water. Into a 50 ml beaker were added: 8.6 g (10 meq) sodium dodecyl benzene sulfonate (Biosoft D-40 brand), 7 g water, and 7 g isopropanol. The Biosoft D-40 solution was run through the column and collected in a 100 ml beaker containing: 0.58 g (12 meq Cu) copper hydroxide mixture and 20 g water. The effluent/copper hydroxide mixture was swirl mixed while collecting the effluent. A 10 g water rinse of the column was added to the copper mixture. Extraction of the beaker's contents was done with 2×25 ml toluene. The toluene solubles were dried with molecular sieve. Stripping, on a rotary evaporator removed the toluene, and the resulting solids were vacuum dried overnight at room temperature.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:7]3[CH:8]=[CH:9][NH:10][C:6]=3[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2cccc(Cl)c2)c2cc[nH]c12

Procedure:
A mixture of ethyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.49 g), 3-chloroaniline (0.46 ml) and methanesulfonic acid (0.28 ml) in 1,4-dioxan (10 ml) was irradiated at 180° C. for 30 minutes with microwaves. The residue was partitioned between ethyl acetate and water, the aqueous layer was separated, basified with an aqueous 2M sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown solid (0.91 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) and N,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8% MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O.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>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([F:22])=[C:2]([C:28]3[NH:27][N:26]=[CH:25][C:24]=3[F:23])[CH:3]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 20.2, 200 mg, 0.497 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (211 mg, 0.472 mmol) and Pd(PPh3)4 (28.7 mg, 0.025 mmol) in DMSO (1.5 mL) in a sealed vial was stirred at 100° C. for 20 h under an argon atmosphere. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 95:5 to 6:4) to give the title product as a white solid. HPLC (Condition 5) tR=7.20 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=400.1 [M+H]+.
Reaction SMILES: N1C=CC=N1.[OH-].[Na+].Cl[C:9]1[N:13]2[N:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.O>COCCOC>[N:11]1[N:10]=[CH:9][N:13]2[C:12]=1[CH:17]=[CH:16][CH:15]=[N:14]2
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1cn[nH]c1
Solvent: O
Solvent: COCCOC
Product: c1cnn2cnnc2c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
0.61 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H)-pyrazole and 5.3 cm3 of a 1N aqueous solution of sodium hydroxide are added to a mixture of 0.5 g of commercial 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine in 15 cm3 of 1,2-dimethoxyethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes before the addition of 92 mg of palladium dichlorobis(triphenylphosphine). The reaction mixture is then stirred at 65° C. for 30 minutes, and then brought back to a temperature in the region of 20° C. and poured into 20 cm3 of water. The mixture obtained is extracted with 3×100 cm3 of dichloromethane and the combined organic phases are washed with 2×100 cm3 of a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The yellow powder thus obtained is purified by chromatography on silica gel (eluent: 98/2 CH2Cl2/MeOH). 0.2 g of 3-chloro-6-(1-methyl-1H)-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine is thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[OH:16].O.O.[OH-].[Li+]>CO>[OH:16][C:5]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCOCC2)cc1O
Temperature: 80 °C

Procedure:
To a stirred solution of 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (4.6 g; 19.4 mmol) in MeOH (120 mL) was added water (60 mL) and lithium hydroxide hydrate (4.08 g; 97 mmol). The resulting mixture was heated to 80° C. for 15 hours. The resulting mixture then was washed with EtOAc (3×60 mL), and cooled to 0° C. and acidified with 2 N aqueous hydrochloric acid to pH 4. The resulting precipitate was collected on a Buchner funnel with suction, washed with water, and air dried to provide the acid (4.16 g; 96%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]1)[C:3](=[O:9])OC(C)(C)C.FC(F)(F)C(O)=O.[N:25]1[O:26][N:27]=[C:28]2[CH:33]=[C:32](C(Cl)=O)[CH:31]=[CH:30][C:29]=12>ClCCl>[C:16]([C@@H:13]1[CH2:12][CH2:11][C@H:10]([N:2]([CH3:1])[C:3]([C:32]2[CH:31]=[CH:30][C:29]3=[N:25][O:26][N:27]=[C:28]3[CH:33]=2)=[O:9])[CH2:15][CH2:14]1)#[N:17]
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc2nonc2c1)[C@H]1CC[C@@H](C#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyl methyl-(4-cyanocyclohexyl)carbamate (710 mg, 3 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (3 ml) was added. The solvent was evaporated after 2 hours, the residue was re-dissolved in a 4N HCl (3 ml) solution in dioxane and the solvent evaporated. Dichloromethane (30 ml) and NEt3 (2 ml) were added to the residue followed by a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (548 mg, 3 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour at room temperature, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The material was purified on a silica gel column eluting with ethyl acetate/chloroform (1:1) to give 170 mg of N-(cis-4-cyanocyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide as a white solid and as the less polar isomer. Mp=222-223° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93 (d, 1H, J=9.0 Hz); 7.85 (s, 1H), 7.42 (d, J=9.0 Hz, 1H); 4.65-4.50 and 3.55-3.40 and 3.15-2.80 (m, 5H) and 2.20-1.30 ppm (m, 8H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].CC1CCCC(C)C1=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: CC1CCCC(C)C1O
Agent: CC1CCCC(C)C1=O
Product: Cc1cccc(C)c1O
Yield: 97 %

Procedure:
Using a procedure similar to that described in Example 2, 100 g/hour of a mixture consisting of 50% by weight of 2,6-dimethylcyclohexanol and 50% by weight of 2,6-dimethylcyclohexanone were converted, at 250° C. and under otherwise identical conditions, over the catalyst described in the stated example. This procedure gave 2,6-dimethylphenol in a yield of 97% of theory.
Reaction SMILES: [CH3:1][C:2](C)=[O:3].[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([OH:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:2]([O:12][CH:11]1[NH:10][C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]1([F:5])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:1]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O

Procedure:
In 10 ml. of acetone was dissolved 8.80 g. (40 m moles) of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, and under ice-cooling, 5.10 g. (50 m moles) of acetic anhydride and 10 ml. of pyridine were added. The mixture was reacted at room temperature overnight. (A sample of the reaction mixture was taken, the solvent was distilled off under reduced pressure and the NMR spectrum of the residue was measured to ensure that there had been produced ethyl 6-acetoxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate
Reaction SMILES: C[O-:2].[Na+].[N+](C)([O-])=O.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1>CO>[CH:9]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:2]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: [Na+]
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1ccc(C=O)cc1OC
Yield: 641 %

Procedure:
To a solution of sodium methoxide (0.260 g, 4.82 mmol) in methanol (200 mL) was added nitromethane (4.03 g, 11.58 mmol) under nitrogen atmosphere and the reaction mixture was stirred and reflux for 30 minutes. Methyl 4-(bromomethyl)-2-methoxybenzoate (10.00 g, 9.65 mmol) in methanol was added and the reaction mixture was refluxed for 7-8 h. The reaction mass was concentrated and diluted with CHCl3. The diluted reaction mass was washed with 2N NaOH solution. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 6.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (m, 6H), 7.36 (d, J=6.6 Hz, 2H), 7.79 (d, J=7.8 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1.I.[F:15][C:16]([F:24])([F:23])[CH2:17][NH:18][C:19](=[NH:22])SC.C(Cl)(Cl)Cl.CO.N>>[F:15][C:16]([F:24])([F:23])[CH2:17][N:18]=[C:19]([NH2:22])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[N:3]=1
Reactant: CSC(=N)NCC(F)(F)F
Reactant: NC(=O)CCCCn1ccc(N)n1
Agent: I
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 5-(3-aminopyrazol-1-yl]valeramide (18.2 mg.) and (2,2,2-trifluoroethyl)-S-methylisothiourea hydroiodide (51 mg.) was heated at 100° for 20 minutes. Preparative high pressure liquid chromatography on silica gel, using CHCl3 /MeOH/ammonia (s.g. 0.880) 8:2:0.5 v/v/v as eluant gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide, m.p. 129°-130° (40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)c(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.