Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4].O[Li].O>CO.O>[CH3:1][O:2][C:3]([NH:5][C:6]1[C:14]([CH2:15]/[CH:16]=[C:17](\[CH3:24])/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([O:25][CH3:26])[C:12]([CH3:27])=[C:11]2[C:7]=1[C:8](=[O:28])[O:9][CH2:10]2)=[O:4]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COC(=O)Nc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Yield: 62.2 %

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35 g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeOH-H2O was heated at reflux for 4 hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexane:ethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5](C)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)cc1I
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)c1

Procedure:
To a solution of 2-chloro-4-iodo-5-methylpyridine (2.00 mmol) in 8 mL toluene is added 1-amino-2-(isopropylsulphonyl)benzene (2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and cesium carbonate (2.20 mmol). The mixture is purged with nitrogen, and can be subjected to microwaves at 100° C. until formation of 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine. The reaction mixture can then be concentrated and purified by silica gel chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][O:9][C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][O:9][C:10]1[C:15]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCOc1nc(Cl)ncc1Br
Reactant: OB(O)c1cccs1
Product: CC(C)(C)OC(=O)CCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedure 11a with the use of 3-(5-Bromo-2-chloro-pyrimidin-4-yloxy)-propionic acid tert-butyl ester and 2-thienyl-boronic-acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.ClCCCC.C1CCCCC1>CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCl
Solvent: CCOCC
Solvent: C1CCCCC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.6 %

Procedure:
A mixture of 100.0 g of methyl 2-methyl-3-nitrobenzoate, 100.0 g of N-bromosuccinimide, 3.0 g of dibenzoyl peroxide and 1000 ml of carbon tetrachloride was refluxed for 24 hours. The reaction mixture was cooled, 3.0 g of dibenzoyl peroxide added, and refluxing continued an additional 24 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude reaction product was dissolved in ether and the organic solution washed sequentially with saturated sodium sulfite (500 ml), water (2×500 ml), 2.5% sodium hydroxide (500 ml), water (2×500 ml) and saturated brine (500 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo giving a pale yellow oily solid. Recrystalllization from 350 ml of 1-chlorobutane/cyclohexane (2:1) gave 73.9 g of methyl 2-bromomethyl-3-nitrobenzoate, m.p. 67°-70°.
Reaction SMILES: [C:1]([C:3]1([CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH2:7][CH2:6][NH:5][C:4]1=[O:8])#[N:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:21]1[N:26]=[C:25]([N:5]2[CH2:6][CH2:7][C:3]([CH:9]3[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]3)([C:1]#[N:2])[C:4]2=[O:8])[CH:24]=[CH:23][N:22]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(C2(C#N)CCNC2=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Cl)n3)C2=O)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a mixture of tert-butyl 3-(3-cyano-2-oxopyrrolidin-3-yl)azetidine-1-carboxylate (1.3 g) obtained in Step C of Example 309, 2,4-dichloropyrimidine (750 mg), cesium carbonate (3.3 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (180 mg) in tetrahydrofuran (12 mL) was added tris(dibenzylideneacetone)dipalladium(0) (93 mg), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (850 mg)
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Ni].N.CO>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:40])[C:16]2[CH:17]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=3)[CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(CN)cc3)cc(Oc3ccc(CN)cc3)c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
0.05 g of Raney nickel was added to 0.3 g (0.54 mmol) of {4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester stirred with 50 ml of 10% NH3-methanol. The reaction mixture was stirred overnight on hydrogen gas pressure (50 psi) at 50° C. The reaction mixture was filtered through celite and concentrated to afford 0.25 g of the required product which was used for the next step without further purification. Percentage purity (LCMS): 70.8%, (M+1)=560.2+1
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].CO.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[OH-].[Na+]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCOCC.CO>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:16][CH:15]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of α-bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p-chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100° bath and stirred at 100° for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous phase is acidified to pH 4 and extracted with ether. The ether extracts are combined and washed with brine, dried over sodium sulfate and stripped to yield N-(p-chlorophenyl)valine.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[C:5]1([O:12][CH3:13])[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7].[OH-].[Na+]>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:12][CH3:13]
Reactant: COc1ccccc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1OC(F)F
Yield: 71.9 %

Procedure:
About 58 g of chlorodifluoromethane are passed into a solution of 55.5 g of guaiacol and 130 g of sodium hydroxide in 300 ml of water and 300 ml of dioxane at 60° C. The mixture is filtered at 10° C. and the organic layer is separated off, dried with anhydrous potassium carbonate and distilled. 56 g (73%) of 1-difluoromethoxy-2-methoxybenzene of boiling point 75°-76° C./0.9 kPa are obtained.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3].C1C(=O)NC(=O)N(C2OC(COP(OP(OC3OC(C(O)=O)C(O)C(O)C3O)(O)=O)(O)=O)C(O)C2O)C=1.C(O)C(N)(CO)CO.Cl.C(O)O.[Na+].[Cl-].CC(N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O)=O>O.C(O)C>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: CC(=O)N[C@@H]1[C@@H](O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H](OS(=O)(=O)O)O[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The enzyme of the present invention (2 μg), hexasaccharide of shark cartilage chondroitin sulfate C, purified by degrading with testicular hyaluronidase, as the acceptor (70 pmol) and UDP-GalNAc (3 nmol), UDP-GlcUA (3 nmol) and UDP-[3H]GalNAc (0.1 nmol, 0.1 μCi) as the donors were added to 50 mM Tris-HCl (pH 7.2) containing 20 mM MnCl2, 0.1 M (NH4)2SO4 and 1 Methylene glycol, and the total volume was adjusted to 50 μl, and then the reaction was carried out at 30° C. for 30 minutes and the enzyme was heat-inactivated. To the reaction solution, 3 volumes of 95% ethanol containing 1.3% potassium acetate was added, and the sample was centrifuged at 10,000×g for 20 minutes. The precipitate was dissolved in 50 μl of distilled water and applied to a Superdex Peptide column (300×φ10 mm: Amersham Biosciences, chromatography conditions; buffer: 0.2 M NaCl, flow rate: 0.5 ml/min), and the eluate was fractionated at 0.5 ml and the radioactivity (count of [3H]) of each fraction was measured using a scintillation counter. Chondroitin synthesizing activity was determined by calculating the amount of radioactivity incorporated into fractions of higher molecular weight than the acceptor substrate. The results are shown in FIG. 3. In FIG. 3, the closed squares indicate radioactivity when hexasaccharide of chondroitin sulfate C was used as the acceptor, open triangles indicate radioactivity when the enzyme reaction product was treated with chondroitinase ABC and closed circles indicates control (wherein heat-inactivated enzyme of the present invention was used).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: NC(=O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(C(N)=O)c1
Yield: 91.9 %

Procedure:
Using Microwave Irradiation. The general procedure described in Example 3 was used with 3-chlorobenzamide (156 mg, 1.00 mmol), 2,6-dimethylphenylboronic acid (180 mg, 1.20 mmol), Pd(OAc)2 (4.5 mg, 0.020 mmol, 2 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (20.0 mg, 0.0391 mmol, 4 mol %), K2CO3 (345 mg, 2.50 mmol), water (3.0 mL), 10 min, 150° C. (microwave irradiation with cooling). The product was isolated as a white solid (207 mg, 92%). Mp=123-125° C. 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.50 (t, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.4 Hz), 7.13 (d, 2H, J=7.2 Hz), 6.87 (br-s, 1H), 6.69 (br-s, 1H), 2.03 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 170.1, 141.6, 140.8, 135.9, 133.8, 132.8, 128.9, 128.1, 127.5, 126.0, 20.96. IR (neat, cm−1): 3347 (br), 3197 (br), 1657, 1602, 1578, 1379, 1102, 770, 737, 703. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71. Found: C, 79.98; H, 6.48.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1C

Procedure:
Step 4—Synthesis of compound vh: (S)-1-ethyl-3-(2-methyl-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.043 g, 0.10 mmol) and 2-Chloropyrimidine (0.0121 g, 0.106 mmol) were combined, nitrogen purged three times, added N,N-Dimethylformamide (1.50 mL, 19.4 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.7, 2H), 8.12-7.99 (m, 3H), 7.72 (s, 1H), 6.67 (dt, J=10.9, 5.0, 2H), 4.90 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.14 (dd, J=17.9, 5.1, 2H), 3.93-3.77 (m, 2H), 3.71 (dd, J=11.2, 2.5, 1H), 3.61 (d, J=12.1, 3H), 3.43 (dd, J=18.5, 7.5, 1H), 3.18-3.06 (m, 2H), 2.74 (s, 2H), 2.26 (s, 3H), 1.25 (d, J=6.6, 3H), 1.08 (t, J=7.2, 3H). LC/MS-m/z+489.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:26]4[CH2:27][O:24][CH2:25]4)[CH2:19][C@@H:18]3[CH3:23])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: O=C1COC1
Reactant: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A mixture of 117b (2.3 g, 6.8 mmol), oxetan-3-one (1.4 g, 20.0 mmol), NaBH3CN (620 mg, 10 mmol), and zinc chloride (1.36 g, 10 mmol) in methanol (20 mL) was stirred at 50° C. for 3 hours. The mixture was added to water (40 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane three times. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 117c (2.0 g, 75%). MS-ESI: [M+H]+ 391.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=1.C([Si](C)(C)[O:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[C:12]([CH3:22])=[C:13]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])[C:5]([CH3:23])=[CH:4][CH:3]=2)[CH2:32][CH2:31]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(Cl)ccc2C)c1C
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCC(O)CC3)ccc2C)c1C
Temperature: 120 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a solution of methyl 3-(6-chloro-3-methylpicolinamido)-2,4-dimethylbenzoate (0.50 g, 0.0015 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.90 g, 0.0045 mol) and Cs2CO3 (2.00 g, 0.006 mol) in toluene (6 ml) is added Pd2(dba)3 (0.14 g, 0.00015 mol) followed by BINAP (0.086 g, 0.00015 mol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 120° C. After 4 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrate is dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a white semi-solid (0.220 g, 29%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[N:7]1)([CH3:5])[CH2:3][OH:4]>C(O)C.[C].[Pd]>[NH2:11][C:9]1[CH:8]=[N:7][N:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])[CH:10]=1
Reactant: CC(C)(CO)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CO)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of the crude 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (36 g) obtained in Step G of Example 103 in ethanol (200 mL) was added 10% palladium-carbon (360 mg), and the mixture was stirred overnight at room temperature under hydrogen atmosphere (at normal pressure). The palladium-carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and the obtained solid was washed with diisopropyl ether to give the title compound (15 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:17]C3[CH2:13][CH:14]([CH2:16][CH:10](C3)[C:9]1=[O:18])[CH2:15]2.[OH-].[Na+]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[OH:7][C:5]12[CH2:6][CH:10]3[CH2:16][CH:14]([CH2:15][CH:8]([C:9]3=[O:18])[CH2:17]1)[CH2:13]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [Na+]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
Into a single neck 500 mL round bottom flask equipped with a magnetic stirrer and water bath, 75 parts of acetic acid containing 5 parts acetic anhydride was added. Twenty five parts of chromium trioxide was added in portions in 40 minutes while the temperature was maintained at 15-20° C. with water bath. Five parts of Adamantan-2-one was added in portions over a period of 15 minutes. Stirring was continued for one hour. The viscous reaction mixture was poured into cold 250 mL of aqueous 20% sodium hydroxide solution. The aqueous layer was extracted with 3×250 mL of ethyl acetate and washed with 2×250 mL of water and dried over sodium sulfate. Solvent was evaporated under reduced pressure and chromatographed on silica gel column using 75% ethyl acetate/hexane. The desired fractions were collected and solvent was evaporated to give a solid, yield 2.6 parts, single spot on silica gel TLC plate. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:3]([NH2:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](=N)OCC)=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]2[NH:1][CH:2]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH:3]([C:4]3[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=3)[N:11]=2)=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(C(N)C(N)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C2NC(c3ccc(Cl)cc3)=NC2c2ccc(Cl)cc2)cc1
Yield: 63.5 %

Procedure:
A solution of 4-[1,2-diamino-2-(4-chloro-phenyl)-ethyl]-benzonitrile (81 mg, 0.298 mmol) and ethyl 4-chloro-benzimidate hydrochloride (55 mg, 0.249 mmol) in ethanol (5 mL) was heated at 72° C. for 5 h. The solvent was removed, and the residue was taken in methylene chloride (10 mL). The reaction mixture was washed with 1 N sodium hydroxide solution (1 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0.5% methanol in methylene chloride yielded 4-[2,5-bis-(4-chloro-phenyl)-4,5-dihydro-3H-imidazol-4-yl]-benzonitrile (62 mg, 76%). HR-MS (EI, m/z) calculated for C22H15N3Cl2 (M+) 391.0643, observed 391.0648.