Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=1)[NH2:17])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:20]=1)[NH:17][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(N)Cc1cccc(NS(C)(=O)=O)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cccc(NS(C)(=O)=O)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 10°-15° C., add benzylchloroformate (15.5 mL) dropwise to a heterogeneous mixture of 3-methanesulfonamido-D,L-phenylalanine ethyl ester (25.00 g) and triethylamine (15 mL) in dioxane (400 mL). Warm to room temperature, stir overnight, and remove the dioxane in vacuo. Partition the mixture between EtOAc (200 mL)/water (500 mL). Wash the EtOAc solution with water (500 mL), 1N HCl (500 mL), 5% NaHCO3 (500 mL), and brine (500 mL). Concentrate the dried (MgSO4) EtOAc solution in vacuo to a residue. Chromatograph the residue on silica gel (40μ, 2200 mL) using EtOAc:hexane (3:7) as eluant to give N-benzyloxycarbonyl-3-methanesulfonamido-D,L-phenylalanine ethyl ester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][N:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:20]=3)=[CH:37][CH:38]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)cc1
Yield: 91.7 %

Procedure:
To a mixture of ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate (0.38 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid as colorless crystals (0.33 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[F:24][C:25]1([F:33])[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1>>[F:24][C:25]1([F:33])[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: NCC1CCC(F)(F)CC1
Agent: Cl
Product: O=C(O)c1ccnc(-c2cn(CCNCC3CCC(F)(F)CC3)cn2)c1
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (4,4-difluorocyclohexyl)methanamine hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.13 (2H, m), 1.75 (4H, m), 1.96 (2H, m), 2.42 (2H, d, J=6.7 Hz), 2.88 (2H, t, J=6.0 Hz), 4.06 (2H, t, J=6.0 Hz), 7.53 (1H, dd, J=4.9 Hz), 7.73 (1H, s), 7.79 (1H, s), 8.25 (1H, s), 8.55 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H22F2N4O2, 365. Found, 365.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[C:16]3[S:20][C:19]([NH:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:18][C:17]3=[O:28])[N:13]=2)[N:8]=[CH:7][C:6]=1C#N)([CH3:3])[CH3:2].C(O[Na])(C)=O.C(OC1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)(C)C>CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH:15]=[C:16]1[S:20][C:19]([NH:21][CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:18][C:17]1=[O:28])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc12
Temperature: 100 °C
Yield: 45.4 %

Procedure:
To a mixture of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one one (34.0 mg, 0.16 mmol) (see Example 4), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 4.5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light brown solid (29.8 mg, 45.4%). HR-ES (+) m/e calcd for C20H18N4O2S2 (M+H)+ 411.0944. found 411.0945.
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:43][CH2:42]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1.CI>C1COCC1>[CH3:1][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34]([N:36]2[CH2:40][C@@H:39]([CH:41]3[CH2:42][CH2:43]3)[C@H:38]([CH2:44][N:45]3[CH2:50][CH2:49][CH:48]([C:51]4[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=4)[CH2:47][CH2:46]3)[CH2:37]2)=[O:35])[CH:27]=[CH:26]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reaction time: 1 h

Procedure:
To a solution of 0.015 g (0.06 mmol) of 18-crown-6 and 0.060 mL (0.06 mmol) of KOtBu (1M in THF) in 2 mL of THF was added 0.15 g (0.34 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine and the mixture was stirred for 15 min after which 0.0062 mL (0.1 mmol) methyl iodide was added. After 2 h another 0.005 mL of methyl iodide was added and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, Waters RCM 8×10 Novapak) (acetone:hexanes, 1:5) to give the title compound. 1H NMR (CD3OD) d (key peaks) 7.58 (m, 2H), 7.15-6.92 (m, 5H), 7.39 (m, 1H), 6.53 (m, 1H), 3.80 (s, 3H), 0.06 (m, 5H); Mass Spectrum (CI) m/e=460 (M+1).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:19][CH:18]([N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=[N:2]1)[CH3:20]
Reactant: CC(C)I
Reactant: CCOC(=O)c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccnn1C(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 1H-pyrazole-5-carboxylate (1 g) (for example, available form Bio-Farma) in acetonitrile (80 ml) was added cesium carbonate (2.32 g). 20 min later 2-iodopropane (0.714 ml) was added and the mixture stirred under nitrogen at 20° C. for 18 h. 2-Iodopropane (0.714 ml) was added and the mixture stirred under nitrogen at 20° C. for 5 h. Then further 2-iodopropane (0.714 ml) was added and the mixture was stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue was partitioned between water (30 ml) and DCM (30 ml). The aqueous phase was extracted with DCM (2×20 ml) and separated by hydrophobic frit. The combined organic layers were concentrated in vacuo. Purification of the residue by chromatography on silica gel (70 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 min gave the title compound (513 mg) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:6]([CH2:7][N:8]([C:12](=[O:25])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:9]2)[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])([OH:26])[CH2:4]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(N(CC)CC)C>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][CH:3]2[CH2:11][CH:10]3[CH:6]([CH2:7][N:8]([C:12](=[O:25])[CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:9]3)[C:5]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])([OH:26])[CH2:4]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=C(Cc1ccccc1N1CCCC1)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4N4CCCC4)CC3C(O)(c3ccccc3F)C2)cc1
Yield: 26.1 %

Procedure:
The procedure is as described for Example 13, starting from 0.2 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol, 0.168 g of p-toluenesulphonyl chloride and 0.124 cm3 of triethylamine, and gives 0.07 g of (3aRS,4RS,6SR,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.CN(C)CCN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CN(C=O)C>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(I)cc3)CC2)CC1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(-n4cncn4)cc3)CC2)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 1′-(4-iodophenyl)-4,4′-bipiperidine-1-carboxylate (17 mg, 0.036 mmol) from Step 1, 1H-1,2,4-triazole (7.5 mg, 0.108 mmol), CuI (0.7 mg, 0.0036 mmol), N,N-dimethylethane-1,2-diamine (1 mg, 0.0072 mmol), K3PO4 (16 mg, 0.0756 mmol) were mixed in a 1 dram vial, followed by addition of DMF (0.1 mL). The reaction vessel was degassed and back-filled with Ar 3 times, before it was heated at 100° C. for 20 hours. The reaction was cooled, diluted with water, extracted with EtOAc, concentrated and purified by PTLC to give the title compound.
Reaction SMILES: [CH:1]([O-])=O.[CH3:4][N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]3)[CH:12]=2)=[N:8][C:7]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[N:24]=2)=[N:6]1.C=O.[BH3-]C#N.[Na+]>CCO>[CH3:4][N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:1])[CH2:19][CH2:18]3)[CH:12]=2)=[N:8][C:7]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:32][CH:33]=3)[N:24]=2)=[N:6]1
Reactant: Cn1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1ccnc(N2CC[NH2+]CC2)c1
Reactant: O=C[O-]
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(c2cc(Cc3nc(-c4nc(-c5ccc(OC(F)(F)F)cc5)no4)nn3C)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(4-((1-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-5-yl)methyl)pyridin-2-yl)piperazin-1-ium formate (100 mg, 0.2 mmol) in EtOH (1 mL), formaldehyde (0.5 mL, 6.0 mmol, 38% in H2O) and paraformaldehyde (100 mg, 3.3 mmol) in EtOH (1 mL) was stirred at RT, then treated with NaBH3CN (63 mg, 1.0 mmol) in one portion. The mixture was stirred at RT for 1 h, and then concentrated to give the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to afford 5-(1-methyl-5-((2-(4-methyl piperazin-1-yl)pyridin-4-yl)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (50 mg, 50%). MS (ES+) C23H23F3N8O2 requires: 500, found: 501[M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (bs, 1H), 8.22 (d, J=7.0 Hz, 2H), 8.05 (d, J=5.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 6.80 (s, 1H), 6.55 (d, J=5.0 Hz, 1H), 4.25 (s, 2H), 4.00 (s, 3H), 3.47 (t, J=4.8 Hz, 4H), 2.50 (t, J=5.3 Hz, 4H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH2:71])=[CH:68][C:67]([C:72]([F:75])([F:74])[F:73])=[N:66]2)[CH:62]=[CH:63][CH:64]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([NH:71][CH2:70][C:69]2[N:65]([C:61]3[CH:62]=[CH:63][CH:64]=[C:59]([Cl:58])[CH:60]=3)[N:66]=[C:67]([C:72]([F:73])([F:74])[F:75])[CH:68]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.229 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (30 mg, 0.229 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (74 mg, 0.229 mmol), N-ethyldiisopropylamine (0.078 mL, 0.458 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (63 mg, 0.229 mmol). The solution was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexane (1:2)) to give 2-(3-chloro-4-methylsulfonyl-phenyl)-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide (example compound D5) (100 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:25]([O:27]CC)=[O:26])=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)[nH]c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc(N3CCOCC3)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 98.7 %

Procedure:
Ethyl 5-(4-chlorophenyl)-2-(4-morpholinophenyl)imidazole-4-carboxylate (53.7 g) was dissolved in ethanol (540 ml) and 3N aqueous sodium hydroxide solution (217 ml), and the mixture was refluxed under heating for 5 hr and concentrated under reduced pressure. Water (100 ml) was added and the mixture was washed with toluene. The aqueous layer was neutralized with 10% aqueous citric acid solution and the precipitated crystals were collected by filtration to give the objective 5-(4-chlorophenyl)-2-(4-morpholinophenyl)imidazole-4-carboxyic acid (49.4 g), melting point 205° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC1CCNCC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidin-4-yl-methanol (Lancaster) to give the title compound. HR-MS (ES, m/z) calculated for C33H35N43O3F3Cl2 [(M+H)+] 648.2002, observed 648.2006.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[F:21])=[O:4].Cl.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>O>[C:23]([NH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:8][C:7]=1[F:21])=[O:4])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Yield: 99 %

Procedure:
A solution of 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol), acetyl chloride (14.4 mg, 0.18 mmol), triethylamine (31 mg, 0.30 mmol) was stirred at 0° C. for 4 h. Then the mixture was diluted with water and the mixture extracted with DCM. The organic layer was then washed with brine, dried, filtered and evaporated to leave the title compound (50 mg, 99%) as a white solid. MS: m/e=335.2 (M++H).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH:19]1C(O)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.C(OCC)(=O)C>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][C@@H:23]1[CH2:6][CH:5]=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Add anhydrous DMSO (3.57 mL, 50.25 mmol) in anhydrous dichloromethane (68.0 mL). Cool to −78° C. and stir. Add oxalyl chloride (2M in dichloromethane, 12.06 mL, 24.125 mmol) dropwise. Stir at −78° C. for 30 minutes. Add (1,4-dibenzyl-piperazin-2-yl)-ethanol (6.241 g, 20.1 mmol) in dichloromethane (12.0 mL) and stir. After 1 hour, add triethylamine (14.01 mL, 100.5 mmol) and stir for another 1 hour. Allow the reaction mixture gradually warm to ambient temperature. Add saturated ammonium chloride. (200 mL). Exact aqueous portion with ethyl acetate three times. Combine the organic solution, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):309.03 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39]Cl)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39][N:52]2[CH2:51][CH2:50][N:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][CH3:41])[CH2:54][CH2:53]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccc(COc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc2OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCOc2cc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)ccc2OCc2ccc(C)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
3-[4-(4-Methylphenylmethoxy)-3-(3-chloropropoxy) benzoyl]-1-(phenylsulfonyl)indole (0.44 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Methoxyphenyl)piperazine (0.20 g), potassium carbonate (0.14 g), and potassium iodide (0.38 g) were added to the resultant solution and the mixture was stirred overnight at 60° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:3), obtaining 0.29 g of 3-{4-(4-methylphenylmethoxy)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}-1-(phenylsulfonyl)indole (0.29 g) as a light yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:20]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixture of 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate (0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12 mL). The resultant solution was purged with nitrogen for 10 minutes before tetrakis(triphenylphosphine) palladium(0) (0.10 g, 0.09 mmol) was added. The reaction mixture was heated to reflux for 65 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL with water/ethyl acetate (1:1, v/v). The aqueous layer was extracted with ethyl acetate, and the combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield the title compound as a gold oil (1.09 g). This material was used without further purification in the next step.