Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22][NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[C:11](=[O:27])[C@:10]([C:29]3([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30]3)([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO)C3CC3)C2=O)CC1
Reactant: NS(=O)(=O)C1CC1
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CNS(=O)(=O)C3CC3)C3CC3)C2=O)CC1

Procedure:
The tile compound was prepared from methyl 143R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate (35 mg, 0.068 mmol; Example 270, Step D) and cyclopropanesulfonamide (25 mg, 0.20 mmol) by a procedure similar to the one described in Example 202, Step C. Purification of the residue by chromatography on silica gel (4 g SiO2, 45% and 60% EtOAc/Hex) provided the title compound as a pale yellow.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[N+]=[N-])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N=[N+]=[N-])c2)COC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cccc(N)c2)COC1

Procedure:
A solution of 740 mg (2.118 mmol) [5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester (Example 31h) in 5 ml THF and 5 ml EtOH was stirred in the presence of 35 mg 10% Pd—C under hydrogen. After 3 h the mixture was filtered over celite, concentrated and crystallized from EtOAc/hexane to give a beige solid. The racemic product was separated via prep HPLC on Chiralpak AD-H 250×4.6 mm column using heptan/EtOH 1:1 as an eluent. The desired compound was the slower eluting (R)-enantiomer. TLC: Rf (Hexane/EtOAc 2:1)=0.15. HPLC: RtH4=1.764 min; ESIMS [M+H]+=324.11 1H-NMR (CDCl3, 360 MHz, broad signals due to hindered rotation): 10.5 (br, 1H), 7.12 (br, 1H), 6.69 (d, 1H), 6.59 (br d, 1H), 4.8-4.0 (m, 8H), 1.48 (br s, 9H).
Reaction SMILES: [CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([N:8](Cl)[Cl:9])[C:5]([O-:7])=[O:6])[CH3:2].C(C(N)(C([O-])=O)N(C(=O)C(C)C)C=O)C.[H][H]>Cl.O1CCCC1.[Pd]>[ClH:9].[CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([NH2:8])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(C(=O)C(C)C)C(C(=O)[O-])N(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CCC(N)(C(=O)[O-])N(C=O)C(=O)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)C)C(N)C(=O)O

Procedure:
Preparation of ethyl-α-N,N-dichloroaminoisobutyrylglycinate: To a solution of 2.16 g (0.01 mol) of ethyl-N-formyl-α-aminoisobutyrylglycinate in 50 ml of dry hydrogen chloride in tetrahydrofuran (1 M), there was added 1 g of 10% palladium-on-charcoal. The mixture was shaken at room temperature under at atmosphere of hydrogen at 50 psi for several days. Following filtration, the solvent was removed under reduced pressure to afford 1.18 g (0.005 mol), 50%, ethyl-α-aminoisobutyrylglycinate hydrochloride, pmr (D2O) δ 4.43 (s, 2H), 4.33 (q, 2H), 1.70 (s, 6H) and 1.23 (t, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=[O:23])[NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=[O:23])[N:16]([CH3:25])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)NC(=O)C3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)N(C)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione from Step D (1.16 g, 3.38 mmol) in DMF (40 mL) was added potassium carbonate (467 mg, 3.38 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Iodomethane (480 mg, 3.38 mmol) was added dropwise and the reaction mixture was stirred for 18 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=358 (M+1).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of the 4-biphenyl acetic acid (106.1 mg, 0.50 mmol), 3-amino benzoic acid methyl ester (113.4 mg, 0.75 mmol), EDCHCl (143.8 mg, 0.75 mmol) and HOBT (101.4 mg, 0.75 mmol) were dissolved in DMF (5.0 mL), and DIPEA (0.13 mL, 0.75 mmol) were added. The reaction mixture was stirred at room temperature overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) gave 3-(2-biphenyl-4-yl-acetyl-amino)benzoic acid methyl ester as a white solid (174 mg, 100% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]([CH3:11])[NH:8][CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[C:16]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH2:14][N:8]3[C@H:9]([CH3:11])[CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][C@@H:7]3[CH3:12])=[C:16]([CH3:31])[C:17]=2[N:18]=1
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Reactant: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To a mixture of 1-methanesulfonyl-3,5-dimethylpiperazine and 6-bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in acetonitrile was added potassium carbonate and the mixture refluxed overnight. After cooling to room temperature, the acetonitrile was removed under reduced pressure. DCM/sat. aq.NaHCO3 extraction and purification on silica gave 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22](=[O:23])[C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]2=[O:28])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:19](=[O:28])[C:20]3[CH2:27][CH2:26][CH2:25][CH2:24][C:21]=3[C:22]2=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(N2C(=O)C3=C(CCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g of powdered potassium carbonate, then 2.6 g of allyl bromide were added to a stirred suspension of 5.0 g of 1A in 25 mL of acetone. The mixture was refluxed for 1 hour, then stirred overnight at room temperature. The solvent was evaporated, water was added to the residue and the pH of the mixture was adjusted to 11 by addition of 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate, the extract was washed with brine and dried (Na2SO4), the solvent was evaporated and the residue was flash chromatographed on silica gel with a 1:9 v:v mixture of ethyl acetate and hexane as eluent to give N-(3-allyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1B), as yellow crystals, m.p.: 88°-90° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3([S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: Sc1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CCC2(Sc1ccccc1)Sc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 9.0 g of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione in 50 ml of dichloromethane and 50 ml of glacial acetic acid is stirred with 18.68 g of thiophenol and 7.5 ml of boron trifluoride ethereate at room temperature under nitrogen. After 50 minutes the solution is diluted with 350 ml of chloroform. The chloroform solution is washed successively with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 11.6 g of an oil. This is dissolved in 1:3 hexane-chloroform and chromatographed on a 200 g-silica gel column. Elution with 1:3 hexane-chloroform and chloroform gives 3.5 of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 2.0 g of the title compound, melting point 249°-250° C (dec.), with consistent spectral data.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]1=O.[CH3:12][CH:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:14]([C:16]1[CH:17]=C(O)[CH:19]=[C:20]([CH:22]=1)[OH:21])[CH3:15].P(Cl)(Cl)(Cl)=O.C1(C=CC=C(O)C=1)O>C1C=CC=CC=1>[OH:21][C:20]1[C:19]2[C:3]3[CH:2]([CH3:1])[CH2:6][S:5][C:4]=3[C:7](=[O:8])[O:9][C:10]=2[CH:17]=[C:16]([CH:14]([CH:13]([CH3:12])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:15])[CH:22]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCC(C)C1=O
Agent: Oc1cccc(O)c1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3C

Procedure:
A solution in dry benzene of equimolar amounts of methyl 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylate and 5-(3-methyl-2-octyl) resorcinol plus phosphorous oxychloride (5 ml. of benzene/g. of the resorcinol) was warmed for 13 days at 35°-37°C. in an oil bath. Most of the benzene and HCl were removed at reduced pressure, and the dark tarry residue was stirred with ether and water until solution was complete. The ether layer was washed successively with dilute solutions of sodium bicarbonate, sodium hydroxide and sodium carbonate, then with water and saturated sodium chloride. Drying and concentrating the final organic solution left a friable brick-red foamy solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=1[F:19].[C:20](=[O:22])=[O:21].C(O)(C(F)(F)F)=O>CCOCC>[F:19][C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: O=C=O
Reactant: Fc1cc(Br)c(F)c(C(F)(F)F)c1F
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Temperature: 20 °C
Yield: 69 %

Procedure:
A solution of n-butyl lithium (2.6 M in hexanes, 9.6 mL, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 mL) stirred under N2 at -78°. After 5 minutes the rxn mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 mL). After 5 minutes TFA (2 mL) was added to this. When the solution had warmed up to 20° C., it was washed with diluted HCl (0.5 M, 20 mL), and extracted with dilute base (0.5 N, 2×50 mL). The combined basic extracts were washed with ether (25 mL), made acidic with concentrated HCl (≈4 mL) and extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL), saturated brine (50 mL) and dried (MgSO4) The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl) benzoic acid (4.21 g, 69%) as white microscopic needles; mp 87°-90° C. Nmr (CDCl3) δ 11.80 (1 H, br s, OH), 8.05 (1 H, d of t, Jd =6 Hz, Jt =9 Hz, aromatic). IR (KBr) 1721, 1636, 1511, 1464, 1424, 1328, 1256, 1154, 928 cm-1. M⊕ 244 (56).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)=[O:16].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:29]2[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To 0.6 g of N-(12-hydroxydodecyl)-6-chloropyridine-3-carboxamide was added 5 ml of 1-ethylpiperazine and the mixture was stirred at 160° C. for 30 minutes. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:23]([CH2:24][C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:9][CH2:8]1.N>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:2]1([N:7]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[N:23]([CH2:24][C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:9][CH2:8]2)[CH2:1][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(Cn2c(NC3CCCNCC3)nc3cccnc32)o1
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCCN(C4CCCCC4)CC3)nc3cccnc32)o1
Yield: 23.9 %

Procedure:
A mixture of 6 parts of N-(hexahydro-1H-azepin-4-yl)-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]-pyridin-2-amine ethanedioate(1:2) and 64 parts of methanol, saturated with ammonia was stirred for 5 minutes at reflux temperature. After cooling, the precipitate was filtered off and the filtrate was evaporated. A mixture of the residue, 5 parts of cyclohexanone, 1 part of a solution of thiophene in methanol 4% and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the ethanedioate salt in a small amount of 2-propanone and ethanol. After cooling, the salt was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 2 parts (23.9%) of N-(1-cyclohexylhexahydro-1H-azepin-4-yl)-3-[(5-methyl-2-furanyl)methyl]-3 H-imidazo[4,5-b]pyridin-2-amine ethanedioate(1:2), hemihydrate; mp. 136.1° C. (compound 206).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=O)=[CH:21][CH:20]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+].C(Cl)[Cl:57]>>[Cl-:57].[OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:21][CH:20]=1)[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCC=O)cc2)c(C)c1
Reactant: C1CCNC1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCCN3CCCC3)cc2)c(C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of N-(3-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.050 g, 0.11 mmol) in 2 mL methylene chloride was added pyrrolidine (0.010 g, 0.14 mmol) and NaB(OAc)3H (0.045 g, 0.21 mmol). The reaction mixture was stirred at room temperature for three days. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (15% methanolmethylene chloride) afforded 0.034 g of the title compound. MS 493.3 (M+1)+
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CC[N:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])C.[OH:34]C[C@H]1CCNC1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:27]4[CH2:28][CH2:30][CH:33]([OH:34])[C@@H:31]4[CH3:32])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: OC[C@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(O)[C@@H]4C)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-(hydroxymethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.47 (s, 1H), 4.14 (s, 1H), 3.65 (m, 2H), 3.45 (m, 3H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 1H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 432 [M+H]
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(CO)c(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 5.30 (2H, s), 5.80 (1H, d, J=2.0 Hz), 7.12-7.14 (1H, m), 7.26 (1H, s), 7.39 (1H, dd, J=1.6 Hz, 4.8 Hz), 7.43 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H15ClN4O, 339; Found, 339.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=Cc1cc(F)c(Oc2cccc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-(trifluoromethyl)phenol.
Reaction SMILES: [CH3:1][CH:2]([N:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH:7]=O)[C:3](=O)[CH3:4].C([O-])(=O)C.[NH4+:22].C(O)(=O)C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:4][C:3]1[N:22]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:2]=1[CH3:1]
Reactant: CC(=O)C(C)N(C=O)c1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1ncn(-c2cccc([N+](=O)[O-])c2)c1C
Yield: 73.4 %

Procedure:
A suspension of N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.17 g), ammonium acetate (3.82 g) and acetic acid (1 ml) in xylene (20 ml) was refluxed for 2 hours. After adding ethyl acetate and an aqueous solution of sodium hydroxide (1N, 100 ml), the mixture was stirred for 10 minutes. The separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 1-3% unethanol/dichloromethane to give 4,5-dimethyl-1-(3-nitrophenyl)imidazole (0.79 g, 73.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]1)[O:5][C@H:6]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To a flask containing (S)-ethyl 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (11.8 g, 25.6 mmol) was added water (32.0 mL), tetrahydrofuran (32.0 mL), and methanol (32.0 mL). Lithium hydroxide monohydrate (2.15 g, 51.2 mmol) was then added. The suspension was stirred at room temperature. After 1.5 h, another (1.07 g, 25.6 mmol) of lithium hydroxide monohydrate was added. After 2 h, the reaction was concentrated. The crude residue was dissolved in water and the solution was acidified to pH=3 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (11.1 g, 100%) as a white gum. 1H NMR (400 MHz, CDCl3, δ): 8.07 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J=8.0, 4.9 Hz, 1H), 2.04-1.92 (m, 1H), 1.89 (s, 6H), 1.87-1.75 (m, 1H), 1.61-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS (M+1): 433.