Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:47]=[CH:46][C:33]([CH2:34][CH2:35][O:36][C:37]2[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:2]([C:40]2[CH:41]=[N:42][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:47][CH:46]=3)=[CH:38][CH:39]=2)[C:7]([CH3:8])=[N:6][C:5]=1[CH3:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)nc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)cc3)nc2)c1N1CCC(C)(C)CC1
Temperature: 85 °C
Yield: 9.2 %

Procedure:
To a mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (30 mg), (6-(4-fluorophenethoxy)pyridin-3-yl)boronic acid (18.9 mg) and Cs2CO3 (42.9 mg) in 1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(PPh3)4 (7.6 mg). The mixture was flushed with nitrogen and then heated at 85° C. for 3 h. The mixture was diluted with water and then extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine and concentrated to give a residue, which was purified by the preparative HPLC to give (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-6′-(4-fluorophenethoxy)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)acetate (3.6 mg). LCMS (M+H)=592.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][NH:23][CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[Si]([N:31]=[C:32]=[O:33])(C)(C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][N:23]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCNC3)cc12
Solvent: CO
Solvent: ClCCl
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCN(C(N)=O)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (0.0030 g, 0.0077 mmol) in DCM (0.5 mL) was added a drop of TMS isocyanate. The reaction was stirred at 0° C. for 30 min. The solution was directly loaded onto Prep TLC (20×20 cm, silica gel, 5% MeOH in DCM) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): δ=1.87 (d, J=7.1 Hz, 3 H), 2.22-2.44 (m, 2 H), 3.46-3.57 (m, 2H), 4.11-4.20 (m, 2 H), 5.27 (d, J=7.3 Hz, 1 H), 6.00 (t, J=2.0 Hz, 1 H), 7.11-7.24 (m, 1 H), 7.34 (dd, J=16.2, 1.8 Hz, 2 H), 8.19 (s, 1 H). MS (ES+): m/z 433.04/434.96 [MH+]. HPLC: tR=3.23 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][N:2]1[CH:7]=[C:6]([O:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:22])[CH:4]=[C:3]1[CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O>[CH:33]([O:1][N:2]1[CH:7]=[C:6]([O:8][CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:22])[CH:4]=[C:3]1[CH2:23][OH:24])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=c1cc(CO)n(O)cc1OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1cc(CO)n(OC(c2ccccc2)c2ccccc2)cc1OC(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
8.1 g (0.0251 mol) of the product of Step (2) was added to dimethylsulfoxide (125 ml) and heated to 100° C. and dissolved. After cooling the solution to room temperature, 5.2 g (0.0375 mol) of potassium carbonate and 5.6 g (0.0375 mol) of sodium iodide and 6.7 ml (0.0375 mol) of benzhydrylchloride were added thereto, and the mixture was reacted at room temperature for 18 hours under stirring. To the reaction solution, ice water was gradually added, and formed precipitates were collected by filtration, washed sequentially with water and ethyl ether/n-hexane (2/1), and dried to obtain 12.3 g (yield: 100%) of the above identified compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C1COCC1.C(O)(C)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:19][C:18]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=3[Cl:16])[CH2:9]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CCN(c2ncc(Br)cn2)C1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (S)-1-(5-bromopyrimidin-2-yl)-pyrrolidine-3-amine (10.0 g, 35.84 mmol) and 30% aqueous sodium hydroxide (1.18 equiv., 4 mL) in water (30 mL), THF (75 mL), and toluene (75 mL). Separate the layers, extract the aqueous layer with 1:1 THF:toluene (50 mL). Combine the organic layers and extract with water (10 mL). Evaporate the organic layer at reduced pressure to give a residue. Combine the residue and toluene (75 mL) and evaporate at reduced pressure to give a residue. Again, combine the residue and toluene (75 mL) and evaporate at reduced pressure to give a residue Combine the residue and toluene (12.9 g) and dry THF (53.2 g), add 2,4-dichlorobenzaldehyde (0.94 equivalent, 33.6 mmol, 6.0 g), and stir. After 1 hour, add sodium triacetoxyborohydride (65.9 mmol, 2.5 equiv., 14.4 g) in 5 portions over about 50 minutes. After 22 hours, slowly add water (16 mL), Stir for 2 hours and then basify to pH=14 by addition of 30% aqueous sodium hydroxide (20 mL). Separate the aqueous layer and extract with 1/1 toluene/THF (120 mL). Combine the organic layers and extract with water (30 mL). Evaporate the solvents at reduced pressure to give a residue. Combine the residue and isopropanol (130 mL) and evaporate at reduced pressure to give a residue. Twice more, combine the residue and isopropanol (130 mL) and evaporate at reduced pressure to give a mass of about 90 g. Slowly cool to room temperature and agitate for about 3 hours to give a solid. Collect the solid by filtration, rinse with isopropanol (10 mL), and dry at 40° C. under vacuum for 15 hours to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C(F)(F)F)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3C(F)(F)F)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 85 mg (0.17 mmol) 6-({5-(4-methoxyphenyl)-6-[2-(trifluoromethyl)phenyl]furo[2,3-d]pyrimidin-4-yl}amino)hexanoic acid methyl ester in 2.5 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 6 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 68 mg (82% of theor.) of the target compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18](Cl)[N:19]=1)([CH3:4])([CH3:3])[CH3:2].C1(NC2C3SCCC=3N=C([N:38]3[CH2:43][CH2:42][N:41]([C:44]4[CH:54]=[CH:53][C:47](C(OCC)=O)=[CH:46][CH:45]=4)[CH2:40][CH2:39]3)N=2)CCCCC1>O1CCOCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[C:15]2[S:23][CH2:22][CH2:21][C:16]=2[N:17]=[C:18]([N:38]2[CH2:43][CH2:42][N:41]([C:44]3[CH:54]=[CH:53][CH:47]=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)[N:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)nc2c1SCC2
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Temperature: 160 °C

Procedure:
1.08 g (2.9 mmol) of tert-butyl[(1S,2S)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopentyl]carbamate (V) (chiral) and is 9.9 mmol of 1-phenylpiperazine (VI) are placed in 14 mL of dioxane, then heated to 160° C. for 2.3 hours. The reaction mixture is concentrated by evaporation, the residue is then purified by HPLC through an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroacetic acid (B)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2].Br[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[F:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:31][C:22]1[C:21]([C:8]2[CH:7]=[CH:6][C:5]([NH2:19])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:26]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(C(F)(F)F)c1Br
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (264 mg, 1.00 mmol, as prepared in Example 17, step A) and 2-bromo-1-fluoro-3-trifluoromethyl-benzene (243 mg, 1.00 mmol) in DME (5 mL) and 2 M aqueous Na2CO3 (4 mL, 8 mmol) was degassed via sonication, placed under argon and treated with Pd (PPh3)4 (115 mg, 0.100 mmol). The resulting mixture was heated at 80° C. for 16 h and allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (10 mL) and washed twice with water (10 mL). The aqueous layer was extracted with additional EtOAc (10 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica (EtOAc/hexanes, 0:100 to 50:50, v/v) to yield 6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl-amine.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2F)c1
Product: Fc1ccccc1Cn1ncc2cc(Nc3ncnc4ccc(-c5nnc(C(F)(F)F)o5)cc34)ccc21

Procedure:
The title compound was prepared according to Procedure A from 1-(2-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.79(1H, bs), 9.53(1H, s), 8.89(1H, s), 8.77(1H, dd), 8.21(1H, s), 8.11(1H, m), 8.10(1H, d), 7.84(1H, d), 7.70(1H, dd), 7.37(1H, m), 7.24 (1H, m), 7.18 (2H, m), 5.76(2H, s); m/z (M+1+) 506.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.O1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:4]2[CH:5]=[CH:6][CH:11]=[C:2]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:3]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc(N3CCOCC3)c2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
The above intermediate (1.49 g, 3.51 mmol) and 1-amino-4-bromonaphthalene (0.69 g, 3.11 mmol) were dissolved in 20 mL anhydrous 1,4-dioxane in a sealable tube under inert gas atmosphere. The solution was degased and purged with nitrogen (2×). Tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) was added and the solution was degassed and purged with nitrogen again (2×). The tube was sealed and heated to 100° C. for 17 h. After cooling to room temperature the mixture was diluted with EtOAc, saturated aqueous potassium carbonate solution (10 mL) was added and the mixture was stirred for 1 h at room temperature. The mixture was filtered over diatomaceous earth and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 0.363 g (1.19 mmol, 38%) of title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:24])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27]>>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:6](=[O:24])[O:7]2)=[CH:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2oc1=O
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2oc1=O)C(=O)O

Procedure:
2-(S)-[(7-Benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-propionic acid was prepared from 7-benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester and L-alanine under conditions analogous to example 49-a. MS ESI(−) m/e: 382.03 (M−1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:32](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN1CCCCC1)C=C2)CO)(C)([CH3:34])[CH3:33]>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]1[CH2:24][CH2:34][CH2:32][CH2:33][CH2:23]1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (9) of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ 7.97 (s, 1H), 7.77 (d, 1H), 7.65-7.58 (m, 3H), 7.40-7.30 (m, 2H), 5.22 (s, 1H), 4.61 (s, 2H), 3.60-3.20 (m, 4H), 2.69 (s, 3H), 2.00-1.90 (m, 4H), 1.80-1.65 (m, 2H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33ClN2O3: 482.0; Found: 481.3, 483.3.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([C:23](=[O:25])[CH3:24])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C(Cl)(Cl)[Cl:27]>>[CH3:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([C:23]([CH3:24])=[O:25])[C:7]=2[CH:8]=1)=[O:3].[ClH:27]
Reactant: ClC(Cl)Cl
Agent: CC(=O)c1cc2c(C(C)=O)c(OCC(O)CNC(C)(C)C)ccc2o1
Product: Cl

Procedure:
8.9 g of (±)-2,4-diacetyl-5-(3-tert-butylamino-2-hydroxy-propyloxy)-benzofuran in solution in CHCl3 are charged in a reactor cooled externally with an ice bath, then a stream of gaseous HCl is bubbled up to saturation. After evaporation of CHCl3 under reduced pressure, a precipitate is obtained which is taken up in CHCl3, triturated drained and dried. 9.2 g of the expected product are obtained, m.p.=214°-216° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)([F:12])[CH3:11]>O.[Ru](=O)=O>[F:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([C@H:2]2[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]2)=[CH:15][CH:14]=1)([F:12])[CH3:11]
Reactant: CC(F)(F)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=Cc1ccc(Br)o1
Agent: O=[Ru]=O
Solvent: O
Product: CC(F)(F)c1ccc([C@@H]2CC[C@H](CO)O2)cc1

Procedure:
The requisite {cis-5-[4-(1,1-difluoroethyl)phenyl]tetrahydrofuran-2-yl}methanol was prepared via Suzuki reaction of 5-bromofuran-2-carbaldehyde with 2-[4-(1,1-difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, followed by hydrogenation in the presence of ruthenium(IV) oxide hydrate.
Reaction SMILES: [N:1]1([C:5]2[N:9](COCC[Si](C)(C)C)[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+]>CN(C=O)C.O>[N:1]1([C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(N2CCC2)nc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2[nH]c(N3CCC3)nc2c1
Temperature: 150 °C
Yield: 98.8 %

Procedure:
Into a sealed vessel was placed crude 2-(azetidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H benzo[d]imidazole (0.55 g) and sodium ethoxide (1.2 g) in DMF (14 mL). The reacted was heated for 30 mins at 150° C. in an oil bath. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give 310 mg of 2-(azetidin-1-yl)-1H-benzo[d]imidazole as yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([NH2:13])=[S:12])[O:6][N:5]=1)([CH3:3])[CH3:2].[O-]CC.[Na+].[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19]>>[NH2:19][C:18]1[N:10]([CH2:9][C:7]2[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)[C:11](=[S:12])[NH:13][C:21](=[O:22])[CH:20]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(C)c1cc(CNC(N)=S)on1
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)c1cc(Cn2c(N)cc(=O)[nH]c2=S)on1
Reaction time: 2 h
Yield: 13.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-[(3-isopropylisoxazol-5-yl)methyl]thiourea (1.11 g, 5.55 mmol, obtained from Example 15(a)), sodium ethoxide (21% w/v, 5.4 mL, 16.7 mmol) and ethyl cyanoacetate (1.8 mL, 16.7 mmol) with the exception that the reaction time after completed addition was 2 h. This provided 0.20 g (14% yield) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@@H:12]([CH3:26])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])(C(C)(C)C)(C)C.[ClH:27]>CO>[ClH:27].[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH3:26])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO
Reaction time: 4 h

Procedure:
To a solution of (2S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C8) (460 mg, 1.16 mmol) in methanol (5 mL) was added a solution of hydrogen chloride (4N in dioxane, 2 mL). After 4 hours, the reaction mixture was concentrated in vacuo to afford the title compound as a clear gum. Yield: 398 mg, 100%. LCMS m/z 282.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.51 (d, J=6.8 Hz, 3H), 3.28-3.32 (m, 2H, assumed; largely obscured by solvent peak), 3.80-3.87 (m, 1H), 3.84 (dd, J=5.3, 5.2 Hz, 2H), 4.29 (dd, half of ABX pattern, J=10.6, 5.8 Hz, 1H), 4.38 (dd, half of ABX pattern, J=10.6, 4.0 Hz, 1H), 7.30 (dd, J=9.0, 4.2 Hz, 1H), 7.38-7.45 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH2:23]([O:22][C:16]1[CH:15]=[C:14]([CH:6]([CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:5][C:4]([OH:32])=[O:3])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1cc(C(C(OCC)OCC)C(C(=O)OCC)C(=O)OCC)ccc1OC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCCCOc1cc(C(CC(=O)O)C(OCC)OCC)ccc1OC
Yield: 47.5 %

Procedure:
Using the same procedure as in Example 1(3), 3-(3-butoxy-4-methoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, was used to obtain a yellow solid of the above-described compound via 3-(3-butoxy-4-methoxyphenyl)-4,4-diethoxybutyric acid (yield 47.5%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[C:8]([CH3:16])[CH:7]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:9]1[S:10][C:6]([CH:5]([N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH2:4][CH2:3][CH3:2])=[CH:7][C:8]=1[CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCCCBr)sc1C1OCCO1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(c1cc(C)c(C2OCCO2)s1)N1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 99.5 %

Procedure:
2-[5-(4-Bromobutyl)-3-methyl-2-thienyl]-1,3-dioxolane (13.3 g) and potassium phthalimide (8.9 g) were stirred at 50° in dry dimethylformamide (130 ml) for 4 h and then at room temperature for 18 h. The mixture was poured into water (1500 ml) and extracted with ether. The organic extract was evaporated to give the title compound as a light yellow oil (16.1 g)