Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Br)=[CH:22][CH:21]=1)#[N:19]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:26]/[CH:25]=[CH:24]/[C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:29][CH:28]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: N#Cc1ccc(C=CCBr)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(/C=C/CN2CCc3nc(N)sc3CC2)cc1
Yield: 49 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 4-cyano-cinnamyl bromide (melting point: 79°-82° C.) in anhydrous dimethylformamide for one hour at 20° C. After the dimethylformamide has been distilled off in vacuo, the evaporation residue is distributed between ethyl acetate and water. After drying, filtering and evaporation of the organic phase, the evaporation residue is crystallised from acetone and the crystals are washed with ether. Yield: 49% of theory, Melting point: 199°-205° C. (decomp.).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C@@H:3]1[NH:17][C:18]([C@@H:20]([O:22][C:23](=O)[O:24]C1C=CC([N+]([O-])=O)=CC=1)[CH3:21])=[O:19].[F:35][C:36]([F:43])([C:39]([F:42])([F:41])[F:40])[CH2:37][NH2:38]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C@@H:3]1[NH:17][C:18]([C@@H:20]([O:22][C:23](=[O:24])[NH:38][CH2:37][C:36]([F:43])([F:35])[C:39]([F:42])([F:41])[F:40])[CH3:21])=[O:19]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 63 %

Procedure:
0.12 g (0.25 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester and 543 μl 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-0 to 75-25) yielded 0.075 g (63%) (2,2,3,3,3-pentafluoro-propyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester as white solid. MS: m/e: 472.1 (M+H+), [α] 589=−76.4° (1% in MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: BrBr
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(Br)c1C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (3.42 g, 20 mmol) in carbon tetrachloride (40 mL) was added a solution of bromine in carbon tetrachloride (10 mL) dropwise at 20° C. After the addition was complete, stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with aqueous NaHCO3 and water, and then dried over Na2SO4. Evaporation of solvent gave ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate as a solid (4.8 g), which was used in the next step without purification. 1H-NMR (CDCl3): δ 9.36 (1H, s), 4.30 (2H, q), 228 (3H, s), 2.26 (3H, s), 1.36 (3H, t). To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:35][CH2:36][CH2:37][C@@H:32]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CNC[C@H](N2CCCC2)C1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N4CCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-(pyrrolidin-1-yl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=9.09 Hz, 1H) 1.72-1.96 (m, 4H) 1.96-2.11 (m, 2H) 2.16 (br. s., 1H) 2.43 (s, 3H) 2.82-3.35 (m, 3H) 3.35-3.87 (m, 5H) 4.26 (br. s., 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 2H) 8.11 (d, J=8.08 Hz, 2H) 8.57 (d, J=2.02 Hz, 2H) 9.83 (br. s., 1H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
To a solution of (3S)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.00 g, 15.0 mmol) (obtained as described in Reference Example 53(2)) in methylene chloride (120 ml) were added methanesulfonyl chloride (1.28 ml, 16.5 mmol) and triethylamine (2.31 ml, 16.5 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3S)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.33 g, yield 100%) as a colorless and transparent syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:26]=[O:27])C>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:26]=[O:27])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCn1ccc2ccc(C(=O)OC)cc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POCl3 (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H2O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CH2Cl2) yields 1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Reaction SMILES: FC1C(O[C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])=C(F)C(F)=C(F)C=1F.[NH2:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl>[C:25]([O:24][C:23](=[O:29])[CH2:22][CH:21]([NH:20][C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])[C:30]([OH:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: CC(=O)SCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3.5 h

Procedure:
Acetylsulfanyl-acetic acid pentafluorophenyl ester (1.6 g, 5.3 mmol) and H-Asp(OtBu)—OH (1 g, 5.3 mmol) were mixed in 20 ml of dry dichloromethane (DCM). Then 1.6 ml of triethylamine (11.5 mmol) was added, and the reaction was allowed to proceed at ambient temperature for 3.5 hours. The organic layer was then extracted with 3×15 ml of 1 M sodium carbonate, the combined aqueous fractions were acidified with 100 ml of 1 M sodium hydrogensulfate and extracted with 3×30 ml ethyl acetate. The combined organic fractions were then rinsed with 30 ml of 1 M sodium hydrogensulfate, 30 ml of 5 M NaCl, dried over sodium sulfate, filtered, and evaporated under reduced pressure to yield 1.97 g of a nearly colorless syrup which was used without further purification. MW=305 (found 306, M+1).
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][CH2:19][CH2:20][C@@H:21]([NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.C(OC(=O)N(CCC[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1)CCN1CCCC1)C1C=CC=CC=1.Cl>C(Cl)Cl.O1CCOCC1>[CH2:22]([C@H:21]([NH:29][C:30]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1)=[O:31])[CH2:20][CH2:19][CH2:18][NH:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@H](CCCN(CCN1CCCC1)C(=O)OCc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H](CCCN(CCN1CCCC1)C(=O)OCc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@H](CCCNCCN1CCCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[(R)-4-(3-Biphenyl-4-yl-ureido)-5-phenyl-pentyl]-(2-pyrrolidin-1-yl-ethyl)-carbamic acid benzyl ester. To a solution of ((R)-4-tert-butoxycarbonylamino-5-phenyl-pentyl)-(2-pyrrolidin-1-yl-ethyl)-carbamic acid benzyl ester (0.06 g, 0.16 mmol) in CH2Cl2 (1.7 mL) was added HCl in dioxane (3 M, 0.6 mL), and the solution was stirred (25° C., 1 h). The solution was concentrated in vacuo, and the residue was dissolved in MeOH (2 mL) and treated with basic resin, and the resulting suspension was stirred (25° C., 1 h). The suspension was filtered and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (2.0 mL). The solution was treated with 4-biphenylisocyanate (0.033 g, 0.17 mmol), and the reaction mixture was stirred for 4 h (25° C.), during which time a precipitate, the desired product, formed. The product was collected as a clear semi-solid (0.064 g, 64%). MS (electrospray): mass calculated for C38H44N4O3, 604.79; m/z found, 605.3 [M+H]+, 627.3 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.09–7.49 (m, 21H), 5.01–5.04 (m, 2H), 3.41 (br s, 1H), 3.14–3.30 (m, 2H), 2.85–2.92 (m, 2H), 2.49–2.58 (m, 8H), 1.17–1.56 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:4]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[N:32]1([C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2cc(C(F)(F)F)on2)cc1)N1CCCCC1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 4-(5-Trifluoromethyl-isoxazol-3-yl)-benzoic acid (Preparative Example 11, 256 mg, 1.0 mmol) in toluene (10 mL) was treated with DMF (˜5 μL) followed by oxalyl chloride (112 μL, 1.3 mmol). The reaction was allowed to stir for 3 hr then concentrated in vacuo to afford crude acid chloride which was dissolved in THF (5 mL) and treated with a THF solution (2 mL) of triethylamine (174 μL, 1.25 mmol) and piperidine (109 μL, 1.1 mmol). The reaction was allowed to stir for 3 hr and concentrated in vacuo to afford crude product which was filtered with the aid of water and solids air dried to afford product as a colorless solid (295 mg, 91%). 1H NMR (CDCl3) 1.55-1.70 (m, 6H), 3.35 (br s, 2H), 3.73 (br s, 2H), 7.04 (s, 1H), 7.52 (d, J=8.3, 2H), 7.86 (d, J=7.9, 2H). 13C NMR 24.7, 25.8, 26.8, 43.4, 49.0, 103.7, 118.0 (q, J=270), 127.3, 127.9, 128.4, 139.2, 162.2, 169.4. 19F NMR −64.6. LC/MS 6.49 min, [M+1]+ 325.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[CH2:25]([O:32][CH:33]1[C:38]([CH2:40][C:41]#[N:42])(O)[C:37]2[CH:43]=[CH:44][C:45]([O:47][CH:48]([CH2:50][CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH3:49])=[CH:46][C:36]=2[O:35][C:34]1([CH3:60])[CH3:59])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[CH2:25]([O:32][CH:33]1[C:38](=[CH:40][C:41]#[N:42])[C:37]2[CH:43]=[CH:44][C:45]([O:47][CH:48]([CH2:50][CH2:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH3:49])=[CH:46][C:36]=2[O:35][C:34]1([CH3:59])[CH3:60])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(CCCc1ccccc1)Oc1ccc2c(c1)OC(C)(C)C(OCc1ccccc1)C2(O)CC#N
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(CCCc1ccccc1)Oc1ccc2c(c1)OC(C)(C)C(OCc1ccccc1)C2=CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
To a solution of 11.5 g (23.7 mmole) dl-5-benzyloxy-4-cyanomethyl-4-hydroxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran in 100 ml dry toluene was added a few grams of molecular sieves and 5 drops of methanesulfonic acid. The mixture was stirred for 16 hours at room temperature, washed with 30 ml water, 2×30 ml saturated sodium bicarbonate solution, dried (MgSO4), filtered and the filtrate evaporated in vacuo to afford a yellow oil. Trituration with ethyl ether, filtration gave 2.60 g colorless solid. Evaporation of the mother liquor to half-volume and addition of petroleum ether afforded a second crop, 3.75 g. Total yield: 6.35 g (60.4%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:20][N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd]>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:21]([N:19]2[CH2:20][CH:17]([N:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)[CH2:18]2)=[O:22])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCN(C2CN(C(=O)c3ccc(-c4ccccc4)cc3)C2)CC1
Agent: [Pd]
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CC(N2CCNCC2)C1
Yield: 160.9 %

Procedure:
A mixture of compound 8e (1.7 g, 2.9 mmol), and 10% Palladium on carbon (300 mg) was hydrogenated (50 psi hydrogen gas) using a Parr apparatus for 18 h. The catalyst was removed by filtration, and the solvent concentrated under reduced pressure to afford crude compound 8f (1.5 g). MS m/z (M+H+) 322.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C@@H:20]([OH:22])[CH3:21])[CH:15]=1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9]([O:22][C@H:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH3:21])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)c1cccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A 534 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in methylene chloride was added to a solution of 74 mg (0.606 mmol) of (S)-1-(3-pyridyl)ethanol and 0.080 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 50% and 90% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.078 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O-:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Na+].Cl[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]>CN(C)C=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[O:13][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc([O-])cc(OC)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC(=O)N2CCOCC2)cc(OC)c1OC

Procedure:
To a solution of 10.15 g (0.049 mole) sodium 3,4,5-trimethoxyphenolate in 100 ml anhydrous dimethylformamide are added gradually, with stirring, 7.5 g (0.050 mole) N-chloroformyl-morpholine.
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O[C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1[C:2]([CH2:10][O:11][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCc1cn2ccccc2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 83.8 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 920 mg of imidazo[1,2-a]-pyridin-2-ylmethanol (prepared as described in Preparation 20), 2.9 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.4 g of tributylphosphine, 1.65 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of benzene were used, to give 3.1 g of the title compound having Rf=0.71 (on silica gel thin layer chromatography using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[C:5]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:4]=2[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:24])[CH2:7][CH:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[C:5]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Yield: 65.3 %

Procedure:
624 mg of 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile were shaken at room temperature under a hydrogen atmosphere in 25 ml of ethanol with 50 mg of 10% palladium-on-charcoal. After 4 hours the mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution. The product was recrystallized from isopropanol to give 410 mg of 3,4-dihydro-2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile of melting point 174°-176° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate (350 mg, 0.67 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) dropwise with stirring and the resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 200 mg (46%) of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid) salt as a brown solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccnc(O)c2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NCC1CCN(c2ccnc(O)c2)CC1

Procedure:
To a solution of 500 mg (2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester in 5 ml CH2Cl2 3 ml TFA was added dropwise at 0° C. After 16 h 20 ml toluene were added and the solvent removed under reduced pressure to yield a brown foam.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, d, 1H, J=3.6 Hz), 7.39 (d, 1H, J=5.2 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.08 (dd, 1H, J=5.2, 3.6 Hz), 7.00 (q, 1H, J=9.5 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.78 (ddd, 1H, J=11.6, 6.4, 2.8 Hz), 6.65-6.60 (m, 1H), 4.18 (t, 2H, J=6.4 Hz), 3.22 and 3.12 (d of ABq, 2H, J=13.6 Hz), 2.98 (t, 2H, J=6.4 Hz), 2.37 (s, 3H), 1.40 (s, 3H).