Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[CH:20][CH:19]=1)=[O:17]>ClCCl>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][S:6][C:3]2[N:4]=[CH:5][NH:1][N:2]=2)=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccc(OCc2c(F)cccc2F)cc1
Reactant: Sc1nc[nH]n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CSc1nc[nH]n1)c1ccc(OCc2c(F)cccc2F)cc1
Reaction time: 0.83 h

Procedure:
To a solution of 1H-1,2,4-Triazole-3-thiol (0.250 g, 2.4 mmol) and triethylamine (2.50 g, 2.4 mmol) in dry dichloromethane (20 ml) was added 2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B, 0.851 g, 2.4 mmol) in dry dichloromethane (5 ml) at room temperature. The reaction mixture was stirred for 50 minutes and then concentrated in vacuo. The crude residue was taken in EtOAc and washed with 0.1M HCl, and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel column (chloroform:methanol, 9:1) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(F)cccc4F)cc3)c2cc1OC
Yield: 74.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, 2,6-difluorophenyl isocyanate (104 mg) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 57 mg of the title compound (yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][S:4][C:3]=1[C:14]([O-:16])=O.[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH2:34])=[CH:21][CH:20]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH:34][C:14]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:2]=2[Cl:1])=[O:16])=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C([O-])c1scc(CN2CCOCC2)c1Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CN2CCOCC2)c1Cl
Reaction time: 0.75 h
Yield: 16 %

Procedure:
To a mixture of sodium 3-chloro4-(morpholin-4-yl)methyl-2-thiophene carboxylate (1.0 g, 3.9 mmol) and N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (0.88 g, 3.1 mmol) in pyridine (20 mL) at −10° C. was added POCl3 (0.40 mL, 4.3 mmol). After 45 minutes, the mixture was poured onto ice-water and the resulting solid collected by filtration. Crystallization from 1-butanol afforded 0.26 g (13% yield) of N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (d, 2), 7.4 (d, 3), 3.6 (s, 2), 3.3 (br, 4), 2.4 (br, 4) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 41.5 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), morpholine (156 μl, 1.79 mmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The mixture is dissolved in ethyl acetate and washed with sodium bicarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography on a 20 g silica column using ethyl acetate/methanol 10% as eluent affording 1-methyl-4-(morpholine-4-carbonyl)-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (40 mg, 41.5%) as a white solid. mp.: 218-220° C. MS: m/z=433.3 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[C:27]([O:31][C:32]([N:34]([CH2:36][C:37]([OH:39])=[O:38])[CH3:35])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(O)(C(F)(F)F)=O>C(Cl)Cl.CC(=O)OCC>[C:27]([O:31][C:32](=[O:33])[N:34]([CH2:36][C:37](=[O:38])[NH:25][CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]([CH3:26])[CH:9]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1)[CH3:35])([CH3:30])([CH3:28])[CH3:29].[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][C:37](=[O:39])[CH2:36][NH:34][CH3:35])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CN(C)C(=O)OC(C)(C)C)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CNC)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
[(2-{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylcarbamoyl)-methyl]-methyl-carbamic acid tert-butyl ester is prepared in analogy to Example 163 by coupling 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine (20 mg, 54 μmol) with (tert-butoxycarbonyl-methyl-amino)-acetic acid (15 mg, 81 μmol); LC-MS: tR=0.84 min; [M+1]+=542.20; 1H NMR (CDCl3): δ1.16 (m, 6H), 1.44 (s, 9H), 2.27 (s, 3H), 2.88 (s, 3H), 2.90-2.99 (m, 2H), 3.61 (q, J=6.5 Hz, 2H), 3.75 (s br, 1H), 3.85 (s, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 8.10 (d, J=8.0 Hz, 2H). This material (18 mg, 30 μmol) is dissolved in DCM (2 mL) and TFA (50 μL) is added. The mixture is stirred at rt for 18 h before it is diluted with EA and washed with sat. aq. NaHCO3 solution. The organic extract is dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC and on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol to give the title compound (12 mg) as a colourless solid; LC-MS: tR=0.64 min; [M+1]+=442.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3]1.C([O:24]CC)C>>[C:19]([C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N+:9]=3[O-:24])[C:5]=2[CH:15]=1)#[N:20]
Reactant: Cc1ccnc(C2CC(C)(C)Oc3ccc(C#N)cc32)c1
Reactant: CCOCC
Product: Cc1cc[n+]([O-])c(C2CC(C)(C)Oc3ccc(C#N)cc32)c1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(4-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-4-methylpyridine N-oxide of melting point 156°-159° C. (from diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[N:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[F:26][CH2:27][CH2:28]N(C1C=CC(C2OC3C=C(OC)C=CC=3N=2)=CN=1)C(=O)OC(C)(C)C>>[F:26][CH2:27][CH2:28][N:16]([C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:25]=[CH:24][C:6]=3[N:7]=2)=[CH:11][N:12]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc2nc(-c3cnc(NC(=O)OC(C)(C)C)nc3)oc2c1
Reactant: COc1ccc2nc(-c3ccc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Product: COc1ccc2nc(-c3cnc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1

Procedure:
The title intermediate was synthesized from tert-butyl [5-(6-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2-yl]carbamate according to the procedure described for tert-butyl (2-fluoroethyl)[5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate to give 128 mg. 1H NMR 400 MHz, Chloroform-d) δ ppm 9.33 (s, 2H) 7.66 (d, 1H) 7.14 (d, 1H) 7.00 (dd, 1H) 4.79 (t, 1H) 4.67 (t, 1H) 4.42 (t, 1H) 4.37 (t, 1H) 3.90 (s, 3 H) 1.57 (s, 9H) MS m/z 389 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: O=c1nc(Cl)cc2n1CCN2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCn2c1cc(Cl)nc2=O
Yield: 53.5 %

Procedure:
A mixture of 7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (700 mg, 4.08 mol), 2-iodopropane (1.04 g, 6.12 mmol) and Cs2CO3 (2.66 g, 8.16 mmol) in acetonitrile (15 mL) was refluxed for 3 h, filtered and concentrated to remove solvent to get crude product (700 mg) without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6]2[CH:8]=[C:9]3[O:14][CH2:13][O:12][C:10]3=[CH:11][C:5]=2[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)(O)[O:3]1.C[NH:26][NH:27][C:28]([NH2:30])=[O:29].[CH2:31](O)C>Cl>[OH:3][C@@H:2]([CH3:1])[CH2:7][C:6]1[C:5]([C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:26][NH:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:11][C:10]2[O:12][CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: CCO
Reactant: C[C@H]1Cc2cc3c(cc2C(O)(c2ccc([N+](=O)[O-])cc2)O1)OCO3
Reactant: CNNC(N)=O
Agent: Cl
Product: CNC(=O)NN=C(c1ccc([N+](=O)[O-])cc1)c1cc2c(cc1C[C@H](C)O)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
In a nitrogen blanketed flask was dissolved 5.17 g (15.70 mmol) of the intermediate of Example 5 in 30 mL of ethanol. To this stirring solution was added 1.75 g (19.7 mmol) of methyl semicarbazide. The mixture was heated to reflux to dissolve the solids and then 5 drops of conc. HCl was added. Over 1 h at reflux, yellow solids precipitated out of solution. After 1 h, HPLC analysis indicated complete reaction, 38.2% and 55.4% of 2 product isomers and no remaining starting material. The yellow slurry was slowly cooled to ambient temperature to stir for 1 h and then stirred for 30 min. in an ice water bath. The mixture was filtered through coarse glass. The solids were washed with ethanol and dried under vacuum at 50° C. to afford 5.08 g (81.2%) of the title compound as a yellow solid, mp=238° C. HPLC assay indicated two isomers, 46.2%+53.1%. MS (FD+)=400. IR: 1692, 1345 cm-1. 1H NMR (DMSO): δ0.90 (t, 3, J=6); 2.22 (m, 2); 2.72 (d, 3, J=5); 3.63 (m, 1); 4.42 (d, 1/2, J=6); 4.58 (d, 1/2, J =6); 6.10 (s,2); 6.69 (d, 1, J=8); 7.05 (d, 1, J=10); 7.32 (br. t, 1, J=4); 7.85 (d, 2, J=9); 8.18 (d, 2, J=9); 8.62 (d, 1, J=8). 13C NMR (DMSO): δ24.27, 24.51, 27.18, 43.30, 43.73, 67.09, 67.47, 102.45, 108.95, 109.19, 111.50, 111.54, 112.41, 112.45, 124.40, 124.48, 124.69, 128.35, 133.47, 133.69, 144.55, 144.61, 144.68, 144.79, 147.71, 147.76, 148.06, 149.39, 149.54, 156.11, 156.23. Anal. Calcd for: C19H20N4O6 : C, 57.00; H, 5.03; N, 13.99; Found: C, 57.72; H, 5.01; N, 13.99.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33].O.Cl>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([O:27][C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:33])[C:23]([O:25][CH3:26])=[O:24])=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](O)CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of methyl (R)-(-)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxy-pentanoate (3.15 g) in pyridine (50 ml) was added 4-nitrophenyl chloroformate (2.3 g), in limited amounts, at room temperature. The mixture was stirred for one hour. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained methyl (R)-(+)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-(4-nitrophenoxycarbonyloxy)pentanoate (4.3 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccs2)c1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (87.3 mg, 0.213 mmol), prepared in Step A of Example 13i, triethylamine (47.3 mg, 0.234 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol). The reaction was stirred for 24 h and additional triethylamine (0.234 mmol) and thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol) were added. The reaction was stirred for an additional 24 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4) filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (63 mg). MS 556 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[C:20](=S)=[S:21]>O1CCCC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][N:11]=[C:20]=[S:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reactant: S=C=S
Solvent: C1CCOC1
Product: S=C=NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Temperature: -10 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of N,N-dicyclohexylcarbodiimide (2.08 g, 10 mmol) in dry tetrahydrofuran (20 ml) was slowly added at -10° C. a solution of N-(4-bromobenzyl)-N-(pyridin-2-yl)-propane-1,3-diamine (3.20 g, 10 mmol) and carbondisulfide (4.3 ml, 70 mmol) in dry tetrahydrofuran (20 ml) under an atmosphere of nitrogen. The mixture was stirred at -10° C. for 3 h and for 48 h at room temperature. The reaction mixture was filtered and the solvent evaporated in vacuo. The residue (5.29 g) was extracted with diethyl ether (3×20 ml) and the combined organic extracts were evaporated in vacuo affording 3.2 g (88%) of N-(4-bromobenzyl)-N-(3-isothiocyanatopropyl)-N-(pyridin-2-yl)amine as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:24][CH2:23][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)([O-:10])=[O:9]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
A solution of 2-fluoronitrobenzene (0.13 mL, 1.3 mmol) and 1-(4-pyridyl)piperidine-4-methylamine (242 mg, 1.27 mmol) in DMF (5 mL) was treated with potassium carbonate (175 mg, 1.3 mmol). After 16 h, the mixture was diluted with EtOAc, the organic layer was washed with water (3×), brine, dried with K2CO3, and concentrated. The residue was dissolved in 5% HOAc in MeOH and loaded onto an SCX ion exchange column. Elution with MeOH followed by 2 M NH3 in MeOH yielded 200 mg of the title compound; which was used without further purification.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(B(O)O)C=CC=CC=1>>[C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2ccc(-c3cc(OC(=O)OC(C)(C)C)n(-c4ccccn4)n3)cc2)cc1
Yield: 98 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of each of 3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (24) prepared in Example B-5 and 4-methoxyphenylboronic acid (manufactured by Aldrich) was used in place of Compound 21 prepared in Example B-2 and phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O>[Si:28]([O:8][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:3]([CH3:18])[C:2]=1[Cl:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)c(Cl)c(C)c1-c1cccc(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
To a solution of 3′-chloro-4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.41 g, 5.41 mmol) and imidazole (1.10 g, 16.2 mmol) in N,N-dimethylformamide (10 mL), was added tert-butyldimethylchlorosilane (1.22 g, 8.09 mmol) at room temperature, and the mixture was stirred at room temperature for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (1.78 g, yield 88%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:13])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(CC1CCN(CC2CC2)CC1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(CC1CCN(CC2CC2)CC1)(c1ccccc1)c1ccc(F)cc1

Procedure:
1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine (Example 429, 1.0 g, 3.6 mmol) was mixed with dry tetrahydrofuran (10 mL). A solution of phenyl magnesium bromide in ether (3.0 M, 3 mL, 9 mmol) was added with stirring. The reaction mixture was stirred for 24 h; poured onto a saturated NH4Cl solution and-extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo. Trituration with ether-hexanes (1:9) and filtration afforded the title compound, a solid, which was dried in vacuo (0.9 g): mp 115°-116° C.; Anal.: Calcd for C23H28FNO: C, 77.36, H, 7.90, N, 3.92, F, 5.32; Found: C, 77.47, 77.41, H, 8.00, 7.92, N, 3.42, 3.52, F, 5.09.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([NH2:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:33][CH:32]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:36]=1)[C:28](=[O:29])[NH:17][C@H:11]([C:10](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)CC(N)C(=O)Nc1ccc(I)cc1F
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of 2-amino-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (364 mg, 1 mmol), (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (1 M in DMF, 1.1 mL, 1.1 mmol), 1-Hydroxybenzotriazole (168 mg, 1.1 mmol) and diisopropylethyl amine (0.53 mL, 3.3 mmol) in N,N-dimethylformamide (5 mL) was added dropwise the solution of O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexaflurorophosphate (474 mg, 1.1 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and the mixture washed with water and brine. The organic layers were successively washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered, and concentrated to give {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-3,3-dimethyl-butylcarbamoyl]-methyl}carbamic acid tert-butyl ester (652 mg, 91%) as a white solid.