Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>O.CO.C(Cl)Cl>[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc2ccc(C(C)=O)cc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc2ccc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of KOH 70 mg, 10 mmol) in water (3.5 mL) was added dropwise to a cooled solution of the ester 168 (640 mg, 2.81 mmol) in MeOH (10 mL) and CH2Cl2 (10 mL) at 0° C. After allowing the mixture to warm to room temperature and stirring for 96 h, excess CH2Cl2 and water were added. The aqueous portion was acidified (pH 2) with 2N HCl and the resulting white precipitate was extracted with EtOAc (×2). The combined EtOAc extracts were washed with water, brine, and dried, to give 7-acetyl-2-naphthoic acid (169). (575 mg, 96%) as a colorless solid. A sample was recrystallised from petroleum ether/CH2Cl2/Et2O: mp 224-228° C.; 1H NMR: (CDCl3) 8 (CO2H not observed) 8.82 (s, 1H), 8.60 (s, 1H), 8.23 (dd, J=8.6, 1.6 Hz, 1H), 8.18 (dd, J=8.7, 1.7 Hz, 1H), 7.97 (c, J=8.7 Hz, 2H), 2.76 (s, 3H). Anal. (C13H10O3) C, H.
Reaction SMILES: C(=[N:8][CH:9]([P:23]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>C(OCC)C>[NH2:8][CH:9]([P:23]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(N=Cc1ccccc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOCC
Product: NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of p-nitrobenzyl N-benzylidene-α-aminodiphenylphosphonoacetate (16.43 g) in ethyl ether (100 ml) is added dropwise over 30 minutes to a stirring solution of p-toluenesulfonic acid monohydrate (6.48 g) in ethyl ether (150 ml). Cyclohexane (100 ml) is added to the mixture and the solvents are decanted from the precipitate. The precipitate is washed with more 2:1 ethyl ether-cyclohexane which is again decanted off. The precipitate is treated with 1 M aqueous dipotassium hydrogen phosphate (60 ml) and extracted with four portions of methylene chloride. The methylene chloride solution is dried over magnesium sulfate, filtered, and evaporated to give p-nitrobenzyl α-aminodiphenylphosphonacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].Br[C:31]1[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][C:32]=1[NH2:41].C([O-])([O-])=O.[Na+].[Na+].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.O.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:31]3[C:32]([NH2:41])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][C:36]=3[CH3:37])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cc(N)c1Br
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A flask with a stirbar was charged with {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 140: step a (752 mg, 1.65 mmol), 2-bromo-3-methyl-5-nitro-phenylamine ((Example 295: step g) 306 mg, 1.32 mmol), aqueous Na2CO3 (2M, 4 mL, 8 mmol), ethanol (4 mL) and toluene (8 mL). The solution was sparged with argon for 10 min and Pd(PPh3)4 (294 mg, 0.25 mmol) was added. The biphasic solution was vigorously stirred under inert atmosphere at 80° C. for 16 h, then was cooled to rt. EtOAc (40 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with saturated NaHCO3 (2×20 mL), brine (20 mL) and was dried over sodium sulfate. Removal of the solvents in vacuo followed by column chromatography (10–40% EtOAc in hexanes) of the residue yielded the title compound (245 mg, 33%) as a yellow solid. 1H-NMR (CDCl3): δ 8.03 (ddd, 1H, J=1.2, 2.1, 8.1 Hz), 7.91 (s, 1H), 7.90 (t, 1H, J=1.6 Hz), 7.69 (t, 1H, J=7.9 Hz), 7.53 (app dd, 1H, J=0.7, 2.3 Hz), 7.50 (dt, 1H, J=1.4, 7.7 Hz), 7.44 (app dd, 1H, J=0.5, 2.3 Hz), 3.70 (s, 2H), 2.59 (s, 3H), 2.00 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[S:7][C:8]2[C:14]([CH:15]3[CH2:20][O:19][CH2:18][CH2:17][O:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)C.[OH-].[K+]>O1CCOCC1.C(O)CO>[O:16]1[CH2:17][CH2:18][O:19][CH2:20][CH:15]1[C:14]1[C:8]2[S:7][C:6]([NH2:5])=[N:10][C:9]=2[C:11]([O:21][CH3:22])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(C2COCCO2)c2sc(N)nc12
Temperature: 100 °C
Yield: 84 %

Procedure:
To a stirred solution of 330 g (9.75 mmol) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester in 200 ml dioxane and 20 ml ethylene glycol was added 200 ml of a 2 N aq. potassium hydroxide solution and the mixture was heated at 100° C. for 2 days. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Flash chromatography (1/9 acetone/dichloromethane) followed by trituration in ethyl acetate afforded 2.18 g (84 %) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine as an off-white solid. [α]D20=+28.2° (c=0.92, CHCl3), ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])C.C(O)(=O)C.IC1C=CC=CC=1.II.CO>C(Cl)Cl>[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[O:21][CH3:19])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: II
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (S)-(−)-N-benzyloxycarbonylproline (10 g, 40 mmol) in CH2Cl2 (500 mL) was added iodobenzene diacetate (26 g, 80 mmol, 2.0 equiv) and iodine (5.2 g, 20 mmol, 0.50 equiv). The resulting mixture was stirred at rt for 5 h. Methanol (20 mL) was added and the reaction mixture was stirred at rt for 1.5 h. The reaction was then quenched by the addition of 10% Na2S2O3 (200 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with 10% Na2S2O3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product (28 g) as a yellow oil. Purification by flash chromatography (silica gel, 10-30% EtOAc/hexane) provided the expected product (9.41 g, 77%) as a yellow oil along with the corresponding hydroxy product (8.85 g, 11%) as a white solid: mp 44-46° C. The hydroxy product could subsequently be quantitatively recycled to the desired methoxy compound by treatment with pyridinium p-toluene sulfonate (PPTS) in MeOH at rt for 20 h. Data for step 1 compound: HPLC (Phenominex 4.6×50 mm) retention time 2.94 min; LC/MS m/z 236 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 5.15-5.29 (m, 3H), 3.52 (td, 1H, J=8.8, 1.3 Hz), 3.32-3.48 (m, 3H), 3.26 (s, 1H), 1.99-2.15 (m, 1H), 1.84-1.98 (m, 2H), 1.67-1.82 (m, 1H). Data for compound 3: LC/MS m/z 222 [M+H]+; 1 H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 5H), 5.47-5.55 (m, 1H), 5.15 (s, 2H), 3.55-3.65 (m, 1H), 3.30-3.42 (m, 1H), 1.78-2.02 (m, 4H).
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:20]([CH3:22])[CH3:21])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][CH:15]=[O:16])[CH:11]=[CH:12][CH:13]=1)([CH3:18])[CH3:19]
Reactant: CC(C)[Si](OCCc1cccc(CCO)c1)(C(C)C)C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[Si](OCCc1cccc(CC=O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 53 (0.170 g, 0.527 mmol) in dichloromethane (4 mL) was added with Dess-Martin periodinane (0.270 g, 0.632 mmol) and stirring was maintained for 4 h at rt. The reaction mixture was filtered through a pad of celite and then concentrated to dryness. The residue so obtained was purified by silica gel column chromatography, using gradients of ethyl acetate in hexanes as eluent, to obtain the desired compound. Yield 77%.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[NH:18]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:19]([C:35]([NH:37][C@H:38]([C:40](O)=[O:41])[CH3:39])=[O:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:18]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[C@H:19]([C:35]([NH:37][C@H:38]([C:40]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:41])[CH3:39])=[O:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Yield: 56.2 %

Procedure:
compound NR36. Same procedure as above with HCl, Trp-OCH3 (255 mg, 1 mmol), N-Boc-Tyr(Bn)-Ala-OH (444 mg, 1 mmol), DCC (259 mg, 1.26 mmol) and HOBt (172 mg, 1.27 mmol) in THF (15 mL). The crude residue was chromatographed over silica gel to afford a white solid (361 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7 Hz, 3H, CH3), 1.29 (s, 9H, (CH3)3), 2.62 and 2.92 (ABX system, 2H, CH2P), 3.08 and 3.13 (ABX system, 2H, CH2β) 3.55 (s, 3H, OCH3), 4.10 (m, 1H, CHα), 4.36 (m, 1H, CHα), 4.49 (m, 1H, CHα), 5.03 (s, 2H, CH2 (OBn)), 6.85-7.50 (m, 15H, 14 aromatic H+1 NH), 7.97 (d, J=7.3 Hz, 1H), 8.34 (d, J=7.0 Hz, 1H), 10.88 (s, 1NH). 13C NMR (75 MHz, DMSO-d6) δ 18.2 (CH3), 26.8 (CH2 Trp), 28.0 ((CH3)3), 36.3 (CH2 Tyr), 47.6, 51.6, 53.0, 55.6 (CHα Ala, Tyr, Trp or OCH3), 69 (CH2 (OBn)), 77.9 (C(CH3)3), 109.0 (aromatic C), 111.2, 114.2, 117.8, 118.3, 120.8, 123.6 (aromatic CH), 126.9 (aromatic C), 127.4, 127.6, 128.2, 130.0 (aromatic CH), 130.2, 135.9, 137.1 (aromatic C), 155.1, 156.7 (Car-O or CO carbamate), 171.2, 171.9, 172.1 (2 CO amide or CO ester). Anal. Calcd. for C36H42N4O7, 0.5H2O: C, 66.34; H, 6.65; N, 8.60. Found: C, 66.29; H, 6.64; N, 8.48.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:15])=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[OH:14]/[N:13]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:3][C:4]=1[CH3:15])\[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C(=N\O)c1nc(N)sc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\O)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Yield: 89.9 %

Procedure:
A solution of ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (8.73 g) in dimethylformamide (60 ml) was treated portionwise with trityl chloride (11.7 g) and dropwise with triethylamine (6.4 ml). The reaction mixture was quenched by water and extracted with ethyl acetate. The combined extracts were washed with water and brine, and were dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(Z)-hydroxyimino-2-(5-methyl-2-tritylaminothiazol-4-yl)acetate (16.15 g).
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH:28]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH2:34][OH:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].O>CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH:28]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH2:34][OH:35])=[O:10])=[CH:36][CH:37]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3ncnc4[nH]c(C5=CCC(=O)CC5)cc34)c2CO)cc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3ncnc4[nH]c(C5=CCC(O)CC5)cc34)c2CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 49 (80 mg, 0.162 mmol) in MeOH/DCM (1:1) were added cerium(III) chloride heptahydrate (66.3 mg, 0.178 mmol) and NaBH4 (6.1 mg, 0.162 mmol). The resulting mixture was stirred at r.t. for 2 hrs. Water was added, and the mixture was extracted three times with DCM/isopropanol (3:1). The combined organic layers were dried, filtered, and evaporated to dryness. The resulting residue was purified using flash chromatography (silica gel, EtOAc/MeOH/N H3 gradient) to yield Example 55.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11]OC)([CH3:7])[CH2:3][C:4](=O)[CH3:5].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl([O-])(=O)(=O)=O.C[NH2+]C.[OH-].[Na+]>[Pt]=O>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH:10]=[CH2:11])([CH3:7])[CH2:3][CH:4]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:5]
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Reactant: C1CCNCC1
Agent: O=[Pt]
Agent: C[NH2+]C
Agent: [Na+]
Product: C=CC(=O)NC(C)(C)CC(C)N1CCCCC1

Procedure:
Following the procedure of Example 1, a mixture of 201 parts (1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide, 170 parts (2 moles) of piperidine, 0.5 parts of platinum oxide and 1 part of dimethylammonium perchlorate is hydrogenated in the Parr apparatus, starting at a pressure of 70 psi. and recharging when the pressure has reached 39 psi. The product is pyrolyzed with sodium hydroxide to yield the desired N-(1,1-dimethyl-3-piperidinobutyl)acrylamide.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH2:4]1.[N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:21])[C@H:16]([C:18](O)=[O:19])[CH3:17].O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.Cl>[O:10]=[C:9]1[CH:3]([NH:2][C:18](=[O:19])[C@@H:16]([N:15]([CH3:21])[C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH3:17])[CH2:4][S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[NH:8]1
Reactant: NC1CSc2ccccc2NC1=O
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)NC1CSc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Yield: 270 %

Procedure:
3-Amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (1.0 g, 5.15 mmol, Eq: 1.00), BOC—N-Me-Ala-OH (1.26 g, 1.62 mmol, Eq: 1.2) and TEA (2.2 mL, 15.45 mmol, Eq: 3.00) were dissolved in DMF (30 mL) and HOBT.H2O (697 mg, 5.14 mmol, Eq: 1.20) and HBTU (2.34 g, 6.18 mmol, Eq: 1.20) were added. After 1 h 20 min. the mixture was diluted with 1 N HCl and extracted with EtOAc. The organic extracts were washed with 1 N NaOH, brine, dried over Na2SO4 and concentrated to afford the title compound (1.66 g, 85% yield) which was used without purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7]1.[CH2:23]([NH:26][C:27]1[CH2:31][S:30][C:29](=[O:32])[N:28]=1)[C:24]#[CH:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8](/[CH:11]=[C:31]2/[C:27]([NH:26][CH2:23][C:24]#[CH:25])=[N:28][C:29](=[O:32])[S:30]/2)[CH2:7]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]pyrrolidine-3-carbaldehyde (1.1 g) in 2-propanol (10 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.782 g) and piperidinium acetate (0.491 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.760 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(Cl)cccc1Cl
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
40% Methanolic Triton B (0.23 mL, 0.49 mM) was added to a solution of the 9-[(2,6-dichlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (146 mg, 0.38 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (119 mg, 0.76 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 83 mg (48%) of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a tan solid. 1H NMR (DMSO-d6) δ 7.5-7.0 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.8 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1). MS (ES) m/e 457, 459.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:26][CH3:27])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35].COC1C2N=C(NC(=O)C3C=CC(CN4CCCC4)=CC=3)SC=2C(C2C=CC=CC=2)=CC=1>>[O:24]1[CH2:25][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:28]=[CH:29][C:3]([CH2:2][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH3:35])=[CH:4][CH:5]=4)=[N:14][C:13]=3[C:15]([O:26][CH3:27])=[CH:16][CH:17]=2)[CH2:20][O:21][CH2:22][CH2:23]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC
Agent: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1

Procedure:
4-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide and N-(2-methoxyethyl)-methylamine were reacted as described for N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide in WO01/97786. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown powder. MS: m/e=486(M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of compound 10.4 (2.1 mmol), p-toluenesulfonic acid monohydrate (0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours. After quenching with saturated aqueous NaHCO3, MeOH was removed under reduced pressure. The residue was extracted with EtOAc, and the combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered through short plug of silica gel. Upon concentration, compound 10.3 was obtained. MS ESI (pos.) m/e 248.1 (M+1). 1H NMR (500 MHz) (DMSO-d6) δ 9.04 (s, 1H); 7.99 (s, 1H); 7.14 (s, 1H); 7.05(m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, 1H); 3.57 (s, 1H); 3.22-3.27(m, 1H); 2.89-2.94(m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=2[CH2:36][CH2:37][CH3:38])[C:8]=1[CH2:39][CH2:40][CH3:41])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:42])=[O:3])=[C:8]([CH2:39][CH2:40][CH3:41])[C:9]=1[O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=1[CH2:36][CH2:37][CH3:38])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 91.9 %

Procedure:
A solution of 2.35 g (0.004 mole) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester in 50 ml of methanol and 20 ml (0.02 mole) of 1.0N sodium hydroxide was stirred at reflux for 90 minutes. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0 with 6N HCl. The gummy product was extracted with methylene chloride. The dried (magnesium sulfate) extract was concentrated in vacuo and the residue was crystallized from methylene chloride-hexane to give 2.06 g (92% yield) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid, mp 74°-77°.