Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][C:6]=2[CH:7]=1)#[N:2].C[OH:17]>O>[NH2:2][C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:6]=2[CH:7]=1)=[O:17]
Reactant: COC(=O)c1ccc2oc(C#N)cc2c1
Reactant: CO
Solvent: O
Product: NC(=O)c1cc2cc(C(=O)O)ccc2o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Methyl 2-cyano-1-benzofuran-5-carboxylate (426 mg, 2.0 mmol) is dissolved in MeOH (10 ml). The solution is cooled to 0° C., is treated with LiOH monohydrate (168 mg, 4.0 mmol) in H2O (4 ml), and the reaction is stirred 6 h at RT. The volatiles are removed in vacuo and the residue is dissolved in H2O (10 ml). The pH of the mixture is adjusted to 1.9 with 12N HCl, the white solid is collected, washed with water, and is dried to give 401 mg (97%) of 2-(aminocarbonyl)-1-benzofuran-5-carboxylic acid as an off-white solid. MS (EI) calcd for C10H7NO4: 205.0375, found 205.0369 (M)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[OH-].[K+]>C(O)C>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring solution of N-hydroxyphthalimide (Aldrich, 1.63 g, 10.0 mmol) in anhydrous ethanol (50 mL) was added 1-bromo-3-methyl-but-2-ene (Aldrich, 1.4 mL, 12.0 mmol) and potassium hydroxide (0.67 g, 12.0 mmol). After the reaction was allowed to stir at 50° C. for 4 hours, it was concentrated in vacuo and then dissolved in ethyl acetate and partitioned with water. The organic layer was washed twice with water, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording a white solid. The collected solid was purified via silica column in 10% methanol in dichloromethane to afford 2-(3-methyl-but-2-enyloxy)-isoindole-1,3-dione (0.53 g, 23%): 1H NMR (400 Mz; DMSO-d6) δ 7.81 (s, 4H), 5.38 (t, 1H, J=1.5), 4.57 (d, 2H, J=7.6) 1.67 (s, 3H), 1.62 (s, 3H); MS (APCI+)=232.0
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[NH2:1][C:2]([C@@:4]1([CH3:23])[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]1(C)C(N)=O

Procedure:
The title compound was prepared (80 mg) using a similar procedure as set out earlier in Description 11 starting from 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D22, 55 mg, 0.17 mmol)) and 2-fluorobenzyl bromide; Rt (HPLC): 5.87 min; MS: (ES/+) 451 m/z: [M+Na+]; C24H29FN2O4 requires 428.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].C(N(CC)CC)C>CN(C=O)C.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>[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[C:23][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=NC2(N=C1N)c1cc(C#CC(C)(C)C)ccc1CC21CCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 0.100 g, 0.31 mmol) in DMF (10 mL) under argon was added 3,3-dimethyl-but-1-yne (0.039 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) and triethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred at r.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol). The reaction mixture was stirred overnight at 65° C. and then partitioned between sat aq. NaHCO3 and EtOAc. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by preparative chromatography to afford the title compound (0.039 g, 38% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.47-1.66 (m, 4H), 1.73-1.84 (m, 1H), 2.09-2.17 (m, 1H), 2.18 (s, 3H), 3.16 (d, 2H), 6.53 (d, 1H), 6.60 (s, 2H), 7.14 (dd, 1H), 7.24 (d, 1H); MS (ES+) m/z 320 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield N-(5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.6 (s, 1H), 8.18 (s, 2H), 7.8 (d, 1H), 7.62-7.77 (m, 2H), 7.42 (d, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]2=1.S(=O)(=O)(O)O>O>[Br:1][CH:14]1[CH:9]2[CH2:15][CH:12]([C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=32)[CH2:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)C1CCC2C1
Agent: O=S(=O)(O)O
Solvent: O
Product: BrC1CC2CC1c1ccccc12
Yield: 90.5 %

Procedure:
10 g of N-bromosuccinimide are added in small portions over approximately two hours to a mixture of 5 g of benzonorbornene, stirred into 10 cm3 of water and 10 cm3 of sulphuric acid and heated to a temperature between 50° C. and 55° C. The progress of the reaction is followed by gas phase chromatography. When the benzonorbornene has been completely converted, the reaction mixture, at room temperature, is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate until the pH of the washings is neutral and is then dried over magnesium sulphate and concentrated. 7 g of crude 2-bromobenzonorbornene are obtained and purified by distillation under reduced pressure. After distillation, 4 g of pure product are obtained. This product is a light-yellow liquid whose boiling point is 70°-75° C. at a pressure of approximately 2.65 10-5 bar. Its proton nuclear magnetic resonance spectrum corresponds to the 2-bromobenzonorbornene structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)COC1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)COC1
Yield: 40 %

Procedure:
The cross coupling reaction of (R)-6-bromo-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.2) with 3,5-dichlorophenylboronic acid yielded the title compound (40% yield) as a light brown foam. MS (ISP): m/z=413.2 [M+H]+ and 415.2 [M+2+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]>>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1ccccc1C
Product: COC(=O)c1cc(S(=O)(=O)Cl)ccc1C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Chlorosulfonic acid (106.2 ml) was carefully added over 1 min with stirring under nitrogen to 2-methyl-benzoic acid methyl ester (55.9 ml, 0.4 mol). The reaction mixture was placed in an oil bath preheated to 100° C. for 15 min, then poured onto ice (1000 ml). The resulting precipitate was filtered and dissolved in ethyl acetate (400 ml). The ethyl acetate solution was washed sequentially with 10×300 ml saturated aqueous sodium bicarbonate, 300 ml water and 300 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield the title compound as a yellowish oil (37.3 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ, 2.74 (s, 3H), 3.96 (s, 3H), 7.52 (d, 1H), 8.04 (m, 1H), 8.58 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:12][C:4]1[S:3][C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][C:5]=1[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1nc(-c2ccco2)c(Br)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(Br)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Compound g (10.0 g, 40.8 mmol) obtained in Reference Example 7 was dissolved in pyridine (136 mL), and under ice-cooling, 4-dimethylaminopyridine (250 mg, 2.04 mmol) and benzoyl chloride (8.05 mL, 69.4 mmol) were added thereto, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=10:1) to afford N-[5-bromo-4-(2-furyl)thiazol-2-yl]benzamide (12.0 g, 84%) as a white solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25]([OH:27])=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:40]([O:47][C:48]([C:50]1[CH:51]=[C:52](O)[CH:53]=[CH:54][CH:55]=1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>CN(C=O)C>[CH2:40]([O:47][C:48]([C:50]1[CH:55]=[C:54]([O:26][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:27])[CH:53]=[CH:52][CH:51]=1)=[O:49])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1nc(C(=O)Oc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Temperature: 115 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A solution of 5-(2-adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) (57 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole(25 mg, 0.16 mmol) in DMF (0.5 ml) was stirred at room temperature for 30 min. 3-Benzyloxycarbonyl-phenol (36 mg, 0.16 mmol) was added and the mixture was stirred at 115° C. for 16 h, then cooled to room temperature. Water (5 ml) was added and the mixture was extracted with ethyl acetate (3×5 ml). The combined extracts were washed with brine, dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash chromatography (silica, DCM/ethyl acetate 9:1) to afford colourless foam (15 mg, 17%). 1H NMR (300 MHz, CDCl3) 7.97 (1H, m), 7.91 (1H, m), 7.39 (4H, m), 5.37 (2H, s), 3.01 (2H, m), 2.52 (3H, s), 1.94 (3H, br s), 1.66 (6H, m), 1.54 (8H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:21][Si](C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:21])=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)(=O)C(C(=O)OC(C)(C)C)=C1Br
Solvent: CC#N
Product: CCOC1=NS(=O)(=O)C(C(=O)OC(C)(C)C)=C1N

Procedure:
To 3-ethoxy-4-bromo-5-t-butyloxycarbonylisothiazole-1,1-dioxide (340 mg, 1.0 mmol) in 5 ml of dry acetonitrile was added hexamethyldisilazane (242 mg, 1.5 mmol) and the solution was stirred at reflux for 7 hours. The reaction mixture was evaporated in vacuo and the residue was refluxed in 10 ml of ethanol for 3/4 hr. Removal of the ethanol in vacuo gave a crude oil which was chromatographed on silica gel. The product was recovered as a viscous yellow oil (210 mg). Trituration in petroleum ether gave a yellow solid, m.p. 128°-130° C. Mass spectral analysis confirmed the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:5])[CH3:2].N.[H][H]>[Pd].CO>[CH2:1]([O:3][C:4]([N:6]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CCOC(=O)N(c1ccccc1)C1(C(=O)OC)CCNCC1

Procedure:
A solution of 16.2 parts of O4 -methyl O1 -(phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-1,4-piperidinedicarboxylate in 200 parts of methanol and 20 parts of methanol, previously saturated with ammonia is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 11.7 parts of methyl 4-[(ethoxycarbonyl)phenylamino]-4-piperidinecarboxylate as an oily residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[F:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7](\[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C/c1cccc(F)c1)c1ccncc1
Yield: 62.2 %

Procedure:
A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and 3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of acetic anhydride (100 mL) and triethylamine (20 mL) was heated under reflux for 5.5 hours. After standing to cool, the reaction mixture was concentrated. The residue was diluted with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution twice and brine, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography (eluent; hexane, hexane:ethyl acetate=9:1), to give the title compound (25.5 g, 62%) as a red-orange oil.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][O:17][C@@H:11]1[CH2:10][C@H:9]([OH:8])[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2
Reactant: [H][H]
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1C[C@H](O)[C@H]2CO[C@@H]1O2

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-2-O-methyl-β-D-ribo-hexopyranose (see Example 3(1)) (4.5 g) in ethanol (20 ml) was added to a suspension of 10% palladium on carbon (0.2 g) in ethanol (50 ml) and the resulting mixture was stirred in a hydrogen atmosphere until uptake of hydrogen had ceased (5 hours). Celite was added and the mixture was filtered through two layers of glass fibre filter paper. The filtrate was concentrated to give a quantitative yield of the title compound as a colourless syrup which crystallised spontaneously. Filtration with the aid of a little hexane gave 2.52 g (88% yield) of crystalline title compound, m.p. 67°-68° C.; [α]D -87.2°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14](=[O:32])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>CN(C=O)C>[N:39]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[C:14](=[O:32])[CH2:13]3)(=[O:11])=[O:10])=[CH:5][CH:4]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Cn4ccnc4)cc3)CC2=O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (430 mg), potassium carbonate (112 mg) and imidazole (83 mg) in DMF (15 ml) was stirred at 70° C. for 1 hour. The reaction solution was concentrated, and to the residue was added water. The mixture was extracted with ethyl acetate, washed with water, sodium bicarbonate solution and brine, dried and concentrated, and the residue was recrystallized from ethyl acetate/hexane to give colorless crystals of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (421 mg).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:13]2)[CH2:11][CH2:10]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]([OH:32])[C:15]2[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:13][N:12]([CH:9]3[CH2:10][CH2:11]3)[C:16]=2[C:17]([F:18])([F:19])[F:20])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)n(C2CC2)n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
LDA (3.70 mL, 6.66 mmol) was added dropwise to a stirred solution of ethyl 1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.1) (1.18 g, 4.75 mmol) in THF (30 mL). After 15 minutes at −78° C., a solution of 4-chlorobenzaldehyde (668 mg, 4.75 mmol) in THF (5 mL) was slowly added. The reaction was stirred at −78° C. for 15 min, quenched with 1 mL of saturated NH4Cl solution, partitioned between EtOAc and water and both phases separated. The aq. phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The crude was purified by silica gel column chromatography (hexane/20% EtOAc) to afford the title product (1.5 g, 3.40 mmol, 71% yield) as a yellow solid. tR: 1.27 min (LC-MS 2); ESI-MS: 389 [M+H]+ (LC-MS 2); Rf=0.22 (hexane/EtOAc 8:2).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2)[CH2:10][NH:11][C@@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O-]S(C(F)(F)F)(=O)=O.C(N(CC)C(C)C)(C)C.[NH2:54][CH2:55][CH2:56][CH2:57][N:58]([CH3:85])[C:59]([CH2:61][CH2:62][N:63]1[CH2:68][CH2:67][CH:66]([O:69][C:70](=[O:84])[NH:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH2:65][CH2:64]1)=[O:60]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:25]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29](=[O:36])[NH:30]2)[CH2:10][NH:11][C@@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:54][CH2:55][CH2:56][CH2:57][N:58]([CH3:85])[C:59]([CH2:61][CH2:62][N:63]2[CH2:64][CH2:65][CH:66]([O:69][C:70](=[O:84])[NH:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=3[C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[CH2:67][CH2:68]2)=[O:60])=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(CCCN)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: C[C@@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1cccc(CC(=O)NCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of (3-{(S)-2-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)acetic acid (135 mg, 0.264 mmol); 2-chloropyridium triflate on Wang resin (polymer-supported Mukaiyama reagent) (1.19 mmol/g loading; 635 mg, 0.775 mmol) and N,N-diisopropylethylamine (132 μL, 0.755 mmol) in DMF (4.78 mL) was stirred at room temperature for 30 min. Biphenyl-2-ylcarbamic acid 1-{2-[(3-aminopropyl)methylcarbamoyl]ethyl}piperidin-4-yl ester (122 mg, 0.278 mmol) was added and this mixture was stirred at room temperature overnight. The mixture was filtered and the resin was washed with DCM (4 mL), MeOH (4 mL) and THF (4 mL). The filtrate was concentrated under reduced pressure and the residue was dissolved in DCM. This solution was washed with water (2×10 mL), saturated aqueous sodium bicarbonate (2×10 mL) and brine (1×10 mL); and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give the title compound (59 mg, 24% yield) as a white solid.