Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][O:12][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:5][CH:4]=1
Reactant: OCCSc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCSc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2-(4-Trifluoromethyl-phenylsulfanyl)ethanol (15.00 g, 67.50 mmol) prepared in the above Step (1) was dissolved in anhydrous DCM (100 ml), pyridine (7.59 ml, 93.81 mmol) and 4-nitrophenyl chloroformate (13.61 g, 67.50 mmol) were added thereto at 0° C. in order, and the mixture was stirred for 2 hours at room temperature. The reaction was stopped by adding distilled water, and the reaction mixture was extracted with DCM. The organic layer thus extracted was washed with aqueous NH4Cl solution, dried over anhydrous MgSO4, and then concentrated. The concentrate was purified by silica gel column chromatography (DCM/n-hexane=5/1, v/v) to give carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (22.54 g, 86.21%) of a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl.N1C=CC=CC=1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=4[N:7]4[C:3]([CH2:2][NH:1][C:34](=[O:36])[CH3:35])=[CH:4][CH:5]=[C:6]34)[CH2:12][CH2:13]2)=[O:18])=[CH:20][C:21]=1[CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccc2n1-c1ccccc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Crude (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone (49 mg, 0.11 mmol) was dissolved in a solution of dry dichloromethane (0.5 mL) and pyridine (0.3 mL) and was cooled to 0° C. Acetic anhydride (52 μL, 0.55 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by the addition of methanol (0.5 mL), concentrated, and purified by reverse phase HPLC [10-99% acetonitrile in water (HCl modifier)] to give N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)acetamide. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.9 Hz, 1H), 7.33-7.21 (m, 2H), 7.13 (d, J=4.2 Hz, 2H), 7.10-7.02 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.26 (d, J=3.4 Hz, 1H), 5.99 (d, J=3.5 Hz, 1H), 5.68 (s, 1H), 4.71 (d, J=4.7 Hz, 2H), 4.64-4.50 (m, 1H), 3.50 (s, 2H), 2.22 (s, 3H), 2.17-1.76 (m, 7H), 1.67 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 487.6. found 488.5 (M+1)+; Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][C:26]([NH:30]CC6C=CC(OC)=CC=6)=[CH:27][CH:28]=5)[N:23](CC5C=CC(OC)=CC=5)[N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:49])[CH:9]=1)[C:5]#[N:6]>C(O)(C(F)(F)F)=O>[NH2:30][C:26]1[N:25]=[C:24]2[NH:23][N:22]=[C:21]([CH2:20][N:16]3[C:15]4[CH:14]=[CH:13][C:12]([Cl:49])=[C:11]([O:10][C:8]5[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=5)[C:5]#[N:6])[C:19]=4[N:18]=[N:17]3)[C:29]2=[CH:28][CH:27]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4nnc5c(Oc6cc(Cl)cc(C#N)c6)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3nc(N)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-chloro-5-{[5-chloro-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (135 mg, 0.195 mmol) was dissolved in TFA (10 mL) and placed in an oil bath at 75° C. After 2 hours, the reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting residue was diluted with CHCl3/EtOAc (4:1, 50 mL) and methanol was added until a solution was achieved. 50% Aqueous sodium bicarbonate (10 mL) was then added. The organic phase was removed and the aqueous was extracted with CHCl3 (25 mL). The combined organic fractions were, dried (MgSO4), filtered and concentrated. The resulting residue was adsorbed onto silica gel with CHCl3/MeOH and purified by automated column chromatography on silica gel (12 g), eluting with 0-5% MeOH/CH2Cl2 to afford the title compound. 1H NMR (DMSO d-6) δ 7.82 (d, J=9.0 Hz, 1H), 7.81 (m, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.58 (m, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.52 (m, 1H), 6.36 (m, 1H), 6.30 (d, J=8.8 Hz, 1H), 6.16 (s, 1H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]2[O:12][C:13]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:15]2[C:14]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=3[O:12][C:11]3[CH:23]=[CH:24][C:8]([CH3:7])=[CH:9][C:10]=3[CH:16]=2)[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(C)ccc1O2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
A solution of 11.35 ml. of titanium (IV) chloride in 135 ml. of benzene is added dropwise with stirring and cooling at 20°-25° C. to a solution of 30 g. of 10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one and 80 ml. of N-ethoxycarbonylpiperazine in 300 ml. of benzene. Then, the mixture is stirred for 4 hours at reflux and cooled. The cooled mixture is poured into a solution of 12 g. of sodium bicarbonate in 300 ml. of water. The precipitated titanium dioxide is removed by filtration and washed well with benzene. The filtrate is washed four additional times with water. The aqueous phases are extracted again with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated in vacuo, and there is obtained 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:22][Si:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]O>CC#N.CN(C1C=CN=CC=1)C>[CH3:22][Si:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(C(=O)OCC[Si](C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A solution of 5-Methyl-thiophene-2-carboxylic acid (23.58 g, 166 mmol) in MeCN (300 mL) is treated with EDCl (33.41 g, 174 mmol) and DMAP (2.03 g, 16 mmol). The mixture is stirred for 5 min and 2-(trimethylsilyl)ethanol (19.61 g, 166 mmol) is added. The mixture is stirred at RT for 16 h and the solvent is evaporated. The residue is partitioned between EtOAc and water. The organic layer is diluted with an equal portion of hexane and dried over anhydrous MgSO4. The solution is passed through a plug of silica gel and the solvents are evaporated to dryness to give 5-methyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester as a clear oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](Cl)=[O:12]>CN(C)C=O>[OH:2][CH2:1][CH2:3][NH:4][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:12]
Reactant: NCCO
Reactant: O=C(Cl)c1ccccn1
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.4 ml of ethanolamine were placed under argon with 30 ml of dimethylformamide and cooled to 0°-5°. A solution of 11.3 g of picolinic acid chloride in 100 ml of dimethylformamide was added dropwise thereto at 0°-10° and the mixture was stirred at room temperature overnight. The dimethylformamide was distilled off under reduced pressure. The residue was dissolved in methylene chloride and separated from the insoluble constituents, and thereafter chromatographed on silica gel; elution agent: methylene chloride, thereafter methylene chloride/methanol (9:1). N-(2-Hydroxyethyl)pyridine-2-carboxamide was obtained as a yellow oil.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1ccc(-c2cccs2)n1
Product: O=C(On1ccc(-c2cccs2)n1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (75%, crystals).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:26]O>>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:26])=[O:19])=[C:14]([C:21]([OH:23])=[O:22])[CH:13]=2)=[CH:6][CH:5]=1)[CH3:25]
Reactant: CO
Reactant: CCN(CC)c1ccc(N=Nc2ccc(C(=O)O)c(C(=O)O)c2)cc1
Product: CCN(CC)c1ccc(N=Nc2ccc(C(=O)OC)c(C(=O)O)c2)cc1

Procedure:
1.6 parts of the anhydride of N,N-diethyl-4(3,4-dicarboxyphenylazo)aniline, (Dyestuff 3), is dissolved in 25 parts of methanol and the solution heated under reflux for 2 hours. The solution is then evaporated in vacuo to give N,N-diethyl-4(3-carboxy-4-carbomethoxyphenylazo)aniline which gives an orange solution in acetone with λmax 453.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][CH2:20][C:17]1[CH:16]=[C:15]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]([C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[F:5])=[N:19][CH:18]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ncc(CBr)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, phosphorus tribromide (37 μL) was added to DMF (1.0 mL) at 0° C. and the mixture was stirred at 0° C. for 5 min. To the obtained white suspension was added (6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methanol (100 mg), and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (88 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 3.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1)
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[N:5]1.C([O-])(=O)C.[Na+]>>[Br:1][C:7]1[C:6]([C:10]([F:12])([F:11])[F:13])=[N:5][N:4]([CH3:3])[C:8]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1cc(C(F)(F)F)nn1C
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1c(Br)c(C(F)(F)F)nn1C
Reaction time: 96 h
Yield: 79.5 %

Procedure:
A total of 61.9 g (388 mmol) of bromine are added dropwise at 0° C. within 2.5 h to a suspension of 60 g (366 mmol) of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole and 30.0 g (366 mmol) of anhydrous sodium acetate in 600 ml of CHC13. On completion of addition, the mixture is allowed to come to 20° C. and is stirred for a further 4 d. After the end of the reaction, the mixture is washed with 30% NaHCO3 solution, the aqueous phase is further extracted twice using 200 ml of CHC13 each time and the combined organic phases are dried over MgSO4 and concentrated. Recystallization results in 70.6 g (291 mmol, 80%) of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]([OH:17])=O)[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][C:19]1(C)OC(=O)CC(=O)[O:20]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19](=[O:20])[CH:18]=[C:15]([OH:17])[CH:11]2[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)norvaline (4.0 g), Meldrum's acid (2.40 g) and 4-(N,N-dimethyl)aminopyridine. (2.90 g) in tetrahydrofuran (60 mL) was added N,N′-carbonyldiimidazole (3.08 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound as colorless crystals (yield: 1.89 g, 43%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([NH2:30])[N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[C:25]([NH2:30])[N:24]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc(Cl)n1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To an ice-cooled mixture of (5)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (226 mg, 0.69 mmol), 4,6-dichloro-[1,3,5]triazin-2-ylamine (125 mg, 0.76 mmol) and IPA (5 mL) was added DIPEA (0.59 mL, 3.45 mmol). The reaction mixture was stirred at RT (room temperature) for 64 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between EtOAc and aqueous Na2CO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant EtOAc) affording the title compound as a colourless foam (quantitative). A portion (50 mg) was further purified by column chromatography (Si—PCC, eluant EtOAc) affording 269 after evaporation from acetone as a colourless foam (31.8 mg). LCMS (Method K): RT 4.06 min [M+H]+ 384.0/385.9. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.69 (1H, bs), 7.66 (1H, dd, J=8.8, 4.9 Hz), 7.60-7.50 (5H, m), 7.07-7.02 (1H, m), 6.78 (2H, bs), 6.77 (1H, dd, J=8.9, 2.4 Hz), 5.21 (1H, quintet, J=7.1 Hz), 1.46 (3H, d, J=6.9 Hz)
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=O>C1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 79.7 %

Procedure:
Thionyl chloride (1,000 g, 8.4 m) was then added to the 2-chloro-4-nitrobenzamide (200 g, 1 m) while the mixture was warmed. After addition, the mixture was refluxed for approximately three hours. The excess thionyl chloride was removed by distillation leaving a reaction mixture residue. Benzene (500 ml) was added to the cold reaction mixture residue to extract the reaction product. The extract was washed with diluted sodium hydroxide solution and water until neutralized and then dried over anhydrous sodium sulfate. The benzene solvent was distilled off and the reaction product was crystallized from methanol to yield 2-chloro-4-nitrobenzonitrile (145 g, 79%, mp 73°-75° C.).
Reaction SMILES: Br[C:2]([CH3:19])([CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[C:2]([CH3:19])([CH3:18])[O:4]1
Reactant: CC(C)(Br)C(=O)c1ccc(Sc2ccccc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(Sc3ccccc3)cc2)OC1(C)C

Procedure:
3 g (0.0551 mol) of 2-bromo-2-methyl-1-(4-phenylsulphanyl-phenyl)-propan-1-one were dissolved in 30 ml of methanol. 1.79 ml of a 30% sodium methylate solution in methanol at room temperature were added. After 15′ the solution was evaporated and the product used without further purification in the following reaction.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][S:19]SC>[Cu]>[CH3:17][C:10]1[C:11]([CH3:16])=[C:12]([S:19][CH3:18])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: CSSC
Reactant: Cc1c(N)ccc(Br)c1C
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1C
Temperature: 77.5 °C
Reaction time: 9 h

Procedure:
603 g (5.85 mol) of tert-butyl nitrite and 375 g of copper powder (5.9 mol) are initially charged in 3000 ml of dimethyl disulfide, and 761 g (3.75 mol) of 4-bromo-2,3-dimethylaniline are added dropwise at from 50 to 58° C. The mixture is subsequently stirred at from 75 to 80° C. for 9 hours. For work-up, the mixture is cooled, the residue is filtered off and the filtrate is washed with saturated aqueous NaHCO3 solution. For purification of the product, the organic phase is separated by distillation. Initially, the excess dimethyl disulfide is separated off at atmospheric pressure. 1870 g of dimethyl disulfide (purity>97% according to GC) are recovered. The residue is subsequently subjected to fractional distillation under reduced pressure (0.1 mbar).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].CN(C1C=CC=CC=1)[CH:19]=[O:20].S(=O)(=O)(O)O>O1CCCC1>[Cl:6][C:7]1[C:8]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:19]=[O:20]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: CN(C=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(F)(F)F)c1Cl
Reaction time: 1.5 h

Procedure:
Butyl lithium (36.4 ml of 1.6M in hexane) was added to a stirred solution at -65° of 1-chloro-2-(trifluoromethyl)-benzene (10 g) in dry tetrahydrofuran (100 ml) over 20 mins. After stirring for 1.5 hours at -65°, a solution of N-methyl-N-phenylformamide (6.85 ml) in tetrahydrofuran (30 ml) was added over 1 hour. The reaction mixture was left at this temperature for 1.5 hours and then allowed to reach room temperature. It was then poured onto 10% sulphuric acid, extracted with ether and the organic extract was washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was distilled (20 mmHg, oven temperature 100°-125°); the distillate was cooled, filtered and the solid washed with petroleum ether (60°-80°) to give the desired aldehyde (3.5 g) as a colourless solid.
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:38][CH3:39])=[C:16]([CH:37]=2)[CH2:17][S:18][C:19]2[N:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:22]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=3[N:20]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.ClCCl>>[N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:38][CH3:39])=[C:16]([CH:37]=2)[CH2:17][S:18][C:19]2[N:23]([CH2:24][C:25]([OH:27])=[O:26])[C:22]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=3[N:20]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)N2CCc3ccccc32)cc1CSc1nc2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3ccccc32)cc1CSc1nc2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
tert-Butyl {2-[5-(2,3-dihydro-indole-1-carbonyl)-2-methoxy-benzylsulfanyl]-5-fluoro-benzoimidazol-1-yl}-acetate (Precursor 5-F-H-17b, 26 mg, 0.047 mmol) in a TFA/dichloromethane mixture (1:1, 0.5 ml) is allowed to stir at rt for 4 h. The solvents are removed under a stream of air. The product is precipitated in Et2O, filtered, rinsed with Et2O and dried under high vacuum. This yields the title compound (22 mg) in 99% as a light pink solid: tR=1.04 min (LC-3), ESI-MS (pos.): m/z 492.11 [M+H]+, ESI-MS (neg.): m/z 490.18 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.88 (t, 2H, NCH2CH2Ar), 3.85 (t, 2H, NCH2CH2Ar), 3.89 (s, 3H, OCH3), 4.54 (s, 2H, SCH2), 4.95 (s, 2H, CH2CO2), 6.97 (t, 1Harom), 7.02-7.09 (m, 4Harom), 7.11 (d, 1Harom), 7.21 (d, 1Harom), 7.38-7.57 (m, 3Harom).