Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:31]([O:33][CH3:34])=[O:32])[C:15]2[NH:29][C:18]3=[N:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=[C:17]3[C:16]=2[N:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:31]([O:33][CH3:34])=[O:32])[C:15]3[NH:29][C:18]4=[N:19][C:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:21][CH:22]=[C:17]4[C:16]=3[N:30]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Temperature: 70 °C
Yield: 50.8 %

Procedure:
A mixture of 3-chlorophenylboronic acid (48.0 mg, 0.307 mmol), methyl 2-bromo-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (100 mg, 0.256 mmol), finely powdered potassium phosphate tribasic (130 mg, 0.613 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (21 mg, 0.051 mmol), and Pd(OAc)2 (5.7 mg, 0.026 mmol) in a microwave vial was flushed with nitrogen. THF (1.3 mL) was added, the vial was capped, and the reaction was heated in a 70° C. oil bath for 24 hr. After cooling, it was partitioned between EtOAc and water. The organic phase was extracted with brine and dried with sodium sulfate. The solvents were removed and radial chromatography (step gradient elution with DCM containing 0 to 50% EtOAc) afforded methyl 2-(3-chlorophenyl)-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (55 mg, 0.130 mmol, 51% yield). MS (ESI) m/z 423.11 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.51 (1H, s), 8.43 (1H, d, J=8.55 Hz), 8.16 (1H, t, J=1.83 Hz), 8.13 (1H, s), 7.99 (1H, d, J=7.93 Hz), 7.42 (1H, t, J=7.78 Hz), 7.33-7.38 (1H, m), 6.67 (1H, d, J=8.85 Hz), 4.08 (3H, s), 3.84-3.91 (4H, m), 3.67-3.75 (4H, m).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[N:11](C(OC)=O)[C@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)OC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Temperature: 25 °C

Procedure:
A solution of dimethyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (5.43 g, 19.16 mmol) and iodotrimethylsilane (3 mL, 28.74 mmol) in chloroform (100 mL) was heated to 65° C. for 3 hours, was cooled to room temperature, concentrated under reduced pressure and flash chromatographed with 35% ethyl acetate/65% hexane to provide the titled compound. MS (DCI/NH3) m/e 226 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1)=[CH2:2].[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>OS(O)(=O)=O>[F:11][C:12]([F:20])([F:19])[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([OH:14])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=Cc1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Product: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a modification of the procedure of Przybilla, described in German Patent No. DE4207261A1 (Sep. 9, 1993), herein incorporated by reference. The (4-vinylphenyl)magnesium bromide solution of Example 1 was cooled to −40 to −30° C. using a dry ice/acetone bath. Subsequently, hexafluoroacetone was introduced below the surface until an excess was achieved (weight added 62 g, 373.45 mmol). The reaction mixture was stirred in the cooling bath for 15 min, then placed in an ice-bath for an additional 15 min, and finally poured into cold 1N H2SO4 (1000 mL). The aqueous solution was extracted with ether, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 101.60 g of a pale yellow oil. This material was purified by vacuum distillation to provide 52.43 g (73%) of a colorless oil: bp 55-6° C. (1.3 mm); 1H NMR (CDCl3) δ 7.69 (d, 2ArH), 7.50 (d, 2ArH), 6.75 (dd, CH═), 5.84 (dd, ═CHH), 5.36 (dd, ═CHH), 3.73 (s, OH),+9% THF.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:23]([C:26]1[CH:32]=[C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:30]=[CH:29][C:27]=1[NH2:28])([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:28][C:27]1[CH:29]=[CH:30][C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:32][C:26]=1[N+:23]([O-:25])=[O:24])=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 45 °C
Yield: 114.4 %

Procedure:
A mixture of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.00 g), 1,1'-carbonyldiimidazole (1.03 g) and dry tetrahydrofuran (25 mL) was heated, under N2, at 45° C. in an ultrasound bath for 0.5 hours. 2-Nitro-4-(phenylsulfonyl)aniline (1.75 g) was added, the mixture was heated at 45° C. for 18 hours, poured onto water (350 mL) and extracted with Et2O. The combined extracts were washed (brine), dried and evaporated to give an orange solid (3.01 g) that was purified by chromatographed, with chloroform as the eluent, to yield the title compound as a pale yellow solid (0.46 g); mp 191-192.5° C.; MS: m/z=419(M+1); NMR: 1.58 (s,3), 7.63-7.76 (m,3), 8.02-8.07 (d,3), 8.34 (dd,1, J=2.2, 8.6), 8.59 (s,1), 8.61 (d,1, J=2.3). Analysis for C16H13F3N2O6S: Calculated: C, 45.94; H, 3.13; N, 6.70; Found: C, 45.95; H, 3.19; N, 6.53.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:7][CH2:8][C:9]([C:14]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:13])[CH3:10]
Reactant: CC(C)(CCl)C(=O)O
Reactant: CNC(=S)NN
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(C)CCl)s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90° C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90° C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:29]([C:30]([C:32]3[CH:49]=[CH:48][C:35]([CH2:36][NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:34][C:33]=3[CH3:50])=[O:31])[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:51])[C:23]=3[NH:22][C:21]=2[CH:52]=1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([N:44]2[CH2:45][CH2:46][CH:41]([CH2:40][CH2:39][C:38](=[O:47])[NH:37][CH2:36][C:35]3[CH:48]=[CH:49][C:32]([C:30]([N:29]4[CH2:28][C:27]5[CH:26]=[N:25][N:24]([CH3:51])[C:23]=5[NH:22][C:21]5[CH:52]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]4=5)=[O:31])=[C:33]([CH3:50])[CH:34]=3)[CH2:42][CH2:43]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CNC(=O)CCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=700.5, 702.5
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([N:8]([CH3:11])[O:9][CH3:10])(=[O:7])=[O:6].Cl[S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])=[O:14].Cl>CCCCCC.C1COCC1>[CH3:11][N:8]([O:9][CH3:10])[S:5]([N:4]([S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])=[O:15])[CH3:3])(=[O:7])=[O:6]
Reactant: O=C(NS(=O)(=O)Cl)Oc1ccccc1
Reactant: CNS(=O)(=O)N(C)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
1.15 g (28.8 mmol) of 60% sodium hydride was washed with n-hexane, and dry THF was added, and the mixture was cooled with ice. To this mixture, a THF solution containing 2 g (13 mmol) of N,N'-dimethyl-N'-methoxysulfamide was dropwise added. After stirring the mixture for 10 minutes, a dry THF solution containing 3.21 g (13.6 mmol) of phenyl N-chlorosulfonylcarbamate was dropwise added thereto. The mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into 500 ml of ice water containing 3.5 g of 35% hydrochloric acid and extracted three times with diethyl ether. The diethyl ether layer was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of phenyl N-[(N-(N-methyl N-methoxyaminosulfonyl)-N-methylamino)sulfonyl]carbamate as slightly yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Yield: 98.2 %

Procedure:
A solution of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.35 g, 3.92 mmol), 2N hydrogen chloride methanol (100 ml) and ethyl acetate (10 ml) was stirred at room temperature for 12 hours and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solution of methanol and ether to obtain the desired product (1.08 g, 98.2%) as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2([CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH2:18][CH:19]3[O:21][CH2:20]3)[C:12]([CH3:23])([CH3:22])[CH2:11]2)[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.[H-].[Na+]>C(O)CC(C)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]2([CH2:11][C:12]([CH3:22])([CH3:23])[N:13]([CH2:18][CH:19]([OH:21])[CH2:20][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:20][CH:19]([OH:21])[CH2:18][N:13]5[C:14]([CH3:17])([CH3:16])[CH2:15][C:8]6([NH:7][C:6](=[O:24])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]6=[O:10])[CH2:11][C:12]5([CH3:22])[CH3:23])=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)[C:14]([CH3:17])([CH3:16])[CH2:15]2)[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: CCCCN1C(=O)NC2(CC(C)(C)N(CC3CO3)C(C)(C)C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: CCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COc3ccc(Cc4ccc(OCC(O)CN5C(C)(C)CC6(CC5(C)C)NC(=O)N(CCCC)C6=O)cc4)cc3)C(C)(C)C2)C1=O

Procedure:
A mixture of 4.0 g of 3-butyl-8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.0 g of bis(p-hydroxyphenyl)methane in 5 ml of isopentyl alcohol with a catalytic amount of sodium hydride was refluxed for 10 hours. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure from the reaction mixture was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of benzene and ethyl acetate, giving the desired Compound No. 351 in the form of white crystals melting at 202°-204° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])([CH3:33])([CH3:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.1 %

Procedure:
The compound (1.4396 g) obtained in Example 24-2 was dissolved in anhydrous chloroform (28 ml) and then added with triethylamine (0.689 ml), followed by ice-cooling. Then, the solution was added with (4-aminobutyl)-carbamic acid t-butyl ester (852.9 mg) and stirred at room temperature for 2.5 hours. After the reaction, the solution was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.4440 g) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24]C)=[O:23])[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3-[4-(cyclohexylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (175 mg, 0.45), (Intermediate #12) was dissolved in methanol (10 mL), treated with 2M aqueous sodium hydroxide solution (1.125 mL) and stirred at ambient temperature for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title product as a white solid. (115 mg, 65%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@@H:16]2[N:25]([C:26]([C@H:28]3[CH2:30][C@@H:29]3[CH2:31][C:32]([O:34]CC3C=CC=CC=3)=[O:33])=[O:27])[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([O:42][CH3:43])[CH:19]=[CH:18][C:17]2=3)=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([C@@H:16]2[N:25]([C:26]([CH:28]3[CH2:30][CH:29]3[CH2:31][C:32]([OH:34])=[O:33])=[O:27])[CH2:24][CH2:23][C:22]3[N:21]=[C:20]([O:42][CH3:43])[CH:19]=[CH:18][C:17]2=3)=[O:15])[CH:5]=[C:6]([F:12])[C:7]=1[Si:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(n1)CCN(C(=O)C1CC1CC(=O)O)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of benzyl 2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate (46 mg, 0.08 mmol) and 10% palladium-carbon (8.06 mg, 0.08 mmol, 50%, wet) in MeOH (15 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 30→100% ethyl acetate/hexane) to give the title compound (31.2 mg, 0.060 mmol, 80%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-methoxyphenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[CH:4][N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24][CH:23]=1)#[N:21]
Reactant: CCOC(=O)c1c(Br)ncn1COCC[Si](C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C#N)cc2)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of ethyl 4-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-5-carboxylate (3.48 g, 9.96 mmol, 1.00 equiv), (4-cyanophenyl)boronic acid (3.0 g, 20.42 mmol, 2.00 equiv), Pd(dppf)Cl2.CH2Cl2 (0.42 g, 0.06 equiv) and potassium carbonate (4.0 g, 3.00 equiv) in N,N-dimethylformamide (20 mL) was stirred under nitrogen at 100° C. for 5 h. The reaction was cooled to room temperature and then diluted with 100 mL of ethyl acetate. The mixture was washed with 4×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 3.05 g (82%) of ethyl 4-(4-cyanophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate as a yellow oil. LCMS (method A, ESI): RT=1.62 min, m/z=372.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[S:7](=[O:13])(=[O:12])[N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:9][C:10]1=[O:11]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the title B compound in Example 9, 2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, (13.87 g, 48.4 mmol) and 4-bromomethylbenzoic acid (10.42 g, 48.4 mmol) in CH2Cl2 (150 mL), DBU (14.5 mL, 96.9 mmol) is added at once and the mixture is stirred at RT overnight. The reaction mixture is washed with 1N aqueous HCl, and brine, dried over anhydrous MgSO4 and evaporated to a small volume to crystallize the product. The solid is collected by filtration, washed with ethyl ether and dried under high vacuum to afford 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid: mp=175-177° C.; [M−1]−=419.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[NH:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1)CCC.Br[C:25]1[N:30]2[N:31]=[CH:32][N:33]=[C:29]2[C:28]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][C@@H:45]4[CH2:47][C@H:42]3[CH2:43][N:44]4[CH:48]([CH3:50])[CH3:49])=[CH:37][CH:36]=2)=[N:27][CH:26]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:48]([N:44]1[CH2:43][C@@H:42]2[CH2:47][C@H:45]1[CH2:46][N:41]2[C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:28]2[C:29]3[N:30]([N:31]=[CH:32][N:33]=3)[C:25]([C:6]3[NH:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=3)=[CH:26][N:27]=2)=[CH:40][CH:39]=1)([CH3:50])[CH3:49]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)n[nH]1
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cnc(Nc3ccc(N4C[C@@H]5C[C@H]4CN5C(C)C)cc3)c3ncnn23)[nH]n1
Yield: 28.7 %

Procedure:
A mixture of ethyl 5-(tributylstannyl)-1H-pyrazole-3-carboxylate (109.0 mg, 0.25 mmol) (Heterocyles, 1992, 813-818), (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-phenyl]amine (163.0 mg, 0.38 mmol), and Pd(PPh3)2Cl2 (27.0 mg, 0.04 mmol) in THF (3 mL) is refluxed for 18 hours. After return to room temperature, solvent is removed under reduced pressure. Purification of the residue by silica gel column chromatography eluting with a mixture of DCM/7N NH3 in methanol (97/3) affords the title compound (35.0 mg, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:42])[CH3:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22](=[O:24])[NH:42][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of tetrahydrofuran, and ethylamine hydrochloride (269 mg, 3.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (168 mg, 0.66 mmol) and triethylamine (367 mg, 3.63 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 4 hours until thin lay chromatography showed the starting material disappeared, and then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, yield >100%) as a white solid.