Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.CCCCCC>[F:10][CH:11]([F:14])[CH2:12][NH:13][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCC(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNCC(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
tert-Butyl bromoacetate (2.72 g) was added to a suspension of 2,2-difluoroethylamine (1.46 g) and potassium carbonate (2.48 g) in acetonitrile (5 mL) and the mixture was stirred at RT for 24 h. The mixture was diluted with EtOAc (10 mL) and hexane (10 mL). The suspension was washed with the mixture of aqueous NaHCO3 (20 mL) and brine (10 mL). The organic extracts were dried and concentrated in vacuo to provide crude product. The crude product was purified by vacuum distillation (12 hPa, 78-80° C.) to afford sub-title compound (1.85 g) as a colourless oil; 1H NMR (300 MHz, CDCl3); 5.82 (1H, tt, J=4.4, 56 Hz), 3.45 (2H, s), 2.98 (2H, dt, J=4.4, 15.1 Hz), 1.45 (9H, s).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCC(O)CN1CCCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.05 (dd, 1H, J=6.0, 10 Hz), 5.47 (s, 2H), 3.80 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.7-2.4 (m, 7H), 2.25 (s, 3H), 1.8-1.4 (m, nH) ppm; Ms (APCI, m/z): 512 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 39.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.9 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[CH:4]=1.[C:11](O)(=[O:13])[CH3:12].Br>O>[OH:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CC(=O)c1ccc(O)cc1O
Temperature: 25 °C

Procedure:
1,3-Dimethoxybenzene (8.00 g, 57.4 % mmol) was combined with acetic acid (500 ml) and 48% hydrobromic acid (300 ml). The solution was stirred and heated to reflux for five days. The reaction mixture was allowed to cool to room temperature then poured into water (500 ml). The aqueous solution was extracted with ether (500 ml, 2×) and concentrated in vacuo to a reddish brown oil. Chromatography by HPLC yielded a small amount of the title product uncontaminated by the resorcinol side product:
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@@H:10]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:11]([CH3:13])[CH3:12])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2].Br[C:51]1[NH:55][C:54]([C@@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:14][C:15]([O:16][CH3:17])=[O:18])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36]([C:51]2[NH:55][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
To a solution of methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C1CCN2C(=NCCC2)CC1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(O)C>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=2)[NH:7]1
Reactant: O=C1Cc2cc(O)ccc2N1
Reactant: CCOC(=O)CBr
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccc2c(c1)CC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of 5-hydroxyindolin-2-one (1 g, 6.70 mmol) in 2-Propanol (10 mL) was added DBU (1.52 mL, 10.06 mmol) and ethyl bromoacetate (1.12 mL, 10.06 mmol) at room temperature. The reaction mixture was refluxed at 80° C. for 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated and water (100 mL) was added. The solid which precipitated was filtered and dried to yield ethyl 2-((2-oxoindolin-5-yl)oxy)acetate as an off white solid (0.75 g, 47.6%) LCMS: RT 0.67 min. LCMS (ES-API), m/z 236.0 (M+H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20].O>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:4][CH3:2])=[CH:12][C:11]=1[F:20]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a mixture of potassium tert-butoxide (3.0 g, 26.9 mmol) in DMF (20 mL), methanol (0.79 g, 24.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then a solution of 1-chloro-2,4-difluoro-5-nitrobenzene (4.0 g, 20.7 mmol) in DMF (20 mL) was added at 0° C. and the reaction mass stirred for 3 hours at room temperature. Water (200 mL) was added to the reaction mixture and reaction mass was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (80 mL), brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. The product was purified by column chromatography on neutral silica gel using 20-25% EtOAc in hexane to give the desired product (3 g, 71%) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:2]([P:10](=[O:14])([O:11][CH2:12][CH3:13])[O:9][CH2:7][CH3:8])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCCBr
Product: C=CCCCP(=O)(OCC)OCC

Procedure:
5-bromo-1-pentene was combined with triethylphosphite in the absence of solvent using microwave conditions at 150° C. to give diethyl 4-pentenylphosphonate. Diethyl 4-pentenylphosphonate was combined with bromotrimethyl silane and subsequently quenched with methanol to afford diethyl 4-pentenylphosphonic acid according to Scheme 8.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH:8]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:8]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=1
Reactant: Cc1cccnc1C(Cl)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a dimethylformamide (5 ml) solution of the 2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94 mg, 0.32 mmol) obtained in Referential Example 14 were added 4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg, 1.92 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diethyl ether (50 ml) was added to the reaction mixture. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate 10:1), whereby the title compound (103 mg, 89%) was obtained as an oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1CCCCC1[O:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][C:30]2[CH:33]=[CH:34][O:35][C:29]=2[C:28]1=[O:36].C(=O)([O-])O.[Na+]>CO>[OH:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][C:30]2[CH:33]=[CH:34][O:35][C:29]=2[C:28]1=[O:36]
Reactant: O=c1c2occc2ccn1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=c1c2occc2ccn1CCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
Pyridinium p-toluenesulfonate (0.21 g, 0.85 mmol) was added to a methanol solution (20 ml) of 6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one (0.45 g, 1.7 mmol), and stirred at room temperature for 2 days. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue to precipitate crystals. The crystals were collected by filtration and dried to thereby obtain 223 mg (yield: 73%) of 6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one as a white powder.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([OH:16])([CH2:13][O:14][CH3:15])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[OH:16][C:10]1([CH2:13][O:14][CH3:15])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COCC1(O)CCNC1

Procedure:
10 g (45 mmol) of 1-benzyl-3-hydroxy-3-methoxymethylpyrrolidine are hydrogenated using 3 g of Pd/active carbon (10% Pd) in 200 ml of methanol at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=O)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[NH:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2[nH]c(=O)[nH]c12
Product: COc1cccc2nc(Cl)[nH]c12

Procedure:
To a round bottomed flask was added 4-methoxy-1H-benzo[d]imidazol-2(3H)-one (1.8163 g, 11.06 mmol). POCl3 (1.031 mL, 11.06 mmol) was added and the reaction was brought to reflux. Upon completion, POCL3 was evaporated off. The residue was taken up in DCM. The reaction mixture was diluted with water and saturated sodium bicarbonate and extracted with DCM. The organic extract was washed with sat. sodium bicarbonate solution, water, brine, dried with, magnesium sulfate, filtered, and concentrated to provide 2-Chloro-7-methoxy-1H-benzo[d]imidazole. [M+H]=182.9.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)=[C:27]([F:37])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:37])[C:28]([O:32][CH2:33][CH:34]5[CH2:36][CH2:35]5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CC3)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (135 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 39 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 0.24-0.30 (m, 2H), 0.50-0.56 (m, 2H), 1.15-1.21 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 3.97 (d, J=7.5 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 2H), 7.35 (s, 1H), 7.60-7.66 (m, 2H), 7.77 (s, 1H), 12.68 (br s, 1H); APCI-MS (m/z) 502.13 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:30]([O:37][C:38]([N:40]([CH2:42][CH2:43]Cl)[CH3:41])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:43][CH2:42][N:40]([C:38]([O:37][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:39])[CH3:41])[C:12]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 51 %

Procedure:
A mixture of 5 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.8 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride, 1.1 g of potassium hydroxide and 70 ml of dimethylsulfoxide is treated in the same manner as described in Example 1-(1). 3.75 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: N[C@H:2]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:5]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:19]2=[O:34])[CH2:4][CH2:3]1.C(C1C(=O)C(=[O:49])C=C(C(C)(C)C)C=1)(C)(C)C.C1COCC1.C(O)(=O)C(O)=O>CO.O>[CH2:27]([O:26][C:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@H:5]2[CH2:4][CH2:3][C:2](=[O:49])[CH2:7][C@H:6]2[NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:19]1=[O:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Yield: 53.5 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-5-amino-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (1.03 g, 2.099 mmol) in methanol (10 ml) was added 3,5-di-tert-butyl-1,2-benzoquinone (0.555 g, 2.52 mmol). This mixture was stirred for 2 hr before THF (6 mL) and water (2 mL) were added along with oxalic acid to pH 4. This mixture was concentrated. The resulting residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated. This was purified via flash chromatography to give 2-(trimethylsilyl)ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-oxocyclohexylcarbamate (0.550 g, 1.123 mmol, 53.5% yield). LC/MS found [M+H]+=491.3.
Reaction SMILES: OO.O.[OH-].[Li+].[CH2:6]([O:26][C@H:27]([CH2:43][CH3:44])[C:28](N1[C@@H](C)[C@@H](C2C=CC=CC=2)OC1=O)=[O:29])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].[O-:45]S([O-])=O.[Na+].[Na+].Cl>O1CCCC1.O>[CH2:6]([O:26][C@H:27]([CH2:43][CH3:44])[C:28]([OH:29])=[O:45])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25]
Reactant: O=S([O-])[O-]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO[C@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO[C@H](CC)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Hydrogen peroxide (35% in water, 0.65 mL, 7.37 mmol) and lithium hydroxide monohydrate (0.15 g, 3.69 mmol) was added to a solution of (4S,5R)-3-((R)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl-5-phenyloxazolidin-2-one (0.95 g, 1.84 mmol) in tetrahydrofuran (12 mL) and water (4 mL) held at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes. 10% Na2SO3(aq) (30 mL) was added, the pH was adjusted to ˜2 with 2M HCl and the mixture was extracted twice with heptane (30 mL). The combined organic extract was dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8→50:50) as eluent. Concentration of the appropriate fractions afforded 0.19 g (29% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.90-1.00 (m, 6H), 1.48 (m, 2H), 1.65 (m, 2H), 1.85 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.55 (m, 1H), 3.60 (m, 1H), 3.88 (t, 1H), 5.35-5.45 (m, 10H); MS (electro spray): 373.3 [M-H]−; [□]D−31° (c=0.088, ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)O)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (CD17) and NaOH in ethanol was stirred at 50° C. for 3 h after which it was cooled to RT and neutralized with conc. HCl. The solvent was removed under reduced pressure to obtain crude 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH2:7].C(N(C(C)C)CC)(C)C.[C:37]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[CH3:2][O:3][C:4](=[O:27])[CH:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH:7][S:43]([C:40]1[CH:39]=[CH:38][C:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNS(=O)(=O)c1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as per the above listed example 656 was added dry dichloromethane (10 ml) followed by diisopropylethylamine (0.095 g, 0.738 mmol) and stirred for 10 min. To this mixture at 0° C. was added Biphenyl-4-sulfonyl chloride (0.062 g, 0273 mmol) and the reaction was stirred at ambient temperature. After 2 hrs the reaction mixture was diluted with dichloromethane and washed with water (20 ml) followed by brine (20 ml). The organic layers were collected and dried over sodium sulfate and concentrated under reduced pressure to yield the 3-(Biphenyl-4-sulfonylamino)-2-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per procedure C to yield the title compound (0.045 g, 50%). 1H-NMR(400 MHz, DMSOd6): 3.65 (m, 2H), 4.85 (m, 1H), 7.78 (m, 4H), 8.02 (d, 2H), 8.17 (m, 7H), 8.27 (m, 4H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS (m/z): 569.1 (M+1).