Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([N:8]=[C:9]([CH:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][CH2:13][NH:12]1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1C(O)=NCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C(O)C1CCCNC1C(O)=NCc1ccccc1
Temperature: 80 °C
Yield: 90.7 %

Procedure:
In a 1.3 liter stirred autoclave fitted with stirrer, temperature sensor, and riser tube, 666 g of pyridine-2,3-dicarboxylic acid N-benzylimide and 28.2 g of 5% by weight palladium-on-carbon were suspended in 959 g of toluene. The autoclave was then flushed, hydrogen was introduced, and the autoclave was heated at a reaction temperature of 80° C. as described in Example 1. Work-up of the reaction mixture as described in Example 1 gave 618 g of piperidine-2,3-dicarboxylic acid N-benzylimide in a purity of 98.7% (GC area percent).
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:23]([Mg]Br)=[CH2:24].Cl>O1CCCC1>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[C:4](=[O:21])[CH:23]=[CH2:24])=[N:14][CH:15]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of N-methoxy-N-methyl-2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (404 mg) in tetrahydrofuran (5 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 5.0 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 2 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (168 mg, yield 46%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH2:36]([N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:42](Cl)=[O:43])[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:42](=[O:43])[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a suspension of 1.05 g (2.3 mmole) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]piperazine-2carboxylic acid hydrobromide (from Step C) in 20 ml of methylene chloride was added 1.23 g (9.5 mmole) of N,N-diisopropylethylamine followed by the dropwise addition of a solution of 523 mg (2.38 mmole) of dipentylcarbamoyl chloride (from Example 1, Step C-2) in 5 ml of methylene chloride. After stirring 24 hours at 25° C., the solution was extracted with 2N HCl, then H2O and dried over MgSO4. The dried methylene chloride solution was concentrated in vacuo and the residue was dissolved in isopropyl ether and was diluted with petroleum ether (bp. 30°-60° C.) until cloudy. The oil which precipitated was then decanted, redissolved in isopropanol and concentrated in vacuo to yield 464 mg (36%) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]-4-(dipentylcarbamoyl)piperazine-2-carboxylic acid as a glassy solid; TLC showed a single spot, Rf 0.75 (Analtech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1C=CC=CC=1.C(O)C>[O:15]=[C:14]1[C:16]2[O:17][C:18]([C:21]#[N:22])=[CH:19][C:20]=2[C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=2[NH:13]1
Reactant: N#Cc1ccc(C(=O)Nc2ccccc2N2CCCCC2)o1
Solvent: c1ccccc1
Solvent: CCO
Product: N#Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12

Procedure:
5-Cyano-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (200 mg) is dissolved in a mixture of benzene (180 mL) and ethanol (20 mL). The solution is irradiated with a 100 W high pressure Hg Lamp at room temperature for 10 h, according to the method described by Kanoka and Itoh [Synthesis, 36 (1972)]. The solvent is removed in vacuo and the residue is purified by preparative thin layer chromatography (“TLC”) (silica gel) to yield the pure product.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[P:20](Cl)([Cl:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C(OCC)C>[P:20]([Cl:29])([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: O=C(NO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NOP(=O)(Cl)Oc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A mixture of benzyl N-hydroxycarbamate (0.35 g, 2.1 mmol) and triethylamine (0.21 g, 2.1 mmol) in diethyl ether is cooled at 0° C. with stirring. To this is added a solution of phenyl dichlorophosphate (0.43 g, 2 mmol) in diethyl ether (1 ml). The resulting suspension is stirred at room temperature for 3 hours. It is then filtered and the solvents evaporated under reduced pressure to give 0.70 g of a colorless oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13].C(N(CC)CC)C.O>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH2:12][C:11]([F:15])([F:14])[F:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCC(F)(F)F
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)CNc1nc(Cl)nc(Cl)n1
Yield: 45 %

Procedure:
166 g (0.9 mol) of cyanuric chloride were dissolved in 1 liter of warm acetone, the solution was filtered off from the small quantity of insoluble substance, and a solution of 90 g (0.9 mol) of 2,2,2-trifluoroethylamine in 101 g (1.0 mol) of triethylamine was added dropwise at 0° to 5° C., while stirring and cooling with ice. The mixture was stirred for some time, approx. 1 liter of water was added, and the crystals which had formed were filtered off under suction. After the product had been dried, 100 g (=45% of theory) of 2,4-dichloro-6-(2,2,2-trifluoroethylamino)-s-triazine of melting point 115° to 118° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15](=[O:34])[CH:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=O)[CH2:31]Br)[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:13][O:14][C:15](=[O:34])[CH:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[N:12]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:11][CH:31]=2)[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(Oc1cccc(C(=O)CBr)c1)c1ccccc1
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Product: COC(=O)C(Oc1cccc(-c2csc(Nc3ccc(Cl)c(Cl)c3)n2)c1)c1ccccc1

Procedure:
{3-[2-(3,4-Dichloro-phenylamino)-thiazol-4-yl]-phenoxy}-phenyl-acetic acid methyl ester was prepared as per procedure I using (3,4-dichloro-phenyl)-thiourea and [3-(2-Bromo-acetyl)-phenoxy]-phenyl-acetic acid methyl ester using Procedure I.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:42]([CH3:43])=[CH:41][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:26]=[C:25]([CH3:27])[N:24]([C@@H:28]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]5)[C:23]=4[CH:40]=3)[S:18][C:14]=2[C:13]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>Cl.CC(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:42]([CH3:43])=[CH:41][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:26]=[C:25]([CH3:27])[N:24]([C@@H:28]5[CH2:32][CH2:31][NH:30][CH2:29]5)[C:23]=4[CH:40]=3)[S:18][C:14]=2[C:13]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@@H]5CCNC5)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
A solution of (R)-tert-butyl 3-(6-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (77 mg, 0.11 mmol) in 1.25 M HCl in i-PrOH (12 mL) was stirred at room temperature for 16 hours. The solution was then concentrated in vacuo to provide the desired product. LCMS-ESI+: calc'd for C34H38ClN4O3S: 617.2 (M+H+); Found: 617.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine) palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl) acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ) δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8.0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[O:19]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: COC(=O)OC
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere, a mixture of sodium hydride (60% dispersion in mineral oil, 887 mg, 22.0 mmol), dimethyl carbonate (15 mL) and 3,4-dihydronaphthalen-1(2H)-one (1.46 g, 10.0 mmol) was stirred at 80° C. for 3.5 hr. The reaction mixture was quenched with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium carbonate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/0-5/1) to give the title compound as a white solid.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH3:31])[C:25]=2[Cl:32])[C:22]2[C:21](=[O:33])[CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][C:17]=2[NH:16][C:15]=1[CH3:41])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O.[H][H]>[Pd].CO>[O:2]([CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:23]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH3:31])[C:25]=2[Cl:32])[C:22]2[C:21](=[O:33])[CH2:20][NH:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH3:41])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC1=C(C(=O)OCCOc2ccccc2)C(c2c(F)ccc(C)c2Cl)C2=C(CN(Cc3ccccc3)CC2=O)N1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)OCCOc2ccccc2)C(c2c(F)ccc(C)c2Cl)C2=C(CNCC2=O)N1
Yield: 55 %

Procedure:
Twelve grams of the above hydrochloride, 125 ml of methanol, 2 ml of concentrated hydrochloric acid, 10 ml of water, and 1 g of 10% palladium on carbon were shaken with hydrogen (50 psig initial pressure) for 24 hours. The mixture was diluted with 500 ml of methanol, heated to reflux and filtered. The filtrate was evaporated to dryness and the residue was slurried with ethanol and filtered. The solid was recrystallized from methanol to obtain 5.2 g of the title compound as the hydrochloride, m.p. 252°-5° C. dec.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:17])[C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[N:24]=[C:23]([N:25]2[CH:30]=[C:29]([CH:31]3[C:37]4[CH:38]=[CH:39][C:40]([CH3:42])=[CH:41][C:36]=4[CH:35]=[CH:34][C:33]4[CH:43]=[C:44]([CH3:47])[CH:45]=[CH:46][C:32]3=4)[C:28](=[O:48])[NH:27][C:26]2=[O:49])[CH:22]=[CH:21][N:20]=1>>[CH3:42][C:40]1[CH:39]=[CH:38][C:37]2[CH:31]([C:29]3[C:28](=[O:48])[NH:27][C:26](=[O:49])[N:25]([C:23]4[CH:22]=[CH:21][N:20]=[C:19]([N:12]5[CH2:13][C@H:14]([OH:16])[CH2:15][C@H:11]5[C:10]([O:9][CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)=[O:17])[N:24]=4)[CH:30]=3)[C:32]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:33]=3[CH:34]=[CH:35][C:36]=2[CH:41]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N3C[C@H](O)C[C@H]3C(=O)OCc3ccccc3)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from trans-4-hydroxy-L-proline benzyl ester hydrochloride (0.928 g) and the product of example 8 step (ii) (0.3 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 50-60% ethyl acetate in isohexane. Yield 0.29 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[S:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[S:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (R)-2-(4-chlorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (11 mg, 0.020 mmol) in DCM (10 mL) was added HCl (4M, 2 mL). The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed to afford (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (9 mg, 100%). LCMS (APCI+) [M+H]+ 460 and 462.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][S:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>Br>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[CH:17][S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc(-c3cscn3)cc2)cc1
Agent: Br
Product: Oc1ccc(-c2cscn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To 4-(4-benzyloxyphenyl)thiazole (1.1 g) was added 47% aqueous hydrogen bromide (10ml), and the mixture was stirred at 100° C. for 30 minutes. Ice-water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried by anhydrous sodium sulfate and then concentrated. Crystals were collected by filtration by using hexane to give 4-(4-hydroxyphenyl) thiazole (466 mg, 63.8%). The crystals were purified by recrystallization from methylene chloride-hexane. m.p. 161.5°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][N:10]=[CH:9][C:8]=1[Cl:15])=[O:6].ClC1C=CC=C(C(OO)=[O:33])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][N+:10]([O-:33])=[CH:9][C:8]=1[Cl:15])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Reaction time: 2 h
Yield: 951.7 %

Procedure:
A chloroform (60 ml) solution of 3.4 g (1 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine (compound No. 244) was cooled with ice, 4.1 g (1.6 mmol) of m-chloroperbenzoic acid was added thereto, followed by stirring under cooling with ice for 2 hours, and stirring was further conducted at room temperature for 2 hours. 30 ml of a 0.5 mol/l aqueous sodium hydroxide solution was added to the mixture to terminate the reaction, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 3.5 g (yield 85%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide (m.p. 160-166° C.).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][N:10]1[CH2:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH2:12][CH2:11]1.Cl[C:26]1[CH:27]=[CH:28][C:29]([N+:34]([O-:36])=[O:35])=[C:30]([O:32][CH3:33])[CH:31]=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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([C:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH:14]=2)[CH:27]=[CH:28][C:29]=1[N+:34]([O-:36])=[O:35]
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(C2=CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A 25 mL glass microwave tube was charged with potassium phosphate tribasic (3.00 g, 13.05 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-isopropyl-1,1′-biphenyl (Strem Chemicals, Newburyport, Mass., 83 mg, 0.174 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 80 mg, 0.087 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Acros Organics, New Jersey, 971 mg, 4.35 mmol) followed by 5-chloro-2-nitroanisole (Sigma Aldrich, 816 mg, 4.35 mmol). The solids were purged with argon and treated with 1,4-dioxane (12 mL) and water (4 mL), scaled and heated at 110° C. in a heating block for 1 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3×30 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (80 g Thomson SingleStep column, using a gradient of 0-20% MeOH in DCM) affording 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (19a; 970 mg, 3.91 mmol, 90% yield) as a rust-brown solid which crystallized upon standing. m/z (ESI, +ve ion) 249.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, d, J=8.4 Hz), 6.99-7.08 (2H, m), 6.17-6.24 (1H, m), 3.97 (3H, s), 3.15 (2H, q, J=2.8 Hz), 2.65-2.74 (2H, m), 2.53-2.62 (2H, m), 2.38-2.46 (3H, m). In a 50 mL glass reactor, 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (940 mg, 3.79 mmol) was treated with palladium hydroxide (20 wt % Pd, dry basis, on wet carbon, degussa type e101 ne/w, 266 mg, 0.38 mmol) and anhydrous EtOH (20 mL). The reactor was purged with hydrogen (5×) and allowed to stir under 50 psi hydrogen at RT for 4 h. The reaction mixture was filtered through a 0.45 urn acrodisc to remove the catalyst residues washing with MeOH and concentrated to dryness under high vacuum affording 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b; 830 mg, 3.77 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 221.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.56-6.74 (3H, m), 3.76-3.89 (3H, m), 3.54-3.76 (2H, m), 2.97 (2H, d, J=11.2 Hz), 2.34-2.47 (1H, m), 2.23-2.34 (3H, 1.95-2.12 (2H, m), 1.70-1.90 (4H, m).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1>O1CCCC1.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])[CH2:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[O:20])=[CH:13][CH:12]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Reactant: Cc1ccccc1[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(Br)cc1
Yield: 63.7 %

Procedure:
To a suspension of copper(I) iodide (63.4 mg, 333 μmol) in tetrahydrofuran (10 ml) was added at 0° C. o-tolylmagnesium bromide solution (2 M in diethyl ether, 3.66 ml, 7.33 mmol) to give a light brown suspension. The reaction mixture was stirred at this temperature for 1½ h, then a solution of (E)-3-(4-bromophenyl)-1-(pyridazin-4-yl)prop-2-en-1-one (963 mg, 3.33 mmol) in THF (5.0 ml) was added, then after 1¾ h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; ethyl acetate/heptane 1:1) afforded the title compound (809 mg, 64%). Light yellow foam; MS: 381.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)=[N:10]1.Cl.[NH:34]1[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:23]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CBr)N2)n1
Agent: Cl
Product: CCOC(=O)Cn1cnc(C2=NC(c3ccc(F)cc3Br)C(C(=O)OCC)=C(CN3CCOC(C(=O)O)C3)N2)n1
Yield: 20.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.13 g, 20%). The compound was characterized by the following spectroscopic data: