Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 91%). 1H NMR (200 MHz, CDCl3): δ 2.54 (s, 3H), 3.50 (s, 4H), 3.90 (s, 4H), 4.15 (s, 3H), 6.89 (d, J=8.7 Hz, 2H), 7.25-7.62 (m, 3H), 7.79 (s, 1H), 7.91 (d, J=9.0 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([N:35]([CH2:38][C:39](O)=[O:40])[CH2:36][CH3:37])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:39](=[O:40])[CH2:38][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCN(CC)CC(=O)O
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and N,N-diethylaminoacetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-diethylamino-ethanone. MS (M+H)+: 459.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].CO.CC(O)=O.[H][H]>C(Cl)Cl.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][C:16]=1[O:23][CH3:24]
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(OC)c2)ccn1
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(OC)c2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(3-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide (400 mg, 1.20 mmol) in a mixture of DCM (5.0 mL), MeOH, (5.0 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (0.8 mL min−1, 60° C., 30 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H6; Rt 1.10 min (Method 2); m/z 304 (M+H)+ (ES+). This sample, containing residual acetic acid, was used without further purification in the next step (below).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[CH2:13][CH2:14][CH:15]([OH:19])[CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([N:23]1[C:22](=[O:27])[CH2:21][N:20]([C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]3[CH2:16][CH:15]([OH:19])[CH2:14][CH2:13][C:12]=3[CH:11]=2)[S:24]1(=[O:26])=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-benzyloxy-6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (90 mg, 0.23 mmol) from preparing Example 45, benzyl bromide (0.033 mL, 0.28 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (2 mL) is stirred at RT for 18 h. The mixture is partitioned between EtOAc and 1 N HCl solution. The organic extract is dried with MgSO4 and concentrated. The residue is purified to give the title compound as an oil: (M+NH4)+=478.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9](O)[N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)[C:11]2=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1OCCCCC)C(O)N(CCc1ccc([N+](=O)[O-])cc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCOc1ccc2c(c1OCCCCC)CN(CCc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
4,5-Dipentyloxy-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (1.04 g, 2.2 mmol, 1.0 eq) was dissolved in dichloromethane (20 ml), and triethylsilane (0.70 ml, 4.4 mmol, 2.0 eq) was added. The mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid (2.2 ml) was added dropwise thereto, and the mixture was further stirred for 4 hours. A saturated aqueous sodium hydrogencarbonate solution (40 ml) was added to this reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 4,5-dipentyloxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (868 mg, 86.8%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[N:22]1([CH2:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[N:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure LL: To a stirring solution of [4-(6-amino-pyridin-3-yl)-phenyl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (1.0 mmol) in 3:1 dichloromethane/pyridine (0.10M), add methanesulfonyl chloride (1.3 mmol) and stir at room temperature for 48 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Using 2N sodium hydroxide, make the aqueous phase basic and extract with 10% isopropanol/dichloromethane. The product remains in the aqueous layer during the acid/base workup. Concentrate the aqueous layer in vacuo and purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 429.2 (M+1)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C1CCN2C(=NCCC2)CC1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:6][CH:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(Cc1ccccc1)NC(=O)Nc1ccc(Cl)cc1
Yield: 98.9 %

Procedure:
To a solution of phenylalanine methyl ester hydrochloride (2.0 g) and DBU (1.4 ml) in acetonitrile (40 ml) was added 4-chlorophenyl isocyanate (1.4 g). The reaction mixture was mixed at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (3.0 g, 97%).
Reaction SMILES: C([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O)=C.C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1C(OC)=O.Cl>C1COCC1.O>[Br:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1[C:4]1[CH2:5][CH2:6][CH2:7][N:3]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: C=CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2=NCCC2)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Treat a solution of 1-vinylpyrrolidin-2-one (2 g, 8.58 mmol) in dry THF (30 mL) with lithium diisopropylamide (LDA) (13 mL, 31.45 mmol) at −20° C. under N2 atmosphere and stir at the same temperature for 30 min. Then add methyl 2-bromo-4-fluorobenzoate (2 g, 8.58 mmol) and stir it over the weekend. Add an HCl (12 N, 9 mL) solution and water (12 mL). Remove the THF and add HCl (12 N, 12 mL) and water (15 mL). Heat it to 100° C. for 15 h. Cool the mixture to RT and add a 5% NaOH solution. Extract the solution with ether, dry over magnesium sulfate, and remove the solvent. Purify the residue by column chromatography (hexane to ethyl acetate) to give the title compound (0.42 g, 27%). MS (ES) m/z 244 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([S:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 72.9 %

Procedure:
3.77 g (13 mmole) 2-propanesulfonyl chloride dissolved in dichloromethane was slowly added to a solution of 3.2 g (13 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde and 2.63 g (26 mmole) triethylamine in 80 ml dichloromethane at 0° C. The temperature was slowly allowed to rise to room temperature and when the starting material was consumed the reaction mixture was poured on to ice. The phases were separated and the organic phase was washed with sodium carbonate, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give 3.3 g (yield 72.8%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 2-propanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])([CH3:20])[CH2:9][S:10][C:11]2([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])([CH3:20])[CH2:9][S:10][C:11]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=1
Reactant: CCOC(=O)C1(SC[C@](C)(NCc2ccc(OC)cc2OC)c2cc(Br)ccc2F)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN[C@@](C)(CSC2(C(=O)O)CCC2)c2cc(Br)ccc2F)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of (R)-ethyl 1-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)cyclobutanecarboxylate (2 g, 3.7 mmol, Eq: 1.00) in ethanol (50 ml) was added 3 N NaOH (2.47 ml, 7.4 mmol, Eq: 2.0). The reaction solution was stirred at 70° C. for 2 hours. 1 N HCl (7.4 ml, 7.4 mmol, Eq: 2.0) was added to the reaction mixture at 23° C. (pH=5-6). After evaporation the residue was triturated with dichloromethane/methanol 9:1 and solid Na2SO4 was added. The solid was filtered off and the filtrate was evaporated to dryness to give the crude (R)-1-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)cyclobutanecarboxylic acid (1.8 g, 3.51 mmol, 94.9% yield) as a white foam, which was used without further purification. MS (ISP): m/z=512.4 [M+H]+ and 514.4 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N+:6]([O-])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1
Product: Cc1ccc(C(=O)O)nc1Cl
Temperature: 105 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
5-Methyl-2-pyridinecarboxylic acid 1-oxide (0.9 g, 5.88 mmol) was added to phosphoryl trichloride (30 mL). The mixture was stirred at 105° C. for 3 h. After that the mixture was cooled to room temperature, added to ice water slowly and extracted with methylene chloride (4×30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product (0.85 g, 84.3%); MS (EI): m/e=172.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH:17]=[C:16]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])[CH:15]=[N:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:16]1[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: Cn1cc(C(CN)C2CCOCC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cn1cc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=382.0, tR (minutes, Method E)=0.52
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH3:100])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH2:92])(=[O:91])=[O:90])=[CH:85][C:84]=1[S:93]([C:96]([F:99])([F:98])[F:97])(=[O:95])=[O:94])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH3:100])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH:92][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:90])=[O:91])=[CH:85][C:84]=1[S:93]([C:96]([F:98])([F:99])[F:97])(=[O:94])=[O:95])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:64])([CH3:66])[CH3:65])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.12 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (88 mg, 0.46 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (3.0 ml) and DIPEA (0.08 ml, 0.46 mmol) were added and the solution was stirred at r.t for 15 min. A solution of (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 28, 0.178 g, 0.23 mmol) in DCM (1.5 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with sodium bisulfate (1N, aq.) followed by a sodium bicarbonate (saturated, aq.). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was dried under vacuum to provide N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 11, STEP 1, 0.26 g) which was used in the preparation of EXAMPLE 11, STEP 2 without further purification.
Reaction SMILES: [S-2].[Na+].[Na+].[S].ClC1C=CC=CC=1C=O.ClCC(OC)=O.C[O-].[Na+].[S:23]1[C:27]([C:28]([O:30]C)=[O:29])=[CH:26][C:25]2[CH:32]=[CH:33][CH:34]=[CH:35][C:24]1=2.[OH-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.CN(C)C=O>[S:23]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[CH:32]=[CH:33][CH:34]=[CH:35][C:24]1=2
Reactant: COC(=O)c1cc2ccccc2s1
Agent: COC(=O)CCl
Agent: C[O-]
Agent: O=Cc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
Into a 200-ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser were fed 14.1 g (0.18 mole) of anhydrous sodium sulfide, 5.8 g (0.18 mole) of sulfur and 45 ml of dimethylformamide. The mixture was stirred at room temperature. Heat generation occurred and the mixture temperature increased to 45° C. After the completion of the heat generation, 21.1 g (0.15 mole) of 2-chlorobenzaldehyde was dropwise added in 10 minutes at 70°-75° C. with slight heating. The mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature. To the mixture being stirred was dropwise added 16.3 g (0.15 mole) of methyl chloroacetate in 10 minutes under spontaneous heat generation. The mixture was stirred at 55°-60° C. for 1.5 hours. 8.1 g (0.15 mole) of sodium methoxide was added at the same temperature, followed by stirring for 30 minutes. The reaction mixture was analyzed by gas chromatography, which indicated the formation of methyl benzo[b]thiophene-2-carboxylate in an amount of 86% by areal ratio. The reaction mixture was stirred for a further 1 hour. 40 ml of water and 6 g of 48% sodium hydroxide were added and the mixture was stirred at 95° C. for 1.5 hours to give rise to hydrolysis. After the completion of the reaction, dilution with 100 ml of water was conducted. 100 ml of toluene was added and extraction was conducted at 75° C. to remove neutral components. The aqueous layer was placed in a 1-litter beaker. Thereto was dropwise added 22.1 g (0.21 mole) of 95% sulfuric acid with stirring. The resulting crystals were collected by filtration and dried to obtain 17.6 g of crude benzo[b]thiophene-2-carboxylic acid. This product was washed with toluene and redried to obtain 17.1 g of benzo[b]thiophene-2-carboxylic acid. The yield was 64.0% and the purity was 99.7%.
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:23])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:17][C@H:16]([CH2:18][OH:19])[CH2:15][C@:14]3([C:21]#[CH:22])[F:20])[C:11]=2[N:12]=1>CC(O)=O.C1COCC1.O>[C:21]([C@:14]1([F:20])[CH2:15][C@@H:16]([CH2:18][OH:19])[O:17][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:23])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)#[CH:22]
Reactant: C#C[C@]1(F)C[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#C[C@]1(F)C[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
15 (0.09 mmol) was stirred in AcOH/THF/H2O (3/6/1) solution at 50° C. for 1 day. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography, C18 (H2O/ACN) Beige lyophilisated powder. Molecular Formula C12H12FN5O5. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 2.57-2.74 (m, 2H), 3.56 (s, 1H), 3.61-3.64 (d, J=12.10 Hz, 1H), 3.79-3.82 (d, J=12.10 Hz, 1H), 3.91-3.93 (d, J=5.40 Hz, 1H), 4.32-4.35 (m, 1H), 5.25 (s, 1H), 6.06-6.10 (d, J=18.20 Hz, 1H), 6.64 (s, 1H), 8.01 (s, 1H), 10.82 (s, 1H) 19F NMR (DMSO-d6, 376 MHz) δ (ppm) −138.4 (s, 1F). Scan ES− 292 (M+H)−, Scan ES+ 316 (M+Na)+, UV λmax 251 nm
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]1([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:32]1[CH2:31][CH:30]2[CH:34]([C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28][C:29]2=[O:35])[CH2:33]1)=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.75 h
Yield: 28.7 %

Procedure:
N,N'-Carbonyldiimidazole (1.62 g) is added to a solution, cooled to +5° C., of (2-tert-butoxycarbonylaminophenyl)acetic acid (2.51 g) in dry dichloromethane (30 cc). The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting 125-cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-[(2-tert-butoxycarbonylaminophenyl)acetyl]-7,7-diphenylperhydro-4-isoindolone (1.5 g) in the form of a yellow meringue-like product.