Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:3]=1[O:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=[C:7]([CH3:18])[N:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]([NH:12][C:9]1[CH:8]=[C:7]([CH3:18])[N:6]=[C:5]([O:4][C:3]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=2[CH3:1])[C:10]=1[NH:11][C:25](=[O:27])[CH3:26])[CH2:16][CH3:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine (250 mg, 0.763 mmol), acetic anhydride (72 mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) in 5 ml of methylene chloride was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 310 mg of the crude material. The crude material was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 250 mg (89% yield) of N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide as tan solid, mp 154–156° C. 1H NMR(CDCl3) δ 6.97(0.64H), 6.86(s,2H), 6.26(0.36H), 6.14(0.64H), 6.12(s,0.36H), 4.80(d,0.64H), 4.40(d,0.36H), 3.2–3.4(m,1H), 2.29(s,3H), 2.26(s,1.9H), 2.17(s,1.1H), 2.16(s,1.9H), 2.06(s,6H), 1.99(s,1.1H), 1.4–1.75(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:11]1(C(C2C(CCC3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(B(O)O)C=CC=CC=1.N1C=CC=CC=1>CC(N(C)C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (14.4 g) synthesized in Example 1, (3) was dissolved in dimethylacetamide (200 mL), phenylboronic acid (25.0 g), copper acetate (36.4 g) and pyridine (32 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1, volume ratio) to give the title object compound (11.4 g, 53%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[N:5]=[C:4]([NH:12][C:13]2[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=C(S)[CH:26]=2)[N:21]=1>C(O)(C)(C)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:11]([S:8][C:6]3[N:5]=[C:4]([NH:12][C:13]4[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=4)[CH:3]=[C:2]([Cl:1])[N:7]=3)[CH:26]=2)[N:21]=1
Reactant: Cc1ccc2cc(S)ccc2n1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc4nc(C)ccc4c3)n2)[nH]n1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (2.02 g, 7.03 mmol) in tert-butanol (20 ml) was added 2-methylquinoline-6-thiol (1.23 g, 7.03 mmol). The mixture was heated to 70° C. for 4 hours, then cooled to ambient and diluted with ethyl acetate/saturated aqueous potassium carbonate. The mixture was filtered to remove unreacted starting material and the organic layer removed form the filtrate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 90 to 100% ethyl acetate/petrol. The title compound was further purified by trituration with dichloromethane. This gave the product as a white solid (514 mg, 19%); MS ES+383.25, ES−381.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]2([OH:27])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:5][CH:4]=1.C[O:29][C:30](=[O:53])[C@H:31]([C@@H:50]([CH3:52])O)[NH:32]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]2([O:27][C@H:50]([CH3:52])[C@@H:31]([C:30]([OH:53])=[O:29])[NH2:32])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccsc2C2(O)c3ccccc3-c3ccccc32)cc1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccsc2C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-[3-(4-methoxyphenyl)thien-2-yl]-9H-fluoren-9-ol (Example 3w) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)c1

Procedure:
The title compound was prepared according to Procedure A from 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.84(1H,bs), 9.54(1H,s), 8.89(1H,s), 8.77(1H,dd), 8.25(1H,s), 8.11(2H,m), 7.87(1H,d), 7.69(1H,dd), 7.39(1H,m), 7.10 (3H,m), 5.73(2H,s); m/z (M+1+) 506.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:25]=1)[CH3:15]
Reactant: CCc1cccc(CC)c1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: CCc1cccc(CC)c1-c1cccc(COc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and (2′,6′-diethylbiphenyl-3-yl)methanol. a yellow oil (yield 80%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C@H:25]([CH3:28])[CH2:26][CH3:27])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=12)=O>ClCCCl>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:29][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=23)[C@H:25]([CH3:28])[CH2:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@@H](C)[C@@H](N)C(=O)NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (2R,3R)-2-amino-N-cyclopentyl-3-methylpentanamide (48.9 mg, 0.246 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. To this mixture was added 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol). The reaction mixture was stirred at room temperature for 1 h and was subsequently concentrated to afford the title compound as a crude intermediate. [M+H] calc'd for C26H38N4O5, 487; found, 487.7.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:15]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl[CH2:29]Cl>>[CH2:15]([N:22]([CH2:23][C:24]([O:26][CH2:27][CH3:29])=[O:25])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: ClCCl
Reactant: COC(=O)CNCc1ccccc1
Product: CCOC(=O)CN(Cc1ccccc1)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl 2-(benzylamino)acetate (6.0 g, 31.05 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (3.10 g, 90% yield) as a yellow oil. [M+H] calc'd for C, 18; H, 19; N, 3O, 6, 374; found, 374.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.[Cl:15][S:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([CH3:29])=[CH:22][N:23]=[CH:24]2)(=[O:18])=[O:17]>>[ClH:15].[ClH:15].[CH3:14][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([CH3:29])=[CH:22][N:23]=[CH:24]2)(=[O:17])=[O:18]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNCC3C)c12
Product: Cl
Yield: 78.2 %

Procedure:
Using 0.40 g of 1-(tert-butoxycarbonyl)-3-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.3 g of the objective compound (white crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[N:4]=1.[S:21](=[O:36])(=[O:35])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][O:33][CH3:34])[NH2:22].N12CCCN=C1CCCCC2>C(#N)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12](=[O:20])[NH:22][S:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:36])=[O:35])[N:6]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COCCOc1ccccc1OS(N)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
1.74 g (0.0063 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are dissolved in 80 ml of acetonitrile, and 1.48 g (0.006 mol) of 2-(2-methoxyethoxy)phenyl sulfamate are added at room temperature. 1.0 g (0.0066 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the reaction mixture is then stirred at room temperature for 18 hours, concentrated, diluted with H2O and acidified with 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.4 g (93% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[2-(2-methoxyethoxy)phenoxysulfonyl]urea of melting point 106°-108° C. are obtained.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:28])[F:27])[C@H:22]2[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:18]3)[CH:16]=1.[F:42][CH:43]([F:53])[C:44]1[N:45]=[CH:46][C:47]([C:50](O)=[O:51])=[N:48][CH:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:53][CH:43]([F:42])[C:44]1[N:45]=[CH:46][C:47]([C:50]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]34[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:27])[F:28])[C@H:22]3[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[N:18]4)[CH:16]=2)=[O:51])=[N:48][CH:49]=1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cnc(C(F)F)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (190 μL, 1.1 mmol) was added to a stirred mixture of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-3-ethyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (100 mg, 0.21 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (57 mg, 0.33 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (170 mg, 0.33 mmol) in dry DCM (1 mL) at RT under nitrogen. The reaction was stirred at this temperature for 16 h, and then partitioned between DCM and NaHCO3 (aq.). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (118 mg, cream foam). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.14 (t, J=7.07 Hz, 3H) 1.56 (s, 9H) 3.96-4.15 (m, 3H) 4.39 (d, J=9.60 Hz, 1H) 4.50 (dd, J=9.73, 2.91 Hz, 1H) 4.53-4.62 (m, 1H) 6.81 (t, J=54.60 Hz, 1H) 7.22 (dd, J=10.74, 8.97 Hz, 1H) 7.76 (dd, J=6.69, 2.65 Hz, 1H) 7.79-7.84 (m, 1H) 8.93 (s, 1H) 9.52 (s, 1H) 9.65 (s, 1H) 10.64 (s, 1H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[SH-:5].[C+4:6].[SH-:7].[SH-].[SH-].[OH-].[K+:11]>C(O)C>[N+:1]([CH:4]=[C:6]([S-:7])[S-:5])([O-:3])=[O:2].[K+:11].[K+:11]
Reactant: [C+4]
Reactant: C[N+](=O)[O-]
Reactant: [SH-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=C([S-])[S-]
Yield: 72 %

Procedure:
4 g (0.03 mol) of nitromethane and 6 ml (0.05 mol) of carbon bisulfide were placed in a 100 ml three-necked flask and 10 ml of ethanol was added as a solvent, and then the solution was stirred. To the resulting solution was added slowly and dropwise the solution of 8 g (0.14 mol) of potassium hydroxide in 40 ml of ethanol at room temperature over nearly 30 min. Since the reaction was exothermic, the rate of addition depended on the reaction temperature which was preferably between 30-35° C. After the addition was complete, the mixture was further stirred for 2 hours, filtered to obtain a crude product, which was a brown yellow powder in 72% yield.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][C:27]4[S:28][C:29]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=5[N:31]=4)[CH:21]=3)[O:16][C:15]=2[CH3:37])[CH:8]=1)(=[O:5])=[O:4].CO>O1CCCC1.ClCCl>[F:39][C:2]([F:1])([F:38])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@@H:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][C:27]4[S:28][C:29]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=5[N:31]=4)[CH:21]=3)[O:16][C@H:15]2[CH3:37])[CH:8]=1)(=[O:5])=[O:4]
Reactant: Cc1oc2ccc(OCc3nc4cc(F)ccc4s3)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1Oc2ccc(OCc3nc4cc(F)ccc4s3)cc2C(=O)[C@H]1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a stirred suspension of 2.59 g (4.48 mmole) product from Example 127 in 100 mL tetrahydrofuran was added dropwise 9 mL (9.40 mmole) UB(sec-butyl)3H (1M in THF, L-Selectride®) at -78° C. The mixture was stirred for 2 hours, then quenched with 5% ammonium chloride. The mixture was poured into water, acidified to ph 1-4 with 1N HCl, and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 2.5% methanol in dichloromethane afforded 1.4 g (54%) of the title product as a solid, mp 183°-185° C. Analysis calculated for C26H20N2S2O5F4 : C, 53.79; H, 3.47; N, 4.83. Found: C, 53.25; H, 3.23; N, 4.45.
Reaction SMILES: [N:1]([C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)=[O:5])=[C:2]=[O:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]([C:2](=[O:3])[NH:1][C:4](=[O:5])[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(C(=O)N=C=O)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)cc1OC
Yield: 81.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using methyl 4-(isocyanatocarbonyl)-2-methoxybenzoate (0.84 g, 3.61 mmol), tert-butyl 2-(2,6-dichlorophenyl)hydrazinecarboxylate (Intermediate-44, 1.0 g, 3.61 mmol) and DCM (20 mL) to afford 1.50 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 9H), 3.80 (s, 3H), 3.87 (s, 3H), 7.28-7.42 (m, 6H), 9.57 (s, 1H), 10.85 (s, 1H); MS (m/z): 511.73 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=3)[CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)nc1
Temperature: 120 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-1,2,3-triazole (268 mg, 1.1 mmol), methyl 6-chloronicotinate (190 mg, 1.1 mmol) and potassium carbonate (305 mg, 2.2 mmol) in DMF (6.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 2 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 100% ethyl acetate in heptane) afforded the title compound (120 mg, 29%) as an off white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[C@@H:25]1[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4].[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[C@H:25]1[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 2 h

Procedure:
Sodium borohydride (164 mg) was added to a stirred solution of 4-(2,4-bis{(tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (1.57 g) in ethanol (50 ml) at 0° C. After 2 hr at 0° C. and then 18 hr at room temperature, the reaction mixture was partitioned between 2M HCl (20 ml), water (40 ml) and ethyl acetate (50 ml) and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (40 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 3:17 v/v) to give the trans-title compound as a white solid (546 mg, 35%), and the cis-title compounds as a white solid (83 mg, 5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.ClCCl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Temperature: 25 °C

Procedure:
2-(3-cyanophenyl)-4-nitroanisole (8.0 g) from Example 111, part a, was dissolved in THF (200 mL) and purged with nitrogen. A 11.0M solution of borane in THF (135 mL) was then added, and the reaction was heated at reflux for 4 hours. When the reaction was complete, the mixture was cooled to room temperature and 4.0N HCl in dioxane (25 mL) was added dropwise over 30 minutes. Methanol (200 mL) was slowly added to the acidified solution, and the solvent was removed in vacuo. The resulting gum was redissolved in methanol (150 mL) and concentrated in vacuo to give a solid. The product was dissolved in dichloromethane (150 mL) and cooled to −20° C. to give 2-(3-aminomethylphenyl)-4-nitroanisole which was collected on a filter and dried in vacuo.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH:13]([OH:26])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].N>>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1CCC(CCC(O)CCC2CCC(C(=O)OC)CC2)CC1
Agent: N
Product: COC(=O)c1ccc(CCC(O)CCc2ccc(C(=O)OC)cc2)cc1

Procedure:
To a stainless steel autoclave was added 143.9 g (0.404 moles) 1,5.bis-(4,-carbomethoxyphenyl)-3-pentanol, 14.4 grams of 0.5% Pd on alumina, and 1,150 mL of cyclohexane. The autoclave was pressurized to 500 psi with hydrogen and then heated to 225° C. Upon reaching temperature, the pressure was adjusted to 1500 psi and these conditions were maintained for 6 hrs. The reaction was then cooled and vented. The product is soluble in the cyclohexane and is separated from the catalyst by filtration. The product is isolated by simple solvent removal in vacuo to give 139.6 grams of product (0.379 moles, 94%) consisting of all three diastereomeric cyclohexyl isomers of 1,5-bis-(4'-carbomethoxycyclohexyl)-3-pentanol. 300 MHz NMR (CDCl3) δ=0.93 (m,2H), 1.10-1.65 (m, 20H), 1.82 (d,1H), 1.96 (d,4H), 2.23 (m,1H), 2.52 (m,1H), 3.53 (s(br),1H), 3.67 (s,3H), 3.69 (s,3H). IR (neat): 1040, 1200, 1740, 3500 cm-1. GC.MS: (a) electron impact 50 eV: all three isomers with identical mass spectra: 368(<1%), 350, 337, 318, 290, 199, 170, 167, 138, 121, 108, 95, 94, 87, 81, 67. (NH3 chemical ionization): three peaks with M+=368.