Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH2:27])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]4[C:23]5[N:24]=[C:25]([NH:27][C:29](=[O:31])[CH3:30])[S:26][C:22]=5[CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Cc2ccc(-c3cc(Oc4cccc5sc(N)nc45)ncn3)cc2O1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc5c(c4)OC(C)(C)C5)ncn3)cccc2s1
Temperature: 85 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-[6-(2,2-dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 133(b)), (0.50 g, 1.3 mmol) was added toluene (7 mL) and acetic anhydride (0.40 mL, 3.8 mmol, Aldrich). The reaction mixture was heated at 85° C. for 2 h. The toluene was removed in vacuum and the resulting orange solid was re-dissolved in dichloromethane (125 mL), washed with water (150 mL), dried over Na2SO4 and concentrated in vacuum. The resulting orange solid was suspended in dichloromethane (100 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 224-225° C. MS (ESI, pos. ion.) m/z: 433 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:12]([CH2:13][CH3:14])[C:10](=[O:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O

Procedure:
1-(4-chlorobenzoyl)-4-ethylsemicarbazide (23.7 g, 9.81×10-2 mole) and 1 molar aqueous NaOH (118 ml, 1.18×10-1 mole) were stirred and warmed to reflux. After refluxing 23 hours, heating was discontinued and the reaction was acidified by the dropwise addition of 1 molar aqueous hydrochloric acid (130 ml, 1.30×10-1 mole). A colorless solid formed as the reaction was acidified and, after cooling in an ice bath, this was collected by filtration. Crystallization from isopropanol gave colorless spars: 18.2 g (83%), mp 188°-189°.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:13]1
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Reactant: ClCC1CC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OC2CN(CC3CC3)CCc3ccccc32)c1

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4, (7.0 g. 0.026 mole), chloromethylcyclopropane (4.6 g, 0.051 mole) and sodium bicarbonate (8.4 g, 0.10 mole) in DMF (85 ml) was warmed at 80°-90° C. for four hours. The reaction mixture was cooled, then concentrated under high vacuum to an oil which was stirred with water and extracted with ether. The ether extracts were twice washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil which was dissolved in ether and then converted to the oxalate salt (7 g, mp 80°-95° C.) using the procedure of Example 1. This material was rebasified, then passed through a silica gel dry column with ethyl acetate as eluent. The desired product was extracted with ethyl acetate then concentrated to an oil (3.3 g). This oil was converted to the oxalate salt using the procedure of Example 1 and then immediately recrystallized from a 20:1 solution of ethyl acetate/methanol to yield 1-(m-chlorophenoxy)-3-cyclopropylmethyl-2,3,4,5-tetrahydro-3-benzazepine oxalate, (3.1 g, d 100°-101° C.)
Reaction SMILES: [OH:1][C@H:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@H:3]([NH:10][C:11](=[O:20])OCC1C=CC=CC=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[CH3:30][CH2:31][OH:32]>[Pd]>[OH:1][C@H:2]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C@H:3]([NH:10][C:11](=[O:20])[CH2:30][CH2:31][O:32][C:24]1[CH:25]=[CH:26][C:21]([CH3:2])=[CH:22][CH:23]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc([C@@H](O)[C@@H](CN2CCCC2)NC(=O)OCc2ccccc2)cc1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: COc1ccc([C@@H](O)[C@@H](CN2CCCC2)NC(=O)CCOc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of benzyl(1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5%, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was filtered over celite and the solvent was removed to dryness. The product was obtained as a colorless oil (63.5 mg, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH2:16][NH2:17].[BH4-].[Na+].ClCCl>CO.ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C)=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1F

Procedure:
1-(3-Fluoro-4-methoxyphenyl)propan-2-one (2.73 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.58 g) were condensed and subsequently reduced with sodium borohydride (2.0 g) by a procedure analogous to that described in Example 1, except dichloromethane was used instead of ethyl acetate in the work-up. Chromatography of the residue on silica gel in 5% methanol-dichloromethane gave N-[2-(3-fluoro-4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 93°-5° C. (diethyl ether) as a 55:45 mixture of diastereoisomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][N:24]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][NH:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:29][C:28]2[N:24]([CH3:23])[N:25]=[CH:26][CH:27]=2)[CH:7]=1
Reactant: Cn1nccc1N
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2ccnn2C)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 52.9 %

Procedure:
2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide (100 mg, 0.30 mmol, Example 2.01), 1-methylpyrazol-5-amine (58.9 mg, 0.61 mmol), cesium carbonate (119 mg, 0.36 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (28.1 mg, 0.05 mmol) and palladium(II) acetate (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) in a sealed tube. The reaction was degased, purged with nitrogen and heated to 100° C. for 18 hours. The reaction mixture was filtered and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound (62 mg, 52.4%) as a pale orange solid. 1H NMR spectrum (500 MHz, DMSO): 2.77 (d, 3H), 3.63 (s, 3H), 6.21 (d, 1H), 6.70 (s, 1H), 7.13 (ddd, 1H), 7.32 (d, 1H), 7.49 (ddd, 1H), 7.55 (d, 1H), 7.71 (dd, 1H), 8.25 (s, 1H), 8.68 (q, 1H), 9.03 (s, 1H), 10.20 (s, 1H); Mass spectrum: ESI+ MH+ 391.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([SiH:10]([Cl:12])[Cl:11])[CH:8]=[CH2:9]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:11][Si:10]([Cl:12])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][CH:8]=[CH2:9]
Reactant: C=CC[SiH](Cl)Cl
Reactant: C=CCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CCCCCC
Yield: 79283.8 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 59.7 g (0.71 mol) of 1-hexene and 80 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 10 g (0.07 mmol) of allyldichlorosilane for 30 rain while refluxing. After confirming by gas chromatography to complete the reaction, vacuum distillation (48°-50° C./0.5 torr) gave 12.5 g (79.3%) of 4,4-dichloro-4-sila-1 -decene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:19])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:13]([CH2:14][OH:15])[CH:12]=[N:11][C:10]=1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a suspension of methyl 5-(benzyloxy)-6-chloronicotinate (3.00 g) in ethanol (40 mL) was added sodium tetrahydroborate (1.02 g), and the mixture was stirred at 60° C. for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.76 g) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:18](I)([CH3:20])[CH3:19]>>[C:1]([O:5][C:6](=[O:17])[CH:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Product: CC(C)C(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 42 %

Procedure:
N-t-Butyloxycarbonyl-β-alanine t-butyl ester (2.0 g) was isopropylated by the same procedure as in Comparative Example 4-(1) using isopropyl iodide (1.8 ml) to yield an oil of N-t-butyloxycarbonyl-α-isopropyl-β-alanine t-butyl ester (990 mg, 42%).
Reaction SMILES: [NH:1]([C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[O:28])[CH:21]=3)=[CH:16][CH:17]=2)[C:12]([Cl:42])=[CH:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:2]1([NH:1][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[C:12]([Cl:42])=[CH:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)c(Cl)cn4C(=O)Nc3ccccc3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)Nc2ccccc2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
After dissolving 260 mg of tert-butyl 4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 200 mg of N1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide as a faint yellow solid. After adding 0.5 ml of formaldehyde (37% in water), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and 5 ml of tetrahydrofuran to the solid, the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added, extraction was performed with ethyl acetate, and the extract was washed once with brine. The obtained ethyl acetate solution was passed through a glass filter coated with NH type silica gel. The silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 210 mg of a faint yellow oil. The oil was solidified from a hexane and ethyl acetate mixed solvent to obtain 90 mg of a powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[C:10]([O:17][CH3:18])[CH:9]=2)[CH:4]=[N:3]1.CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:10]([O:17][CH3:18])[CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1cc(-c2cnn(C)c2C)ccc1NC=O
Product: COc1cc(-c2cnn(C)c2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 8 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,5-dimethy-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 77) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane followed by a second chromatography eluting with, 50-90% EtOAc in cyclohexane. The residue was passed through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH to give the title compound (5 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]2[CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(C(O)=O)=CC=1.N>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(c3ccccc3)c3cccc(Cl)c3)CC2)cc1
Agent: Br
Agent: N
Agent: O=C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1

Procedure:
(+)-1-[(3-Chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine (4.62 g, 10.48 mmol) was stirred in 30% hydrobromic acid-acetic acid solution (20 ml) in the presence of 4-hydroxybenzoic acid (5.06g, 36.66 mmol) at room temperature for two days. 28%-Aqueous ammonia was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the crude product obtained by removing the solvent by evaporation in vacuo was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si](CC)(CC)CC)[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21]CC1C=CC([N+]([O-])=O)=CC=1)=[O:20].Cl.O.C(=O)(O)[O-].[Na+:52].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C1COCC1.O.[Pd]>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20].[Na+:52]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3COCCO)[C@H](C)[C@H]12
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3COCCO)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
4-Nitrobenzyl (1R,5S,6S)-2-[[(Z)-2-[4-(2-hydroxyethoxy)methylthiazol-5-yl]ethen-1-yl]thio]-1-methyl-6-((1R)-1-triethylsilyloxy ethyl)-1-carbapen-2-em-3-carboxylate (3.82 g) was dissolved in 170 ml of THF and 70 ml of water. 1 N aqueous hydrochloric acid (2.8 ml) was added to the solution, and the mixture was stirred at room temperature for 50 min. The reaction solution was adjusted to pH 3.0 by the addition of saturated sodium bicarbonate water. A 1/15 M sodium phosphate buffer solution (pH 6.8) (170 ml) and 3.10 g of 10% Pd—C (hydrous, water content 53%) were added thereto, and the mixture was stirred under a hydrogen atmosphere for 1.5 hr. 10% Pd—C was removed by filtration and was washed with water, and the filtrate was adjusted to pH 7.0 by the addition of saturated sodium bicarbonate water, followed by washing with 300 ml of ethyl acetate. The aqueous layer was concentrated to about 20 ml, and the residue was purified by column chromatography on Cosmosil 40C18-PREP (5% methanol-water) to give 1.91 g of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:19]
Reactant: c1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of isoquinoline (1-Im-9, 5 g, 1.0 eq) in 50 mL of CHCl3, mCPBA (2.0 eq) was added. The mixture was stirred at rt for 1 h. The reaction was washed with 5% aqueous Na2SO3 and aqueous Na2CO3, then concentrated and the residue was purified by silica column chromatography to give isoquinoline 2-oxide (2-Im-9).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55](OC3C=CC=CC=3)=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(#N)C.C(OCC)(=O)C>[C:38]([O:42][C:43]([N:45]1[C:53]2[C:48](=[CH:49][C:50]([NH:54][C:55]([NH:14][C@@H:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:18]3)=[O:16])=[O:56])=[CH:51][CH:52]=2)[CH:47]=[N:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)Oc3ccccc3)ccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc3c(cnn3C(=O)OC(C)(C)C)c2)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Temperature: 60 °C
Reaction time: 64 h
Yield: 61.2 %

Procedure:
In a dry flask (3R,4R)-4-Amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (72 mg, 0.171 mmol) was dissolved in acetonitrile (2 mL) and triethylamine (25 μL, 0.179 mmol) and 5-(phenoxycarbonylamino)-1-indazolecarboxylic acid 1-tert-butyl ester (72 mg, 0.204 mmol) were added. The reaction mixture was stirred for 64 hours while heating to 60° C. The reaction mixture was cooled, diluted with ethyl acetate, washed twice with water and once with brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (71 mg, 61%). 1H NMR (300 MHz, CDCl3), δ: 8.09 (m, 2H), 7.90 (2s, 1H), 7.44 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.83 (m, 2H), 4.90 (bs, 1H), 4.43 (bd, 1H, J=11), 4.22 (bs, 2H), 3.98 (bm, 2H), 3.14 (t, 1H, J=13), 2.75 (bm, 4H), 2.45 (bm, 3H), 1.94 (bm, 3H), 1.73 (2s, 9H), 1.48 (m, 9H), 1.45 (bm, 3H), 1.22 (bm, 1H). HRMS (ESI), C36H48FN6O6 m+/z: calc.=679.3619, found=679.3621.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:12](=[O:35])[CH:11]=2)=[C:6]([F:36])[CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][OH:23])=[O:21])[C:12](=[O:35])[CH:11]=2)=[C:6]([F:36])[CH:5]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
Water (312 mL) and 1 N aq HCl (23.9 mL, 23.9 mmol) were added to a solution of (2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (74.7 g, 144.1 mmol) in ethanol (126 mL). The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was allowed to cool and the solid was collected via filtration and washed with water until the filtrate had a pH of −5. The solid was dried under vacuum to afford the title compound as a white solid (46.48 g, 74%). MS (LCMS) m/z 435.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 3 H) 2.09-2.21 (m, 1 H) 2.44 (d, J=5.27 Hz, 1 H) 3.10 (s, 3 H) 3.77 (td, J=11.90, 5.07 Hz, 1 H) 4.04 (td, J=11.95, 4.98 Hz, 1 H) 6.51 (d, J=7.02 Hz, 1 H) 7.44 (dd, J=8.29, 2.05 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.62 (dd, J=9.95, 1.95 Hz, 1 H) 8.04 (d, J=5.85 Hz, 1 H) 9.22 (s, 1 H) 11.05 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=O)[CH:11]=2)[CH2:6]1)=[O:4].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl.C(=O)([O-])O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N1CCc2cc(CN3CCCCC3)ccc2C1)C(F)(F)F
Reaction time: 15 h

Procedure:
2-(2,2,2-Trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (2 g, 7.78 mmol) and piperidine (660 mg, 7.78 mmol) were dissolved in 1,2-dichloroethane (24 ml), and sodium triacetoxyborohydride (2.29 g, 10.89 mmol) was added. The reaction mixture was stirred for 15 h, then diluted with dichloromethane, and sat. sodium hydrogen carbonate solution (100 ml) was added. After phase separation, the aqueous phase was extracted with dichloromethane (3×100 ml). The combined organic phases were washed with sat. sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate/dichloromethane/methanol 10:1:1+ammonia solution (25% aq.)). Yield: 1.88 g (74%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].O=[CH:24][C:25](=C)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH:24]=[C:25]([CH3:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-dichlorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 33%), melting at 136-138° C.