Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[O:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.O.CCOCC>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[O:6][CH:5]([C:3]([OH:4])=[O:2])[O:12][C:11]=2[CH:13]=1
Reactant: COC(=O)C1Oc2ccccc2Cc2ccc(OC)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)OC(C(=O)O)Oc1ccccc1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-3-methoxy-12H-dibenzo[d,g][1,3]-dioxocin-6-carboxylate (0.32 g, 1.07 mmol) was dissolved in 20 ml of tetrahydrofuran and 3.0 ml of 2 M sodium hydroxide was added. The mixture was stirred at ambient temperature overnight. It was then diluted with 20 ml of water and 50 ml of ether and the layers separated. The organic layer was extracted with water and the aqueous extract combined with the original aqueous layer. The resulting solution was acidified with 10 percent aqueous hydrochloric acid and then extracted with 4-25 ml portions of ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound as a yellow-white foamed solid amounting to 0.26 g (85 percent of theory) and melting at 149°-153° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1)[CH3:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:27]=1)[CH3:23]
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (143.2 mg, 0.5 mmol), 3-aminobenzoic acid ethyl ester (123.9 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture wag stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid ethyl ester as a white solid (194.4 mg, 89.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccn1
Reactant: OCc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1COc1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2 ml (18.0 mmol) of (2,6-difluorophenyl)methanol in 15 ml of dry tetrahydrofuran stirred at 0° C. was admixed with 865.9 mg (21.6 mmol) of sodium hydride (60% in mineral oil), followed by 1.72 ml (18.0 mmol) of 2-bromopyridine. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The organic phase was removed, dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 800 mg (15% of theory, 77% pure) of the target compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([F:23])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[S:18]1[C:14]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[F:23])[NH:10][N:9]=2)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
To a solution of 152 mg of 3-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-f in a mixture of 2 ml of tetrahydrofuran and 2 ml of methanol was added 1 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at 55° C. for 2.5 hours. After standing to cool, 5.5 ml of 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was recrystallized from tetrahydrofuran-ethyl acetate, to give 104 mg of the title compound as pale red crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].CC([N-]C(C)C)C.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]1=[O:7]
Reactant: CN1CCCC1=O
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-methylpyrrolidin-2-one (5.05 mL, 52.5 mmol), LDA (43.8 mL, 78.8 mmol, 1.8 M), and THF (125 mL). The reaction mixture stirred at −78° C. for 1 hour. Methyl chloroformate (6.06 mL, 78.8 mmol), was added, and the reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (4 hours). Water (125 mL) was added, and the aqueous layer was extracted with EtOAc (3×250 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford the crude product 7.35 g (89%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.28-3.25 (m, 2H), 2.85 (s, 3H), 2.62-2.67 (m, 1H), 2.13-2.22 (m, 1H), 1.99-2.06 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.BrCl>CN(C)C=O.ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:57]([C:55]1[NH:54][C:53]2[CH:62]=[CH:63][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 85 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in dimethylformamide. Yield: 85%; Rf value: 0.60 (silica gel; dichloromethane/methanol=95:5); C22H22BrClN4O3 (505.80); mass spectrum: (M+H)+=503/505/507 (bromo-chlorine isotope).
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)C>CCOCC>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:9][CH:10]=1)#[N:13]
Reactant: CCOC(COc1ccc(C#N)cc1)OCC
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc(OCC=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
A 5N HCl (25 mL) solution is added to a stirred solution of 4-(2,2-diethoxy-ethoxy)-benzonitrile (2.00 g, 8.50 mmol) in Et2O (25 mL). The two-layered solution is stirred vigorously at ambient temperature under nitrogen for 24 hours. Another 50 mL Et2O is added to the mixture. The organic layer is separated, washed with an aqueous solution (30 mL) containing saturated NaHCO3 (0.5 mL), dried over MgSO4, filtered and concentrated at ambient temperature to give 1.36 g of the crude (4-cyano-phenoxy)acetaldehyde as oil. The oil is diluted in Et2O to form a stock solution (25 mg/mL), which is used for the subsequent reaction. 1H NM (CDCl3): δ4.66 (s, 2H), 9.85 (s, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:31][CH2:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[S:25](=[O:27])(=[O:26])[C:19]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC2=C(C=CCC2)S(=O)(=O)c2cc(C(F)(F)F)ccc21
Solvent: O
Solvent: c1ccncc1
Product: O=S1(=O)c2ccccc2NC(=S)c2ccc(C(F)(F)F)cc21
Yield: 84.2 %

Procedure:
Phosphorus pentasulphide (1 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one-5,5dioxide (1 g, 3 mmol) in pyridine (20 ml) and heated under reflux for 6.5 hr. A further 500 mg of phosphorus pentasulphide was added and the mixture heated for a further 6 hr before being allowed to cool overnight. The mixture was added to hot water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as a yellow solid (650 mg, m.p. 275°-278° C., Rf 0.4, hexane/EtOAc 2:1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C1C=CC=CC=1>O.ClC(Cl)=C(Cl)Cl.C1(C)C=CC=CC=1>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of L-aspartic acid (133 g.; 1.00 mole), benzyl alcohol (650 g.; 6.00 moles), p-toluenesulfonic acid monohydrate (194 g.; 1.02 moles), and dry benzene (400 ml.) was heated at reflux for 6.5 hours. Although benzene has been used, it is within the scope of the invention to employ other solvents such as, for example, toluene and tetrachloroethylene. The water formed in the reaction (46 ml.) was removed by means of a Dean-Stark trap. The resulting solution was cooled to room temperature then diluted with benzene (400 ml.) and ether (1200 ml.). On cooling to 10°, a white solid precipitated. This material was collected on a filter, washed with ether (1.0 l.), and dried; yield of crude (I), 384 g. (79%). A 304 g. portion of the product was recrystallized from methanol (425 ml.) to give 186 g. (61.2% recovery) of material suitable for further transformation; m.p., 155.5°-158°; literature m.p., 158°-160° .
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>>[CH3:29][O:28][C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Reactant: C=CC(=O)OC
Product: COC(=O)/C=C/c1ccc2nc3c4c(cccc4c2c1)N(C)c1ccccc1-3
Yield: 66 %

Procedure:
The general procedure (Method M, described below) applied to 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (160 mg, 0.5 mmol) and methyl acrylate (0.064 mL, 1.5 eq) gave the title compound (120 mg, 0.33 mmol, 66%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:12][C:13]1([F:24])[CH2:19][CH2:18][NH:17][CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]1=2>>[F:24][C:13]1([F:12])[C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[CH2:16][N:17]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:18][CH2:19]1
Reactant: FC1(F)CCNCc2ccccc21
Reactant: Clc1nc(Cl)c2sccc2n1
Product: NCCCNc1nc(N2CCC(F)(F)c3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamne, followed by reaction with 5,5-difluoro-2,3,4,5-tetrahydro-1H-benzo[c]azepine. MS obsd. (ESI+) [(M+H)+]390, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (d, J=5.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.35-7.41 (m, 1H), 7.27-7.34 (m, 1H), 7.08 (d, J=5.3 Hz, 1H), 4.97 (s, 2H), 4.23-4.31 (m, 2H), 3.70 (t, J=6.6 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.41-2.53 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.O[CH2:11][C:12]1[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:11]([C:12]3[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: Nc1cc(Br)cnc1N
Product: OCc1ccc(-c2nc3cc(Br)cnc3[nH]2)o1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 5-hydroxymethyl-2-furaldehyde.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH:32]([S:35]([NH2:38])(=[O:37])=[O:36])([CH3:34])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25][NH:38][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: CC(C)S(N)(=O)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C(C)C)C2CC2)C1=O

Procedure:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A, 59.3 mg, 0.129 mmol;) and isopropyl sulfonamide (48.7 mg, 0.395 mmol) were coupled by the procedure as described in Example 202, Step C to form the title compound isolated after silica gel chromatography as an off-white solid. MS (ESI) m/z=563 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[CH:13]=[N:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)=[CH:4][C:3]=1[S:18](Cl)(=O)=O.C(O)C.Cl.O>[Zn].C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[CH:13]=[N:12][C:11]([C:14]([F:15])([F:16])[F:17])=[N:10]2)=[CH:4][C:3]=1[SH:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)c(-n2cnc(C(F)(F)F)n2)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer was placed 3.44 g (9.6 mmol) of 2,4-dimethyl-5-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)benzenesulfonyl chloride, followed by addition of 3.14 g (48 mmol) of zinc, 16 ml of ethanol and 8 ml (80 mmol) of 35% hydrochloric acid. The mixture was stirred at room temperature for 30 minutes and then refluxed with heating, for 4 hours. The mixture was cooled to room temperature. Thereto were added 50 ml of water and 50 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 50 ml of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Vacuum distillation was conducted to distill off ethyl acetate to obtain a title compound as 2.25 g of a crystal. Yield: 86%
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12]
Reactant: CC1=NCCc2c(Cl)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2c(Cl)cccc21

Procedure:
In close analogy to the procedure described above, 5-chloro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 44, tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.20 mmol) in MeOH (5 mL), was added 10% palladium on carbon (10 mg) and the mixture was stirred under an atmosphere of H2 (60 psi) for 16 hr. The mixture was filtered through Celite® and the solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as an oil. To a solution of this amine in DCM (5 mL), DIPEA (0.1 mL, 9.6 mmol), PyBOP (0.16 g, 0.3 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (78 mg, 0.22 mmol) were added and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL) and washed with water (10 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a solid (122 mg). To this solid (122 mg, 0.18 mmol) in MeOH (1 mL), a solution of HCl (4 M in 1,4-dioxane, 3.2 mL, 12.9 mmol) was added and the resulting solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. Purification by preparative HPLC gave 190 as an off-white solid (40 mg, 44% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.19 (s, 1H), 8.24 (s, 1H), 7.59-7.48 (m, 3H), 7.33-7.23 (m, 2H), 3.69 (s, 3H), 3.26-3.02 (m, 4H), 2.98-2.73 (m, 4H), 1.01 (s, 3H). Alkyl NH and OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:46])[CH:30]([NH:38]C(OC(C)(C)C)=O)[CH:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:46])[CH:30]([NH2:38])[CH:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OC(C)(C)C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OC(C)(C)C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution containing crude 43 (340 mg, 0.53 mmol) in DCM (10 mL) was cooled to 0° C. TFA (3 mL) was added. After 2 h, the reaction mixture was quenched by the slow addition of cold, aqueous K2CO3. The reaction mixture was extracted with DCM and the resultant organic phase was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 283 mg of 44 as an amber-colored foam which was used without further purification. Mass spectrum, m/z [537.3] (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:72](OC)[O:73]C)[CH2:67][C:68]([F:71])([F:70])[F:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C.ClCCl.O>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][C:68]([F:69])([F:71])[F:70])[CH:72]=[O:73])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:52])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: COC(OC)[C@H](CC(F)(F)F)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(C=O)CC(F)(F)F)C(C)(C)C
Yield: 5.5 %

Procedure:
94 mg (0.86 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[3,3,3-trifluoro-1(S)-(dimethoxymethyl)propyl]-L-leucinamide were stirred in a mixture of 4 ml of trifluoroacetic acid, 4 ml of dichloromethane and 30 mg of water at room temperature for 30 minutes. Thesolution was evaporated to dryness in a vacuum and the residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (120:15:3:2) for the elution. There were obtained 41 mg of 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (7:1 mixture of diastereoisomers) as a white solid. MS: m/e 873 [M+H]+.