Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:38][O:39][C:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:40]3([O:39][CH3:38])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
To a solution of 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-hydroxymethyl-1H-imidazole (14) (33 mg, 0.1 mmol) prepared in accordance with the method as described in WO 96/10019 and p-toluenesulfonic acid pyridinium (27.6 mg, 0.11 mmol) in toluene (1.5 mL) was added 1-methoxycyclohexene (112 mg, 1.00 mmol) under ice-cooling, and stirred at room temperature for 6 hours. A drop of triethylamine was added to the reaction mixture, and the mixture was filtered to remove the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on an alumina column (eluate: toluene) to give the compound 15 (37.0 mg, 70%) as oil. Rf 0.16 (Al2O3 60, Type E, toluene).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Product: COc1ccc(Br)c2oc(N3CCCCC3)nc12

Procedure:
Starting from 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (10.0 g) and piperidine (3.8 ml). Purification by chromatography on silica eluting with 30-100% ethyl acetate in hexane afforded the title compound as an off-white solid (10.7 g).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.N1(C2C=CC(CC(C(O)=O)C(O)=O)=CC=2)C=NC=N1.[CH3:41][C:42]1([CH3:50])[O:47][C:46](=[O:48])[CH2:45][C:44](=[O:49])[O:43]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:45]3[C:46](=[O:48])[O:47][C:42]([CH3:50])([CH3:41])[O:43][C:44]3=[O:49])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)C(Cc1ccc(-n2cncn2)cc1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)O
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
L-Proline (1.81 g, 15.6 mmol) was added to a stirring, heterogeneous mixture of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (13.5 g, 78.0 mmol, Intermediate 82: step a) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11.2 g, 78.0 mmol) in ethanol (520 mL) at 23° C. After 1.5 hours, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (19.7 g, 78.0 mmol) was added in one portion. After 16 hours, the ethanol was removed by rotary evaporation at 35° C. to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was stirred for 10 minutes at 23° C. The mixture was filtered and the filter cake was washed with isopropanol (150 mL). The solids were collected and dried under vacuum to provide the titled compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)c1cc(C(F)(F)F)cc(N)c1N1CCCCC1
Yield: 48 %

Procedure:
To a solution of ethyl 3-nitro-2-piperid-1-yl-5-trifluoromethylbenzoate (4.9 g; 1 eq.) in ethanol (50 ml) are added cyclohexene (10.5 ml; 7.5 eq.) and 10% Pd/C (0.6 g), and the mixture is stirred at reflux for 5 hours. After removing the catalyst by filtration and concentrating to dryness, the pasty solid is purified by chromatography on silica (eluent: 4/1 pentane/ether). 2.15 g of ethyl 3-amino-2-piperid-1-yl-5-trifluoromethylbenzoate are obtained in the form of a reddish oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C@H:10]1[NH:13][C:12](=[O:14])[CH2:11]1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([S:21]([O:8][CH2:9][C@H:10]2[NH:13][C:12](=[O:14])[CH2:11]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1C[C@@H](CO)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](COS(=O)(=O)c2ccccc2)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
Triethylamine (5.74 g, 56.8 mmol) was added by syringe to a solution of (S)-4-hydroxymethylazetidin-2-one (3.79 g, 37.5 mmol) and benzenesulfonylchloride (10.0 g, 56.8 mmol) in dry methylene chloride (38 ml) at 0° C. The resulting mixture was stirred at 0° C. for 4 hrs., then diluted with methylene chloride (100 ml), washed with water (50 ml) and brine (25 ml) and dried over magnesium sulfate. Solvents were removed in vacuo to give a brown gum which was chromatographed on silica gel (100 g) (ethylacetate) to yield 6.6 g (73%) of (S)-4-benzenesulfonyloxymethyl azetidin-2-one as a white solid, m.p. 102°-105° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][C:12]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:16](=[O:17])[O:15][C:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116.5 %

Procedure:
Racemic α-(aminomethyl)benzenemethanol (13.7 g) and bis(1,1-dimethylethyl)carbonate (21.8 g) were dissolved in methanol (200 ml) and 10% aqueous sodium carbonate (200 ml) added. The mixture was stirred at room temperature for 24 h, poured into 2M hydrochloric acid and extracted with ethyl acetate. Evaporation of the extract and trituration with ethyl acetate/hexane gave the sub-title compound as a pale yellow solid (27.6 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[NH2:27][OH:28]>C1COCC1>[OH:28][NH:27][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: NO
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)NO)cc1OCC2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with hydroxylamine hydrochloride (8 mg, 0.1 mmol) in THF to provide 173. LC/MS (ESI+): m/z 355 (M+H)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[N:32]3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]>CCO.Cl>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:29]=4)=[CH:20][C:19]=3[CH2:30][N:31]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[N:32]3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1Cn1ccc(C(F)(F)F)n1
Agent: Cl
Solvent: CCO
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2Cn2ccc(C(F)(F)F)n2)c1C

Procedure:
To the solution of N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)-2'-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl][1,1'-biphenyl]-2-sulfonamide in 3 ml of 95% EtOH, 3 ml 6N HCl was added. The mixture was refluxed for 1 hr and concentrated. 10 ml H2O was added and the mixture was extracted with 3×30 ml EtOAc. The combined organic extracts were washed with brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 24% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 76% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (87 mg, 77% for two steps) as a white solid. m.p. 108°-114° C. (amorphous).
Reaction SMILES: C(NC[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[CH3:11][C:12]([C:15]1[CH:16]=[C:17]([S:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[S:32][CH2:33][C:34]([N:36]([CH3:45])[CH2:37][CH2:38]C2C=CC=CN=2)=[O:35])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])[CH3:13]>>[CH3:22][C:21]([C:19]1[CH:18]=[C:17]([S:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[S:32][CH2:33][C:34]([N:36]([CH2:37][CH3:38])[CH2:45][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:35])[CH:16]=[C:15]([C:12]([CH3:13])([CH3:11])[CH3:14])[CH:20]=1)([CH3:23])[CH3:24]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: CCNCc1ccncc1
Product: CCN(Cc1ccncc1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Substituting 4-(ethylaminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-ethyl-N-(4-pyridinylmethyl)acetamide.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:5][S:6][CH:7]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:23][C:14]1[C:13]([CH2:24][NH:25][CH3:26])=[CH:12][N:11]([S:8]([C:4]2[C:3]([C:1]#[N:2])=[CH:7][S:6][CH:5]=2)(=[O:9])=[O:10])[C:15]=1[C:16]1[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cscc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cscc2C#N)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of tert-butyl {[1-[(4-cyano-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (181 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 116 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[S:34][C:22]2[CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C:21]=2[C:20]=1[C:35](=[O:37])[NH2:36]>C1COCC1.C(Cl)Cl>[C:35]([C:20]1[C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23][C:22]=2[S:34][C:19]=1[NH:18][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])(=[O:37])[NH2:36]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a stirred solution of 4-chlorophenyl isocyanate (325 mg, 2.12 mmol) and triethylamine (444 μL, 3.18 mmol) in anhydrous THF (10 mL) was added tert-butyl 2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (632 mg, 2.12 mmol) and the reaction mixture was stirred at rt for 8 h. The reaction mixture was concentrated in vacuo to afford oil, which was taken up in DCM and washed with water (×2). The organics were then dried with anhydrous Na2SO4 and concentrated in vacuo. The product was purified by Isolera system (SiO2 gel as stationary phase, 25 g HP column, dry loading) using DCM-DCM/MeOH (0%-8% MeOH in DCM) to afford the title compound as a tan solid (633 mg, 57% yield). LRMS [M+H]451.
Reaction SMILES: ClCCl.Cl.[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:7]=1[NH2:8].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:7]=1[NH:8][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccccc2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dichloromethane 5.0 mL solution of 2-methyl-5-phenoxyaniline hydrochloride 0.50 g were added pyridine 0.34 mL and acetic anhydride 0.24 mL under ice cooling, and it was stirred at room temperature for 6 hours and 30 minutes. The solvent was removed under reduced pressure,1.0 mol/L hydrochloric acid and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(2-methyl-5-phenoxyphenyl)acetamide 0.44 g of white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:14]([CH3:22])[C:15](=[O:21])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C2N=NN(O)C2=CC=1.N.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:53][CH2:54][C:55]1[C:56]([OH:63])=[N:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>ClCCl>[CH3:61][C:60]1[CH:59]=[C:58]([CH3:62])[NH:57][C:56](=[O:63])[C:55]=1[CH2:54][NH:53][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH:14]([CH3:22])[C:15](=[O:21])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:2]=1[CH3:1])=[O:12]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)C(=O)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)C(=O)N3CCCC3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
2-Methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylic acid (90 mg, 0.30 mmol) was dissolved in dichloromethane (15 mL), and then N-hydroxybenzotrizole (0.45 mmol, 60 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45 mmol, 86 mg), and triethylamine (1.69 mmol, 2 ml) was added to the mixture. After the mixture was stirred at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.30 mol, 50 mg) was added. The mixture was stirred at room temperature for 18 hours. Then washed with water (20 mL), extracted with dichloromethane (20 mL). The organic layer was separated, and concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxamide (60 mg, 70%). LCMS (M+H+) m/z: calcd 434.23. found 434. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.75-7.72 (m, 2H), 7.42 (d, J=5.7 Hz, 1H), 7.10-7.06 (m, 2H), 5.89 (s, 1H), 5.49-5.44 (m, 1H), 4.32-4.30 (m, 2H), 3.42-3.32 (m, 3H), 3.28-3.16 (m, 1H), 2.61 (s, 3H), 2.26 (s, 3H), 2.12 (m, 3H), 2.02-1.96 (m, 1H), 1.70-1.57 (m, 3H), 1.42 (d, J=5.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=4[F:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=95%.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([OH:19])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:17]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:19])[CH3:25]
Reactant: CCNCC
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccccc2n1
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)c2ccccc2n1

Procedure:
The process is carried out as for Example 1, starting from 2 g of 4-phenyl quinoline 2-carboxylic acid, 6 ml of thionyl chloride and 8.3 ml of diethylamine. After treatment, 2.3 g of N,N-diethyl 4-phenyl quinoline 2-carboxamide are isolated in the form of an orange oil. After crystallization from a 50/50 hexane-ether mixture, the product has a melting point lower than 50° C.
Reaction SMILES: [CH:1]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OOS([O-])=O.[K+].[CH3:17][OH:18]>>[CH:1]1([C:9]([O:18][CH3:17])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCCCC1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)C1CCCCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cyclooctanecarbaldehyde (5.0 g) in methanol (300 mL) was added Oxone (22 g). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (300 mL) and washed with 1N aqueous HCl, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:17])[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]1>CCOC(C)=O>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][CH:12]2[CH2:13][CH2:14][CH2:15][CH:10]([NH2:17])[CH2:11]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NC1CCCC(N)C1
Solvent: CCOC(C)=O
Product: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 120 °C
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (2.500 g, 9.13 mmol) and cyclohexane-1,3-diamine (4.44 mL, 36.5 mmol) was heated at 120° C. in a capped vial for 2 hours. While warm, the reaction mixture was treated with EtOAc and washed with water (3×). The organic layer was dried and concentrated to give 2.62 g of the crude title compound. This material was carried into the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccc(C(F)(F)F)c2)ncn1Cc1ccccc1
Yield: 92 %

Procedure:
out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-trifluoromethylbenzoyl chloride, instead of benzoyl chloride, to obtain 3.56 g 1-benzyl-4-(3-trifluoromethylbenzoylamino)-5-imidazolecarboxamide (yield 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[O:11][C:10](=[O:20])[NH:9]2)[C:5]([F:21])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[CH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:5]1[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[O:11][C:10](=[O:20])[NH:9]2)=[CH:7][C:2]([C:30]#[C:29][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccccc2F)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)ncc2F)[C@@H](c2ccccc2F)O1
Temperature: 90 °C

Procedure:
A suspension of optically-enriched (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(2-fluorophenyl)oxazolidin-2-one (38 mg, 0.107 mmol) in triethylamine (1.1 mL, 8.03 mmol) was degassed by bubbling with nitrogen for 30 min. To this was added ethynylbenzene (15 μl, 0.134 mmol) and triphenylphosphine (3.7 mg, 0.014 mmol). After bubbling 5 min longer, the reaction was treated with copper(I) iodide (0.408 mg, 2.14 μmol) and bis(triphenylphosphine)palladium(II) chloride (1.8 mg, 2.6 μmol), bubbled briefly with nitrogen, sealed, and heated at 90° C. for 5 h. The reaction was concentrated, dissolved in a minimum of dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% EtOAc/Hex) gave a mixture of the two regioisomers. This material was further purified by chiral prep HPLC (Chiralcel OD, 40% EtOH/heptane/0.1% DEA) to give 9.6 mg (23%). 1H NMR (CDCl3) δ: 8.49 (d, J=1.2 Hz, 1H), 7.76 (d, J=5.8 Hz, 1H), 7.58-7.67 (m, 2H), 7.51 (td, J=7.5, 1.5 Hz, 1H), 7.35-7.48 (m, 4H), 7.23-7.28 (m, 1H), 7.16 (ddd, J=9.8, 8.9, 0.8 Hz, 1H), 6.28 (br. s., 1H), 5.62 (d, J=5.8 Hz, 1H), 5.17 (d, J=5.8 Hz, 1H). 13C NMR (CDCl3) δ: 160.1, 158.4, 156.2, 140.8, 139.2, 135.3, 132.2, 131.4, 129.5, 128.6, 127.5, 125.2, 124.9, 124.5, 121.8, 116.2, 90.2, 87.3, 79.3, 56.6. 19F NMR (CDCl3) δ: −117.69 (d, J=8.7 Hz, 1F), −132.34 (d, J=8.7 Hz, 1F). Mass spec.: 377.2 (MH)+.