Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl/[C:44](/[C:47]1[CH:52]=[CH:51][C:50]([C@@H:53]2[CH2:58][O:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:49][CH:48]=1)=[N:45]\[OH:46]>C1COCC1>[C:8]([O:12][C:13]([N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])[C:23]1[C:28]([C:29]2[O:46][N:45]=[C:44]([C:47]3[CH:48]=[CH:49][C:50]([C@@H:53]4[CH2:58][O:57][CH2:56][CH2:55][N:54]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:51][CH:52]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(/C(Cl)=N/O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
Et3N (54.34 mg, 74.85 μL, 0.5370 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 4 (224.5 mg, 0.4475 mmol) and tert-butyl (3R)-3-[4-[(Z)—C-chloro-N-hydroxy-carbonimidoyl]phenyl]morpholine-4-carboxylate 13 (183 mg, 0.5370 mmol) in THF (4 mL) and the resulting solution stirred at rt for 30 min and then heated at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica, using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-50% EtOAc, 8 g column) Product began to elute at 33% EtOAc. Product fractions were combined and concentrated in vacuo to leave the product as a cream coloured solid (144 mg, 40% yield); 1.20 (6H, d), 1.30 (18H, s), 1.42 (9H, s), 3.07 (1H, m), 3.50-3.60 (3H, m), 3.73-3.85 (3H, m), 4.32 (1H, m), 5.06 (1H, s), 7.53 (2H, m), 8.07 (5H, m), 8.64 (2H, m) and 9.51 (1H, s) ppm
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:39][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[N:6]=1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(C(=O)O)c1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic acid (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and Et3N (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated to 100° C. for 1 h. To the mixture was added 8 M NaOH aqueous solution (4.3 mL) at 0° C. The mixture was stirred at room temperature for 1 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (704 mg, 65% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 173 (3H, s), 6.21 (2H, s), 7.85 (1H, d, J=9.4 Hz), 7.90 (1H, d, J=6.4 Hz), 8.33 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:22][O:21][N:20]([CH3:19])[C:15]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:14]1)=[O:17]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (2.30 g, 9.78 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.14 g, 11.73 mmol) in THF (45 mL) was added EDCl (2.06 g, 10.76 mmol), HOBt (1.45 g, 10.76 mmol), N,N-diisopropylethylamine (5.11 mL, 29.33 mmol). The reaction was stirred at rt for 16 h. The mixture was partitioned between ethyl acetate (75 mL) and H2O (75 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was filtered through a plug of silica gel, eluting with 3:1 ethyl acetate/hexanes to afford 1.66 g (61%) of the desired product after concentration of the filtrate. ES-MS m/z 279.03 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>>[C:1]([CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24])([C:4]([C:7]([C:10]([C:13]([C:16]([F:19])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
By causing 23 g. of C6F13I and 5 g. of ethyl acrylate to react under the conditions of Examples 3 to 7, there was obtained C6F13C2H4COOC2H5 and a dimer of the formula: ##STR6##
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OO.C(OCC)(=[O:43])C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2=[O:43])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CN(CCCN1C(=O)CSC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)CS(=O)C1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)-ethyl]amino]propyl]-1,3-thiazolidin-4-one (0.30 g) obtained in Example 26-A or 26-B in acetic acid (5 ml) was added 35% aqueous solution of hydrogen peroxide (0.20 g), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was added to a mixture of ethyl acetate and a 5% aqueous solution of sodium carbonate and stirred. The organic layer was separated, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 0.12 g (39%) of the title compound as a colorless oil. MS (m/z): 558 (M+) NMR (CDCl3) (200 MHz) δ: 1.41 (18H, s), 1.4-2.0 (2H, m), 2.28 (3H, s), 2.3-2.7 (2H, m), 2.72 (2H, t, J=5.7 Hz), 2.9-3.2 (1H, m), 3.37 and 3.69 (2H, ABq, J=16 Hz), 3.8-4.2 (3H, m), 5.40 (1H, s), 5.61 (1H, s), 5.87 (2H, s), 6.1-6.8 (3H, m), 6.94 (2H, s)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](=[S:13])[NH2:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:17][C:16]1[N:12]=[C:11]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:5])[CH3:6])[CH3:10])[S:13][CH:15]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=S
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: Cc1csc(C(C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of BOC-alanine-thioamide (1.39 g, 6.81 mmoles), chloroacetone (0.65 mL, 8.18 mmoles) and calcium carbonate (1.0 g, 10.22 mmoles) were refluxed in ethanol (25 mL) for 4 h. The reaction was cooled to room temperature and quenched with 2OmL of saturated aq. NaHCO3 solution. Ethanol was evaporated under reduced pressure and extracted with ethyl acetate (2×30 mL). The combined organic layers was dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel (20% ethyl acetate/80% hexane) to yield 48% of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[CH2:25])[C:21]3[C:20](=[O:26])[N:19]([CH3:27])[C:18](=[O:28])[N:17]([CH3:29])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:23]([N:22]1[C:21]2[C:20](=[O:26])[N:19]([CH3:27])[C:18](=[O:28])[N:17]([CH3:29])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:24]=[CH2:25]
Reactant: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1c(N2CCNCC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
A mixture of 4-(7-allyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (1.5 g), trifluoroacetic acid (3 ml), and dichloromethane (10 ml) was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Water (10 ml) and 5 M potassium carbonate aqueous solution (5 ml) were added to the residue, extracted with dichloromethane, then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 750 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.CC(N(C)C)=O.[NH:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:25]=[CH:24]1>>[CH:11]1([CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH:29]=[CH:30][C:31]4=[N:23][CH:24]=[N:25][C:26]4=[CH:27]3)=[CH:4][CH:5]=2)=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1cc2[nH]cnc2cn1
Reactant: O=C(CC1CCCC1)c1ccc(CCl)cc1
Solvent: CC(=O)N(C)C
Product: O=C(CC1CCCC1)c1ccc(Cn2ccc3ncnc-3c2)cc1
Temperature: 115 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
The product of Example G (270 mg, 0.0011 moles) was dissolved in 5 mls of dimethylacetamide containing 135 mg (0.0011 moles) of 1H-imidazo[4,5-c]pyridine and stirred under nitrogen at 80° C. for 24 hours and at 115° C. for an additional 6 hours. The reaction appeared to be complete by TLC. After cooling, the solvent was removed by vacuum distillation. Chromatography of the crude product (twice) on silica gel using CH3OH/CH2Cl2 /NH4OH (5/95/1) as the eluent gave 200 mg (57%) of the title compound as a monohydrate m.p.=153°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([C:24](OCC)=[O:25])[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].B.CSC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][OH:25])[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:32])[F:31]
Reactant: CCOC(=O)c1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of ethyl 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-4-oxo-1,4-dihydro-5-pyrimidinecarboxylate (2.36 g, 4.87 mmol) in dry THF (20 mL) was added borane-methyl sulfide complex (2.0M in toluene) (7.30 mL, 14.60 mmol) dropwise under argon at 0° C. The mixture was stirred at 0° C. for 0.5 h, and warmed to room temperature for 1 h, then quenched with acetone. Purification via reverse phase flash chromatography then afforded the title compound (921 mg, 2.080 mmol, 42.7% yield). LCMS: rt=3.28 min, [M+H]=443
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.[CH:25]1([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.[NH2:34][C:35]1[N:36]=[CH:37][N:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:39]=1[C:40]([NH2:42])=[O:41]>CN(C)C=O>[CH2:43]([N:38]1[C:39]([C:40]([NH2:42])=[O:41])=[C:35]([NH:34][C:31](=[O:33])[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[N:36]=[CH:37]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(O)CC1CCCC1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CC2CCCC2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 54.2 %

Procedure:
4.14 ml (20 mmol) of diphenyl chlorophosphate and 2.8 ml (20 mmol) of triethylamine were added to a solution of 2.5 ml (20 mmol) of cyclopentylacetic acid in 20 ml of N,N-dimethylformamide while cooling with ice. The solution was stirred for one hour while cooling with ice. A solution of 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 in 200 ml of N,N-dimethylformamide was added to the reaction solution, followed by stirring overnight. After concentration under vacuum, 5% aqueous solution of sodium hydrogencarbonate was added to obtain a solid precipitate. The precipitate was collected by filtration using a funnel equipped with a glass filter, washed with 5% aqueous solution of sodium hydrogencarbonate and distilled water, and dried under vacuum to obtain a crude product. This crude product was purified by suspension in hot methanol to obtain 1.77 g of 1-benzyl-4-cyclopentylacetylamino-5-imidazolecarboxamide (yield 54%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:33][CH2:32]3)[N:21]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]>>[C:1]([N:34]1[CH2:35][CH2:36][CH:31]([N:22]2[N:21]=[C:20]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH3:19])=[C:11]([O:10][CH2:8][CH3:9])[CH:12]=3)[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23]2=[O:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCN(C(C)=O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from acetic anhydride and starting compound A2 as described for compound 1. Crystallised from diethyl ether. M.p. 148-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=O)=[CH:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)=[CH:18]1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])(=O)C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.FC(S(O)(=O)=O)(F)F>>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:13]1[O:14][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=2)=[N:9][CH:12]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [I+2]c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ncc(-c3c(Cl)cccc3Cl)o2)cc1

Procedure:
4-Nitrobenzonitrile and 2,6-dichlorophenyl methyl ketone can be reacted with phenyliodine (III) diacetate and trifluoromethylsulfonic acid by the method of R. S. Varma, et al, J. Heterocyclic Chem., 1998, 35(6), 1533–1534 to give 5-(2,6-dichlorophenyl)-2-(4-nitrophenyl)-1,3-oxazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. Reaction of this aniline with 2,2-dichloroacetyl chloride and triethylamine can then give 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(1,3-oxazolyl)]phenyl]acetamide.
Reaction SMILES: Br[CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:6]=1.[C-]#N.[Na+].[CH3:34][N:35](C)C=O>O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([N:7]2[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:9][C:5]([CH2:4][CH:3]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH2:2][C:34]#[N:35])=[N:6]2)=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc(CC(CBr)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cc(CC(CC#N)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
To a screw-cap vial were added 3-(3-bromo-2-m-tolyl-propyl)-1,5-di-p-tolyl-1H-pyrazole (prepared by the method of Example 67; 300 mg, 0.65 mmol, 1.0 equiv), sodium cyanide (160 mg, 3.3 mmol, 5.0 equiv) and N,N-dimethylformamide (3.0 mL). The sealed mixture was then heated at 100° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with diethyl ether (3×10 mL). The combined extracts were washed with water (4×10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (25% ethyl acetate/hexanes) giving the desired nitrile (171 mg, 65%). MS (ESI): mass calculated for C28H27N3, 405.22; m/z found, 406.2 [M+H]+.
Reaction SMILES: ClCCCl.[CH:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1)=O.[Cl:29][C:30]1[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][CH2:5][C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH:33]=[CH:32][C:31]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
Solid NaBH(Oac)3 (113 mg, 0.54 mmol) was added to a DCE solution (4 mL) of methyl 2′-formyl-3′-methoxy-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (121 mg, 0.36 mmol) and 2,4′-dichloro-[1,1′-biphenyl]-4-amine (93 mg, 0.39 mmol), and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and water, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][NH:31][C@H:26]([CH3:25])[CH2:27]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@@H]1CNCCN1
Solvent: CCCCO
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 112 mg of R-(+)-2-methylpiperizine in 1 mL of BuOH. Purified by reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH2:43])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Si:14]([O:31][C@H:32]([CH3:44])[C@H:33]([NH:43][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Cesium carbonate (242 mg) and ethyl bromoacetate (103 μl) are added to a solution of (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine obtained in Example 26 (274 mg) in DMF (5 ml), and the reaction solution was stirred at room temperature for 11 hours. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with half-saturated brine and brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:diethyl ether=19:1) to obtain 190 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (1.92 g) and methanesulfonyl chloride (955 μl) in dichloromethane (30 ml) was added dropwise triethylamine (1.99 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid and brine and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methylpyrrolidine (2.49 g).