Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH:30][CH3:31])[CH2:27][CH2:28][CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([N:30]([CH2:26][CH2:27][CH2:28][CH3:29])[CH3:31])=[O:11])[CH:7]=1
Reactant: CCCCNC
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(C)C(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 26.7 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-butylmethylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (115 mg, yield 27%). MS calcd for (C20H26BN3O5S): 431.2. MS found (ESI negative): (M−H)−=430.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.80 (s, 1H), 9.17 (bs, 1H), 7.45 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (d, J=8, 2 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.94 (bs, 2H), 4.87 (s, 2H), 3.77 (s, 2H), 3.15 (m, 2H), 2.85 (s, 3H), 1.39 (m, 2H), 1.30 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:5][C:4]=1[Cl:28].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:24]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:4]([Cl:28])[N:5]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: CCCCc1nc(Cl)c(CNC(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(ethoxycarbonylaminomethyl)imidazole was prepared from 5-aminomethyl-2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole using ethyl chloroformate and the Schotten-Baumann procedure described in Example 209, Part B: m.p. 144.0°-147.0°. NMR (200 MHz, DMSO-d6) δ 12.74 (s, 1H); 7.73 (d, 1H, J=7Hz); 7.63-7.27 (m, 5H); 7.03 (d, 2H, J=10Hz); 5.27 (s, 2H); 4.60 (bd, 2H, J=7Hz); 3.90 (q, 2H, J=7Hz); 3.34 (s, 2H); 2.47 (t, 2H J=7Hz); 1.48 (t of t, 2H, J=7,7Hz); 1.24 (t of q, 2H, J=7,7Hz); 1.06 (t, 3H, J=7Hz); 0.78 (t, 3H, J=7 Hz). Anal. Calcd. for C25H28ClN3O4.(H2O)0.33 : C, 63.17; H, 6.06; N, 8.83. Found: C, 63.30; H, 6.35; N, 8.44.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26]Cl)[N:17]=[CH:16]2)[C@H:6]1[F:29])(=[O:3])[CH3:2].F[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:28])[CH2:26][N:41]=[N+:42]=[N-:43])[N:17]=[CH:16]2)[C@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Agent: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Compound (38) (60 mg) obtained in item (5) above was dissolved in N,N-dimethylformamide (1.2 ml), to which sodium azide (27 mg) was added and the mixture so obtained was stirred at room temperature for 2 hours. The resulting reaction solution was concentrated and the residue as formed was extracted with chloroform. The solution in chloroform thus formed was washed with water, dried over anhydrous sodium sulfate and then concentrated to afford the titled compound (39) (56 mg) as a syrup. Yield: 92%.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([N:6]=[C:7]=[S:8])=[O:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:9])[CH3:1])=[S:8])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)=CC(=O)N=C=S
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: CC(C)=CC(=O)NC(=S)N1CCCC1
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
To a solution of 3-methylbut-2-enoyl isothiocyanate (500 mg, 3.54 mmol, Eq: 1.00) in benzene (10.0 ml) was added a solution of pyrrolidine (252 mg, 293 μl, 3.54 mmol, Eq: 1.00) in benzene (5.00 ml). The mixture was stirred for 30 minutes. The solvent was evaporated affording 3-methyl-but-2-enoic acid (pyrrolidine-1-carbothioyl)-amide (824 mg/110%) as a light yellow solid. MS: m/e=213.1 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.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]>[CH3:1][N:2]1[C:6]([C:17]2[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Nc1cccc(Br)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.181 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.048 g in 47% yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][NH:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35]([CH3:42])[C:36](=[O:41])[CH2:37][C:38]([CH3:40])=O>>[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][N:24]([CH:38]([CH3:40])[CH2:37][C:36]([N:35]([CH3:42])[CH3:34])=[O:41])[CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CNC1
Reactant: CC(=O)CC(=O)N(C)C
Agent: Cl
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CN(C(C)CC(=O)N(C)C)C1
Yield: 50 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide hydrochloride salt Example 75 was coupled with N,N-dimethylacetoacetamide using the same methodology as for the equivalent step in Example 76 to give the title product (58 mg, 50%) as a white powder; 1H NMR Spectrum: (CDCl3) 1.05 (d, 3H), 2.22 (m, 1H), 2.41 (s, 3H), 2.45 (m, 1H), 2.92 (s, 3H), 2.98 (m, 1H), 3.03 (s, 3H), 3.31 (m, 2H), 3.61 (m, 2H), 3.96 (s, 2H), 3.98 (s, 3H), 5.33 (brs, 1H), 7.17 (m, 2H), 7.24 (s, 1H), 7.51 (brs, 1H), 7.87 (brs, 1H), 7.99 (s, 1H), 8.44 (m, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 558.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:19]([C@H:21]2[CH2:25][N:24]([C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:36])[CH2:22]2)[CH3:20])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.CCN(CC)CC.N(CC)CC>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:19]([C@H:21]2[CH2:25][N:24]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:36])[CH2:22]2)[CH3:20])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(OCc4ccccc4)cc4ncsc34)CC2=O)cc1
Agent: BrB(Br)Br
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](c1ccc(O)cc1)N1C[C@H]([C@@H](C)Oc2cc(O)cc3ncsc23)CC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(R)-4-((R)-1-(5-(benzyloxy)benzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (500 mg, 1.0 mmol) was dissolved in DCM (10 mL) under Ar and the resulting solution was cooled to −78° C. A 1.0 M solution of BBr3 (10 mL, 10 mmol) was added dropwise over 5 min, and the resulting mixture was warmed to r.t. After 45 additional min, the reaction mixture was cooled in an ice water bath and MeOH (4 mL. 99 mmol) was added over 2 min. Et3N (5.6 mL, 40 mmol) was added followed by Et2NH (0.25 mL, 2.4 mmol) and the resulting mixture was warmed to r.t. After stirring an additional 30 min, the reaction mixture was concentrated, dissolved in MeOH (20 mL), and concentrated again. The resulting concentrate was partitioned between EtOAc (100 mL) and water (75 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (30 mL), and the combined organic phase was washed with a mixture of 0.2 M aqueous HCl (30 mL) and brine (30 mL) followed by a mixture of saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford (R)-4-((R)-1-(5-hydroxybenzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-hydroxyphenyl)ethyl)pyrrolidin-2-one that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C21H23N2O4S: 399.1; found 399.2.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:36])=[C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:28]3[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=[CH:26][C:27]=3[CH3:36])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(C)c(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)ccc3C)CC2)c(OC)nc1C
Yield: 66 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-methoxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:20][C:7]1=2)=[O:4].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C1(C)C=CC=CC=1>[N:25]1([CH2:2][C:3]([NH:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:20][C:7]2=3)=[O:4])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)CCl)c1ccccc1CO2
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)C(NC(=O)Cn1ccnc1)c1ccccc1CO2

Procedure:
Crude methyl 11-chloroacetamido-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate, 3.0 g, was heated to reflux for 4 hours in 100 ml of toluene together with 0.9 g of imidazole. After allowing to cool, the solvent was distilled off under reduced pressure. The obtained residue was extracted with 300 ml of methylene chloride. The extract was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography .(eluting solvent; chloroform:methanol=10:1) to give 1.6 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22].C(O)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[C:9]=1[CH:21]=[O:22])[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(C=O)c(F)c1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 3,5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1.5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aquoeus phase was extracted with diethyl ether (4×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3,5-difluoro-4-formylbenzonitrile (0.5 gm, 31.25%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:32](OCC)=[O:33].[O-]CC.[Na+].Cl>C(O)C>[OH:33][CH:32]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C(C)(C)C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Temperature: 78 °C
Yield: 81 %

Procedure:
2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.634 g, 1.63 mmol) and ethyl formate (0.39 mL, 4.89 mmol) were dissolved in anhydrous ethanol (3.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.05 mL, 8.16 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.548 g, 1.32 mmol, 81%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10]>>[C:9]([OH:12])(=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: O=C(O)C=Cc1ccccc1
Yield: 19 %

Procedure:
Kalnin, Helv. Chim. Acta 11, 977 (1928) describes various salts as catalysts. 1 mol of benzaldehyde and 1.5 mol of acetic anhydride are refluxed at 180° C. for 8 hours with 0.65 mol of catalyst. The yields of cinnamic acid are, following work-up, for potassium acetate 72%, for potassium carbonate 59%, for sodium carbonate 40%, for sodium acetate 39%, for sodium phosphate 36%, for potassium phosphate 20% and for potassium sulphide 32%. As well as potassium and sodium salts, amines are also possible as catalysts. For 0.33 mol of triethylamine, the yield is 19%.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21](Cl)=[O:22])[O:3]1.[OH-].[NH4+:25]>O1CCCC1>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([NH2:25])=[O:22])[O:3]1
Reactant: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)Cl)O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Yield: 96.2 %

Procedure:
To (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonyl chloride (120 mg, 0.368 mmol) in tetrahydrofuran (1 mL) was added ammonium hydroxide (3 mL, 23.11 mmol) dropwise. One hour later, the reaction mixture was extracted with ethylacetate (10 mL×3) and the combined organic layer was dried over magnesium sulfate, filtered, and concentrated to obtain (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxamide (114 mg, 0.354 mmol, 96% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.66 (d, J=5.49 Hz, 1H) 4.88 (d, J=5.49 Hz, 1H) 7.37-7.68 (m, 11H) 7.79 (s, 1H). Mass spec.: 307.1 (MH)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([S:13][C@@H:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C@H:15]2[NH:23][C:24](OCC)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([S:13][C@@H:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C@H:15]2[NH:23][CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Sc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN[C@@H]1Cc2ccccc2[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a stirred suspension of LiAlH4 (0.22 g, 5.7 mmol) in dry diethyl ether (10 ml) under nitrogen was added a solution of (±) trans 1-(phenylthio)-2-ethoxycarbonylaminoindane (0.36 g, 1.15 mmol) in diethyl ether (15 ml). After stirring overnight at room temperature the reaction was worked up as described in Preparation 4 to give the title compound as a brown oil (0.27 g) which was used in the next stage without purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 8.3 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (2.50 g, 14.3 mmol), 2-chloro-4-fluorophenylboronic acid (2.98 g, 17.2 mmol), cesium carbonate (5.58 g, 17.2 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro-methane complex (1:1) (1.16 g, 1.43 mmol) in dioxane (50 mL) was heated at 100° C. for approximately 2.5 days. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate and filtered through a plug of silica on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (0.32 g).
Reaction SMILES: [H][H].[CH2:3]([O:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25]CC3C=CC=CC=3)=[CH:13][C:14]=2[O:17]CC2C=CC=CC=2)[O:9][CH:8]1[C:33]1[CH:38]=[CH:37][C:36]([O:39]CC2C=CC=CC=2)=[C:35]([O:47]CC2C=CC=CC=2)[CH:34]=1)[CH:4]=[CH2:5]>[Pd].C(OCC)(=O)C.C(O)C>[OH:47][C:35]1[CH:34]=[C:33]([CH:8]2[CH:7]([O:6][CH2:3][CH2:4][CH3:5])[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][C:12]([OH:25])=[CH:11][C:10]=3[O:9]2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: C=CCOC1Cc2c(OCc3ccccc3)cc(OCc3ccccc3)cc2OC1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOC1Cc2c(O)cc(O)cc2OC1c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
To a suspension of 20% palladium on carbon (80 mg) in 1:1 ethyl acetate/ethanol (15 mL) which had been stirred vigorously under 1 atmosphere of hydrogen for 10 minutes then cooled with an ice/methanol bath was added 3-Allyloxy-5,7-bis-benzyloxy-2-(3,4-bis-benzyloxy-phenyl)-chroman (200 mg). The ice bath was removed and the reaction was stirred for 2 h under 1 atmosphere of hydrogen. The mixture was filtered and concentrated, and purified by preparative reverse phase HPLC using a gradient of 5% to 100% acetonitrile/water over 10 min The appropriate fractions were frozen and lyophilized to yield 2-(3,4-Dihydroxy-phenyl)-3-propoxy-chroman-5,7-diol as a white powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.FC1C=CC=CC=1C(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[O:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2ccccc2F)on1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2F)on1
Reaction time: 8 h
Yield: 22 %

Procedure:
DIPEA (167 mg, 1.3 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid (76 mg, 0.37 mmol) in DMF (2 mL) (prepared by the method used for the synthesis of Intermediate 25, starting from 2′-fluoroacetophenone) followed by HOBt (52 mg, 0.38 mmol) and EDCI.HCl (74 mg, 0.39 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (125 mg, 0.37 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by washing with methanol to afford the 40 mg (34% Yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 492, 92.84%. 1H NMR (300 MHz, DMSO-d6): δ8.8 (t, 1H), 8.0 (m, 1H), 7.6 (m, 1H), 7.4 (m, 3H), 7.25 (m, 3H), 7.2 (d, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).