Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42](O)=[O:43])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:45]([CH3:47])[CH3:46])[NH:27][N:26]=1)(=[O:3])[CH3:2].Cl.[NH2:49][C@H:50]([C:52]([NH2:54])=[O:53])[CH3:51].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42](=[O:43])[NH:49][C@H:50]([C:52](=[O:53])[NH2:54])[CH3:51])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:45]([CH3:47])[CH3:46])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)N[C@@H](C)C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-2-methylpropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole (0.13 g) in N,N-dimethylformamide (2 mL) were added L-alanine amide hydrochloride (46 mg), triethylamine (0.08 mL), 1-hydroxybenzotriazole (38 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=20/1-10/1) to give the title compound (0.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1c[nH]cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.0 g) and pyridine hydrochloride (390 mg) were dissolved in methanol (8 ml). The solution was stirred at 60° C. for 2 h. The solution was cooled and neutralized with saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled off and the residue was filtered and washed with ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=30:1→10:1), then recrystallized from ethyl acetate to give the titled compound (454 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][C:24]4[N:28]([CH3:29])[N:27]=[C:26]([CH:30]5[CH2:32][CH2:31]5)[CH:25]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.CO>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:7]2=[C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][C:24]4[N:28]([CH3:29])[N:27]=[C:26]([CH:30]5[CH2:32][CH2:31]5)[CH:25]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cn1nc(C2CC2)cc1NC(=O)Nc1cccc(C(=O)c2cc(Br)n3ncnc(N)c23)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1nc(C2CC2)cc1NC(=O)Nc1cccc(C(=O)c2ccn3ncnc(N)c23)c1
Reaction time: 4.5 h

Procedure:
The above crude 99A was dissolved in EtOAc (20 mL) and MeOH (20 mL) and treated with 10% Pd/C. The reaction mixture was stirred under a hydrogen atmosphere for 4.5 hours and then filtered to remove the catalyst. The filtrate was concentrated and the resulting solid was collected by filtration, rinsed with EtOAc and dried to give the desired product (23 mg). Compound 99B had an analytical HPLC retention time=2.433 min. (Chromolith SpeedROD column 4.6×50 mm, 10%-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=417+.
Reaction SMILES: F.C([Si](C)(C)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[N:16]=[C:15]([CH3:35])[N:14]=1)(C)(C)C>C(#N)C.ClCCl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:25]2[CH2:26][CH2:27][N:22]([C:17]3[N:16]=[C:15]([CH3:35])[N:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[C:18]=3[N+:19]([O-:21])=[O:20])[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: Cc1nc(OCCCCO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc(OCCCCO)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
0.590 g (14.5 mmol) of hydrofluoric acid (47-51% in water) were slowly added to a solution of 0.375 g (0.723 mmol) of the 4-[4-(tert-butyl-dimethyl-silanyloxy)-butoxy]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidine in 10.0 ml of acetonitrile and 5.0 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 1 hour. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.181 g (0.448 mmol, 61.9% of theory) of the 4-{6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-butan-1-ol as a light yellowish oil; MS: [M+H]+=405.
Reaction SMILES: Cl.Cl.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)[CH:4]([CH3:6])[CH3:5].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:3]([O:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:30])[CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:16][CH2:15]2)[CH:13]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 4-isobutoxy-6-(piperazin-1-yl)pyrimidine dihydrochloride and 2-((tert-butoxycarbonyl)amino)acetic acid.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: CCOC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 360 (M+H+, 100), was prepared in accordance with the general method of example 27 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and ethyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+:32]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O-:28])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1.[Na+:32]
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 3.62 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid (Example 7) and 25 ml. of ethanol-water (9:1) containing 0.400 g. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml. of ethanol-water (9:1) and dried in vacuo for 24 hours to yield sodium 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:18](O)[CH2:19][OH:20].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:5]2([CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])[CH2:4]2)[O:8]1
Reactant: CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2

Procedure:
To a solution of 2.45 g of 4-methyl-3-(phenyl-sulfonyl)-cyclohexan-1-one in 40 ml of benzene, were added 0.7 ml of 1,2-ethanediol and 0.2 g of paratoluenesulfonic anhydride. The resulting mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was recrystallized from ether, whereby 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals (yield: 97%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc2c(-c3ccc(F)cc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccc(F)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-fluorophenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-:15].[K+].C(O)COCCO.Cl.[OH2:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]([OH:25])=[O:15])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O
Reactant: [OH-]
Reactant: COc1ccc(C2(C#N)CCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: OCCOCCO
Product: COc1ccc(C2(C(=O)O)CCC2)cc1

Procedure:
A mixture of 1-(4-methoxyphenyl)cyclobutane carbonitrile (41 g), potassium hydroxide (20 g) and diethylene glycol (160 ml) was heated under reflux for 3.5 hours. The mixture was added to water, acidified with dilute hydrochloric acid and extracted with ether. The extract yielded 1-(4-methoxyphenyl)cyclobutane carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[CH2:10]O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[CH2:10][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: COc1ccccc1C(C)CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccccc1C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
As shown in step 4-iii of Scheme 4, a mixture of 2-(2-methoxyphenyl)-1-propanol (1.31 g, 7.08 mmol), phthalimide (1.09 g, 7.44 mmol), and PPh3 resin (3.43 g, 10.6 mmol) was stirred at room temperature for 15 minutes to allow the resin to swell. Diisopropylazodicarboxylate (2.29 g, 2.24 mL, 10.6 mmol) was added and the reaction was stirred for 18 hours. The reaction mixture was filtered through diatomaceous earth, which was subsequently washed with EtOAc and DCM. The filtrate was concentrated under reduced pressure and purified by medium pressure chromatography on silica gel (10 to 20% EtOAc in hexanes) to give 2-(2-(2-methoxyphenyl)propyl)isoindoline-1,3-dione as a clear, colorless oil (Compound 2010, 2.15 g, quantitative yield): 1H NMR (CDCl3) δ 7.81 (dd, J=5.5, 3.0 Hz, 2H), 7.69 (dd, J=5.5, 3.0 Hz, 2H), 7.34-7.24 (m, 1H), 7.19 (ddd, J=8.1, 7.5, 1.7 Hz, 1H), 6.94 (td, J=7.5, 1.1 Hz, 1H), 6.76 (dd, J=8.2, 0.9 Hz, 1H), 4.03-3.69 (m, 3H), 3.66 (s, 3H), 1.32 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: CN1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1F
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CN1CCN(C(=N)Nc2ccccc2-c2ccccc2F)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.1 g) and N-methylpiperazine (1.5 g) in ethanol (25 ml) was heated at 90°-95° C. for 3 hours to yield the free base which was reacted with fumaric acid (1.78 g) in methanol (70 ml) to give N-(2'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine difumarate (m.p. 201°-202° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]([Cl:18])=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu].[Zn]>[CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH3:19])[C:15]([Cl:18])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2nc(SCc3ccccc3)nn2c(Cl)c1Cl
Agent: [Cu]
Agent: [Zn]
Product: Cc1nc2nc(SCc3ccccc3)nn2cc1Cl
Yield: 88 %

Procedure:
This material was prepared by reduction of 2-benzylthio-6,7-dichloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine with zinc-copper couple following the general procedure described in Example 21. The desired product was isolated in 88% yield as a solid, m.p. 160°-161° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N:1]1C(Cl)=NC(Cl)=N[C:2]=1Cl.CN.O.C(=O)([O-])O.[K+].[CH3:18][NH:19][C:20]1[N:25]=[C:24]([NH:26][CH3:27])[N:23]=[C:22](Cl)[N:21]=1>C(#N)C>[CH3:18][NH:19][C:20]1[N:25]=[C:24]([NH:26][CH3:27])[N:23]=[C:22]([NH:1][CH3:2])[N:21]=1
Reactant: CNc1nc(Cl)nc(NC)n1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: CN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNc1nc(NC)nc(NC)n1
Temperature: 0 °C
Yield: 78 %

Procedure:
After 18.5 g (0.1 mol) of cyanuric chloride was dissolved into 150 ml of acetonitrile, the resulting mixture was cooled to 0° C. and 15.5 g (0.2 mol) of 40% aqueous solution of methylamine was added dropwise in 1 hour thereto under stirring in such a manner that the reaction temperature did not exceed 5° C. While further stirring, 100 ml of water including 20.0 g (0.2 mol) of potassium hydrogencarbonate was added dropwise at the same temperature. Thereafter, the reaction temperature was gradually raised, and stirred at 45° C. for 8 hours. After confirming that an inversion to 2.4-bis(methylamino)-6-chloro-1,3,5-triazine was completed, the reaction solution was cooled and products were filtered off. The filter cake was fully washed with water, and then the resulting 2,4-bis(methylamino)-6-chloro-1,3,5-triazine was suspended into 100 ml of water, and 31.1 g (0.4 mol) of 40% aqueous solution of methylamine was added, and further heated under reflux for 6 hours. After cooling, the deposited crystal was filtered, washed fully with water and dried to give 13.1 g (yield: 78%) of the titled compound. Melting point 133° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S(=O)(=O)(O)O.[CH:15](O)(C)C>>[C:1]([O:7][CH:8]([CH3:15])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(C)O
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)CC(=O)OC(C)C

Procedure:
A solution of ethyl acetoacetate (250 g.) and concentrated sulphuric acid (10 ml.) in isopropanol (1500 ml.) was heated at reflux for 3 hours. The solvent was removed by distillation, the residue was neutralised by treatment with barium carbonate, filtered and distilled under reduced pressure to give isopropyl acetoacetate (139 g.), b.p. 79°-82° C./20 mm Hg, in the form of a colourless liquid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N:22]=[C:23]=[O:24])(C)C.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:23]([NH2:22])=[O:24])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CCNC(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.47 g, 2.0 mmol) in tetrahydrofuran (10 mL) under an argon atmosphere was added trimethylsilyl isocyanate (0.42 mL, 3.1 mmol). The resulting mixture was heated at reflux for 1 h, was allowed to cool to room temperature and then was stirred overnight. The reaction mixture was again heated to reflux for an additional 5 h and allowed to cool to room temperature. Ammonium chloride was added, and the mixture was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water. The organic extract was washed successively with 10%. hydrochloric acid and water and dried (potassium carbonate). Removal of the solvent in vacuo and purification of the residue by flash chromatography, eluting with 3% methanol/methylene chloride, provided the urea as a white solid: m.p. 136°-37° C. Analysis Calc. for C15H22 N2O3 : C 64.73, H 7.97, N 10.06; found: C 64.66, H 7.97, N 10.28.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])(C)(C)C.[C:17]([C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:28][O:29][CH3:30])[C:25](=[O:27])[S:26][C:22]=2[CH:21]=1)(=[O:19])[CH3:18].CCOC(C)=O>C1COCC1>[OH:19][C:17]([C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH2:28][O:29][CH3:30])[C:25](=[O:27])[S:26][C:22]=2[CH:21]=1)([C:11]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9][CH:10]=1)[CH3:18]
Reactant: COCn1c(=O)sc2cc(C(C)=O)ccc21
Reactant: c1cnn(C2CCCCO2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1c(=O)sc2cc(C(C)(O)c3ccnn3C3CCCCO3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Add 1-tetrahydropyran-2-yl-pyrazole (1.5 Eq, 202 mmoles, 30.8 g)(Aldrich) and THF (900 mL) to a flame dried 2 L 3 neck round bottom flask and cool to −78° C. (dry ice/acetone bath). Add t-butyl lithium (2.5 M in THF)(1.5 Eq, 202 mmoles; 81.0 mL) dropwise, maintaining at least −68° C., and stir for 60 min at −78° C. Add a solution of 6-acetyl-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one (32.0 g, 134 mmoles) in THF (450 mL) dropwise over 45 min, and stir at −78 for 30 min. Remove the dry ice bath and allow to warm to −50° C. and stir for 1 hr. (do not let temp. rise above −45° C.). Quench the reaction with MeOH (80 mL). Transfer to a separatory funnel, add EtOAc (2000 mL), and wash with water (500 mL) and then brine (500 mL). The organic layer is dried over Na2SO4, filter and concentrate to give a crude yellow oil. Purify the material by HPLC, eluting with hexanes/EtOAc (6:4) to yield 6-[1-hydroxy-1-(1-tetrahydropyran-2-yl-1H-pyrazol-5-yl)ethyl]-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one as a white foam (44 g, 113 mmoles, 84% yield) (Racemic mixture of diasteromers). LCMS (Low) rt=1.76 min., M+1=288, and rt=1.86 min., M+1=288
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[NH:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:21])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)cc2)cc1)C(=O)O
Yield: 46.9 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21 mmol) and 2-chloro-1H-benzimidazole (37.6 mg, 0.25 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 40.7 mg (48%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 11.05 (br s, 1H), 8.05 (d, 2H), 7.85 (m, 4H), 7.65 (d, 2H), 7.40 (m, 2H), 7.10 (m, 2H), 3.35 (s, 2H), 1.25 (s, 6H). LC-MS m/z 414.3 (MH+), ret. time 2.27 min.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:34])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:4](=[O:34])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[NH:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(3-phenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 8 ml) were reacted, to afford the title compound (1.58 g) as a yellow solid.