Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[C:14]([NH:15][C:16]([CH3:18])=[O:17])=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]=1[C:19]([OH:21])=O)[C:2]([CH3:4])=[O:3].NC1C(N)=CC2OCCOC=2C=1C(O)=O.[N:37]1([CH:43]([NH2:46])[CH2:44][CH3:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:43]([NH:46][C:19]([C:6]2[C:7]3[O:12][CH2:11][CH2:10][O:9][C:8]=3[CH:13]=[C:14]([NH:15][C:16]([CH3:18])=[O:17])[C:5]=2[NH:1][C:2]([CH3:4])=[O:3])=[O:21])[CH2:44][CH3:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCC(N)N1CCCCC1
Reactant: CC(=O)Nc1cc2c(c(C(=O)O)c1NC(C)=O)OCCO2
Agent: Nc1cc2c(c(C(=O)O)c1N)OCCO2
Product: CCC(NC(=O)c1c(NC(C)=O)c(NC(C)=O)cc2c1OCCO2)N1CCCCC1

Procedure:
In the same manner as described in Example 53, the 6,7-diacetamino-1,4-benzodioxane-5-carboxylic acid (prepared by acetylation of the 6,7-diamino-1,4-benzodioxane-5-carboxylic acid) was condensed with the 1-piperidinopropylamine in the presence of the isobutyl chloroformiate. The N-(1-piperidinopropyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide was obtained (M.P.: above 260° C. with decomposition). The structure was confirmed by nuclear magnetic resonance analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:22])[NH:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32]>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:20]1[CH2:21][CH:18]([NH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:22])[CH2:19]1)=[O:32])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(NC1CNC1)OCc1ccccc1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CC(NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of Azetidin-3-yl-carbamic acid benzyl ester trifluoroacetate (prepared by standard protection and deprotection procedures from 3-Amino-azetidine-1-carboxylic acid tert-butyl ester) in 10 ml of DCM, 1.9 g of triethylamine was added and the mixture was cooled to 0° C. Then, 938 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 1 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.4 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:8])O[CH:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:16]=1[NH2:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:23]([C:19]1[CH:18]=[C:16]([N:17]2[CH:7]=[C:2]([Cl:1])[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]2[CH3:8])[C:15]([CH3:14])=[CH:21][C:20]=1[CH3:22])([O-:25])=[O:24]
Reactant: COC(=O)c1c(C)occ(Cl)c1=O
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)n(-c2cc([N+](=O)[O-])c(C)cc2C)cc(Cl)c1=O

Procedure:
A solution of 10.1 g (0.05 mol) 5-chloro-3-methoxycarbonyl-2-methyl-4-pyranone, 8.5 g 2,4-dimethyl-5-nitroaniline and 0.1 g p-toluenesulfonic acid monohydrate in 100 ml of toluene are refluxed for 8 h in a water separator apparatus. The mixture is allowed to cool and the precipitating product is filtered off, washed with a small amount of ethylacetate/petrolether and dried. Yield: 15.0 g (85.5%) 1-(3'-nitro-4',6'-dimethylphenyl)-5-chloro-3-methoxycarbonyl-2-methyl-4-pyridone, mp. 266° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])/[CH:20]=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[CH:20]=[CH:21][CH2:22][OH:23])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CC(/C=C/CO)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.99 g (10 mmol) of 2,6-dichloroquinoxaline, 2.13 g (11 mmol) of (E)-4-(4-hydroxyphenoxy)-2-penten-1-ol, 1.73 g (12.5 mmol) of powdered, anhydrous potassium carbonate and 50 ml of dry acetonitrile was warmed at reflux under nitrogen for a period of 3 hours. The mixture was cooled to room temperature, and the solid filtered off and washed well with ether. The filtrates were combined and evaporated to dryness, and the residue partitioned between ether and 2 percent aqueous sodium hydroxide. The aqueous layer was separated and extracted again with ether. The combined organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residual solid was purified by preparative scale HPLC, eluting with 7:3 hexane: ethyl acetate, to give a solid which was recrystallized from toluene. This gave 2.60 g (73%) of the desired pentenol as pale yellow crystals, having a melting point (m.p.) of 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C(O)C>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH:13]=[CH:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C=CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)C=CC(=O)O)c1

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-2-butenoate (Step E) in abs ethanol at low temp, add aqueous sodium hydroxide, after an hour, concentrate and purify by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:17][C:18]([OH:20])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:46][C:47]([F:58])([F:57])[C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[CH2:53][NH:52][CH2:51]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[O:20]=[C:18]([N:52]1[CH2:51][C:50]2[C:54](=[CH:55][CH:56]=[C:48]([C:47]([F:46])([F:58])[F:57])[CH:49]=2)[CH2:53]1)[CH2:17][N:3]1[CH2:4][CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)acetic acid from Example 266D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-(trifluoromethyl)isoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (t, J=12.0, 4H), 7.42 (dd, J=8.2, 20.4, 3H), 4.91 (d, J=16.7, 4H), 4.23 (dd, J=16.2, 36.5, 2H), 3.83 (t, J=8.3, 1H), 3.77-3.62 (m, 2H), 2.74-2.54 (m, 1H), 2.32-2.16 (m, 1H); MS (DCI) m/z 457.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.[CH2:23](N(C(C)C)C(C)C)C.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]([O:22][CH3:23])[CH2:10][N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Agent: c1nc[nH]n1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=Nc2cc(OC)c(F)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 3.0 g (0.0094 mole) of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia), 11.8 mL of ethyl diisopropyl amine, 4.62 g of 1,2,4-triazole and 45 mL of tetrahydrofuran at 0° C., was added 1.575 mL of phosphorous oxychloride. After 20 minutes, the cooling bath was removed, and the mixture was stirred at room temperature for another 60 minutes. Then, 17 mL of 4.37 M sodium methoxide in methanol solution was added to the reaction mixture. After stirring for 2 hours, another 5 mL of sodium methoxide solution was added, and the mixture stirred overnight. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 3.2 g of 5-(2-chlorophenyl)-7-fluoro-2,8-dimethoxy-3H-1,4-benzodiazepine (intermediate Va), which was of sufficient purity to use in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:13][C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 82 mg, 2.1 mmol) was added to a solution of 4-(methylsulfonyl)phenol (281 mg, 1.6 mmol) in dimethylformamide (9 mL) and the mixture was stirred at room temperature for 20 min. A solution of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 551 mg, 1.6 mmol) in dimethylformamide (5 mL) was added, and the reaction mixture was stirred at room temperature for 3.5 h. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×90 mL). The organic layer was washed with water (3 times) and brine, dried (sodium sulfate), filtered, evaporated and purified on a flash silica column (40 mm×4″) eluting with 66-75% ethyl acetate/hexanes to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 52%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.92-2.02 (m, 4H), 2.94-3.05 (m, 2H), 3.28-3.30 (m, methyl sulfone and water peak), 4.04-4.12 (m, 2H), 4.94-5.06 (m, 1H), 7.59-7.64 (m, 2H), 8.01-8.06 (m, 2H), 8.37 (s, 1H), 8.54 (s, 1H). Mass spectrum (ES) MH+=474.
Reaction SMILES: O[C:2]1[C:3](=[O:21])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:64][C:65]([F:74])([F:73])[C:66]1[CH:67]=[CH:68][C:69]([SH:72])=[N:70][CH:71]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([S:72][C:69]3[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:73])[F:74])=[CH:71][N:70]=3)[C:3]2=[O:21])=[CH:9][C:10]=1[CH3:20]
Reactant: FC(F)(F)c1ccc(S)nc1
Reactant: Cc1cc(-n2ccnc(O)c2=O)ccc1OCC(C)(C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-n2ccnc(Sc3ccc(C(F)(F)F)cn3)c2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
A mixture of 3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one (100 mg, 0.344 mmol), PyBOP (314 mg, 0.603 mmol) and EtN(iPr)2 (0.180 mL, 1.033 mmol) in DMF (6 mL) was stirred at RT for 3 hours prior to addition of 5-(trifluoromethyl)pyridine-2-thiol (74.1 mg, 0.413 mmol). After stirring for 3 days, The reaction was diluted with aq. saturated NaHCO3 (15 ml) prior to extraction with EtOAc (20 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 30×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 30 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). After concentration, the residue in EtOAc (30 ml) was converted to the free base by washing with aq. saturated NaHCO3 (30 ml). The EtOAc layer was dried over Na2SO4 and concentrated. To yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-one (22.76 mg, 14%) as off-white solid. MS (M+1=452). 1H NMR (500 MHz, chloroform-d) δ ppm 8.88 (1H, s), 7.89-7.99 (2H, m), 7.16-7.24 (3H, m), 7.07 (1H, d, J=4.40 Hz), 6.90 (1H, d, J=8.52 Hz), 3.84 (2H, s), 2.30 (3H, s), 1.39 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])O.[Na+].CCCCCC>CC(CC)=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH2:23][CH3:24])[C:15]=2[CH2:16][C:17]([NH2:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)CBr
Reactant: NC(=O)CCc1ncccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCc1cn2cccc(OCc3ccccc3)c2c1CC(N)=O
Yield: 48.2 %

Procedure:
A mixture of the pyridine derivative (16, 4.00 g, 15.6 m mol), 1-bromo-2-butanone (3.53 g, 23.4 m mol) and sodium hydrogencarbonate (6.55 g, 78 m mol) in methylethylketone (30 ml) was heated under reflux for 60 hours. The solid was filtered off. The volatile materials were removed by distillation under reduced pressure. The residue was chromatographed on silica gel eluting with hexane:ethyl acetate (1:2) and with ethyl acetate. The first fraction was crystallized from benzene:hexane to give 2.32 g (48.2% yield) of the titled compound 17b and, mp, 117-119° C.
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Cl:41][CH:42]([Cl:54])[C:43]1[CH:53]=[CH:52][C:46]([O:47][CH2:48][C:49](Cl)=[O:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH2:18]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:49](=[O:50])[CH2:48][O:47][C:46]1[CH:52]=[CH:53][C:43]([CH:42]([Cl:54])[Cl:41])=[CH:44][CH:45]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(Cl)COc1ccc(C(Cl)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)C(=O)COc1ccc(C(Cl)Cl)cc1
Reaction time: 16 h
Yield: 92 %

Procedure:
Dihexadecylamine (8.88 g, 0.019 mole) was dissolved in a solution of methylene chloride (75 ml) and triethylamine (2.02 g, 0.020 mole). 4-Dichloromethylphenoxy acetyl chloride (3.97 g, 0.02 mole), dissolved in methylene chloride (25 ml), was then added dropwise over a period of 10 minutes, and the resulting clear solution was stirred for 16 hours. The reaction mixture was then washed with water (2×100 ml), saturated sodium bicarbonate solution (2×100 ml) and saturated sodium chloride solution (2×100 ml), dried over sodium sulfate, filtered, and concentrated under vacuum to the desired amide: oil, 10.83 g (92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14][CH:15]=[CH2:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:10][OH:11])([CH2:13][CH2:14][CH:15]=[CH2:16])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCCC(CO)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A solution of the 2-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (7.5 g, 24.9 mmol) and triethylamine (3.01 g, 29.9 mmol, 4.15 mL) in THF (10 mL) was cooled to −40° C. and treated with ethyl chloroformate (2.97 g, 27.4 mmol, 2.65 mL). After stirring for 30 minutes, the precipitate (triethylamine hydrochloride) was removed by filtration and the filtrate was collected and cooled to −40° C. A solution of sodiumborohydride (950 mg, 24.9 mmol) in water (10 mL) was added and the resulting solution was stirred for 30 minutes. After quenching the reaction mixture with 3 N hydrochloric acid (5 mL), the mixture was diluted with ethyl acetate (150 mL), washed with water (1×50 mL) and extracted with ethyl acetate (1×150 mL). The combined organic layers were concentrated, dried over MgSO4, filtered and purified using a combiflash system (80 g silica gel column, eluting with 10-50% ethyl acetate in heptanes) to give ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate (5.6 g, 78%). 1H NMR (CDCl3) δ 5.71-5.62 (m, 1H), 5.52 (bs, 1H), 4.96-4.87 (m, 2H), 4.20-4.12 (m, 2H) 4.07-4.03 (m, 2H), 3.73 (d, J=12.0 Hz, 1H), 2.22-1.62 (m, 4H), 1.37 (m, 9H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([OH:40])=[C:16]([CH:39]=2)[C:17]([NH:19][C:20]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][C:21]=2[C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])[CH2:5][CH2:4]1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([OH:40])=[C:16]([CH:39]=2)[C:17]([NH:19][C:20]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][C:21]=2[C:22]([OH:24])=[O:23])=[O:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (10 mL) was added to the obtained tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and a 30% aqueous solution of methanol (16 mL) was added to the residue. After adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 1.1 g of 2-(5-(2-(4-ethylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([CH2:10][C:11]2[S:15][C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[O:18])=[N:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([CH2:7][S:8]([CH2:10][C:11]2[S:15][C:14]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[O:18])=[N:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Reaction time: 1 h

Procedure:
0.072 g of tert-butyl trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetate (0.13 mmol, 1 eq.) is placed in 2 mL of dichloromethane with stirring. 1 mL of TFA (13.46 mmol, 104 eq.) is added. After 1 hour, the reaction medium is evaporated and the residue is triturated in ethanol to give 0.055 g of trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetic acid.
Reaction SMILES: [OH-].[Na+].C([N:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])[CH2:7][C:8]([O:10]CC)=[O:9])(=O)C>C(O)C>[NH2:32][C:26]1[C:22]2[C:23](=[O:25])[CH:24]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[C:14]([F:33])[CH:15]=3)[O:20][C:21]=2[C:29]([F:30])=[CH:28][C:27]=1[F:31]
Reactant: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCC(=O)O)c(F)c3)cc(=O)c12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 102.3 %

Procedure:
30 ml ethanol and 4.3 ml of a 2N aqueous solution of sodium hydroxide were added to 560 mg (1.43 mmol) of Compound 44 obtained in Example 44 and the mixture was stirred at 50° C. for 10 minutes. The reaction solution was cooled to room temperature and the precipitated crystals were collected by filtration to give 533 mg (97%) of Compound 45.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[S:34](Cl)(=[O:36])=[O:35])[CH2:26]1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][O:22][C:23]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[S:34]([N:18]2[CH:16]3[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=2)[CH2:17]3)(=[O:36])=[O:35])[CH2:26]1)=[O:24]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: FC(F)(F)Oc1ccc(N2CC3CCCC(C2)N3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 50 °C

Procedure:
A mixture of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane (60 mg, 0.21 mmol), 4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (120 mg, 0.44 mmol), potassium carbonate (200 mg, 1.4 mmol), and acetonitrile (3 mL) were heated at 50° C. for 2 h. The mixture was filtered through Celite, concentrated, and purified by silica gel chromatography (9:1→4:1; hexanes:ethyl acetate) to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester: MS (ESI): 525.5 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][CH3:34])[N:32]=1)[C:27]([OH:29])=O.[F:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH2:40][CH2:39]2.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]([N:41]2[C:42]3[C:38](=[CH:37][C:36]([F:35])=[CH:44][CH:43]=3)[CH2:39][CH2:40]2)=[O:29])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.965 g (3.00 mmol) TBTU was added at RT to 0.500 g (2.67 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.366 g (2.67 mmol) 5-fluoroindoline and 0.421 mL (3.00 mmol) triethylamine in 10.0 mL DMF. The mixture was stirred for 2 h at RT and then purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac.