Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(C)(=O)=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (833 mg, 1.86 mmol) in anhydrous CH2Cl2 (27 ml) was added methanesulfonyl chloride (0.95 ml, 12.2 mmol) and Triethylamine (2.34 ml, 16.3 mmol). The reaction stirred at room temperature for 2 hours, was diluted with dichlormethane and washed with sat. NaHCO3, and brine, dried and filtered to give a yellow oil. Purification by silica gel chromatography (Isco) gave the product as an off white solid, (662 mg, 68% ). Calcd for C27H34FNO4S (M+H) 525.62, Found 526.3
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[C:8]([O-:11])(=O)[CH3:9].[Na+].O>C(O)C>[CH2:6]([N:1]1[C:8]([OH:11])=[CH:9][C:4]([CH3:5])=[C:3]([C:2]#[N:1])[C:2]1=[O:7])[CH2:5][CH2:4][CH3:3]
Reactant: CC(=O)[O-]
Reactant: O=c1cccc[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCn1c(O)cc(C)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 239.9 %

Procedure:
To a mixture of 1.0 grams (4.85 mmol) of the pyridone and 6.6 grams (48.5 mmol, 10 eq) of sodium acetate in 50 mL of ethanol was added 1.27 grams (4.85 mmol, 1 eq) of 4-diazo-N,N'-diethylaniline tetrafluoroborate. The reaction mixture turned blue immediately upon addition of the diazo compound. The mixture was stirred at room temperature for two hours and 50 mL of water was added. The blue solid was collected and washed with water and dried. This material was recrystallized from approximately 200 mL of ethanol to give 1.2 grams (65% yield) of the desired product. This material decomposes at 180°-185° C. with effervescence.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11](C(=O)CBr)=[C:12]([F:17])[CH:13]=2)[N:8](CC)[CH:7]=1)=[O:5])[CH3:2].C(N(CC(N)=S)CC)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Agent: CCN(CC(N)=S)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(N-acetyl-N-ethylamino)thioacetamide in ethanol gave 1-ethyl-7-2-[(N-acetyl-N-ethylamino)methyl]-4-thiazolyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 160°-161° C. which was then hydrolyzed in refluxing 6N hydrochloric acid to afford the title compound, mp 289°-300° C. (dec).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:27]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]4[S:22][N:21]=[CH:20][N:19]=4)(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH2:3][C@@H:2]1[CH3:1])=[O:36])[CH:28]=[CH:27]2
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Reactant: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1C(=O)CCn1ccc2cc(Cl)ccc21

Procedure:
Synthesized according to general procedure 9, method A. The reaction was set up with 0.1 mmol (S)-4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.15 mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.15 mmol BOP reagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=545.0; tR=3.25 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=1.Br[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1c1cncc(O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1cncc(OCCNC(=O)OC(C)(C)C)c1
Yield: 34.3 %

Procedure:
(S)-5-(1-Methylpyrrolidin-2-yl)pyridin-3-ol (preparation 10) (175 mg, 0.98 mmol), tert-butyl 2-bromoethylcarbamate (550 mg, 2.45 mmol) and potassium carbonate (676 mg, 4.9 mmol) in DMF (7 mL) were heated at 90° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, dried over MgSO4 and evaporated. The crude product was purified by flash chromatography (5%→10% MeOH in DCM) to give the title compound as a yellow oil (108 mg, 34%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][NH:10][C:11](=[S:14])[NH:12][NH2:13]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:13][NH:12][C:11]([NH:10][CH3:9])=[S:14])=[O:7]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccco1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Furoyl chloride (31 g. or 0.238 mole) was added dropwise to a slurry of 4-methylthiosemicarbazide (25 g. or 0.238 moles) in dry pyridine (200 ml.) cooled to -10°. The slurry was allowed to come to ambient temperature and stirred overnight. The reaction mixture was poured into 1500 ml. of crushed ice, the precipitate was collected, dried and recrystallized from EtOH to give 1-(2-furoyl)-4-methyl thiosemicarbazide (28.0 g.). This melted at 204°-206° C. (dec.) and was found to contain by analysis 42.4% C, 4.6% H, 21.2% N, 16.1% O, 15.9% S; C7H9N3O2S requires 42.2% C, 4.5% H, 21.1% N, 16.1% O, 16.1% S. The structure was confirmed by its infrared spectrum and nuclear magnetic resonance spectrum.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)([OH:8])=[O:7].[CH3:20]O>>[CH3:20][O:7][C:6]([CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: O=C(O)CC1COc2ccccc2C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1COc2ccccc2C1
Yield: 98 %

Procedure:
1.5 ml of sulphuric acid (100% strength) are added to a solution of 7.69 g (40 mmol) of 3-carboxymethylchroman in 150 ml of methanol and the whole is boiled under reflux for 3 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in diethyl ether and washed, while cold, with water, sodium hydrogen carbonate and again with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.08 g (98%) of 3-methoxycarbonylmethylchroman are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[Br:12][C:13]1[C:14]([Cl:20])=[C:15](F)[CH:16]=[CH:17][CH:18]=1>>[Br:12][C:13]1[C:14]([Cl:20])=[C:15]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2c(s1)C(O)CNC2
Reactant: Fc1cccc(Br)c1Cl
Product: Cc1cc2c(s1)C(Oc1cccc(Br)c1Cl)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C1(C)C=CC=C(C)C=1.CC1[C:15]2C[O:17][C:18](=[O:19])[C:14]=2[C:13](O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=[C:12](C/C=C(/CCC(O)=O)\C)[C:11]=1OC.Br.[C:45]([OH:48])(=[O:47])[CH3:46]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:18]([OH:19])(=[O:17])[C:14]1[CH:13]=[CH:12][CH:11]=[C:46]([C:45]([OH:48])=[O:47])[CH:15]=1
Reactant: CC(=O)O
Reactant: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: [Co+2]
Agent: [Mn+2]
Agent: Br
Solvent: Cc1cccc(C)c1
Product: O=C(O)c1cccc(C(=O)O)c1

Procedure:
An example of the liquid-phase oxidation reaction is as follows. For example, using an apparatus with a commercial scale, m-xylene is subjected to liquid-phase oxidation by air (reaction temperature: 200 [° C.]; reaction pressure: 1.6 [MPaG]) in the presence of cobalt acetate, manganese acetate and hydrobromic acid in hydrous acetic acid to obtain a crude isophthalic acid slurry (the concentration of isophthalic acid: 33% by weight; the concentration of water in the hydrous acetic acid that is a dispersing medium: 14% by weight), and the resulting slurry is then introduced into crystallization vessels connected in series to subject the slurry to sequential pressure drop.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=2)[CH:17]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O.C(OCC)(=O)C.CCCCCC>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=2)[CH:17]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C=Cc2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C=C(C=O)c2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To anhydrous N,N-dimethylformamide (0.078 mL, 1.02 mmol) at 0° C. was added phosphorus oxychloride (0.042 mL, 0.44 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, and 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (156 mg, 0.34 mmol) in dichloromethane (3 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (154 mg, 1.56 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane,) afforded 6-benzyloxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester as a colorless oil (85 mg, 52% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:25][Cr](O[Cr]([O-])(=O)=O)(=O)=O.O>CN(C=O)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:25])=[O:1])[CH:10]=[CH:9][N:8]=1)#[N:12]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: N#Cc1cc(CCCO)ccn1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(CCC(=O)O)ccn1
Reaction time: 16 h

Procedure:
A solution of K2CO3 (1.67 g, 12.1 mmol) in H2O (30 ml) was added to a stirred solution of 3-(2-cyanopyridin-4-yl)propyl acetate (4.94 g, 24.2 mmol) in MeOH (130 ml). After 25 min, the MeOH was removed under reduced pressure, then the aqueous phase was extracted three times with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish 4-(3-hydroxypropyl)pyridine-2-carbonitrile: m/z (ES+)=163.1 [M+H]+. A solution of this alcohol (500 mg, 3.1 mmol) in DMF (20 ml) was treated with PDC (7 g, 18.6 mmol) and H2O (0.5 ml). The reaction was stirred for 16 h, before being partitioned between H2O and EtOAc. The aqueous phase was extracted twice with EtOAc, then the combined organic extracts were washed with brine, before being dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES−)=177.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][CH:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44]#[CH:45])[CH2:37][CH2:36]1)[CH3:34]>CN(C)C=O.CO.CS(C)=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:45]#[C:44][CH2:43][CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][N:35]([CH:33]([CH3:34])[CH3:32])[CH2:36][CH2:37]2)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCN1CCN(C(C)C)CC1
Reactant: CCCCc1nc(N)c2c(n1)c(I)cn2COCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(C(C)C)CC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a degassed solution of 5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine (223 mg, 0.511 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) under a nitrogen atmosphere at room temperature was added copper(I) iodide (19 mg, 0.10 mmol), bis(triphenylphosphine)palladium(II)dichloride (40 mg, 0.057 mmol) and finally triethylamine (0.128 mL, 0.920 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes and then a solution of 1-(1-methylethyl)-4-(4-pentyn-1-yl)piperazine (159 mg, 0.818 mmol) in anhydrous degassed N,N-dimethylformamide (0.5 mL) was added. The reaction mixture was stirred at 55° C. for 40 minutes. A solution of 1-(1-methylethyl)-4-(4-pentyn-1-yl)piperazine 60 mg (0.309 mmol) in anhydrous degassed N,N-dimethylformamide (0.5 mL) was added. The reaction mixture was stirred at 55° C. for 30 minutes. The reaction was evaporated in vacuo to yield a dark yellow oil. The oil was partitioned between water and dichloromethane. The organic layer was separated and the aqueous back extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and evaporated in-vacuo to yield a dark yellow oil. The oil was dissolved in MeOH:DMSO (1:1) (4×1 mL) and purified by MDAP (Method B) Appropriate fractions were combined and evaporated in vacuo to yield the title compound as a yellow oil (80 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
5-{4-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.63) (0.35 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.22 g) which was subsequently deprotected.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:30].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[C:24]1([CH2:23][O:22][C:20](=[O:21])[CH2:19][N:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:8][CH:2]([NH:1][C:39]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)=[O:40])[C:3]2=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(RS)-amino-1,3-dihydro-1-phenylmethyloxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 220°-222° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:24]=1)[C:19]([OH:21])=[O:20].[C:44](=O)(O)[O-].[Na+].CI>CN(C=O)C>[CH3:44][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:24]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[OH:1])[CH:17]=1
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)OC)c1
Reaction time: 144 h
Yield: 67.9 %

Procedure:
A mixture of 0.15 g (0.25 mmol) of 3-[[6-(2,3-dihydroxyphenyl) hexyl]oxy]-5-(octadecyloxy)benzoic acid, 0.05 g (0.6 mmol) of sodium bicarbonate and 0.64 ml (10 mmol) of methyl iodide in 3 ml of DMF was stirred and heated at 40° for 5 days. An additional 0.32 ml of methyl iodide and 0.05 g of sodium bicarbonate were added and heating at 40° was continued for 6 days. The solvent was removed at reduced pressure, the residue was extracted with ethyl acetate and the extract was washed with water. The dried extract was concentrated to an oil which was purified by chromatography on 4 g of silica gel using 25% ethyl acetate-hexane to give 0.104 g (68% yield, mp 82°-84°) of 3-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[N:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: Clc1nccnc1C1CCCC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2C2CCCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.98 g, 4.11 mmol), cesium carbonate (1.34 g, 4.11 mmol), and 2-chloro-3-cyclopentylpyrazine (0.38 g, 2.05 mmol) in 1-methyl-2-pyrrolidinone (2 mL) under argon was heated to 140° C. for 24 h. The mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The resulting layers were separated and the organic layer was washed with 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 385.2 (M+1). IC50 (uM) ++++.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[CH2:7])([CH3:3])[CH3:2].C1C(=O)N([Cl:27])C(=O)C1.CCOCC>C1COCC1>[Cl:27][CH:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:14]([CH3:16])[CH3:15])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](OC(=CCl)c1ccccn1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Crude 2-{1-[(triisopropylsilyl)oxy]vinyl}pyridine (131.5 g, assumed 0.413 mmol) is placed in a 2 L, 1N round bottom flask and dissolved in anhydrous THF (Aldrich Sure Seal, 0.6 L). The flask is equipped with a reflux condenser and the apparatus is placed under nitrogen. NCS (60.66 g, 0.454 mol, 1.1 eq.) is added and the mixture is heated to reflux and maintained at reflux for 2 hours. The reaction mixture is cooled to room temperature, poured into a 4 L separatory funnel containing ether (1.5 L), and is washed with saturated aq. NaHCO3 (2×0.7 L). The organic phase is separated, dried (Na2SO4), and concentrated in vacuo affords the target (117.5 g, 91%) as a yellow-orange oil. The crude material is not further purified, but is immediately carried into the next step.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[OH:35])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[O:35][CH2:2][CH2:3][CH2:4][OH:5])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: OCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCO)c1
Yield: 79.6 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (5.2 mmol, 7.4 eq) of 3-iodo-1-propanol and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 270 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=79%