Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][NH:12][C:13]1[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][NH:12][C:13]1[N:18]=[C:17]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: CNc1nccc(C=O)n1
Reactant: Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1nccc(CNc2ccccc2C(=O)O)n1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (0.55 g, 4.0 mmol), 2-methylamino-pyrimidine-4-carbaldehyde (Step B, 0.72 g, 5.2 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 20 mL of anhydrous toluene was stirred at reflux for 1 h, and cooled to RT. NaBH4 (0.41 g, 10.8 mmol) was added, and the mixture was stirred at RT for 30 min. The mixture was quenched with MeOH, the volatiles were removed under reduced pressure, and the residue was taken up in water. AcOH was added to bring the pH to 4 and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and the residue was purified by flash column chromatography to give the titled compound. MS (ES+): 259.0 (M+H)+. Calc'd for C13H14N4O2-258.28
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:23])=[C:20]([F:31])[CH:19]=3)[C:10]2=[S:32])=[CH:5][C:4]=1[C:33]([F:36])([F:35])[F:34])#[N:2].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH3:44][S:45]([O:28][CH2:27][CH2:26][CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:29]=[CH:30][C:18]([N:11]2[C:10](=[S:32])[N:9]([C:6]3[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([C:33]([F:35])([F:34])[F:36])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:13][CH2:14][CH2:15]3)=[CH:19][C:20]=1[F:31])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCCO)c(F)c3)C2=S)cc1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-hydroxypropyl)benzamide (Compound 306, 80 mg, 0.15 mmol) and triethylamine (22 μL, 0.16 mmol) in THF (5 mL) was cooled to 0° C. Methanesulfonyl chloride (23 μL, 0.3 mmol) was added dropwise and the mixture was stirred at room temperature overnight. Brine and EtOAc were added and the aqueous layer was extracted with EtOAc (2×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford crude 3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propyl methanesulfonate that was used as is.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=1.Cl>COCCOCCOC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[Br:17]
Reactant: COC(=O)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: COCCOCCOC
Product: OCc1ccc(F)c(Br)c1
Yield: 91.2 %

Procedure:
First 3.8 g (0.1 mole) of sodium borohydride and then 4.5 g (0.033 mole) of aluminum chloride were added in portions to a solution of 23.3 g (0.1 mole) of 4-fluoro-3-bromobenzoic acid methyl ester in 50 ml of diglyme at 5° C. The mixture was subsequently stirred, without cooling, until the exothermic reaction had ended (a rise in temperature up to about 50° C.) and the reaction was then allowed to go to completion in the course of 1 hour at 100° C. The reaction solution was then poured onto a mixture of 125 ml of icewater and 12 ml of concentrated hydrochloric acid and the benzyl alcohol which had separated out was separated off and distilled in vacuo. 18.7 g (91% of theory) of 4-fluoro-3-bromobenzyl alcohol were obtained in this manner as a colorless oil with a boiling point of 65° to 70° C. (0.1 mbar). "One-pot process"
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.C(OOC(C)(C)C)(C)(C)C.C([O:22][C:23](=O)[CH:24]=[CH2:25])C>>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5]2([O:8][C:23](=[O:22])[CH2:24][CH2:25]2)[CH2:4][CH2:3]1
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CCC(O)CC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC1(C)CCC2(CCC(=O)O2)CC1
Temperature: 160 °C
Yield: 69.5 %

Procedure:
In a 500 ml three necked round bottom flask was charged 4,4-dimethyl-cyclohexanol (100 g, 0.78 mol) and heated up to 160° C., while adding over 4 hours tBuOOtBu (11.4 g, 0.08 mol) and ethylacrylate (39.2 g, 0.39 mol). 10 minutes after the end of the addition, the mixture was cooled to 50° C. and lights were distilled off. Then, 30% w/w aqueous NaOH (61 g) and MTBE (200 g) were added. Stirring was continued during the night at 40° C. and the aqueous phase was separated. The aqueous phase was re-extracted four times with MTBE (200 g). Afterwards, MTBE (200 g) was added to the aqueous phase, and the pH adjusted to 1 with 50% w/w aqueous H2SO4. The organic phase was washed with water and concentrated to yield 49.4 g of crude 8,8-dimethyl-1-oxa-spiro[4.5]decan-2-one (GC purity: 96.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:13])=[O:12]
Reactant: COc1ccccc1N
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 95.7 %

Procedure:
Using o-anisidine (0.585 ml, 5.0 mmol) and 4-(chlorosulfonyl)benzoic acid (1.15 g, 5.0 mmol), the procedure of Reference Example 2 was repeated to obtain 1.47 g (95.5%) of the title compound in the form of pink powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].I[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:15])[C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CI
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4-chloro-3-nitropyridin-2(1H)-one (3.0 g, 17 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% w/w, 1.0 g, 25.5 mmol) in batches at 0° C. The mixture was stirred at room temperature for 30 minutes. Then iodomethane (2.9 g, 20.4 mmol) was added dropwise to the above solution at room temperature. The resultant solution was stirred at room temperature for 12 hours. Once starting material was consumed, the reaction mixture was quenched with ice water (100 mL) at 0˜10° C., and extracted with ethyl acetate (100 mL*3). The organic phase was washed with brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-chloro-1-methyl-3-nitropyridin-2(1H)-one (3 g, 94%) as a yellow solid. LRMS (M+H+) m/z: calcd 188.0. found 188.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)([OH:22])=[O:21]
Reactant: COC(=O)CCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 194.9 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide (16.8 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (17.2 mg).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:12][C:13](=[O:27])[CH:14](OC(=O)C)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11].CCOCC>O>[CH2:8]([O:12][C:13](=[O:27])[CH:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
A solution containing 2.4 mmol. of phenyl lithium in benzene-ether was added dropwise at -78° under argon to a solution of 700 mg. (2.4 mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 15 ml. of dry ether. The mixture was stirred for 2 hours at -78°, then for 1 hour at 25°. The mixture was diluted with water, the layers were separated and the ether layer was washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel with methylene chloride to give a crude product which was rechromatographed on basic alumina to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1.ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:37][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:9][N:8]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C(=O)NCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ncc(-c3ccc4c(c3)CCC(=O)N4)s2)cc1OC
Temperature: 200 °C
Reaction time: 3 h

Procedure:
There were mixed, each in a powdery state, 500 mg of 6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent). The mixture was stirred at 200° C. with heating. After 3 hours, the reaction was completed. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=49:1 by v/v). A solid obtained from the eluate was recrystallized from ethanol to obtain 98 mg of 2-(3,4-dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl)thiazole as a white powder.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[C:7]([B:27]([OH:28])[OH:26])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
5-iso-Butyl-N-tert-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol, see step (b) above) was dissolved in THF (165 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 60.19 mL, 0.096 mol) was added via a syringe. The reaction mixture was stirred at −20° C. for 4 h. The tri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine, dried and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8].BrC1C=C2C=C(C3C=CC(F)=CC=3)OC2=NC=1Cl.[OH-].[Na+]>C(Cl)Cl.CC(O)=O.CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Agent: Fc1ccc(-c2cc3cc(Br)c(Cl)nc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A 4:1 inseparable mixture of methyl 5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (2.38 g, 6.19 mmol) and 5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine (0.265 g, 0.812 mmol) was taken up in a 1:1:1 mixture of MeOH (50 mL), THF (50 mL), 1M NaOH (50 mL). The entire mixture was heated in an oil bath to an internal temp of 65° C. This mixture was allowed to stir at this temp for 1 h. The solution was then concentrated to an aqueous mixture. This mixture was diluted with EtOAc and 1 M HCl (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to give a white solid. This solid was adsorbed onto SiO2 and flashed on silica gel eluting with a 0-10% MeOH in DCM solution containing 1% AcOH to give 5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (1.85 g, 4.99 mmol, 81% yield). LCMS: m/e 371 (M+H)+ LCMS retention time: 3.30 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N1CCCCC1.C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]=[C:34]4[S:30][C:31](=[O:36])[NH:32][C:33]4=[O:35])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=O)cc3)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Yield: 68.5 %

Procedure:
A mixture of 2 g (4.85 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl 4-methoxy-1-benzenesulfonate and 0.8 g (6.8 mmole) 2,4-thiazolidinedione, 0.4 g piperidine, 0.3 g acetic acid and 20 ml toluene was refluxed with water separation in a Dean-Stark apparatus for 2.5 hours. The solvent was evaporated in vacuo, the residue was dissolved in dichloromethane and washed with potassium hydrogensulfate solution and with water, dried with magnesium sulfate, filtered and the solvent was concentrated in vacuo. 1.2 g of crystals were filtered off and the mother liquid was purified by chromatography on silica gel using dichloromethane/diethylether (gradient) as eluent to give 0.5 g more, totally 1.7 g (yield 69%) of 5-(4-[2-(4-(4-methoxyphenylsulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[O:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=4[O:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Oc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 76 %

Procedure:
The compound of example 152 was prepared analogous to compound of example 98 by hydrolysis of compound of example 151.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14]C=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#N.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>O>[CH:13]1[C:10]2[CH:11]=[CH:12][C:6]3[CH:5]=[CH:4][CH:3]=[CH:17][C:7]=3[S:8][C:9]=2[CH:16]=[C:20]([C:19]([OH:22])=[O:21])[CH:14]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2

Procedure:
2.0 G. 3-cyanodibenzo[b,f]thiepin are refluxed in a mixture of 25 cc. concentrated HCl and 25 cc. glacial acetic acid for 19 hours; the acid separates from the hot solution. After cooling, the mixture is diluted with water and the light yellow solid is filtered and washed well with water. The yield of dibenzo[b,f]thiepin-3-carboxylic acid is 2.07 g. (95.8%), m.p. 251° C.-254° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)(O)[O-:13].[Na+].O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([F:10])=[C:6]([CH2:8][OH:13])[CH:7]=1
Reactant: Cc1cc(Br)cc(CBr)c1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Br)cc(CO)c1F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred solution of 5-bromo-1-(bromomethyl)-2-fluoro-3-methylbenzene (6.56 g, 23.3 mmol) in acetone (150.0 mL) was added sodium bicarbonate (2.44 g, 29.1 mmol) and water (250.0 mL). The reaction was refluxed overnight. The reaction was cooled to room temperature and extracted 3× with ethyl acetate. The organic extracts were combined and washed with brine, dried over sodium sulfate and concentrated. The resultant oil was flash chromatographed (80 g silica, 5-10% ethyl acetate/hexanes gradient) to yield 2.5 g of (5-bromo-2-fluoro-3-methylphenyl)methanol as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]3[O:22][C:21](C)(C)C(C)(C)[O:19]3)=[C:14](CO)[CH:13]=2)=[CH:7][C:6]=1[O:29][CH3:30])[CH3:2].Cl.C1(B(O)O)C=CC=CC=1>CO>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[B:18]([OH:19])[O:22][CH2:21][C:14]=3[CH:13]=2)=[CH:7][C:6]=1[O:29][CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(CO)c2)cc1OC
Agent: Cl
Agent: OB(O)c1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1OC
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of compound 9 (2.0 g, 4.67 mmol) in methanol (50 mL) was added 6N HCl (10 mL) and phenylboronic acid (2.85 g, 23.36 mmol). The resulting mixture was stirred at rt O/N. The solvent was removed under reduced pressure to give crude product, which was purified by reverse phase prep HPLC using CH3CN/H2O (with 0.1% acetic acid) as the eluent to afford the title compound (D35) (0.66 g, 39%) as a white solid after lyophilization. Mp 64.9-65.2° C. 1H NMR 400 MHz (DMSO-d6) δ: 9.20 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.16 (dd, J=8.2, 2.0 Hz, 1H), 6.80 (s, 1H), 6.60 (dd, J=8.6, 2.3 Hz, 1H), 4.98 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ES) m/z: 329 (M+1)+; HPLC purity: 99.46% (220 nm), 100% (254 nm).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:5])[CH3:4].Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1.CN(C)C=O>[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][N:11]([CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:12]([CH3:15])(=[O:13])=[O:14])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C=Cc1cccc(CBr)c1
Reactant: CCCCCC(CCCNS(C)(=O)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(CCCN(Cc1cccc(C=CC(=O)OCC)c1)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Sodium hydride (0.59 g., 0.025 mole) is suspended in benzene (20 ml.) and dimethylformamide (35 ml.). N-(4-acetoxynonyl)methanesulfonamide [Example 1, Step B] (6.1 g., 0.022 mole) is added and stirred 1 hour at room temperature. Ethyl m-bromomethylcinnamate (6.68 g., 0.025 mole) is added dropwise with stirring over 1 hour. The suspension is stirred at room temperature for 20 hours and then separated between ethyl acetate and water. After being washed with water, the organic layer is dried over anhydrous magnesium sulfate. Removal of the ethyl acetate by evaporation in vacuo gives an oil which, after chromatograpy on silica gel, gives ethyl m-[N-(4-acetoxynonyl)-methanesulfonamidomethyl]cinnamate, 4.1 g. (40% yield). Anal. Calcd. for C24H37NO6S: C, 61.64; H, 7.98; N, 3.00 Found: C, 61.36; H, 8.40; N, 3.07
Reaction SMILES: [CH2:1]1[O:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([NH2:15])[CH2:12][CH2:13][NH2:14]>CO>[CH2:11]([NH:15][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][NH:14][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC1CO1
Reactant: NCCCN
Solvent: CO
Product: CCCCCCCC(O)CNCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-nonene oxide (120 g.) and 1,3-propanediamine (31.2 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,3-propylene)-bis[2-hydroxynonylamine] (I: R = CH3 (CH2)6, R' = H, X = (CH2)3, Z = H) (13.2 g., m.p. 107.0°-109.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][CH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH3:76])([CH3:75])[O:73][B:72]([OH:77])[C:71]=2[CH:78]=1>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:64][CH2:65][CH2:66][C:67]5[CH:68]=[CH:69][C:70]6[C:74]([CH3:75])([CH3:76])[O:73][B:72]([OH:77])[C:71]=6[CH:78]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.76 mmol) and HATU (456 mg, 1.2 mmol) in DMF (18 mL), DIPEA (310 mg, 2.4 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) can be added. The reaction mixture can be continued to stir overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.