Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1>O1CCOCC1>[F:40][C:37]([F:38])([F:39])[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:16])=[CH:47][CH:46]=3)[CH2:28][CH2:27]2)=[CH:35][CH:34]=1)([OH:45])[C:41]([F:44])([F:43])[F:42]
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 26.5 %

Procedure:
Phenyl pyridin-4-ylcarbamate (1.680 mmol, 0.36 g) was added to a stirred solution of 2-(4-((4-(4-aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.120 mmol, 0.5 g) in dioxane (20 mL) and the mixture heated in a microwave for 10 minutes at 130° C. followed by 5 minutes at 130° C. The mixture was washed with water (10 mL) and the organic phase dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure to afford the title compound (168 mg). MS (ESI) m/z 567.5 [M+H]+
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12](SC)=[N:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][S:18][CH:17]=1)=O>C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:13]=[C:14]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CSC(=NC(=O)c1cscc1C)c1c(F)cccc1Cl
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A solution of methylhydrazine (2.02 mL, 1.75 g, 38 mmol) in toluene (5 mL) was added at a rapid dropwise rate to a solution of methyl 2-chloro-6-fluoro-N-[(4-methylthien-3-yl)carbonyl]benzenecarbimidothioate (4.15 g, 12.7 mmol) in dry toluene (100 mL) at 55° C. The reaction was stirred at this temperature for 10 minutes and then left at room temperature for 14 hours. Another identical portion of methylhydrazine in toluene was added at room temperature and the reaction was heated at 80° C. for 3 hours and refluxed for an additional 3 hours. After cooling to room temperature, the reaction mixture was washed with water (100 mL), dilute hydrochloric acid (0.05 N, 2×100 mL) and brine (70 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give white cubes. The mother liquor was chromatographed (eluant, 30:9:1 hexane/methylene chloride/acetonitrile to afford the product (3.25 g, 84%): mp 153–155° C.; 1H NMR (CDCl3) δ 7.54 (d, 1H), 7.26–7.38 (m, 2H), 7.06–7.13 (m, 2H), 3.98 (s, 3H), 2.35 (d, 3H); 19F NMR (external reference)—110 ppm; EI/MS 307 m/e (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[C@H:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[CH:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
To a solution of rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester prepared in Example 28 (0.9 g, 1.5 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 h, and concentrated. The residue was then neutralized with saturated aqueous NaHCO3 solution, and then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated, dried under reduced pressure to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide as a white solid (0.8 g, 100%)
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[O:10]=[C:8]([CH3:9])[CH:3]([NH:2][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(N)C(C)=O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of methyl 2-amino-3-oxobutanoate hydrochloride (0.50 g, 3.0 mmol) in CH2Cl2 (30 mL) was cooled in an ice bath. Pivaloyl chloride (0.37 mL, 3.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) were slowly added, and the reaction was allowed to slowly warm to room temperature overnight. The reaction was washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-3% MeOH—CH2Cl2) to obtain methyl 3-oxo-2-(pivalamido)butanoate (0.48 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 6.82 (bs, 1H), 5.21 (d, J=6.1 Hz, 1H), 3.82 (s, 3H), 2.39 (s, 3H), 1.24 (s, 9H) ppm. LC/MS: m/z 216.5 (M+H)+ at 1.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:11](=O)([O-])[O-].[Ca+2].C(O)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:11][NH:10][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N)c(N)c1
Agent: [Ca+2]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
4-Methoxy-1,2-phenylenediamine (5.00 g, 36 mmol) was dissolved in formic acid (10 ml) and heated at reflux for 2 hours. The solution was allowed to cool to room temperature overnight then treated with calcium carbonate (5.0 g). After dilution with ethanol (150 ml) the mixture was heated at reflux for 1 h then filtered, the residue being washed with hot ethanol (50 ml). The combined filtrates were evaporated at reduced pressure to give an oil from which a solid crystallised. The material was slurried with diethyl ether (50 ml) then filtered to give an orange solid which was recrystallised from ethyl acetate to give 5-methoxybenzimidazole (5.33 g, 99%) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-(tetrahydropyran-4-carbonyl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 324.40 (C15H20N2O4S) was obtained in this way; MS (ESI): 325 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][NH:29][CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Temperature: 25 °C

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (1.0 g, 2.73 mmol) in MeOH (8 mL) was added ethylamine (2M in THF; 5 mL, 10 mmol), followed by acetic acid (0.23 mL, 4.09 mmol). Sodium cyanoborohydride (0.260 g, 4.14 mmol) was then added, and the reaction was stirred at room temperature and monitored by analytical LCMS. The reaction never reached completion, so the mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-6% MeOH in CH2Cl2) to give (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:22])[C:5]1([C:17]([O:19]CC)=[O:18])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([O-:14])=[O:13])[N:6]1[CH:15]=[O:16].O>C(O)C>[F:22][CH:4]([F:3])[C:5]1([C:17]([OH:19])=[O:18])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[N:6]1[CH:15]=[O:16]
Reactant: C=C1CC(C(=O)[O-])N(C=O)C(C(=O)OCC)(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C1CC(C(=O)O)N(C=O)C(C(=O)O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96 %

Procedure:
0.68 ml of 1N sodium hydroxide were added to a solution of 54 mg of the product of Step A in 4 ml of ethanol. The mixture was stirred at ambient temperature for 60 hours. 4 ml of water were added and the pH was neutralized to about 6 with Amberlyst 15 resin. After filtering and evaporating to dryness the residue was taken up in 8 ml of water and lyophilized to obtain 47 mg of the desired product in the form of its sodium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12]C(=O)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].O.[OH-].[K+]>C(O)C>[NH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:13][OH:12]
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(CO)c1ccc(F)c(F)c1
Yield: 87.2 %

Procedure:
To a solution of (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.39 mmol, 0.27 g) in 5.0 mL ethanol was added 5.0 mL of water and pellets of potassium hydroxide (5.0 mmol, 0.28 g). The resulting solution was then heated to reflux overnight. The solvent was removed in vacuo and the resulting residue was extracted with EtOAc (2×50 mL). The organic extracts were washed with brine and the organic layer was dried over Na2SO4. It was filtered and the solvent was removed in vacuo to obtain (+)-2-amino-2-(3,4-difluorophenyl)-ethanol as a white solid (0.21 g, 87% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[NH:11][N:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:11]([CH3:17])[N:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=[N:3]1
Reactant: CI
Reactant: Cn1ncc2c1CCCc1[nH]ncc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1CCCc1c-2cnn1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 19.4 g of 4,5,6,7-tetrahydro-3-methyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole in 70 ml of N,N-dimethylformamide was added, dropwise, to a suspension of 2.64 g of sodium hydride in 200 ml of N,N-dimethylformamide and the resulting mixture was stirred at room temperature for 15 minutes. A solution of 12.5 ml of methyl iodide in 20 ml of N,N-dimethylformamide was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted several times with dichloromethane and the combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a tan powder which was shown to be a 50:50 mixture of the 2,7-dimethyl and 3,7-dimethyl products as shown by 1H NMR. The tan powder was recrystallized from toluene to give a tan solid which was again recrystallized from toluene to give 4,5,6, 7-tetrahydro-3,7-dimethyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole as tan needles melting at about 191°-195° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:21][O:20][N:19]([CH3:18])[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 8 h

Procedure:
2(S)-(tert-Butoxycarbonylamino)hexanoic acid (24.6 g, 0.106 mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol), EDC hydrochloride (22.3 g, 0.117 mol) and HOBT (14.3 g, 0.106 mol) were stirred in dry, degassed DMF (300 mL) at 20° C. under nitrogen. N-Methylmorpholine was added to obtain pH 7. The reaction was stirred overnight, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:16]>O.O.O.[Cu](Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:16])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: Nc1nc2c(Br)cccn2n1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1nc2c(Br)cccn2n1
Reaction time: 18 h

Procedure:
To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+. 68b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+. 68c) N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (95.0 mg, 0.294 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (32.0 mg, 0.0585 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a light brown foam (0.077 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (s, 1H), 8.11 (d, J=6.5, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 3.33-3.25 (m, 4H), 3.13 (s, 3H), 2.70-2.57 (m, 4H), 2.39 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc(CNc2ccc(OC)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(OC)cc2)cc1
Yield: 46.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and [(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.88 g) as starting materials, N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) was obtained. melting point: 89-90° C.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.C(Cl)Cl>[C:9]1([C@@H:4]2[C@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[CH2:5]2)[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCN(C(=O)N2CCCCC2)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
A round bottom flask was charged with 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.050 g, 0.17 mmol, Example #5, Step J), TEA (0.10 mL, 0.69 mmol) in THF (1.6 mL). The reaction mixture was stirred for about 5 min at ambient temperature and then piperidine-1-carbonyl chloride (0.019 g, 0.13 mmol) was added. The reaction was heated at about 45° C. for about 18 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in DCM (5 mL) and washed with water (3 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method f) to give ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(piperidin-1-yl)methanone (0.018 g, 8%): LC/MS (Table 1, Method b) Rt=1.80 min; MS m/z 367 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[C:15]([OH:22])(=[O:21])[CH2:16][CH2:17][C:18]([CH3:20])=O.S(=O)(=O)(O)O>O>[CH3:20][C:18]1[NH:11][C:8]2[C:9]([C:17]=1[CH2:16][C:15]([OH:22])=[O:21])=[CH:10][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:6][CH:7]=2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1[nH]c2ccc(OC(F)(F)F)cc2c1CC(=O)O
Temperature: 80 °C
Reaction time: 6 h
Yield: 33.5 %

Procedure:
A mixture of 4-trifluoromethoxyphenylhydrazine hydrochloride (1 g), levulinic acid (1.3 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 80° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate and the organic layer was concentrated under reduced pressure. Saturated sodium bicarbonate water was added to the obtained residue and vigorously stirred therewith, and then dichloromethane was added and the mixture was again vigorously stirred. The aqueous layer was collected, rendered acidic with concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, to obtain 0.40 g of the title compound as a colorless powder (31% yield).
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@H:13]2[CH2:16][C@H:15]([CH2:17][CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14]2)=O)=CC=1)([O-])=O.CC(O)=O>O1CCOCC1>[CH2:20]([O:19][CH2:18][CH2:17][C@H:15]1[CH2:14][C@H:13]([OH:12])[CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O[C@H]1C[C@H](CCOCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O[C@H]1C[C@H](CCOCc2ccccc2)C1
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
Aqueous NaOH (0.4 mol/L, 52 mL, 20.8 mmol) was added to a stirred solution of trans-3-(benzyloxyethyl)cyclobutyl 4-nitrobenzoate (3.7 g, 10.4 mmol) in 80 mL 1,4-dioxane at ambient temperature. After 40 min, AcOH (0.9 mL, 15.4 mmol) was added drop by drop. After 5 min, the reaction mixture was concentrated by rotovap. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (2×50 mL). The organic phase was dried over MgSO4 and solvent evaporation gave light yellow oil (2.09 g, 97.5%). 1H NMR (CDCl3, 300 MHz): δ 1.71-1.78 (m, 2H), 1.94 (bs, 1H), 2.03-2.07 (m, 3H), 2.60-2.74 (m, 1H), 3.40-3.45 (t, J=6.9, 2H), 4.49 (s, 2H), 7.27-7.37 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 24.58, 36.11, 37.90, 39.95, 66.63, 69.17, 73.10, 127.65, 127.69, 128.45, 138.60.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([CH2:25][N:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[CH:30]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(CN2CCOCC2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CN2CCOCC2)n[nH]1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.147 g, 0.56 mmol), 3-(morpholinomethyl)-1H-pyrazole-5-carboxylic acid (0.119 g, 0.56 mmol), HOBt (0.114, 0.84 mmol), DIPEA (0.29 mL, 1.69 mmol) and EDCI (0.162 g, 0.84 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 0.256 g. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 2.44 (m, 4H), 3.59 (s, 2H), 3.67 (m, 4H), 4.35 (m, 2H), 4.55 (m, 1H), 6.62 (bs, 1H), 6.74 (d, 1H), 7.69 (d, 1H), 7.76 (d, 1H), 7.88 (m, 1H), 8.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5]O.B(Br)(Br)[Br:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5][Br:23]
Reactant: BrB(Br)Br
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CO)cc2Cl)ccc1O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-(4′-hydroxy-3′-iso-propyl-phenoxy)benzyl alcohol in CH2Cl2 (5.0 mL) at −78° C. is added BBr3. The reaction mixture is stirred at room temperature for 16 h, poured into ice water and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel, eluting with acetone-hexanes to afford 3,5-dichloro-4-(4′-hydroxy-3′-iso-propyl-phenoxy)benzyl bromide.