Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)([CH3:12])[C:10]#[N:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)([CH3:12])[C:10]#[N:11]
Reactant: Sc1ccccc1
Reactant: CC(C)(C#N)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C#N)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 71.4 %

Procedure:
A mixture of thiophenol (9.09 g 0.0826 m), 2-methyl-2-(3-nitro-4-bromophenyl)propionitrile (18.68 g, 0.0694 m), sodium carbonate (16.0 g, 0.151 m) and absolute ethanol (300 ml) was stirred and heated at reflux for 5 hours. The cooled mixture was then poured onto ice-water and the resultant yellow solid filtered off. The crude solid was slurried with water/SVM (1.1, 300 ml) and the solid filtered and mixed with water/SVM (1:1, 150 ml. The solid was crystallised from methanol to give yellow needles (14.78 g, 65%) mpt. 146°-147° C. Calcd., for C16H14N2SO2 : C, 64.4 H, 4.7 N, 9.4; S, 10.7 Found: C, 64.5; H, 4.6; N, 9.3; S, 10.8
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:24][CH2:25][O:26][CH3:27])[CH2:19][CH2:18]3)=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Reactant: COCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCC(COC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
(Piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate from the previous step (2.15 g, 7.10 mmol), 2-bromoethylmethylether (0.67 mL, 7.10 mmol) and DIPEA (1.36 mL, 7.81 mmol) were dissolved in DMF (30 mL) and stirred overnight at 70° C. and then concentrated in vacuo. The residue was dissolved in DCM (300 mL) and then washed sequentially with sat aq NaHCO3 solution (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 98:1:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-phenylpiperazine-1-carboxylate (0.798 g, 31.1% yield) as a viscous yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[CH:9]/N(C)C)=[CH:4][CH:3]=1.Br[CH2:14][C:15]#[N:16].C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]#[N:16])=[CH:9][N:8]=2)[N:7]=1
Reactant: N#CCBr
Reactant: CN(C)/C=N/c1ccc(Br)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#Cc1cnc2ccc(Br)nn12
Yield: 53.5 %

Procedure:
(E)-N′-(6-Bromopyridazin-3-yl)-N,N-dimethylformimidamide (2.5 g, 10.9 mmol), bromoacetonitrile (3.92 g, 32.7 mmol) and NaHCO3 (1.8 g, 21.8 mmol) in i-PrOH (15 mL) were heated at 75° C. for 8 h while stirring the contents. Subsequently, the dark reaction mixture was diluted with water and the resulting solid was collected by filtration. The solid was purified by flash chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 15-30-50% EtOAC/hexanes as an eluting solvent) to obtain 1.3 g of 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 7.77 (d, J=9.5 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 17 (0.400 g, 1.66 mmol) was placed in ethanol (10 ml) and stirred in an ice-water bath while sodium borohydride (0.063 g, 1.66 mmol) was added. The reaction was brought to room temperature and stirred for 2 hours. The reaction was quenched with water (2 ml), diluted with a saturated NH4Cl solution, and extracted with ethyl acetate. The solution was concentrated in vacuo to yield 18 as a pale orange solid (0.390 g, 99% yield). The product was used in the next step without further purification. Methyl 3′-(hydroxymethyl)bi-phenyl-4-carboxylate 18 (0.210 g, 0.867 mmol) was dissolved in dichloromethane (4 ml) and placed under argon in an ice-water bath. To this solution was added dropwise 0.870 ml of 1.0 M phosphorous tribromide in dichloromethane. The reaction was stirred at room temperature for 2.5 hours and then quenched with 1:1 saturated NaHCO3:water followed by extraction with diethyl ether. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 19 as a white solid (0.277 g, quant. yield). The product was used for the next reaction without further purification. Methyl 3′-(bromomethyl)biphenyl-4-carboxylate 19 (0.278 g, 0.876 mmol) and sodium azide (0.113 g, 1.73 mmol) were heated to 70° C. in DMF (4 ml) overnight with vigorous stiffing. After 12 hours, the reaction was quenched with water (10 ml) and the product extracted with ethyl acetate (3×10 ml). The organic layers were washed with brine (15 ml), dried over Na2SO4, and concentrated in vacuo to yield 20 as a yellow oil. The product was purified by column chromatography (6:1 Hexane:ethyl acetate) to afford 3′-(azidomethyl)biphenyl-4-carboxylate as a pale orange solid (0.225 g, 92%). 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 4.42 (s, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.55-7.60 (m, 2H), 7.66 (d, J=8.4 Hz, 2H), 8.11 (d, J=8.4 Hz, 2H). 3′-(azidomethyl)-biphenyl-4-carboxylate 20 (0.150 g, 0.561 mmol) was heated to reflux in EtOH (4 ml, 80° C.) in the presence of hydrazine monohydrate (0.96 ml of a 20.63 M solution), and the solution was left to stir overnight (12 hours). The reaction was then concentrated in vacuo to remove excess ethanol. Water (10 ml) was added, and the product extracted with ethyl acetate (5×10 ml), dried over Na2SO4, and concentrated in vacuo to yield 5 as a pale yellow solid. The product was isolated by crystallization in 2:1 ethanol:ethyl acetate (0.127 g, 85%). 1H NMR (400 MHz, (CD3)2SO) δ 4.51 (s, 2H), 7.39 (d, J=7.2, 1H), 7.50 (t, J=7.6, 1H), 7.68-7.75 (m, 4H), 7.91 (d, J=8.0 Hz, 2H) 13C NMR (100 MHz, (CD3)2SO) δ 54.0, 127.0, 127.4, 128.1, 128.5, 130.0, 132.8, 136.9, 140.0, 142.6, 165.9; MS (ESI) calculated for C14H13N5O [M+H]+: m/z 268.3. found [M+H]+: 268.2
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C(O)C>[C:1]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)Nc1ccc(C=CC(=O)O)cc1
Reaction time: 14 h
Yield: 81.1 %

Procedure:
To a solution of ethyl 4-propionamidocinnamate (160 mg) in ethanol (5 ml) was added 1N aqueous sodium hydroxide solution (1.5 ml) at ambient temperature. The mixture was stirred at same temperature for 14 hours, and then at 40° C. for 2 hours. 1N-hydrochloric acid (1.5 ml) was added to the reaction mixture and evaporated in vacuo. The residue was diluted with 10% methanol-dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 4-propionamidocinnamic acid (115 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[OH-].[K+].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.N#N>CN(C=O)C.CCOCC>[C:1]([C:4]1[N:5]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: Fc1ccc(I)cc1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)c1cc2ccccc2n1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
To a solution of 2-carboxy-1H-indole (50 g) in DMF (600 ml) were added potassium hydroxide (40 g) and 4-fluoroiodobenzene (90 g). Reflux in an inert N2 stream for 6 hours. H2O/DMF was distilled off to obtain a constant boiling point of 148° C. After cooling to room temperature ether (500 ml) was added. The precipitated material was filtered off and water (500 ml) was added. Undissolved material was filtered off. To the alkaline water phase was added ethyl acetate (500 ml) and pH was adjusted to 2 by addition of dil. aqueous HCl. The organic phase was worked up as yielding 2-carboxy-1-(4-fluorophenyl)-1H-indole (41 g) which melted at 213° C. The thus obtained carboxyindole (38 g) was added cautiously to a suspension of LiAlH4 (7.5 g) in dry THF (350 ml) at such a rate that the temperature was kept below 50° C. The mixture was finally stirred at 50° C. for 1.5 h. After cooling 5M NaOH solution was added under vigorous stirring. Precipitated inorganic material was filtered off and washed thoroughly with dichloromethane. After evaporation of the combined organic phases 1-(4-fluorophenyl)-2-hydroxymethyl-1H-indole (35 g) was isolated as a crystalline product. Mp: 65°-66° C. The hydroxymethyl derivative (35 g) was dissolved in ethanol (600 ml). The solution was hydrogenated in a Parr apparatus with 15% Pd/C as catalyst at 3 ato. for 20 h. The catalyst was filtered off and ethanol evaporated leaving the crude title compound 23a as an oil. Purification by elution (dichloromehtane/heptane 1:1 as eluent) through silica gel afforded the pure 1-(4-fluorophenyl)-2-methyl-1H-indole (18 g) as a crystalline product. Mp: 43° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:2]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[C:28]([NH2:29])[CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]=[CH:14][CH:15]=3)[CH:2]=1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1cccnc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: NC(CCn1ccnc1)=c1c2cccc3cccc(c32)n1Cc1cccnc1
Yield: 73.8 %

Procedure:
A mixture of 2.75 g of 1-(3-pyridinylmethyl)-benz[cd]indole-2(1H)-thione (Cg), 1.4 g of 1H-imidazole -1-propanamine, 150 ml of ethyl alcohol and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.7 g of the desired product, mp. 139°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][N:31]=2)=[CH:34][CH:35]=1
Reactant: CCc1cnc(Oc2ccc(I)cc2)nc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: CCc1cnc(Oc2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)nc1
Yield: 75.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (50.0 mg) was reacted with 2-(4-iodophenoxy)-5-ethylpyrimidine (54.1 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(5-ethylpyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (62.2 mg). Column chromatography (chloroform) and thin layer chromatography (cyclohexane/ethyl acetate=1/2) were used for purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)C(OCC)=O)=O)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[O:43]1CCC[CH2:44]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC.C(OCC)(=O)C>[CH2:7]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:34][C:33]=2[CH2:44][OH:43])=[CH:26][CH:27]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CCNc2ccccc2CO)cc1
Temperature: 0 °C

Procedure:
To a solution of 42.36 ml of 1 molar lithium aluminum hydride in either is added dropwise under argon over 20 minutes a solution of ethyl 3-[[[4-(tetradecyloxy)phenyl]acetyl]amino]benzoate in 50 ml of either and 50 ml of tetrahydrofuran. The mixture is refluxed for 3 hours, cooled to 0° C. and ethyl acetate added. Saturated sodium sulfate is added followed by ether. The mixture is filtered and the cake washed with ether. The filtrate is evaporated and the residue chromatographed on silica gel using 9:1 chloroform:ethyl acetate. The product fractions are combined and evaporated to a residue which is crystallized from hexane to give 4.5 g of the desired product as a white solid, m.p. 67°-70° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (J. Med. Chem. 1998, 41, 2492–2502, 3.0 g, 13.1 mmol), dibenzylamine (2.5 mL, 13.1 mmol) and diisopropylethylamine (3.4 mL, 19.7 mmol) in dichrolomethane (150 mL) was added PyBroP (bromo-tris-pyrrolidino-phosophonium hexafluorophosphate) (6.1 g, 15.7 mmol) was added at 0° C. The mixture was stirred at ambient temperature for 18 h and partitioned between dichloromethane and water. After extraction with dichloromethane, the combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (6:1) to afford 4.0 g (75%) of the title compound as a colorless amorphous powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].CO>O>[CH:21]([N:18]1[CH2:19][CH2:20][CH:16]([O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:17]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Temperature: 100 °C

Procedure:
A mixture of 2.05 g (6 mmol) 5-(1-Isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester and 0.299 g (7 mmol) lithiumhydroxide monohydrate 30 ml THF, 30 ml methanol and 15 ml water was heated to 100° C. for 2 h. The organic solvents were removed and aq. 1N HCl was added to adjust the pH of the solution to 2-3. Subsequently, the mixture was evaporated to dryness and the mixture was used without further purification in the next step. MS (m/e): 289.1 (MH+, 100%).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: Brc1ccccc1Br
Agent: [Cu+2]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc(CCCCCCBr)cc1
Yield: 45 %

Procedure:
In the same manner as described in Example 1, a Grignard solution in a mixture containing 450 ml of toluene and 40 ml of tetrahydrofuran was prepared from 58.8 g (0.4 Mol) of 1,4-dichlorobenzene. A solution of 146.4 g (0.6 Mol) of commercially available 1,6-dibromobenzene in 100 ml of toluene and a catalytic amount of dilithium tetrachlorocuprate were added to this solution. The full mixture was refluxed for 7 hours. The precipitate was then filtered off, the filtrate was acidified, and the phases were separated. The organic phase was washed, dried and evaporated, and the residue was fractionated. About 50 g of 1-(6-bromohexyl)-4chlorobenzene (45 percent yield) were obtained at a pressure of 0.2 hPa and at 106° to 109° C.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:28])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1.N1C(C)=CC(C)=CC=1C.Cl[C:39]([O:41][CH3:42])=[O:40].C(OCC)(=O)C>C1(C)C=CC=CC=1.S(=O)(=O)(O)O.O>[CH3:42][O:41][C:39](=[O:40])[N:28]=[C:3]([S:2][CH3:1])[C:4]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Agent: O=S(=O)(O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of 0.784 g of 2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester in 21.1 ml of toluene there were added 0.393 ml of collidine and 0.304 ml of methyl chloroformate under a nitrogen atmosphere, and the mixture was stirred at 80° C. for 15 hours. After cooling the reaction mixture, 150 ml of ethyl acetate and 50 ml of water were added and the pH was adjusted to 4 with a few drops of sulfuric acid. The organic layer was washed with 50 ml of water and 50 ml of saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.436 g) as a light yellow solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:7][CH2:8][C:9]#[CH:10].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([OH:24])[C:10]#[C:9][CH2:8][CH2:7][CH2:6][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:21][CH:20]=1
Reactant: C#CCCCOC1CCCCO1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(C#CCCCOC1CCCCO1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
61.5 ml of 1.6M solution of n-butyllithium (98,4 mmol) in hexane are added dropwise to a solution, cooled to −78° C. under argon, of 13.25 g (78.8 mmol) of 2-(pent-4-yn-1-yloxy)tetrahydro-2H-pyran in 130 ml of anhydrous tetrahydrofuran. Stirring is continued at −78° C. for 1 hour and then a solution of 12.18 g (86.6 mmol) of 4-chlorobenzaldehyde in 40 ml of tetrahydrofuran is added dropwise. Stirring is continued at −78° C. for 2 hours and then the solution is reheated to 0° C. and is poured onto 300 ml of a saturated aqueous ammonium chloride solution. Extraction is carried out with 450 ml of ethyl acetate. The organic phase is washed with 50 ml of water and then with 50 ml of a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 70/30 mixture of n-hexane and of ethyl acetate, to produce 16.64 g (53.88 mmol) of product in the form of a colourless oil.
Reaction SMILES: [Li+].[OH-].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])[CH2:14][CH:13]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].O1CCOCC1.Cl>O.C1COCC1>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])[CH2:14][CH:13]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=2)=[CH:10][CH:11]=1)([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(C)C1CCN(c2ccc(C(C)C)cc2)C(c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)c1ccc(N2CCC(C(C)C(=O)O)CC2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 110 °C

Procedure:
A solution of LiOH (27 mg, 1.1 mmol) in H2O (0.5 ml) was added to a stirred solution of the ester (Step 1, 100 mg, 0.22 mmol) in THF (1 ml) at room temperature. After 60 hours an extra portion of LiOH (30 mg) and dioxane (1 ml) were added. The mixture was heated at 110° C. for 16 hours. After cooling to room temperature the mixture was acidified with 5N HCl. The mixture was partitioned between EtOAc/H2O. The layers were separated and the aqueous layer was further extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC to give the acid as a 3:2 mixture of diastereomers (90 mg, 94%) as colourless solid. 1H NMR (500 MHz, CDCl3) δ: 1.12-1.14 (6H, m), 1.21-1.26 (3H, m), 2.01-2.25 (3H, m), 2.26-2.40 (1H, m), 2.50-2.59 (2H, m), 2.78-2.83 (1H, m), 3.48-3.51 (1H, m), 3.91-3.95 (1H, m), 4.35-4.40 (1H, m), 7.12-7.14 (2H, m), 7.24-7.26 (2H, m), 7.42-7.53 (4H, m); M/Z (ES+) 420 (MH+).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH2:12])[CH2:2]1)[CH2:8]2.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[CH2:11][NH:12][C:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: NCC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC1CN(C3)C2)c1ccc2[nH]ccc2c1

Procedure:
The product of Example 2B was reacted with indole-5-carboxylic acid, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-di(methylamino)pyridine in pyridine as described in Example 3 to afford the title compound: 1H NMR (methanol-d4, 500 MHz) δ 1.91 (br s, 2 H), 1.94-2.01 (m, 3 H), 2.11-2.18 (m, 2 H), 2.24 (t, J=7.93 Hz, 1 H), 3.16-3.21 (m, 2 H), 3.59-3.65 (m, 4 H), 6.54 (dd, J=3.05, 0.92 Hz, 1 H), 7.22-7.28 (m, 1 H), 7.32 (d, J=3.05 Hz, 1 H), 7.41-7.44 (m, 1 H), 7.60 (dd, J=8.54, 1.83 Hz, 1 H), 7.63-7.70 (m, 1 H), 8.10 ppm (d, J=1.83 Hz, 1 H); MS (ESI) m/z 310 (M+H)+.