Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([OH:9])=[O:8].[CH2:25](O)[CH3:26]>C(OCC)(=O)C>[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][CH2:25][CH3:26])=[O:8]
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
3.9 cm3 of thionyl chloride are added to a stirred suspension of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid (Nε-CBZ-D-lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature in the region of −25° C. The mixture is stirred for 3 hours at this temperature and is then allowed to warm to about 20° C. After leaving for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with aqueous sodium carbonate solution and then with aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-carbonyl]amino}hexanoate are obtained in the form of a pale yellow oil. (αD20=−11.7±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][C:17]=1[Cl:21])[CH:23]=[CH2:22]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 83.5 %

Procedure:
3-(1-BOC-2-(S)-Azetidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.65 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine) palladium (100 mg) and allyltributyltin (0.99 mL, 3.18 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (750 mg, 83%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.43 (d, 2H, J=6.5 Hz), 3.88 (t, 2H, J=7.0 Hz), 4.12 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 5.10-5.20 (m, 2H), 5.92 (m, 1H), 7.18 (d, J=3.0 Hz), 7.98 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 339 (M+H)+.
Reaction SMILES: ClCCl.Cl[C:5]1[N:6]=[C:7]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[CH2:29]([Mg]Br)[CH3:30].O1CCCC1>C1(C)C=CC=CC=1.CCOCC.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:29]([C:5]1[N:6]=[C:7]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH3:30]
Reactant: Fc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncccc34)s2)cc1
Reactant: CC[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1nc(NCc2ccc(F)cc2)sc1Cc1c[nH]c2ncccc12
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Into a round bottom flask, under an atmosphere of nitrogen, [1,1′-bis(diphenyl phosphino) ferrocene] dichloro palladium (II), complex with dichloromethane (1:1), was placed with toluene (15 mL, 140 mmol). [4-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (P-0156, 145 mg, 0.4 mmol) was added in 5 ml of toluene at room temperature. The mixture was stirred for 10 minutes. To the stirring reaction, a solution of 3.13 M ethyl magnesium bromide in ether (1.86 mL) was added dropwise at room temperature. The opaque solution was heated to 60° C. Tetrahydrofuran (10 mL) was added to the warm solution. The mixture was heated to reflux for an additional two hours. After cooling to 0° C., the reaction was quenched with a solution of citric acid at pH 4-5 in ice-water and stirred to room temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography, eluting with a gradient of ethyl acetate:hexanes (20:100), gave a yellow solid that was further washed with ethyl acetate to give P-0162 (15 mg,10%) as an off-white solid. MS (ESI) [M+H+]+=367.2.
Reaction SMILES: [OH-].[K+:2].[C:3]([O:15]C)(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C1C=CC=CC=1>CO>[C:8]([O:10][CH3:11])(=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([O-:15])=[O:14])=[CH:5][CH:6]=1.[K+:2]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)[O-])cc1

Procedure:
Potassium monomethyl terephthalate was prepared by adding dropwise a solution of 85.5 grams (1.286 mole) potassium hydroxide (85% pellets) in 675 ml methanol to a stirred solution of 250 grams (1.286 mole) of dimethyl terephthalate in 1600 ml. of benzene at 60° C. over 1 hour. The mixture was refluxed for 15 minutes, cooled, and filtered. The white solid on the filter was washed with acetone and sucked dry. It weighed 263 grams (93 mole % yield). It did not melt below 400° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[CH2:12][C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:10]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[CH2:12][C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:10]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1)(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(N)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(NS(C)(=O)=O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 16 h

Procedure:
To 50 mg (0.12 mmol) of the product from Step B in 2 mL of methylene chloride was added 0.047 mL (0.58 mmol) of pyridine followed by 0.019 mL (0.24 mmol) of methanesulfonyl chloride. The reaction mixture was stirred for 16 h, concentrated in vacuo, and the residue purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 0% to 65% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 511.0 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]([NH:11][C:12](=[O:34])[CH2:13][O:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[C:24]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[NH:10])=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[C:9]([NH:11][C:12](=[O:34])[CH2:13][O:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[C:24]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N=C(N)NC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 60 °C
Yield: 52 %

Procedure:
190 mg (0.408 mmol) of N—(N-(tert-butoxycarbonyl)carbamimidoyl)-2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetamide were dissolved in 2 ml of ethanol before adding 1.020 ml (4.08 mmol) of a 4N hydrochloric acid solution in dioxane. The solution was heated to 60° C. for 2 h. The solvent was evaporated in vacuo. By cooling, the crystallised solid was filtered and washed with ethanol. 85 mg (yield=52%) of N-carbamimidoyl-2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)acetamide hydrochloride were obtained as a yellow solid. LC-MS: m/z=366 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 11.36 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.55 (d, J=28.4 Hz, 4H), 7.92-7.71 (m, 4H), 7.44-7.31 (m, 3H), 4.99 (s, 2H), 4.40 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9](O)=[CH:8][C:7](O)=[CH:6][C:5]=1O)=[O:3].C(Cl)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Na+].[Cl-]>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCc1ccccc1
Product: CC(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of 1.68g of phloroacetophenone and 12.7 g of benzyl chloride in 20 ml of DMF is added 5.53 g of anhydrous K2CO3. The mixture is stirred for 16 hours at 65° under argon. The mixture is diluted with 100 ml of 5% NaCl and extracted with ethyl acetate (2 × 50 ml). The extracts are washed with 5% NaCl and 2% NaOH, dried over MgSO4 and concentrated to a red oil which is purified on a dry 250 g silica gel columning CCl4 as eluent. This yields 2,4,6-tribenzyloxyacetophenone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:11][OH:12])=[CH:9][N:8](CO)[C:5]2=[N:6][CH:7]=1.[OH:15]S(O)(=O)=O>CC(C)=O.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:12])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: OCc1cn(CO)c2ncc(Br)nc12
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1c[nH]c2ncc(Br)nc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 107.3 %

Procedure:
To a stirred solution of (2-bromo-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (0.525 g, 2.03 mmol) in 200 mL of acetone at 40° C. was added a solution of CrO3 (0.832 g, 8.32 mmol) and H2SO4 (1.32 g, 13.4 mmol) in water (3 ml). Then the reaction was stirred at 40° C. for 16 hours then filtered through Celite. The filtrate was evaporated at 40° C. under reduced pressure to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.527 g) as an off-white solid. LCMS: (M+H)+=264; 1H NMR (300 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 5.63 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12].C(N(C(C)C)CC)(C)C.CS(O[CH:27]([C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])[CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH:12][CH:27]([C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])[CH2:28][N:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: NCCCc1c(F)cccc1F
Reactant: Cc1cccc(C)c1C(CN1CCCC1)OS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1C(CN1CCCC1)NCCCc1c(F)cccc1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
140 mg (0.81 mmol) of 3-(2,6-difluorophenyl)propylamine (Example 34.1) and 2 ml of diisopropylethylamine are added to a solution of 190 mg (0.63 mmol) of 1-(2,6-dimethylphenyl)-2-pyrrolidin-1-ylethyl methanesulfonate (Example 34.3) in 2 ml of acetonitrile. The mixture is stirred for 6 hours at 80° C., evaporated down and the residue is purified by flash chromatography. Yield: 13 mg of yellow oil, MS: m/z 373 [(M+H)+].
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH2:9].[CH:11]([CH:13]=O)=O>C(O)C>[NH:3]1[CH:4]2[CH:5]3[NH:9][CH2:8][CH2:7][N:6]3[CH2:11][CH2:13][N:10]2[CH2:1][CH2:2]1
Reactant: NCCNCCNCCN
Reactant: O=CC=O
Solvent: CCO
Product: C1CN2CCN3CCNC3C2N1
Temperature: 23 °C
Reaction time: 17 h

Procedure:
In a suitable 2 L reactor, maintained under nitrogen atmosphere, 50 g (305 mmol) of straight hydrated TETA and 1 L of absolute ethanol are loaded. To the solution 44.5 g (305 mmol) of a 40% glyoxal solution are added. After completion of the addition, the solution is kept under magnetic stirring at 23° C. for 17 hours. The resulting solution is concentrated under partial vacuum to an oily residue.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([NH:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:19])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2]
Reactant: CN1CCN(CCN)CC1
Reactant: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)NCCN4CCN(C)CC4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Yield: 20 %

Procedure:
A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (0.331 mmol), 2-(4-methyl-piperazin-1-yl)-ethylamine (0.993 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.397 mmol) in N,N-dimethylformamide (1 mL) under nitrogen was stirred for 17 h at room temperature. The reaction was concentrated in vacuo and purification by Gilson reverse phase HPLC afforded the title compound as a solid (20%). ESMS [M+H]+: 503.4
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-])=O)[C:8]=2[N:7]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:15][C:14]1[C:8]2[N:7]=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCNc1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCNc1nc2c(N)cccc2[nH]1
Yield: 86.6 %

Procedure:
To a solution of 2-[2-(dimethylamino)ethylamino]-4-nitro-1H-benzimidazole (105 mg) in ethanol (4 ml) were added iron (reduced, 118 mg) and acetic acid (0.24 ml) at room temperature and the mixture was refluxed for 6 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of chloroform and methanol (5-1) and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol-ammonia solution (28%)=160-32-1) to give 4-amino-2-[2-(dimethylamino)-ethylamino]-1H-benzimidazole (80 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[N:31][N:30]=2)=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:19]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH2:38][NH:11][C@@H:9]4[CH2:10][C@H:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]4)=[CH:40][CH:41]=3)=[N:31][N:30]=2)=[CH:27][CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(C=O)cc3)o2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nnc(-c4ccc(CC(C)C)cc4)o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.181 g, 1.01 mmol), triethylamine (0.10 mL, 0.72 mmol) and dichloromethane (8 mL) was stirred at room temperature for 30 minutes. 4-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (0.181 mg, 1.04 mmol) was added to the reaction mixture and stirred for 2 hours. Sodium triacetoxyborohydride (0.213 g, 1.01 mmol) was added to the reaction mixture and stirred for 16 hours. Additional cis-3-amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.100 mg, 0.773 mmol) and sodium triacetoxyborohydride (0.213 g, 1.01 mmol) was added to the reaction mixture and stirred for 72 hours. The reaction mixture was concentrated in vacuo and the resulting residue was triturated with water, filtered and dried to provide the title compound (0.303 g, 88% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:22][C:23]1[S:27][C:26]([S:28]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:16](=[O:21])[CH2:17]2)(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Br)s3)CC2=O)CC1
Yield: 49 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (500 mg) in ethyl acetate (15 ml) and sodium bicarbonate solution (10 ml) was added at 0° C. 5-bromo-2-thiophenesulfonyl chloride (440 mg), and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give colorless solid of the title compound (430 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13].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.[CH2:56]([SH:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>O.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].O1CCOCC1>[CH2:56]([S:63][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: SCc1ccccc1
Reactant: O=c1[nH]cc(F)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1[nH]cc(F)c2cc(SCc3ccccc3)ccc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A vial was charged with 6-bromo-4-fluoroisoquinolin-1(2H)-one (3.88 g, 16.03 mmol), Xantphos (0.464 g, 0.802 mmol), and Pd2(dba)3 (0.367 g, 0.401 mmol). The flask was flushed with Ar (g), then dioxane (32.1 ml), benzyl mercaptan (2.086 ml, 17.63 mmol), and n,n-diisopropylethylamine (5.60 ml, 32.1 mmol) were added in sequence. The reaction was heated to 110° C. and stirred for one hour. The reaction was diluted with water and stirred for 30 minutes. The solution was filtered and the solids were washed with water and dried under a nitrogen blanket overnight. The solids were triturated in ethyl acetate, stirred for two hours, and filtered. The solids were washed with ethyl acetate and vacuum dried to afford 6-(benzylthio)-4-fluoroisoquinolin-1(2H)-one as a yellow/green solid. (ESI) 286.2 (M+H)+.
Reaction SMILES: O.COC1C=CC(C[O:11][C@@H:12]([C@@H:54]([CH3:64])[CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@H:13]([C@H:15]([O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:16]([CH3:45])[CH2:17]/[C:18](/[CH3:44])=[CH:19]\[C@H:20]([CH3:43])[C@H:21]([C@@H:30]([CH3:42])[CH2:31][O:32]CC2C=CC(OC)=CC=2)[O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:14])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH3:25][C:24]([Si:23]([CH3:28])([CH3:29])[O:22][C@H:21]([C@@H:20]([CH3:43])/[CH:19]=[C:18](/[CH3:44])\[CH2:17][C@H:16]([CH3:45])[C@@H:15]([O:46][Si:47]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:52])[CH3:53])[C@H:13]([CH3:14])[C@@H:12]([OH:11])[C@@H:54]([CH3:64])[CH2:55][O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C@@H:30]([CH3:42])[CH2:31][OH:32])([CH3:27])[CH3:26]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OCc2ccc(OC)cc2)[C@@H](C)COCc2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C/C(=C/[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)COCc1ccccc1
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
Water (3 mL) is added to a solution of (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S)-2-[(4-methoxyphenyl)methoxy]-1,3-dimethyl-4-(phenylmethoxy)butyl]-5-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadec-7-ene (1.0 g, 1.19 mmol) in CH2Cl2 (30 mL) at 23° C. and stirred for 5 min. DDQ (1.62 g, 7.14 mmol, 6 eq) is added at once and stirred for 15 min. The product mixture is concentrated. The residue is filtered through celite and washed with hexane. The hexane layers are dried and concentrated. The crude product is chromatographed (from hexane to 10% EtOAc in hexane) to give 630 mg (89%) of the desired compound as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11].Br[C:23]1[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:23]2[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=2)[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: Cc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2C(=O)O)c(Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)O)C2)s1
Temperature: 55 °C

Procedure:
Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-3-carboxylic acid hydrochloride (Intermediate 79; 1.84 g) was dissolved in anhydrous DMF (20 ml) under an argon atmosphere in a 100-ml round bottom flask. Methyl 2-bromothiazole-5-carboxylate (1.43 g) was added followed by N,N-diisopropylethylamine (3.6 ml) at room temperature. The reaction was heated to 55° C. for 14 h cooled to room temperature. The reaction mixture was diluted with EtOAc (250 ml) and washed with a saturated aqueous ammonium chloride solution (125 ml), followed by a saturated aqueous sodium chloride solution (100 ml). The EtOAc solution was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-10% CH3OH in DCM. The recovered product was recrystallised from EtOAc to further enhance the diastereomeric excess, increasing it from a 90:10 cis:trans mixture to a 96:4 cis:trans mixture (by HPLC analysis). The recrystallised product was carried on to the next reaction (2 g). MS (ES−(M+H)+): 461, 463 for C17H18Cl2N4O5S; NMR: 1.71 (m, 1H), 1.91 (m, 1H), 2.16 (s, 3H), 2.81 (dt, 1H), 3.42 (m, 2H), 3.74 (s, 3H), 3.86 (m, 1H), 4.34 (m, 2H), 7.43 (d, 1H), 7.88 (s, 1H), 8.50 (brs, 1H), 12.06 (s, 1H).