Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[C:7]1[C:8]2[C:15]([Cl:16])=[CH:14][S:13][C:9]=2[N:10]=[CH:11][N:12]=1.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][NH2:24].C(N(CC)CC)C>C(OCC)(=O)C.O>[Cl:16][C:15]1[C:8]2[C:7]([NH:24][CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:18])[CH:27]=[CH:26][CH:25]=3)=[N:12][CH:11]=[N:10][C:9]=2[S:13][CH:14]=1
Reactant: Clc1csc2ncnc(Cl)c12
Reactant: NCCc1cccc(O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1cccc(CCNc2ncnc3scc(Cl)c23)c1
Temperature: 33 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 250-mL, 3-necked, round-bottom flask, equipped with a mechanical stirrer, condenser, dropping funnel, and thermocouple temp monitor, under an atmosphere of nitrogen was added N,N-dimethylformamide (75 mL) , 4,5-dichlorothieno[2,3-d]pyrimidine (7.47 g, 36 mmol), 3-hydroxyphenethylamine hydrochloride (5.0 g, 28.8 mmol), and triethylamine (10.7 mmol). After exothermic mixing of the reagents raised the temperature of the reaction mixture to 33° C., the mixture was allowed to stir overnight while returning to 25° C. Then the mixture was poured into water and extracted with warm (60° C.) ethyl acetate (5×70 mL). The combined organic phases were washed with water (2×70 mL), brine (70 mL), dried (MgSO4), filtered through silica gel/Celite plug, and most of the solvent removed in vacuo to give a yellow oil. The oil was dissolved in ethyl acetate (100 mL), heated to reflux, and allowed to cool to 25° C. A yellow crystalline solid formed, and was removed via suction filtration; the product was air dried on the funnel for 3 h, to give 6.34 g, 20.8 mmol, 72 percent yield, 164-165° C.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:61])[C@H:55]([CH2:57][C:58](=[O:60])[NH2:59])[NH2:56])(C)(C)C>>[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33]([NH:56][C@@H:55]([CH2:57][C:58]([NH2:59])=[O:60])[C:54]([OH:61])=[O:53])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-asparagine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-succinamic acid is obtained; mp 165-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[N:16]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[CH3:19][N:17]([CH3:18])[C:15]1[N:16]=[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:35]([NH:34][C:25]4[CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=[CH:29][C:24]=4[F:23])=[O:36])=[C:3]([F:22])[CH:4]=3)[C:12]2=[N:13][CH:14]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CN(C)c1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-N,N-dimethylpyrido[3,2-b]pyrazin-3-amine and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid. Yield: 40 mg (66%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.CCOCC>[ClH:24].[F:22][C:20]([F:21])([F:23])[CH2:19][C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
To a solution of 0.91 mmol 4-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 30 ml dioxane was added dropwise 18.2 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 90 min. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a light brown crystalline solid (yield 73%). MS (m/e): 252.3 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[NH2:32].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[C:4]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[N:3]=2)[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3c2cnn3C2CCCCO2)c1
Temperature: 200 °C

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (50 mg, 0.130 mmol), 3-fluoro-4-morpholinoaniline (23.00 mg, 0.117 mmol) and Cs2CO3 (50.9 mg, 0.156 mmol) were dissolved in toluene (5 mL) in a sealable microwave compatible reaction tube, then Pd2(dba)3 (2.386 mg, 2.61 μmol) and Xantphos (3.01 mg, 5.21 μmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (60 min, 200° C., 3 atm). Reaction progress was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and compound was purified by column chromatography. 1H NMR (400 MHz, CD3OD): δ 8.64 (s, 1H), 8.26 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.82 (dd, 1H, J=2.4 and 15.2 Hz), 7.68 (m, 1H), 7.48 (t, 1H, J=7.6 Hz), 7.35 (dd, 1H, J=1.6 and 8.8 Hz), 6.95 (t, 1H, J=8.8 Hz), 6.43 (m, 2H), 5.87 (dd, 1H, J=2.4 and 10.4 Hz), 5.80 (dd, 1H, J=2.8 and 8.8 Hz), 4.11 (m, 1H), 3.82 (m, 4H), 3.75 (m, 1H), 3.00 (m, 4H), 2.60 (m, 1H), 2.13 (m, 1H), 1.97 (m, 1H), 1.83-1.73 (m, 3H); ESI-MS: [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9]>CO>[F:3][C:4]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccc(F)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
An aqueous sodium hydroxide solution (22.4 ml) was added to a solution of ethyl 2-(2,4-difluorophenoxy)-2-methylpropanoate (2.74 g) in methanol (27.4 ml) under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 1M hydrochloric acid was added thereto followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (2.38 g) as a colorless oily product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(Cl)Cl>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:20][CH2:17][CH2:18][CH3:19])=[CH:4][CH:5]=1)#[N:16]
Reactant: CCCN
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: ClCCl
Product: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
10.84 g of 4-bromomethyl-2'-cyano-biphenyl are mixed at room temperature with 20 ml of propylamine. The mixture is stirred for 30 minutes, during which heating to reflux temperature occurs, is then diluted with 400 ml of CH2Cl2 and washed with 200 ml of NaHCO3 solution. The organic phase is dried over Na2SO4 and freed of the solvents in vacuo to leave a yellow oil. Purification of the latter by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (98:2) as eluant yields pure N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine that has an Rf value of 0.15 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(OC(C)(C)C)=O>O1CCOCC1>[F:20][C:19]([F:21])([F:22])[O:18][C:15]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([NH2:8])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: C1COCCO1
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The above benzoic acid (120 g, 0.37 mol) is suspended in 1,4-dioxane (200 mL), stirred and warmed to 80° C. until dissolved. The solution is allowed to cool to room temperature and hydrogen chloride is bubbled into the reaction mixture for 30 minutes. Stirring is continued for 2 hours, during which time a precipitate forms. The precipitate is collected and washed with ice-cold water (1000 mL) and Et2O (500 mL) to give 5-trifluoromethoxyanthranilic acid as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:5]2[NH:6][C:7]([CH3:11])=[CH:8][C:9](=O)[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: Cc1cc2[nH]c(C)cc(=O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)n2nc(C)cc2n1
Yield: 77 %

Procedure:
2,5-Dimethyl-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.5 g, 21 mmol) in phosphorus oxychloride (20 mL) was stirred at reflux. After 3 hours the dark purple reaction was cooled and then extracted from ice water with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium bicarbonate, dried (Na2SO4) and then concentrated under reduced pressure to give the title compound (3.0 g, 77%) as a brown solid: +APcI MS (M+1)+ 182; H NMR (CDCl3) δ: 6.74 (s, 1H), 6.42 (s, 1H), 2.55 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:18])[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[C:16]([Cl:18])[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1
Product: CC(=O)Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)pyrimidine-4-carboxamide (10 mg, 0.03 mmol, Step-1) and acetyl chloride (7 mg, 0.08 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:5]2.C(O)(=O)C.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]3[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:18])[C:16]=3[CH3:17])=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(=O)CC)Cc2cc(N)c(F)cc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Temperature: 100 °C
Yield: 80.5 %

Procedure:
The diketone from step 1 (0.51 g, 1.73 mmol) was treated with acetic acid (5 mL,) and aqueous 6N HCl (5 mL). The resulting solution was stirred and heated in an oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into a slurry of solid NaHCO3 in CH2Cl2, then filtered through a pad of silica gel and the product was washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 4:1 to 3:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide 7-amino-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.40 g, 83%) as a yellow solid
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: [H][H]
Reactant: Cc1nn2ccccc2c1C(=O)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nn2ccccc2c1C(=O)C1=CNCCC1

Procedure:
Ten g of 2-methyl-3-nicotinoyl pyrazolo[1,5-a]pyridine was dissolved in 150 ml of absolute ethanol and 2 g of 10% palladium carbon was added to the solution. The mixture was hydrogenated in an autoclave at 13 atm. of hydrogen at a temperature in the range of 55° to 58° C. for 3 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure in order to remove the solvent. The residue was recrystallized from ethyl acetate to afford the title compound in yield of 8.5 g, mp 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8](C)[C:9](=O)OC(C)(C)C)=[CH:6][C:5]([F:17])=[CH:4][N:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][C:5]([F:17])=[CH:4][N:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(F)cnc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(F)cnc1Cl
Temperature: 50 °C
Reaction time: 14 h

Procedure:
Tert-butyl (2-chloro-5-fluoropyridin-3-yl)(methyl)carbamate (Intermediate 36) (0.920 g, 3.53 mmol) was dissolved in trifluoroacetic acid (20 mL) and heated at 50° C. for 90 minutes. The solution was allowed to cool to room temperature and stir for another 14 hours. The reaction mixture was evaporated to dryness under reduced pressure and water (80 mL), saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL) were added. The phases were mixed and separated and the organic phase was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in dichloromethane gradient) gave 2-chloro-5-fluoro-N-methylpyridin-3-amine as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][CH:10]1[CH2:11][CH2:12][O:7][CH2:8][CH2:9]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(O)CN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)CNC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.75 g of 1-amino-2-methylpropan-2-ol are dissolved in 20 ml of MeOH. 1.71 ml of glacial acetic acid are added dropwise under an inert atmosphere. 2 g of tetrahydropyran-4-one in 10 ml of MeOH are added, the mixture is stirred for 30 minutes at room temperature and 1.98 g of sodium cyanoborohydride are added. The resulting mixture is stirred under an inert atmosphere for 15 hours. The reaction medium is poured into saturated aqueous NaHCO3 solution (100 ml). The resulting mixture is stirred for 30 minutes and then extracted with 4 times 100 ml of DCM. The organic phase is dried over Na2SO4, filtered and evaporated without heating. The MeOH contained in the aqueous phase is evaporated off and the extraction, drying, filtration and evaporation operation is repeated 3 times. 2.8 g of 2-methyl-1-((tetrahydro-2H-pyran-4-yl)amino)propan-2-ol are recovered in total.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[C:10](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(-c3ccccc3)c21
Yield: 124.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.05 g), aminoguanidine hydrochloride (0.021 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (5 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 147) (0.04 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+]>>[C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1ccccc1
Reaction time: 15 h

Procedure:
α-Phenylmethylpropionate can be obtained under similar conditions, by reacting a mixture of phenylacetic acid, dimethyl carbonate and K2CO3, in a 1:20:2 molar ratio, in autoclave at a temperature of 225° C., for 15 hours.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[C:13]([C:16](OC)=[O:17])[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1>[O:7]1[C:11]2[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(c1)OCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a stirred solution of lithium aluminium hydride (6.1 g, 250 mmol) in THF (300 mL) was added a solution of methyl 2,3-dihydrobenzofuran-6-carboxylate (17.8 g, 100 mmol) in THF at 0□. The mixture was stirred at room temperature for 1 h. A saturated aqueous NaOH solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to afford (2,3-dihydrobenzofuran-6-yl)methanol (13.8 g, 92.0% yield). 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=7.2, 1H), 6.84 (d, J=7.2, 1H), 6.81 (s, 1H), 4.62 (s, 2H), 4.58 (t, J=8.4, 2H), 3.20 (t, J=8.4, 2H),) 1.67 (br s, 1H).
Reaction SMILES: CN(C)C=[CH:4][CH:5]1[CH:7]([CH2:8][C:9](=[O:11])[CH3:10])[C:6]1([CH3:13])[CH3:12].[O:15]=[O+][O-]>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[CH:7]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]1[CH:4]=[O:15]
Reactant: CC(=O)CC1C(C=CN(C)C)C1(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(=O)CC1C(C=O)C1(C)C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To a solution 2.4 g of 1-(3-(2-(dimethylamino)ethenyl)-2,2-dimethylcyclopropyl)-2-propanone, the product of Embodiment I, in 50 ml of methylene chloride was added 0.6 g of ozone over 20 min at -80° C. The resulting mixture was purged with air and 1.5 g of triethylamine was added dropwise at -30° C. The resulting mixture, after stirring and warming to room temperature, had a negative test to starch iodide paper. The reaction mixture was poured into 25 ml 1 N hydrochloride acid solution. The resulting mixture separated into two phases and the methylene chloride phase was washed with water, dried with MgSO4, filtered and stripped to yield 1.6 g of the desired product as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: OC1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoic acid (1 g, 3 mmol) in DCM is treated with 2 drops of DMF followed by oxalylchloride (3 mL, 6 mmol, 2M solution in DCM), stirred at room temperature for 2 hours and concentrated in vacuo. The resultant residue is dissolved in DCM, treated with 3-pyrrolidinol (0.3 mL, 3.6 mmol), stirred at room temperature for 8 hours then concentrated to give 1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol identified by HPLC and MS [398.4 m/e (M+H)].
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.C(OCC)(=O)C.O1CCOCC1>[NH2:8][C@@H:9]([CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([NH:41][CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C(=O)NC4CCCC4)cc3s2)CC1
Reaction time: 8 h

Procedure:
(S)-2-(4-(2-(tert-Butoxycarbonylamino)-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylic acid (0.084 g, 0.155 mmol), cyclopentylamine (0.015 ml, 0.155 mmol), diisopropylethylamine (0.11 ml, 0.62 mmol) and HBTU (0.076 g, 0.20 mmol) were dissolved in DMF (4 ml) and the resulting mixture stirred overnight. The resulting mixture was then diluted with ethyl acetate (9 ml), washed with 1N HCl (3×5 ml), brine (5 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed eluting with dichloromethane/methanol (97:2) to yield a residue which was dissolved in 1,4-dioxane (1 ml) and treated with 4M HCl in 1,4-dioxane for three days. The resulting solid was filtered, washed with ether (3×) and dried to yield (S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)-N-cyclopentylbenzo[d]thiazole-6-carboxamide (Compound #26).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:27])[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H]1CCN(Cc2ccccc2)C1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)N[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
A solution of 1a (0.80 g, 2.06 mmole) in 40% trifluoroacetic acid/dichloromethane (15 mL) was stirred at room temperature for 4 h. The solvent was removed by rotary evaporation, and the resulting organic residue was carefully partitioned between dichloromethane and a saturated solution of sodium bicarbonate (30 mL each). The organic extract was dried over anhydrous sodium sufate, filtered, and concentrated to give 2a as a light brown oil. This amine was used without further purification.