Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(NC1Cc2ccc3[nH]ncc3c2CN(Cc2ccncc2)C1=O)OCc1ccccc1

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with 4-(aminomethyl)pyridine followed by treatment with acetic acid in refluxing toluene to give (8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 65% yield. MS (ESI) 442 (M+H); Rf=1.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>C1COCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=2)[CH2:4][O:3]1
Reactant: Nc1ccnc(Cl)n1
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2nccc(N)n2)O1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of solketal 58 (34.4 g, 260 mmol) in THF (150 mL) was added NaH (10.4 g, 260 mmol) at room temperature and the mixture stirred for 1 h. 2-chloro-4-aminopyrimidine 97 (15.0 g, 115 mmol) was then added, and the mixture was stirred at 70° C. for 48 h. The reaction mixture was concentrated and the crude residue was purified by flash chromatography (dichloromethane:methanol=15:1-10:1) to give 98 (18.2 g, 70% yield) as an oil. The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccn1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N[C@@H](Cc2ccccn2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 878 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.55 g of the compound obtained in Step 84-2 as starting materials, 0.38 g (Isomer A, pale yellow amorphous) and 0.61 g (Isomer B, pale yellow amorphous) of the respective diastereoisomers of the title compound sere obtained by a similar method to Step 4-2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (3.0 g, 6.8 mmol) in chloroform (90 mL) was added valeryl chloride (0.97 mL, 8.2 mmol) and tin (IV) chloride (1.2 mL, 10 mmol). This reaction mixture was allowed to stir at ambient temperature for three hours. It was then refluxed for a total of 17.5 hours. During refluxing was added valeryl chloride (1.94 mL, 16.4 mmol) in two portions and tin (IV) chloride (2.4 mL, 20 mmol) in two portions. The reaction mixture was allowed to cool to ambient temperature. It was then poured into ice water and diluted with additional chloroform. The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered, and solvent evaporated. The residue was then purified several times by flash chromatography using (1) 20%–50% methylene chloride in hexane and 100% methylene chloride, (2) 100% hexane, 1–10% ethyl acetate in hexane and (3) 100% hexane and 5–40% 1,2-dichloroethane in hexane and 100% methylene chloride. Further purification was done by IPLC using 90% acetonitrile (0.1% formic acid) in water as the mobile system. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 30 minutes yielded [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as a clear, light brown gum (0.0979 g, 2.72%); 1H NMR (400 MHz, DMSO-d6): δ8.23 (d, 1H, J=8.81 Hz), 8.06–8.14 (m, 3H), 7.94–7.96 (m, 1H), 7.72 (dd, 1H, J=8.81 Hz and 1.79 Hz), 7.44–7.52 (m, 3H), 5.11 (s, 2H), 4.19 (q, 2H, J=7.11 Hz), 2.37 (t, 2H, J=7.30 Hz), 1.18–1.20 (m, 2H), 1.38–1.45 (m, 2H), 0.9–1.05 (m, 3H), 0.56 ppm (t, 3H, J=7.37 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:36][C@H:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:38][OH:39])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: N[C@@H](CO)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Intermediate 17 (0.25 g, 0.86 mmol), EDC (0.23 g, 1.2 mmol) and HOBT (0.139 g, 1.03 mmol) were suspended in DMF (5 ml) and the suspension was stirred at room temperature. After 25 min, (2R)-2-Amino-2-phenylethanol (0.13 g, 0.95 mmol, commercially available from Aldrich) was added, and the mixture was stirred at room temperature for 20 hours. Solvents were removed in vacuo and the residue was dissolved in DCM (50 ml) and washed successively with water (25 ml) and 5% sodium hydrogen carbonate solution (25 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and applied to a SPE cartridge (silica, 10 g), which was eluted with a gradient of ethyl acetate—petroleum ether (1:2, 1:1 and 1:0). Fractions containing the desired material were combined and concentrated in vacuo to afford Intermediate 42 as a white foam (0.318 g). LCMS showed MH+=410; TRET=2.55 min.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C

Procedure:
A solution of the acid (146) (53 mg, 0.084 mmol), and carbonyldiimidazole (29.4 mg, 0.181 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (50.3 mg, 0.415 mmol) and DBU (34.1 mg, 0.224 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between AcOEt and diluted HCl, the organic layer was washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc/CH2Cl2, 2:8) provided the desired product which was subsequently dissolved in a minimum of ethanol and diluted with water. Filtration of the precipitate afforded the title compound (14.8 mg, 24%) as a white powder, m/z=734 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1/[C:22](=[N:24]/O)/Cl>C1COCC1.O>[CH:7]1([C:10]2[O:16][N:24]=[C:22]([C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[O:19][C:18]([F:17])([F:30])[F:31])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1
Reactant: O/N=C(\Cl)c1ccccc1OC(F)(F)F
Reactant: COC(=O)CC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1C1CC1

Procedure:
Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was suspended in THF (100 mL) and the mixture was stirred. A solution of methyl 3-cyclopropyl-3-oxopropanoate (11 g, 77.5 mmol, 1.06 equiv) in 50 ml THF was added to the above stirred mixture and stirred fo(30 min at −10°C. To this reaction mixture was added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime (17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at −5°C. and then allowed to stir fo(6 h at 35°C. The reaction mixture was diluted with 200 mL of H2O, extracted with ethyl acetate (2×300 mL). The organic layer was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and then purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:100-1:20) eluent to afford methyl 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate as a white solid.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:10]([OH:9])[CH2:11][C@H:12]1[C:22]([O:24][CH3:25])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.7 g) as colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1ccc(F)c(Oc2cnccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc(F)c(Oc2cnccn2)c1

Procedure:
The product of Example 128B and LiAlH4 were processed according to the method of Example 124B to provide the product. MS (ESI+) m/z 221 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([OH:7])[C:3]([F:6])([F:5])[F:4].[CH3:8][C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=1)=[O:11]>O1CCCC1>[CH3:8][C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:7][CH2:2][C:3]([F:6])([F:5])[F:4])[N:21]=1)=[O:11]
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2ccnc(S(C)(=O)=O)n2)c1
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2ccnc(OCC(F)(F)F)n2)c1
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
0.10 g sodium metal was covered under nitrogen with 15 mL anhydrous tetrahydrofuran and 1 g trifluoroethanol was added dropwise with stirring. Stirring was continued for 1.5 h at which time the sodium was completely reacted. A solution of 0.4 g 2,2-dimethyl-N-[4-methyl-2-[2-(methylsulfonyl)-4-pyrimidinyl]phenyl]propanamide was added via syringe and stirring continued overnight under nitrogen. The reaction mixture was quenched with water and extracted with ether. The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 40:1 chlorobutane/ethyl acetate mixture as eluent to yield 0.38 g of the title compound as white crystals melting at 126°-128° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 2.40 (s,3H), 4.85 (q,2H), 7.30-8.6 (5H), 11.9(s,1H,NH).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:18][O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of isovanillin (5.00 g, 32.9 mmol) in N,N-dimethylformamide (300 ml) were added potassium carbonate (5.00 g, 36.1 mmol) and chloromethyl methyl ether (2.91 g, 36.1 mmol), and the mixture was stirred for 4 hours at 50° C. The mixture was allowed to cool to room temperature, followed by addition of water. The mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=3:1) to give the subject compound (5.80 g, 89.9%).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:71]2[N:72]=[C:73]([NH:76]C(OC(C)(C)C)=O)[S:74][CH:75]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42]([CH2:60][CH2:61][CH2:62][NH:63]C(OC(C)(C)C)=O)[C:43]([NH:52]C(OC(C)(C)C)=O)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:63][CH2:62][CH2:61][CH2:60][N:42]([CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:71]3[N:72]=[C:73]([NH2:76])[S:74][CH:75]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[C:43]([NH2:52])=[NH:44]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)N(CCCN)Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 8.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2,3-bis(tert-butoxycarbonyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)guanidino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (118 mg, 99 μmol), DCM (2 mL) and TFA (2.0 mL, 26 mmol). The crude residue was purified via reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (5.1 mg, 8%). LCMS: Rt=0.28 min, m/z=629.4 (M+1). Method 2m_acidic.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNC
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)C)s2)c(C)[nH]c1=O
Yield: 61 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with dimethylamine as described in Step 5, Example 24 to give the title compound as a solid (61% yield). LC/MS: RT 3.68 min; m/e 327 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 7.61 (1H, d), 7.38 (1H, s); 7.28 (1H, d); 2.69 (6H, s), 2.39 (2H, q), 2.33 (3H, s), 1.07 (3H, t).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:39](=[CH:40][CH:41]=2)[O:38][C:15]2([CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][N:29]=[C:30]5[CH:33]5[CH2:35][CH2:34]5)=[C:25]([O:36][CH3:37])[CH:24]=4)=[O:22])[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:42])[CH:7]=[N:6][CH:5]=1.[OH-].[Na+:45].Cl>CO.C1COCC1>[Na+:45].[CH:33]1([C:30]2[C:31]3[C:26](=[C:25]([O:36][CH3:37])[CH:24]=[C:23]([C:21]([N:18]4[CH2:17][CH2:16][C:15]5([CH2:14][C:13](=[O:42])[C:12]6[C:39](=[CH:40][CH:41]=[C:10]([C:8]7[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=7)[C:3]([O-:43])=[O:2])[CH:11]=6)[O:38]5)[CH2:20][CH2:19]4)=[O:22])[CH:32]=3)[CH:27]=[CH:28][N:29]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OC)c5ccnc(C6CC6)c5c4)CC2)O3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc2c(C3CC3)nccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-{1′-[(1-Cyclopropyl-5-methoxy-isoquinolin-7-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid methyl ester (1.80 g, 3.11 mmol) was suspended in MeOH (18 mL) and THF (9 mL), and 1N NaOH (9.34 mL) was added thereto. After stirred at room temperature for 5 h, 1N HCl aq. (6.23 mL) was added to the reaction mixture and the solvents was removed in vacuo. The residue was purified by ODS column chromatography (H2O/MeOH=100/0 to 60/40) to obtain the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.92 (1H, d, J=1.7 Hz), 8.76 (1H, d, J=2.4 Hz), 8.36 (1H, d, J=5.6 Hz), 8.31-8.28 (1H, m), 8.08 (1H, s), 8.00-7.96 (2H, m), 7.74 (1H, d, J=5.6 Hz), 7.23 (1H, d, J=9.3 Hz), 7.19 (1H, s), 4.41-4.26 (1H, br m), 4.01 (3H, s), 3.60-3.46 (1H, br m), 3.39-3.27 (2H, br m), 2.97-2.87 (1H, m), 2.95 (2H, s), 2.19-2.02 (1H, br m), 2.02-1.72 (3H, m), 1.15-1.04 (4H, m). ESI-MS [M+Na]+=586.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[C:3]=1[C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25](=[O:38])(=[O:37])[NH:26]C(OCC3C=CC=CC=3)=O)=[CH:23][C:17]=2[S:16](=[O:40])(=[O:39])[N:15]=1>CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[C:3]=1[C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([NH2:26])(=[O:38])=[O:37])=[CH:23][C:17]=2[S:16](=[O:39])(=[O:40])[N:15]=1
Reactant: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)c1=O
Yield: 90.4 %

Procedure:
A solution of the product of Example 457E (40 mg, 0.068 mmol) in methanol (5 mL) was stirred with 10% palladium on carbon (22 mg) under hydrogen atmosphere at 25° C. for 4 hours. The reaction was filtered and the filtrate concentrated under reduced pressure to provide the title compound (28 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3 H) 0.94 (s, 3 H) 1.58 (m, 3 H) 3.98 (m, 2 H) 6.32 (d, J=4.41 Hz, 1 H) 7.36 (s, 2 H) 7.47 (m, 1 H) 7.60 (m, 2 H) 8.06 (s, 1 H) 10.00 (s, 1 H) 13.97 (s, 1 H) 14.23 (s, 1 H). MS (ESI−) m/z 454 (M−H)−.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]([Cl:16])([Cl:15])[C:11](=N)OC>C(O)(=O)C>[Cl:9][C:10]([Cl:16])([Cl:15])[C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.0 Gram of an o-phenylenediamine compound [compound (207)] of the formula (XII) in which X is H and Z is CF2CF2O was dissolved in 20 ml of acetic acid. 1.4 Grams of methyl trichloroacetoimidate was added thereto at room temperature. The resulting mixture was stirred for 12 hours. The reaction solution was poured into ice water, and precipitated crystals were filtered off. The crystals were dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 1.0 g of a 2-(trichloromethyl)benzimidazole compound [compound (107)] of the formula (XI) in which X is H and Z is CF2CF2O.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])[C:7](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reaction time: 2 h

Procedure:
N-[3-(3-Aminopropyl)-4-(4-bromophenyl)-thiazol-2(3H)-ylidene]-aniline hydrochloride (730 mg) obtained in Example 132 and triethyl-amine (0.77 ml) were dissolved in N,N-dimethylformamide (5 ml), and thereto were added dropwise acetic anhydride in an ice bath under nitrogen atmosphere. The mixture was stirred at the same temperature for 2 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (580 mg).