Azzindani/Open_Reaction_Data huggingface dataset:
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]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[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]([NH:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CCOCCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCOCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-ethoxyethylamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=6.95 Hz, 3 H) 2.43 (s, 3 H) 3.42-3.49 (m, 4 H) 3.49-3.55 (m, 2 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.75-7.85 (m, 1 H) 8.06-8.27 (m, 1 H) 8.42 (d, J=6.82 Hz, 2 H) 8.80 (t, J=5.18 Hz, 1 H) 8.88-8.96 (m, 1 H) 12.86-13.47 (m, 1 H). MS m/z [M+H]+ 392.2.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[N:8]([CH2:24][C:25]2[CH:29]=[C:28]([C:30]3[S:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:27][N:26]=2)[C:7]=1[CH3:36].Cl>CO>[Cl:35][C:32]1[S:31][C:30]([C:28]2[O:27][N:26]=[C:25]([CH2:24][N:8]3[C:9]([C:12](=[O:23])[NH:13][CH:14]4[CH2:15][CH2:16][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19]4)=[C:10]([CH3:11])[C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]3[CH3:36])[CH:29]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)CCc1c(C)c(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C
Agent: Cl
Solvent: CO
Product: Cc1c(CCC(=O)O)c(C)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)NC1CCN(C(C)C)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 34 mg (0.06 mmol) of 3-[1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester in MeOH (4 mL) 1 M aqueous LiOH-solution (0.3 mL) was added and the resulting mixture was stirred at 60° C. for 5 h. The mixture was acidified by the addition of a 1 M HCl-solution (pH 5) and concentrated under reduced pressure. Final purification by preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid as a colorless amorphous material. The product was obtained as its hydroformiate (11 mg). MS (ESI+): m/e=534 [M+H]+, chloro pattern.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: COc1ccc(N)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 250 °C
Yield: 160.3 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml) and 2-methyl-4-methoxyaniline(6.1 ml, 46 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours, diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91% of yield.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCCOc2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 53 mg, 0.2 mmol), 1-(2-bromo-ethoxy)-benzene (48.3 mg, 0.22 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in acetone (0.8 ml) is refluxed for 3 h. The suspension is cooled to rt and filtered through a short pad of silica-gel. The volatiles are removed in vacuo and the residue is dried under high vacuum affording the title compound as a colourless oil. This material was used in the next step without further purification: tR=2.55 min (LC-2), MS (pos.): m/z 385.2 [M+H]+; 1H NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBu), 3.96 (m, 2H, SCH2), 4.48 (t, 2H, OCH2), 4.90 (s, 2H, CH2CO2), 6.90 (d, 2Harom), 7.24-7.38 (m, 5Harom), 7.86 (m, 1Harom).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)([OH:33])[CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CO.Cl>C(O)C.C(O)(C)C.C(Cl)(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)([OH:33])[CH:27]2[CH2:28][CH2:29][N:30]([CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]3[C:3]([O:2][CH3:1])=[CH:4][C:5]4[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=4[CH:12]=3)[CH2:31][CH2:32]2)=[CH:22][CH:21]=1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
Method C (5 d at 45° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 4-[bis(4-fluorophenyl)hydroxymethyl]piperidine; yield 45%; fusion point 220°-221° C. (from methanol and chloroform). Hydrochloride: method G; yield 99%; fusion point 172°-174° C. (from isopropanol and ethanol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[O:9][CH:8]=[CH:7][CH2:6]1)(=[O:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].CCOCC>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11][N:23]=[N+:24]=[N-:25])[O:9][CH:8]=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1CC=CO[C@@H]1COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)O[C@H]1CC=CO[C@@H]1CN=[N+]=[N-]
Reaction time: 24 h
Yield: 60.2 %

Procedure:
4-O-Acetyl-3-deoxy-6-O-tosyl-D-glucal (550 mg.) and sodium azide (550 mg.) were dissolved in hexamethylphosphoramide (50 ml.) and the mixture was stirred at 25° for 24 hours. The reaction mixture was poured into ether and extracted with water and the ether extract was dried (MgSO4) and evaporated and the product was chromatographed on a silica gel column (58 × 2.5 cm) using 7% acetone in hexane as the eluent to give 4-O-acetyl-6-azido-3,6-dideoxy-D-glucal (200 mg.) as a colorless oil, (Found: C, 48.84; H, 5.33; N,21.49. C8H11N3O3 requires: C, 48.72; H, 5.62; N, 21.31%), [α]D26 = 158.8° (CH3OH), νmax (film) 2100, 1720, 1660, 1220, 1050 cm.-1, δ(CDCl3) 2.09 (3H, s, OAc), 4.72 (1H, ddd, H = 6Hz, J = 4.5Hz, J = 3Hz, H2) and 6.39 ppm (1H, ddd, J = 2Hz, J = H1. )
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].O>CN(C)C(=O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.76 g, 6.4 mmol) and the mixture stirred at -10° to -15° C. for one hour. 4-(2-Pyrimidylsulfonyl)benzenamine (1.00 g, 4.2 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic portions were washed with water, dried (MgSO4), filtered, and the solvent distilled to yield a tan solid. Flash chromatography of the solid (eluted with 10% v/v ethyl acetate in methylene chloride) and evaporation of the eluent yielded the title propanamide (1.05 g, 66%) as a white solid; mp 187°-190° C. 1H-NMR (300 MHz, d6 -DMSO): 1.60 (s, 3H, CH3), 7.59 (s, 1H, OH), 7.79 (t, 1H, J=4.9 Hz, aromatic), 7.96 (d, 2H, J=8.9 Hz, aromatic), 8.06 (d, 2H, J=8.9 Hz, aromatic), 9.02 (d, 2H, J=4.8 Hz, aromatic), 10.49 (s, 1H, NH). MS (CI, CH4): 376 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([NH:20][CH:21]2[CH2:23][CH2:22]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34](=[O:35])[N:20]([C@H:10]2[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:21]2[CH2:22][CH2:23]2)=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2NC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc(F)cc1)N(C1CC1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of 2.27 g (6.94 mmol) rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-amine, 987 mg (7.64 mmol) DIPEA, 8.48 mg (0.07 mmol) DMAP and 1.27 g (7.29 mmol) 4-fluorophenyl chloroformate in 40 mL DCM at 0° C. was stirred at room temperature over night and evaporated to dryness. the residue was purified by column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 1.64 g (51%) of the title compound as colorless viscous oil. MS m/e: 465.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].C[O:8][C:9](=O)[C@@H:10]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C@H:11]([OH:13])[CH3:12].Cl>CO>[Br:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[C:15]([NH:14][C@H:10]([C:9]([NH:2][OH:3])=[O:8])[C@H:11]([OH:13])[CH3:12])=[O:24]
Reactant: NO
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(F)c(Br)c1)[C@@H](C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(F)c(Br)c1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of hydroxylamine hydrochloride (66 mg, 0.95 mmol) in anhydrous MeOH (2.0 mL) at 0° C. under N2 atmosphere was added sodium methoxide (25 wt % in MeOH, 360 mg, 1.67 mmol). A precipitate formed immediately and the cloudy white solution was stirred for 10 minutes at 0° C. A solution of methyl (2S,3R)-2-[(3-bromo-4-fluorophenyl)carbonylamino]-3-hydroxybutanoate (2) (284 mg, 0.850 mmol) in MeOH (2.0 mL) was added and the reaction stirred 2 h at 0° C. and then warmed gradually to room temperature overnight (17 h total). Aqueous 1.0 M HCl (10 mL) was added and the solution extracted with 4:1 chloroform/isopropyl alcohol (4×20 mL). The organic layers were combined, dried over Na2SO4 and concentrated to give a pink foam. The crude solid was triturated with diethyl ether (2×8 mL) and dried in vacuo to give 3-bromo-4-fluoro-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide 3 as a white foam: mp 152-153° C. Rf (10:1 CH2Cl2/MeOH on silica gel)=0.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1ccccc1B(O)O
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: O
Product: COc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.056 g (78%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].COC1C=C(C=C(OC)C=1OC)C=O.C[Si]([C:36]1[NH:41][C:40](=[O:42])[N:39]([Si](C)(C)C)[C:38](=[O:47])[C:37]=1[F:48])(C)C.FC1C(=O)NC(=O)NC=1>ClCCl.C(O)CO>[OH:14][CH2:15][CH2:16][O:17][CH:13]([N:41]1[CH:36]=[C:37]([F:48])[C:38](=[O:47])[NH:39][C:40]1=[O:42])[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: COc1cc(C2OCCO2)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: ClCCl
Solvent: OCCO
Product: COc1cc(C(OCCO)n2cc(F)c(=O)[nH]c2=O)cc(OC)c1OC

Procedure:
2-(3,4,5-Trimethoxyphenyl)-1,3-dioxolan (20.3 g) prepared from 3,4,5-trimethoxybenzaldehyde and ethylene glycol was dissolved in dichloromethane (50 ml). To the solution bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 7.2 g of crystalline 1-[α-(2-hydroxyethoxy)-3,4,5-trimethoxybenzyl]-5-fluorouracil.
Reaction SMILES: [ClH:1].C(O)C.C([O:12][C@H:13]1[CH2:17][NH:16][C@H:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)[CH2:14]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].CO>[ClH:1].[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH3:25])[CH2:18][C@H:15]1[NH:16][CH2:17][C@H:13]([OH:12])[CH2:14]1
Reactant: Cc1ccc(C[C@@H]2C[C@@H](OCc3ccccc3)CN2)cc1F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C[C@@H]2C[C@@H](O)CN2)cc1F
Reaction time: 16 h
Yield: 95 %

Procedure:
By adding 2 M hydrochloric acid/ethanol solution (15 mL) to (2R,4R)-4-(benzyloxy)-2-(3-fluoro-4-methylbenzyl)pyrrolidine (1.45 g, 4.84 mmol) which had been synthesized according to Example 1 (1e)-20, a suspension was prepared. Methanol (10 mL) was added thereto to yield a homogenous solution. 20% Palladium hydroxide-carbon (wet, 50 wt %, 483 mg) was added thereto for hydrogenation under atmospheric pressure for 16 hours. The reaction solution was filtered. The solvent was distilled off under reduced pressure. The residue was added with diethyl ether to yield a suspension, which was then filtered and washed with diethyl acetate to give the title compound as a white solid (1.13 g, yield 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:36]([O:35][C:34]([NH:33][C@@H:9]([CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=2)=[CH:3][CH:4]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccc(C(=O)OC)cc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 120 °C
Yield: 70 %

Procedure:
tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (as prepared in Example 6, Step A) (0.114 mmol, 0.070 g) and 4-(methoxycarbonyl)phenylboronic acid (0.148 mmol, 0.027 g) were added to a 5 mL microwave vessel equipped with a magnetic stir bar. Dioxane (2 mL) and Na2CO3 (1 mL of a 2 M aq. soln.) were then added and the reaction vessel was flushed with nitrogen gas. PdCl2(dppf) (0.006 mmol, 0.004 g) was added, the reaction vessel was sealed and placed in a microwave reactor and heated to 120° C. for 15 minutes. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This crude material was directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording methyl 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate (53A) as a clear oil. (0.08 mmol, 0.054 g, 70% yield). ESI-MS: m/z 669.4 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:9](OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[Na].[C:15]1([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2CBr)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+]>O>[C:15]1([C:21]2[CH:22]=[CH:25][CH:26]=[CH:27][C:28]=2[CH2:9][CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Temperature: 130 °C
Yield: 92.8 %

Procedure:
188 g (1 mol) of diethyl ethylmalonate dissolved in 100 cm3 of H2O-free EtOH are added dropwise at room temperature to 23 g (1 mol) of sodium in 400 cm3 of H2O-free EtOH. 247 g (1 mol) of 2-phenylbenzyl bromide in 300 cm3 of H2O-free EtOH were subsequently added dropwise, and the mixture was refluxed for 3 hours. 170 g (3 mol) of KOH dissolved in 300 cm3 of H2O were added at room temperature, and the mixture was refluxed for a further 4 hours. The solvent was removed in vacuo, H2O was added to the residue until the latter had dissolved completely, and the mixture was subsequently acidified to pH 1 by means of concentrated aqueous HCl. The precipitate which formed was filtered off with suction, dried and heated at 130° C. for 1 hour, giving 236 g (93%) of 13 as a viscous oil.
Reaction SMILES: C(Br)C1C=CC=CC=1.OC1C=CC(C(NC=O)CC2C=CC(F)=CC=2)=CC=1.[H-].[Na+].[C:30]1([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([NH:53]C=O)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>O.CN(C=O)C>[C:30]1([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([NH2:53])[CH2:45][C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CNC(Cc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Agent: BrCc1ccccc1
Agent: O=CNC(Cc1ccc(F)cc1)c1ccc(O)cc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(Cc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 104.9 %

Procedure:
To a -20° C. CH2Cl2 (100 mL) solution of N-[1-(4-methoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (1.6 g, 5.86 mmol) (for preparation see step A of Example 48) was added 11 mL of 1N BBr3 in hexane. After warming to 0° C. and stirring for one hour, an additional 5 mL of BBr3 solution was added. After 40 minutes, the reaction was complete by HPLC analysis. The reaction was quenched upon transferal into a stirred 4° C. aqueous NaHCO3 solution and extracted with CH2Cl2 (3×). The organic phases were washed with pH 4 NaH2PO4, brine, dried over Na2SO4 and concentrated to yield 1.4 g of N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide as a yellow solid. To a 50° C. DMF (10 mL) containing benzyl bromide (400 mg, 2.3 mmol) and N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (450 mg, 1.7 mmol) under N2 was added 60% NaH (200 mg, 5 mmol). After one hour the reaction was quenched with H2O, extracted with EtOAc (3×). The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 1 g of crude product. Flash chromatography on silica gel using 1:1 EtOAc/hexane eluted 300 mg of N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide. A 1:1 ETOH/H2O solution (10 mL) containing N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (300 mg, 0.86 mmol) and NaOH (200 mg, 5 mmol) was refluxed for 40 hours, diluted with H2O and extracted 3× with EtOAc. The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 290 mg of α-(4-phenylmethoxyphenyl)-4-fluorobenzeneethanamine.