Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][N:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)[CH2:37][CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCOCC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (360 mg, 0.92 mmol), 1-(tetrahydropyran-4-yl)piperazine (250 mg, 1.47 mmol) and molecular sieves (4 Å, powdered, 1.5 g) in DCE (10 mL) was stirred at ambient temperature for 6 h. Sodium triacetoxyborohydride (530 mg, 2.50 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 80:20 to 2:98) to afford 495 as a cream foam (439 mg, 87%). LCMS (Method I): RT=2.50 min, M+H+=546. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.76 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 4.03 (d, J=11.3 Hz, 2 H); 3.87 (m, 7 H); 3.78 (s, 2 H); 3.42-3.29 (m, 4 H); 2.64 (m, 8 H); 1.79 (m, 3 H); 1.62 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([Br:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].CN[C@H]1CCCC[C@@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Br:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]=1[CH3:12]
Reactant: O=C1CCCN1
Reactant: Cc1c(Br)nc2cc(F)cc(F)c2c1Br
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Temperature: 110 °C
Reaction time: 2 h

Procedure:
The 2,4-dibromo-5,7-difluoro-3-methylquinoline (500 mg, 1.50 mmol), pyrrolidin-2-one (0.110 mL, 1.50 mmol), copper (I) iodide (14 mg, 0.074 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.023 mL, 0.150 mmol) and potassium phosphate tribasic (630 mg, 3.00 mmol) were slurried in dioxane (5 mL) and stirred in a microwave reactor at 110° C. for 2 h. The resulting slurry was dissolved and partitioned between water and EtOAc (2×75 mL). The combined organic layers were washed with brine (1×50 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 0 to 100% EtOAc:DCM) to give 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one. Mass Spectrum (ESI) m/e=341.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[SH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1>C(O)C.O>[N+:11]([C:5]1[C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]([S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=C(O)CCS
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: O=C(O)CCSc1ccc([N+](=O)[O-])c2nonc12

Procedure:
A solution of 4-chloro-7-nitro-2,1,3-benzoxadiazole (1 mmole) and 3-mercaptopropionic acid (Sigma-Aldrich, Fine Chemicals) (1 mmole) was made to react in 6 ml of ethyl alcohol: water 0.3:1 containing 2.5 mmoles of pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:44]3[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(F)cc3)c2)c1CCC(=O)OCC
Yield: 51.7 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 4-fluoro-phenylboronic acid (141 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (161 mg, 52%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47FO7 (M+Na)+ 645.3198. found 645.3196.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:18]C(C)C.C([Li])CCC.Cl.[OH-].[Na+].OO>C1COCC1.CCCCCC.C1(C)C=CC=CC=1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:13]([C:12]3[CH:11]=[CH:10][C:9]([OH:18])=[CH:8][C:7]=3[CH2:6][CH2:5]2)=[CH:14][CH:15]=1
Reactant: Ic1ccc2c(c1)CCc1cc(I)ccc1-2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.8 g (20.4 mmol) of 2,7-diiodo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF, and, after addition of 7.0 ml (30.5 mmol) of triisopropyl borate at −70° C., 16.5 ml of a 15 percent solution of n-butyllithium in hexane are added. After 1 h, the batch is hydrolysed using 2 N hydrochloric acid and warmed to room temp. The solution is extracted twice with MTB ether, dried over sodium sulfate, the solvent is removed in vacuo, and the crude product obtained is suspended in 80 ml of toluene and 30 ml of 2 N sodium hydroxide solution with vigorous stirring. After addition of 8 ml of 30 percent hydrogen peroxide, the batch is stirred at 30-40° C. for 30 min with cooling, 200 ml of water are added, and the mixture is acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 7-iodo-9,10-dihydro-phenanthren-2-ol as a colourless solid.
Reaction SMILES: Cl.Cl.[CH2:3]([C@@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][N:8]1[C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:4][CH2:5][CH3:6].[CH3:27][O:28][C:29](=[O:41])[CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH2:39]Cl)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH3:27][O:28][C:29](=[O:41])[CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH2:38][N:11]2[CH2:10][CH2:9][N:8]([C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)[C@H:7]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12]2)[CH:37]=1
Reactant: COC(=O)COc1cc(C)cc(CCl)c1
Reactant: CCCC[C@@H]1CNCCN1c1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[C@@H]1CN(Cc2cc(C)cc(OCC(=O)OC)c2)CCN1c1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
A mixture of 2-((R)-2-butylpiperazine-1-yl)-6-trifluoromethoxybenzothiazole dihydrochloride (170 mg), (3-chloromethyl-5-methylphenoxy)acetic acid methyl ester (108 mg), potassium carbonate (270 mg), potassium iodide (65 mg) and dimethylformamide (4 mL) was stirred at room temperature for 24 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (203 mg). Yield: 94%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH3:23])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>CO.C1COCC1>[Br:25][CH2:23][C:22]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:24]
Reactant: CC(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(OCCCO)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
1-{3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone (O2.059; 3.4 g) was dissolved in methanol/THF (50/50 ml) and admixed while stirring with phenyltrimethylammonium tribromide (4.21 g). After stirring at RT for 3 h, 20% citric acid solution was added and the mixture was stirred for 1 h. Then EA was added and the EA phase was removed. The EA phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified by means of silica gel (80 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 2.49 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40]Br>>[Br:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: COc1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: BrCc1ccccc1Br
Product: COc1ccc(CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)c(Br)c1

Procedure:
Compound 110.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of with 2-bromobenzyl bromide, with 2-bromo-1-bromomethyl-4-methoxybenzene (prepared by N-bromosuccinimide bromination from 2-bromo-4-methoxy-1-methylbenzene; 1H NMR: 7.56, d, 1H, 7.23, s, 1H, 7.0, d, 1H, 4.74, s, 2H; 3.8, s, 3H). 4-[3-(2-Bromo-4-methoxybenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained. (Molecular weight 495.04 (C21H17BrF3N3O3); 1H NMR: 8.38, d, 1H, 8.25, s, 1H, 8.1, d, 1H, 7.5, d, 1H, 7.22, s, 1H, 6.95, d, 1H, 4.6, s, 2H, 3.79, s, 3H, 1.4, s, 6H.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](OC(=O)C)=[O:14]>C1(C)C=CC=CC=1>[CH:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])=[O:14]
Reactant: CC(=O)OC=O
Reactant: COc1cc2cc[nH]c2cc1O
Solvent: Cc1ccccc1
Product: COc1cc2cc[nH]c2cc1OC=O
Yield: 30 %

Procedure:
A solution of 12 g (0.0735 mole) of 6-hydroxy-5-methoxyindole and 12.95 g (0.147 mole) of acetic formic anhydride in 100 ml of toluene is brought to reflux for 16 hours under nitrogen. After the mixture is cooled, 30 g of silica 60 are added to the reaction medium, the mixture is filtered and the filtrate concentrated two-fold. The white precipitate obtained is filtered off and then recrystallized again in 30 ml of toluene. After being dried under vacuum, 4.2 g of the derivative 19 (white powder, 30% yield) are obtained.
Reaction SMILES: [Cl:1][CH:2]([F:10])[C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].C([O:16][N:17]=O)CC(C)C.C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:1][CH:2]([F:10])[C:3](=[O:9])[C:4](=[N:17][OH:16])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC(=O)C(F)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=NO)C(=O)C(F)Cl

Procedure:
To a solution of methyl 4-chloro-4-fluoro-3-oxobutyrate (31 g) and isopentylnitrite (25.8 ml) in dichloromethane (120 ml) was added dropwise acetylchloride (13 ml) under ice-cooling with stirring and the mixture was stirred for 3 hours at 5° C. to 10° C. The resulting solution was poured into water (300 ml) and adjusted to pH 3.0 with saturated aqueous sodium bicarbonate. The separated organic phase was washed with water (300 ml) and dried with magnesium sulfate and evaporated in vacuo to give methyl 4-chloro-4-fluoro-2-(hydroxyimino)-3-oxobutyrate.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:15]=[C:16]([CH2:18][N:19]([C:21](=[NH:23])[NH2:22])[CH3:20])[OH:17].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[C:1]([NH:23][C:21](=[NH:22])[N:19]([CH2:18][C:16]([OH:17])=[O:15])[CH3:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(CC(=O)O)C(=N)N
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the dodecanoyl chloride solution, 7.34 g (56 mmol) of creatine is suspended, with stirring, in 50 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between about −15° C. and 0° C. When the target temperature is reached the drop wise addition of dodecanoyl chloride is commenced. Addition of dodecanoyl chloride continues, with cooling and stirring, until all of the dodecanoyl chloride is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine, and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(3-dodecanoyl-1-methylguanidino)acetic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C@@H:21]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)[CH2:20]1)(=[O:18])=[O:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C@@H:21]([CH2:38][N:39]2[CH2:40][CH2:41][C:42](=[O:45])[CH2:43][CH2:44]2)[CH2:20]1)(=[O:17])=[O:18]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(O)CC2)cc1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(=O)CC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A solution of 2.0 M solution of oxalyl chloride in CH2Cl2 (162 μL, 0.323 mmol, Sigma-Aldrich, St. Louis, Mo.) was diluted with CH2Cl2 and then chilled to −78° C. To this solution was added DMSO (45.9 μL, 0.647 mmol). The mixture was stirred for 30 min, and then a solution of 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinol (115 mg, 0.216 mmol) in CH2Cl2 was added to slowly to the mixture. The reaction was stirred for 1 h at −78° C. and then triethylamine (150 μl, 1.078 mmol) was added. Afterwards, the mixture was stirred for 15 min and allowed to slowly warm to room temperature and stirred for additional 4 h. Saturated aqueous NaHCO3 was added and the mixture was concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone (40 mg) as a mixture of two isomers.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C>[F:14][C:9]1[CH:8]=[C:7]([B:15]([OH:18])[OH:16])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: OB(O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
91.5 ml of tert-butyllithium are added at −78° C. to 20 g of 1-bromo-3,5-difluorobenzene in 300 ml of diethyl ether. The reaction mixture is stirred for 1 hour at −78° C. and 14.2 ml of trimethyl borate are then added. The reaction mixture is stirred for 1 hour at −78° C. and then for 12 hours at room temperature. 200 ml of aqueous 1 N hydrochloric acid solution are added. The resulting mixture is extracted with diethyl ether, the organic phase is washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. The residue is taken up in cyclohexane and the precipitate obtained is isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]I
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanone (410 mg, 1.32 mmol) in 10 mL THF was added methylmagnesium iodide (0.88 mL, 2.63 mmol) at 0° C. After stirring at 0° C. for 3 h, the reaction was quenched with saturated NH4Cl and concentrated under residue pressure. The residue was extracted with DCM three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the title compound as a white solid (430.0 mg, 95%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 5.98 (s, 1H), 3.99 (s, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+=328, tR=4.55 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mn]([O-])(=O)(=O)=[O:24].[K+]>O.C(Cl)Cl>[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13]([OH:24])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (100 g) was diluted with water (750 ml) and this solution was cooled to room temperature and added to a solution of 2-hexyldecanol (242 g) in methylene chloride (600 ml). The solutions were stirred together beneath a reflux condenser and solid potassium permanganate was added in portions during 5 hours so as to maintain gentle boiling of the methylene chloride. The mixture was filtered to remove precipitate manganese dioxide, and the organic layer was separated and washed with water. The solvent was distilled leaving 2-hexyldecanoic acid (222 g) as a nearly colourless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:26]([C:32](OCC)=[O:33])[C:27](OCC)=[O:28])#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:7]([CH:26]([CH2:27][OH:28])[CH2:32][OH:33])[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC#CC(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCC#CCC(CO)CO
Reaction time: 48 h
Yield: 56.5 %

Procedure:
A mixture of 1.8 g of lithium aluminum hydride in 150 ml of ether is prepared at 0° C. To this is added a solution of 11.7 g of 2-nonadecynylpropanedioic acid, diethyl ester in ether. This mixture is refluxed for 4 hours then the reaction is quenched with aqueous sodium sulfate. After stirring for 2 days, the reaction is diluted with ethyl acetate and filtered. The residue is treated with methanol, 1N sodium hydroxide and tetrahydrofuran and then evaporated. The residue is dissolved in ether and washed with brine and purified by flash chromatography, (4:6 ethyl acetate:petroleum ether), to give 5.3 g of the desired product as white plates, mp. 55° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[C:32]([OH:39])[CH:31]=1.[OH-].[Na+].Cl>C(Cl)Cl>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:35])=[C:32]([OH:39])[CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1O
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (9.00 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.50 mmol) of triethylamine and a solution of 1.45 g (7.70 mmol) of 4-chloro-2-hydroxybenzoyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.35 g (47%) of 4-[2-(4-chloro-2-hydroxybenzoylamino)benzoylamino]butanoic acid as a white solid.