Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[ClH:17].Cl.[NH2:19][C:20]1[C:29]([NH2:30])=[C:28]2[C:23]([CH:24]=[C:25]([C:32]([OH:34])=[O:33])[CH:26]=[C:27]2[OH:31])=[CH:22][CH:21]=1.S(=O)(O)[O-].[Na+]>CCO.O>[ClH:17].[C:11]1([C:10]2[C:3]([O:2][CH3:1])=[C:4]([C:5]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[C:27]([OH:31])[CH:26]=[C:25]([C:32]([OH:34])=[O:33])[CH:24]=5)[C:29]=4[N:30]=3)[CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1c(C=O)cccc1-c1ccccc1
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(-c2ccccc2)cccc1-c1nc2c(ccc3cc(C(=O)O)cc(O)c32)[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To an agitated solution of 2-methoxy-3-phenylbenzaldehyde (0.020 g, 0.08 mmol) in EtOH (0.80 mL) was added 7,8-Diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.02 g, 0.07 mmol) and sodium bisulfite (0.02 g) in water (0.20 mL). The solution was heated to 60° C. and agitated over 18 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The tan residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.008 g, 20%) MS(ES) m/z 411 [M+H].
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1[C:10]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])=[CH:9][C:8]([OH:17])=[C:7]([OH:18])[CH:6]=1>CO>[CH3:1][O:14][C:13]([C@@H:12]([NH2:16])[CH2:11][C:10]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([OH:17])[CH:9]=1)=[O:15]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 15 °C
Yield: 117.3 %

Procedure:
A 3-Liter three-necked round-bottom flask equipped with a cooling bath, a thermometer and a condenser was charged with 1.5 Liters methanol, and acetyl chloride (119 ml, 1.2 mol) was carefully added thereto at 0° C. The cooling bath was replaced with a heating mantle and the mixture was heated to 15° C. 60 grams (0.3 mol) of L-3-(3,4-dihydroxy-phenyl)alanine was then added and the reaction mixture was refluxed for 3 hours and thereafter concentrated under reduced pressure at 60° C. to afford 74.3 grams (100% yield) of Compound 2 (see, Scheme 1). The product structure was confirmed by 1H-NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)[N:16]([CH3:24])[CH:15]=3)[C:11]([NH:37][S:34]([C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:35])=[O:36])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Reactant: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reaction time: 20 h

Procedure:
4-Dimethylaminopyridine (151 mg) was added to a solution of 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetic acid (the product of Example 68, 480 mg, 1.24 mmol) in anhydrous dichloromethane (10 ml) at ambient temperature. 2-Methoxy-4-methyl-1-benzenesulfonamide (from Preparation 11, 300 mg, 1.48 mmol) was added to the solution, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg, 1.83 mmol), and stirring was continued for 20 hours. The solution was washed twice with 2N hydrochloric acid, and dried (magnesium sulphate) and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and crystallised from dichloromethane and diethyl ether mixture to give the subtitle compound (535 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: COc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Yield: 46.9 %

Procedure:
The method described in Stage 12.1 is followed, starting from 5.4 g (28.64 mmol) of 2-chloro-4-methoxy-5-nitropyridine (WO2003/080610) and 4.53 g (63 mmol) of pyrrolidine. The product obtained is, in this case, purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate. In this way we isolate 3 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)([CH3:18])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.[OH-:30].[Na+].Cl>C(O)C.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([NH:19][C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:28])=[O:30])[CH:22]=3)=[O:29])([CH3:18])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1
Reactant: [OH-]
Reactant: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(C(N)=O)c1
Temperature: 0 °C
Yield: 30.3 %

Procedure:
To a solution of N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-cyanoisonicotinamide (300 mg, 724 umol) in ethanol (20 mL) at room temperature, was added a solution of sodium hydroxide (275 mg, 7.06 mmol) in water (6 mL). The reaction was microwaved at 80° C. for five minutes, and upon completion was cooled 0° C., neutralized with 1N HCl, concentrated and purified by flash chromatography (1/9 methanol/dichloromethane). The purified product was washed with hot ethanol and the solid was collected by vacuum filtration and dried under vacuum at 50° C. to yield N4-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)pyridine-2,4-dicarboxamide (95 mg, 29%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.50 (s, 6 H), 4.38 (s, 2H), 6.62 (d, J=0.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 1 H), 7.47 (t, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.86 (dd, J=5.2 Hz, 1H), 8.19 (s, 1H), 8.35 (s, 1H), 8.39 (s, 1H), 8.69 (s, 1H), 8.73 (dd, J=4.8 Hz, 1H), 10.99 (s, 1H). MS 433 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2=[O:20].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:27][S:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:5]2=[O:20])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Yield: 14.5 %

Procedure:
To a solution of tert-butyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (14 g, 50.7 mmol) in THF (100 ml), pyridine (8.20 ml, 101 mmol) was added followed by methanesulfonyl chloride (7.74 ml, 101 mmol), and the resulting mixture was heated to reflux for 5 hours. The volatiles were removed under vacuum, the residue was dissolved in DCM (200 ml) and washed with 0.2M HCl (3×50 ml) and brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The resulting solid was triturated with ethyl acetate, and the title compound was recovered by filtration (12.5 g). The mother liquors were evaporated in vacuo and purified by silica gel chromatography (DCM:AcOEt 10:1), affording additional 2.6 g of the title compound. These two batches were dissolved in DCM, combined, and the solvent was evaporated in vacuo to afford tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (15.1 g, 42.6 mmol, 84% yield, MS/ESI+ 354.9 [MH]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH:38]=[C:37]([CH3:47])[C:33]=1[C:34](O)=[O:35]>>[CH3:47][C:37]1[CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH:40]=[C:32]([CH3:31])[C:33]=1[C:34]([NH:19][CH2:18][CH2:17][CH:16]([N:13]1[CH2:12][CH2:11][CH:10]([CH:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)[CH2:15][CH2:14]1)[CH3:20])=[O:35]
Reactant: Cc1cccc(OC(c2ccc(C(F)(F)F)cc2)C2CCN(C(C)CCN)CC2)n1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Product: Cc1cccc(OC(c2ccc(C(F)(F)F)cc2)C2CCN(C(C)CCNC(=O)c3c(C)cc(-c4ccncc4)cc3C)CC2)n1
Yield: 47.6 %

Procedure:
Using general procedure E, 3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (see EXAMPLE 23) (40 mg, 0.10 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (24 mg, 0.11 mmol) afforded COMPOUND 50 (30 mg, 50%). 1H NMR (CDCl3) δ 0.50-1.10 (m, 2H), 0.95, 0.96 (d, 3H, J=6.1 Hz), 1.47-2.06 (m, 5H), 2.20, 2.22 (s, 3H), 2.26-2.45 (m, 1H), 2.42 (s, 6H), 2.56-2.87 (m, 4H), 3.24-3.41 (m, 1H), 3.76-3.94 (m, 1H), 5.16, 5.23 (d, 1H, J=8.1 Hz), 6.29 (dd, 1H, J=8.4, 4.5 Hz), 6.57 (dd, 1H, J=7.5, 2.7 Hz), 7.18-7.24 (m, 3H), 7.36-7.40 (m, 4H), 7.50 (d, 2H, J=4.8 Hz), 8.35, 8.47 (br s, 1H), 8.61-8.64 (m, 2H). 13C NMR (CDCl3) δ 13.17, 13.39, 19.42, 23.99, 24.03, 28.26, 28.90, 29.08, 29.87, 30.78, 31.32, 39.58, 39.69, 42.28, 44.06, 44.16, 51.95, 52.10, 60.03, 60.38, 79.67, 79.83, 106.97, 107.01, 116.03, 121.47, 124.06 (q, J=272 Hz), 124.88, 124.92, 125.93, 127.35, 129.43 (q, J=32 Hz), 135.25, 137.90, 137.97, 138.77, 139.38, 144.73, 147.70, 150.32, 156.19, 162.20, 169.26, 169.54. ES-MS m/z 631 (M+H). Anal. Calcd. for C37H41F3N4O2: C, 70.06; H, 6.58; N, 8.83; F, 8.98. Found. C, 70.15; H, 6.50; N, 8.79; F, 8.78.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
1.0 g (3.9 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride was suspended in 20 ml of dimethylformamide (DMF), and potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto followed by stirring at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1), then concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) as light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:8][CH:7]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:8][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Reaction time: 4 h

Procedure:
A 15 ml round bottom flask charged with 4-(2-(4-(4-hydroxybutyl)phenyl)ethoxy) quinazoline (0.25 g, 0.77 mmol) is dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate/hexanes) to give the product.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:24](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4]>FC(F)(F)C(O)=O>[NH2:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4]
Reactant: NC(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Yield: 139.1 %

Procedure:
2-Amino-3-((1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.203 g, 0.331 mmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was refluxed for 1 h. The reaction was concentrated to an oil under high vacuum. The oil was triturated with ether. The product was filtered, washed with ether, dissolved in 50/50 acetonitrile/water, and lyophilized to give 171.0 mgs (106%) of product. ESMS: Calcd. for C17H21N7O3, 371.17. Found, 372.0 [M+H]+1 Analytical HPLC, Method B, Rt=9.48 min, Purity=95%.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].COC(C)(C)C>FC(F)(F)C(O)=O>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:19]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: COCCCC(=O)Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 384 h
Yield: 50 %

Procedure:
4.5 g (0.02 moles) of carnitine hydrochloride were dissolved in 6 ml of trifluoroacetic acid. To this solution 4-methoxybutyryl chloride was added. The resulting mixture was kept under stirring at room temperature for 16 days. Subsequently tert-butyl methyl ether was added to the mixture. An oil precipitated which was treated with anhydrous acetonitrile in order to remove the undesired carnitine. To the acetonitrile solution tert-butyl methyl ether was added and 4-methoxybutyryl carnitine precipitated. Yield 50%.
Reaction SMILES: O.C(=O)(O)[O-].[Na+].[N:7]1([CH:13]=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Br:15][CH2:16][CH2:17][C:18]([N:10]1[CH2:11][CH2:12][N:7]([CH:13]=[O:14])[CH2:8][CH2:9]1)=[O:19]
Reactant: O=C(Cl)CCBr
Reactant: O=CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=CN1CCN(C(=O)CCBr)CC1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
A mixture of 15 ml of water and 25 ml of methylene chloride containing 3.0 g (36 mmole) of sodium bicarbonate and 2.82 g (24.7 mmole) of 1-piperazinecarboxaldehyde is stirred and treated with 5.0 g (30.9 mmole) of 3-bromopropionyl chloride in 10 ml of methylene chloride over a 15 minute period while maintaining a temperature of about 20° C. After stirring for an additional 20 minutes, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are drive (Na2SO4), filtered and concentrated under high vacuum to yield 4.35 g (70.2%) of product as a colorless solid: mp 96°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7](Br)[O:6]1)=[O:4].[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[O:6]1)=[O:4]
Reactant: COC(=O)[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(C=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 72.1 %

Procedure:
44.1 g (111 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro-pyran-2-carboxylic acid methyl ester is reacted analogously to Example LE1a with 14 g of 4-hydroxy-benzaldehyde, and after working-up and purification, 35.1 g (80 mmol, 72%) of the title compound is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([O:19][CH3:20])=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:21][O:22][C:23]1[C:24](=O)[C:25](=[O:29])[C:26]=1[O:27]C>CO>[CH3:21][O:22][C:23]1[C:26](=[O:27])[C:25](=[O:29])[C:24]=1[NH:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([O:19][CH3:20])=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(Cl)c(N)c1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of 2.54 g of methyl (R)-1-(3-amino-4-chlorobenzenesulfonyl)pyrrolidine-2-carboxylate and 5.68 g of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 50 ml of methanol was heated at 60° C. overnight. The solvent was evaporated off and the residue was chromatographed on silica gel eluted with heptane/ethyl acetate (4:1, 2:1, and pure ethyl acetate). 0.92 g of methyl (R)-1-[3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate was obtained. Yield=23%.
Reaction SMILES: [CH2:1]([Li])CCC.[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=O)[CH:24]=[CH:23][C:21]=3[N:22]=2)=[C:14]([F:35])[CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[O:8]1[CH2:9][CH2:10][CH2:11][O:6][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH2:1])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[C:14]([F:35])[CH:13]=1
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 1.80 mL, 4.50 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.78 g, 5.00 mmol) in THF (10 mL) at −78° C. and the mixture was warmed to 0° C. over 30 min. The suspension (1 mL, about 3 equiv Wittig reagent) was added to a suspension of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-benzo[d]thiazol-6-yl)(pyridine-2-yl)methanone (0.09 g, 0.21 mmol) in THF (1 mL) and the mixture was stirred for 16 h at RT. The solvent was remove under vacuum and the resulting oil was purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-(pyridin-2-yl)vinyl)benzo[d]thiazole as a white solid. MS (ESI) m/z: Calculated: 418.1; Observed: 419.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH:29]=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[C:33]1=[O:47].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:34]4[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:32]([CH3:31])[C:33]4=[O:47])[CH2:42][CH2:43]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
To a stirred solution of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6 mmol) in CH2Cl2 (20 mL) were added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirred for 20 min. NaBH(OAc)3 (0.65 g, 30.6 mmol) was added and stirred under nitrogen for 2 h. Saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C34H41F3N6O3, 638.32. m/z found, 639.3 [M+H]+, 661.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1)([F:7])[F:6])C.[NH2:18][NH2:19]>CO>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]([F:7])([F:6])[C:4]([NH:18][NH2:19])=[O:3])=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: NN
Reactant: CCOC(=O)C(F)(F)c1ccc2occc2c1
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2occc2c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of the compound prepared in step c (127 mg, 0.53 mmol) and hydrazine (0.28 mL, 8.9 mmol) in dry methanol (3 mL) was stirred at reflux for 3 hr, cooled to RT and evaporated in vacuo to afford a semisolid product (0.12 g) 99%. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.90 (s, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.5, 1.5 Hz, 1H), 7.09 (d, J=1.3 Hz, 1H)
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN([CH:17]=[O:18])C>>[CH2:11]([O:12][C:17](=[O:18])[CH2:6][CH2:7][CH2:8][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([O:13][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:12])[NH2:1])=[CH:9][CH:8]=1)[CH3:2]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
Potassium tertbutylate (3.36 g, 30 mmoles) is added to a solution of tyrosine 4-1 (5 g, 21 mmoles) in 100 ml of DMF, followed by agitating for 30 minutes while cooling down in a water+ice bath, then the bromoester (ethyl 4-bromobutanoate) (3.6 ml, 25 mmoles) in solution in 10 ml of DMF is added. The reaction medium is agitated overnight at ambient temperature, followed by evaporating under reduced pressure, taking up the dry extract in a water/ethyl acetate mixture, decanting, drying the organic phase, filtering, evaporating then purifying by chromatography eluting with a Heptane/ethyl acetate gradient (100/0→0/100). 5.2 g of the expected product 4-2 is obtained.