Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[OH:23][CH2:24][CH:25]([NH2:28])[CH2:26][OH:27]>C(O)(C)C>[F:20][C:16]1[CH:15]=[C:14]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[C:2]([NH:28][CH:25]([CH2:26][OH:27])[CH2:24][OH:23])=[N:3][C:4]=2[C:21]#[N:22])[CH:19]=[CH:18][CH:17]=1
Reactant: NC(CO)CO
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Product: COc1ccc2c(NC(CO)CO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
A suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile (50 mg) and [2-hydroxy-1-(hydroxymethyl)ethyl]amine (146 mg) in 2 mL isopropanol was heated at 160 C in a microwave reactor for 8 h. The reaction was concentrated and purified by flash chromatography (0% to 5% MeOH in EtOAc) to give a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][CH:16]=[C:15]([Cl:23])[C:9]=1[C:10](OCC)=[O:11].O>O1CCCC1>[Cl:7][C:8]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][CH:16]=[C:15]([Cl:23])[C:9]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1c(Cl)ccc(OCOC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Cl)c(CO)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminum hydride (347 mg) in tetrahydrofuran was dropwise added a solution of ethyl 2,6-dichloro-3-(methoxymethoxy)benzoate (2.55 g) in tetrahydrofuran at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature and for 18 hour at ambient temperature. Water was dropwise added thereto at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane:ethyl acetate=6:1, V/V) to give 2,6-dichloro-3-(methoxymethoxy)benzyl alcohol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0 g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated over platinum dioxide (0.5 g) at room temperature. After 2/3 of the theoretical amount of hydrogen had been absorbed, the mixture was filtered and a fresh portion of platinum dioxide (0.5 g) was added. The hydrogenation was continued until the theoretical amount of hydrogen was absorbed. The reaction mixture was cooled in ice, dried over magnesium sulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and 4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature for 1.75 hours, the mixture was evaporated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed three times with saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature to give a solid which was collected by filtration and rinsed with isopropyl ether to give 2.2 g of title compound (31% yield). A 0.5 g portion was dissolved in hot isopropyl alcohol, filtered hot, isopropyl ether was added, and the mixture was cooled. The resulting suspension was filtered, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from isopropyl alcohol/water and dried under high vacuum at 60° C. to give 0.37 g of the title compound, mp 157°-158.5° C.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][N:8]2[CH2:38][CH2:37][C:11]3([N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][N:13]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[C:12]3=[O:36])[CH2:10][CH2:9]2)[CH2:5][O:4][C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]1=2.Cl>O1CCOCC1>[O:1]1[CH:6]([CH2:7][N:8]2[CH2:9][CH2:10][C:11]3([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:14][N:13]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[C:12]3=[O:36])[CH2:37][CH2:38]2)[CH2:5][O:4][C:3]2[CH:39]=[CH:40][CH:41]=[CH:42][C:2]1=2
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CC4COc5ccccc5O4)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CC4COc5ccccc5O4)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.17 g, 0.3 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.16 g, 99%); 1H NMR (DMSO-d6): δ 1.96 (d, 2H, J=14 Hz), 2.91-3.02 (m, 2H), 3.45-3.71 (m, 6H), 4.03-4.08 (m, 1H), 4.36 (d, 1H, J=9.2 Hz), 4.61-4.66 (m, 4H), 4.92 (br, 1H), 6.81-6.97 (m, 5H), 7.04 (d, 2H, J=8 Hz), 7.24 (t, 2H, J=8.4 Hz), 7.49-7.59 (m, 2H), 8.89 (d, 2H, J=8.8 Hz), 10.83 (br, 1H), 13.04 (br, 1H); MS for C30H31N3O5 m/z 513.99 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35]O.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:35][CH2:34][CH2:33][C:32]#[C:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCC#CCOCCCc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC#CCOCCCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Triphenylphosphine (2.89 g) in dichloromethane (20 ml) was added dropwise to a solution of 6-[3-(2-pyridinyl)propoxy]-4-hexyn-1-ol (2.33 g) and carbon tetrabromide (3.65 g) in dichloromethane (30 ml) cooled in an ice-bath. The reaction mixture was stirred at room temperature for 1 h, the solvent was evaporated and the residue was purified by FCC eluting with hexane-ether (1:1) to give the title compound as an orange oil (2.0 g), t.l.c. (hexane-ether 1:1) Rf 0.2.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2,4-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.059 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (3.61 g, 19.00 mmol) in anhydrous DMF (22 mL) at 0° C. was treated with thiomorpholine (2.254 g, 21.85 mmol) (TCI America) in 3 mL of DMF and potassium carbonate (3.28 g, 23.75 mmol). The suspension was slowly warmed to RT and stirred at RT for 2 h. The reaction was quenched with 30 mL of ice water, stirred at RT for 30 min, and the solid was collected by filtration, and rinsed with water followed by ether to give 4-((6-fluoropyridin-3-yl)methyl)thiomorpholine (3.33 g, 15.69 mmol, 83% yield) as an off-white crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 8.12 (s, 1H); 7.89 (td, J=8.20, 2.2 Hz, 1H); 7.14 (dd, J=8.10, 2.80 Hz, 1H); 3.53 (s, 2H); 2.63-2.59 (br. 8H). m/z (ESI, +ve ion) 213 (M+H)+.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[CH:32]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: O=C1OC(c2ccccc2)CCN1Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CCC(c2ccccc2)OC1=O

Procedure:
A mixture of 3-[2-iodo-5-(trifluoromethyl)benzyl]-6-phenyl-1,3-oxazinan-2-one (Intermediate 1, 51 mg, 0.11 mmol), 2-methoxy-5-isopropylphenyl boronic acid (86 mg, 0.11 mmol), potassium carbonate (76 mg, 0.55 mmol) and palladium acetate (7.4 mg, 0.011 mmol) in acetone (5 mL) and H2O (1 mL) was degassed and heated at reflux under N2 for 1 h. The reaction mixture was concentrated, diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-6-phenyl-1,3-oxazinan-2-one as a colorless solid. LCMS=484.2 (M+1)+. 1H NMR present (500 MHz, CDCl3): δ 7.69 (br d, J=3.5 Hz, 1H), 7.62 (br d, J=8.0 Hz, 1H), 7.41-7.30 (m, 5H), 7.28 (d, J=2.5 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 5.24 (dd, J=9.6, 2.5 Hz, 1H), 4.68 (d, J=3.2 Hz, 1H), 4.59 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.18-3.04 (m, 1H), 3.04-2.88 (m, 2H), 2.11 (m, 1H), 2.02 (m, 1H), 1.12 (d, J=7.1 Hz, 6H). The racemic material was separated by chiral HPLC using 15% IPA/heptane and an AD column.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH:21]=[CH2:22])[CH2:11][CH2:10][CH:9]([O:12][Si](C(C)(C)C)(C)C)[CH2:8][CH2:7]1)=[O:5])[CH3:2].OC1CCC(C)(C(OCC)=O)CC1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH:21]=[CH2:22])[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)OCC)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CCOC(=O)C1(C)CCC(O)CC1
Product: C=CCC1(C(=O)OCC)CCC(O)CC1

Procedure:
1-Allyl-4-hydroxy-cyclohexanecarboxylic acid ethyl ester was prepared by deprotecting Intermediate 98 using a method analogous to the method used to prepare Intermediate 67.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCCC1CCNCC1
Product: OCCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed as in Example 4 (step 4.1). Starting with 2 g (12.20 mmol) of 2-chloroquinoline and 1.58 g (12.20 mmol) of 2-(4-piperidyl)-ethanol, and after chromatography on silica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 2.36 g of pure product are obtained in the form of a pale yellow oil that crystallizes at room temperature.
Reaction SMILES: C(O[C@@H](C1C(C)=C([F:23])C2C(=CC=C(Cl)C=2)C=1O)C(OCC)=O)(C)(C)C.[C:26]([O:30][C@@H:31]([C:37]1[C:46]([CH3:47])=[CH:45][C:44]2[C:39](=[CH:40][C:41]([F:49])=[CH:42][C:43]=2[F:48])[C:38]=1[O:50]S(C(F)(F)F)(=O)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C@@H:31]([C:37]1[C:46]([CH3:47])=[C:45]([F:23])[C:44]2[C:39](=[CH:40][C:41]([F:49])=[CH:42][C:43]=2[F:48])[C:38]=1[OH:50])[C:32]([O:34][CH2:35][CH3:36])=[O:33])([CH3:27])([CH3:29])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(Cl)ccc2c1O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(F)cc(F)cc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2c(F)cc(F)cc2c1O

Procedure:
(S)-ethyl 2-tert-butoxy-2-(4,5,7-trifluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate was prepared in a similar way as (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate in Example 7 except (S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CO.C1COCC1>[NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Yield: 64 %

Procedure:
A mixture of 3-amino-5-chloro-2-nitrobenzoic acid (43.2 g) and HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium, commercially available) (76 g) in MeOH (81 mL), Et3N (83 mL) and THF (300 mL) was stirred at room temperature for 3 h. When TLC showed no starting material, the solvent was removed in-vacuo and the residue was then diluted with EtOAc (2 L). It was then washed with brine (1 L×3) and dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:8 to afford the desired product as a yellow solid (29.5 g, yield 64%). 1H NMR (300 MHz, CDCl3): δ ppm 3.90 (s, 3H, s), 5.85 (br s, 2H), 6.80 (d, 1H, J=2.4 Hz), 6.90 (d, 1H, J=2.4 Hz); LC-MS: m/e=231 [M+1]+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[CH:18]([O-])([O-])OCC>>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([CH:18]=[N:2][N:1]=3)[CH:5]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CCOC([O-])[O-]
Reactant: NNc1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Product: O=[N+]([O-])c1ccc(-c2ccc3nncn3c2)cc1

Procedure:
2-Hydrazino-5-(4-nitrophenyl)pyridine is treated with ethyl orthoformate to give the product of the Example.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1
Product: CSc1nc(Nc2ccccc2Cl)c(C=O)c(-c2ccccc2Cl)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chlorophenylboronic acid to give the title compound 4-(2-chloro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.58 (s, 3H), 7.01-7.59 (m, 7H), 8.61 (d, 1H, J=4.7 Hz), 9.65 (s, 1H), 11.48 (br s, 1H). LC MS (m/e)=390 (MH+).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])C1C=CC=CC=1.[ClH:33]>C(O)C.C(O)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23].[ClH:33]
Reactant: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reaction time: 24 h

Procedure:
Examples 11p and 11q, Step 9: To a solution of the isomeric mixture of 1-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol (166 mg, 0.38 mmoles) in 5 ml of ethanol and 1 ml of acetic acid was added about 150 mg of Pd(OH)2 on carbon (20%, wet, Aldrich), and the mixture was stirred under hydrogen (52 psi) for 24 hours. After removal of the catalyst by filtration. The solvents were evaporated off to give an oily residue. The residue was dissolved in methanol and 1 ml of 1N—HCl was added. It was evaporated and azeotroped with toluene twice to remove the excess acid and water, and dried under vacuum to give 1-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol as a bis-HCl salt.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:5](=[O:15])[C:4]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(OCC)(=O)C>[CH3:32][C:31]([NH:35][C:36]([N:16]([C:4]1[C:5](=[O:15])[O:6][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:3]=1[OH:2])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:37])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: O=c1oc(-c2ccccc2)cc(O)c1NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)N(Cc1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Reaction time: 2.5 h

Procedure:
To a suspension of 4-hydroxy-6-phenyl-3-(phenylmethyl)amino-2H-pyran-2-one, monohydrochloride (0.153 mmol) in ethyl acetate (10 ml) was added N-methylmorpholine (2.0 ml) and tert-butyl isocyanate (2.0 ml). The reaction was allowed to stir for 2.5 hrs and then quenched by dilution with ethyl acetate. The organic layer was washed with 5% citric acid and saturated sodium chloride and was dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 5% methanol in dichloromethane as eluents. 1H NMR (250 MHz, DMSO-d6) δ 1.24 (s, 9H), 4.47 (dd, 2 H), 5.45 (bs, 1 H), 7.23 (m, 5 H), 7.51 (m, 3 H), 7.75 (m, 2 H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:20])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:20])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:12][CH2:13]1
Reactant: CCOC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N(C)C1CCNCC1
Yield: 61 %

Procedure:
49 g of the compound obtained in Stage A dissolved in 500 ml of acetic acid in the presence of 1 g of 5% Pd/C are hydrogenated at 50° C. under 5 Kg. The catalyst is filtered off, the filtrate is evaporated, recovered with diethyl ether and rendered basic in the cold with 50 ml of sodium hydroxide solution. The ethereal phase is dried and evaporated to yield the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[CH:12]([O:14]CCCC)=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: C=COCCCC
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(C)=O)cn1
Reaction time: 0.25 h

Procedure:
A mixture of 1.07 g (5 mmol) of N-(5-bromo-pyridin-2-yl)-acetamide, 1.00 g (10 mmol) of butyl vinyl ether, 0.245 g (0.8 mmol) of tri-o-tolylphosphine, 0.090 g (0.4 mmol) of palladium acetate, and 1.10 mL (7.9 mmol) of triethylamine in 10 mL of acetonitrile containing 15 mg of hydroquinone was heated at reflux for about 18 hours. The reaction mixture was then cooled, concentrated, and the residue was taken up in 10 mL of 6 M hydrochloric acid and stirred for about 15 minutes. The mixture was then diluted with 40 mL of ethyl acetate, adjusted to pH 8 with 6 M sodium hydroxide, and the aqueous phase was saturated with sodium chloride. The ethyl acetate layer was separated, dried, and concentrated. The residue was chromatographed on silica gel (2:1 ethyl acetate-hexanes), to afford 0.578 g of N-(5-acetyl-pyridin-2-yl)-acetamide as white needles, mp 146-147° C. (recrystallization solvent=1:4 ethanol-hexanes); 1H nmr (deuteriochloroform): δ=8.82 (br s, 1 H), 8.21 (m, 3 H), 2.56 (s, 3 H), 2.22 (s, 3 H); ms (NH3Cl): m/z=179 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]([O:29][C:30](=[O:40])[CH2:31][CH:32]([NH2:39])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30](=[O:40])[CH2:31][C@H:32]([NH:39][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:26])([CH3:28])[CH3:27]
Reactant: CON(C)C(=O)C(N)CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Reaction time: 16 h
Yield: 92 %

Procedure:
To 2-benzyloxy-benzenesulfonyl chloride (3.11 g, 11 mmol) in dichloromethane (50 mL) and pyridine (2.6 mL, 3 equiv) was added 3-amino-N-methoxy-N-methyl-succinamic acid tert-butyl ester (1 equiv). The reaction stirred for 16 h and was washed with 10% sulfuric acid, water, and then brine. To give (S)-3-(2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a yellow oil (4.82 g, 92%) that was sufficiently pure for further use. 1H NMR (CDCl3) 7.88(d,1H), 7.57(d,2H), 7.40(m,3H), 7.17(d,1H), 7.03(m,2H), 5.92(d,1H), 5.25(s,2H), 4.73(bs,1H), 3.57(s,3H), 2.86(s,3H), 2.63-2.39(AB quartet, 2H), 1.40(s,9H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1I.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+]>[Cu].[Cu]I>[CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:18][C:17]1[C:19]([CH3:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=1[Cl:15]
Reactant: Cc1cc(Cl)cc(Cl)c1N
Reactant: Cc1ccc(I)c(CC(=O)N(C)C)c1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Product: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)N(C)C)c1

Procedure:
N,N-Dimethyl-5-methyl-2-iodophenylacetamide (3.5 g, 11.5 mmol) and 2,4-dichloro-6-methylaniline (4.1 g, 23 mmol) are stirred in xylenes (100 ml) with copper powder (0.18 g, 2.9 mmol), copper(I) iodide (0.55 g, 2.9 mmol) and anhydrous potassium carbonate (1.6 g, 11.5 mmol). The reaction is heated to reflux temperature for 48 hours. While still slightly warm (40°) the brown suspension is filtered through a pad of Celite, which in turn is rinsed with toluene (75 ml). The filtrate is evaporated on a rotovap and flash chromatographed on silica gel (Rf 0.30 in 40% EtOAc/hexane) to give N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamide as an off-white crystalline solid, m.p. 119-124°.