Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl.N1C=CC=CC=1.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(F)c(Cl)c1)OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
147.0 g (3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 540 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 145.8 g (1.04 mol) p-toluenesulfonylchloride in 200 ml of dichloromethane was added. After 5 h at room temperature additional 20 ml of pyridine, 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added. The solution was stirred at room temperature for 7 h and then refluxed for additional 4 h. Again 29.16 g (0.15 mol) p-toluene-sulfonylchloride and a catalytic amount of DMAP were added and the mixture was stirred overnight. For workup, the solution was washed twice with 2 N HCl and twice with saturated NaHCO3-solution. The organic layer was dried with MgSO4 and evaporated. Final silica gel chromatography (heptane/ethyl acetate 4:1) gave 155 g of the title compound as a yellow oil. Rt=1.80 min (Method B). Detected mass: 370.2 (M-OMe−).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]([NH2:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1.CCN(CC)CC.[C:59](Cl)(=[O:61])[CH3:60]>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][C@H:48]([NH:50][C:59](=[O:61])[CH3:60])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)N)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](C[C@@H](C)NC(C)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 1.0 mmol of (R and S)-2-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethylamine, 4.0 mmol of Et3N in 25 ml of CH2Cl2 are added 2.0 mmol of acetyl chloride at 0° C. and the resulting mixture is stirred for 1 h. The reaction mixture is diluted with water and extracted with CH2Cl2. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The resulting diastereomeric mixture is separated by flash chromatography (SiO2 60 F) to afford:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]3[CH3:25])=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].O>C(Cl)Cl>[CH3:36][S:33]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]3[CH3:25])=[CH:10][CH:9]=2)[CH2:3]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.1 %

Procedure:
3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone (520 mg, 1.19 mmol) and triethylamine (0.33 mL, 2.32 mmol) were mixed in methylene chloride and cooled on an ice bath. Mesyl chloride (0.12 mL, 1.55 mmol) was dripped in and stirred for 10 minutes at room temperature. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was washed with distilled water, and dried by anhydrous magnesium sulfate. The residue was concentrated to dryness, and the target compound (553 mg) was thus obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH3:19])[CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[NH:8]2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 6-ethoxy-2-(4-nitro-phenyl)-indole-1-carboxylic acid tert-butyl ester (8.1 g, 21.2 mmol) in CH2Cl2 (8 mL) was added TFA (8 mL). This mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted in EtOAc and washed with sat.aq. NaHCO3. The organic layer was concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane, followed by 100% CH2Cl2) to provide 6-ethoxy-2-(4-nitro-phenyl)-1H-indole (4.5 g, 68%) as an orange-red solid.
Reaction SMILES: Cl.[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[C:18](Cl)(Cl)=[O:19].[CH3:22][NH:23][OH:24]>>[C:2]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][NH:11][C:18]([N:23]([OH:24])[CH3:22])=[O:19])=[CH:6][CH:7]=1
Reactant: NCCOc1ccc(-c2ccccc2)cc1
Reactant: CNO
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN(O)C(=O)NCCOc1ccc(-c2ccccc2)cc1

Procedure:
This hydrochloride was converted to the title compound by treatment with phosgene and N-methylhydroxylamine as in Example 32 above. Recrystallization from methanol-water provided a white powder (0.46 g, 25% yield), mp 178°-179° C. (dec).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=[O:34])[CH2:30][CH:31](C)C.C(O[C@H]1CC[C@H](N)CC1)CC.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:28][CH:23]([CH3:24])[CH2:22][CH2:21][N:7]([CH:1]1[CH2:2][CH2:3][CH:4]([O:34][CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: CC(C)CC=O
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CCCO[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CCCOC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
{2-[3-(3-Methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-propoxy-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[CH3:24]>>[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:24]
Reactant: CCOCCN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOCC)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
31.8 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-ethoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[C:15]([F:24])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](Cl)=[O:18].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:15]([F:24])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.9 g (0.16 mol) of magnesium are initially introduced into 8.6 ml of ethanol and the reaction is started with carbon tetrachloride. A solution of 23.1 g (0.144 mol) of diethyl malonate in 16.3 ml of ethanol is added dropwise at an internal temperature of 50°-60° C. such that this temperature is maintained. The mixture is then subsequently stirred at 60° C. for one hour. Thereafter, a solution of 31.3 g (0.148 mol) of 3-chloro-2,4-difluorobenzoyl chloride in 16 ml of toluene is added dropwise at -10° to -5° C. and the mixture is subsequently stirred at 0° C. for one hour and then overnight, while warming to room temperature. The reaction mixture is poured onto ice-water, acidified with 10 ml of concentrated sulphuric acid and extracted with toluene. The extract is washed with saturated sodium chloride solution and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(N1CCCC1C1NC(C2C=CC3C(=CC=C([C:60]4[CH:65]=[CH:64][C:63]([C:66]5[NH:67][C:68]([CH:71]6[CH:76]7[CH2:77][CH:73]([CH2:74][CH2:75]7)[N:72]6[C:78](=[O:88])[CH:79]([NH:83][C:84]([O:86][CH3:87])=[O:85])[CH:80]([CH3:82])[CH3:81])=[N:69][CH:70]=5)=[CH:62][CH:61]=4)C=3)C=2)=CN=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:60]4[CH:61]=[CH:62][C:63]([C:66]5[NH:67][C:68]([CH:71]6[CH:76]7[CH2:77][CH:73]([CH2:74][CH2:75]7)[N:72]6[C:78](=[O:88])[CH:79]([NH:83][C:84]([O:86][CH3:87])=[O:85])[CH:80]([CH3:82])[CH3:81])=[N:69][CH:70]=5)=[CH:64][CH:65]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 24 %

Procedure:
This compound was synthesized using the procedure used to make (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester using 2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.154 g, 0.203 mmol) giving the title compound (0.041 g, 24% yield) as a white solid. LCMS-ESI+: calc'd for C46H54N8O6: 814.42 (M+); Found: 815.49 (M+H+).
Reaction SMILES: BrCC([C@@:5]([C:17]([OH:19])=[O:18])([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])=O.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:32]1CC[CH2:34][CH2:33]1>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH:5]([NH:6][C:33](=[O:32])[CH2:34][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[C:17]([OH:19])=[O:18])=[CH:9]1
Reactant: C1CCOC1
Reactant: N[C@@](Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)CBr
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(CN1CCN(c2ccccc2)CC1)NC(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 200 ml of tetrahydrofuran in a 500 ml round bottom flask under a nitrogen atmosphere was added (+-)-α-(bromoacetyl)tryptophan (3.25 mg, 0.01 mol), followed by 4-phenylpiperazine (3.24 mg, 3.1 ml, 0.02 mol), added portionwise over five minutes. Three minutes after addition of the 4-phenylpiperazine, a precipitate formed. The reaction mixture was stirred at room temperature for about 18 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:10]=[CH:11]/[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9].C(O)(=O)C1C=CC(O)=C(OC)C=1.C1(OC)C(=CC=C(C=1)CC=C)O>>[CH2:12]([OH:13])/[CH:11]=[CH:10]/[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(/C=C/C=O)ccc1O
Agent: C=CCc1ccc(O)c(OC)c1
Agent: COc1cc(C(=O)O)ccc1O
Product: COc1cc(/C=C/CO)ccc1O

Procedure:
The yield of coniferyl alcohol was 3226 ppm. This corresponds to 43.5% of theory. In addition, a further 1738 ppm (25% of theory) of ferulic acid were also obtained, as well as 12 ppm of coniferyl aldehyde and 8 ppm of vanillic acid. At the end of the process, 496 ppm (7.3%) of unreacted eugenol were still present.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC#N>[F:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cnc(Cl)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone (30 mg, 96 μmol), 2-chloro-5-fluoropyrimidine (18 μl, 144 μmol) and anhydrous DIPEA (50 g, 288 μmol) in CH3CN (2 mL) was heated at 100° C. for 3 days. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 409 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C=O)C>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(OC(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3-chloroisonicotinic acid, 1.04 g of (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].[CH2:12]1[O:15][CH:13]1[CH3:14]>CN(C)C=O>[OH:15][CH:13]([CH3:12])[CH2:14][N:6]1[C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[N:4]([CH2:12][CH:13]([OH:15])[CH3:14])[C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)N(CC(C)O)C(C)(C)C1=O
Temperature: 50 °C

Procedure:
A mixture of 217 g of 5,5-dimethylhydantoin (1.695 mols) 3.61 g of lithium chloride (5 mol per cent) and 560 ml of dimethylformamide is stirred at 50° C. 230 g. of propene oxide (propylene oxide) (3.955 mols) are added dropwise to the clear solution over the course of 4 hours, at 50°-55° C. The reaction is slightly exothermic. After the dropwise addition, the temperature is slowly raised to 90° C. After 5 hours at 90° C. the dimethylformamide is distilled off in a waterpump vacuum and thereafter the product is dried to constant weight at 100° C. and 0.1 mm Hg. 415 g of a pale yellow highly viscous oil (100 % of theory) are obtained. The crude product is distilled at 0.1 to 0.2 mm Hg and 170°-172° C.: 386.0 yield of pure material (93.5 % of theory). On cooling the 1,3-di(β -hydroxy-n-propyl)-5,5-dimethylhydantoin solidifies to give white crystals of melting point 65°-67° C. The elementary analysis shows 11.81 % N (calculated, 11.47 % N), and the molecular weight was determined by vapour pressure osmometry to be 247 (theory 244). The infrared spectrum shows the absence of N--H-- amide frequencies at 3.1 to 3.2 μ and the presence of C--OH frequencies at 2.90 μ.
Reaction SMILES: [C:1](=O)([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[O:2]C(C)(C)C.C(Cl)([Cl:20])=O.ClC1C=C(Cl)C(Cl)=CC=1O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:20][C:1]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
T-Butyl 2,4,5-trichlorophenyl carbonate is a known compound and one method for its preparation is described in an article by W. Broadbent, J. S. Morley and B. E. Stone in the Journal of the Chemical Society (C), 1967 pages 2632-2637. Briefly, in this method a solution of phosgene in toluene is treated with 2,4,5-trichlorophenol at -10° C, followed by addition of dimethylaniline at such a rate that the reaction temperature is maintained at 5°-10° C. The mixture is heated to 20°-24° C and maintained at this temperature for 12 hours. The mixture is cooled by addition of ice and the suspension filtered. From the organic layer in the filtrate, 2,4,5-trichlorophenyl chloroformate is isolated. A solution of the crude 2,4,5-trichlorophenyl chloroformate in methylene chloride is reacted with a solution of t-butanol and quinoline in methylene chloride. The reaction mixture is maintained at 20°-24° C for 12 hours. The mixture is cooled by addition of ice and the suspension is filtered. From the organic layer in the filtrate t-butyl 2,4,5-trichlorophenyl carbonate is isolated.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H) MS (ES)+m/e 280.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:34]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:33]([CH2:40][CH2:41][CH3:42])(N)[NH:32][C:27]=3[CH:28]=[N:29][C:30]=2[CH:31]=1.C([N:45](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:45][C:28]1[C:27]2[N:32]=[C:33]([CH2:40][CH2:41][CH3:42])[N:34]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:15])=[O:14])=[CH:31][C:30]=2[N:29]=1
Reactant: O=S(=O)(Cl)CCc1cccc2ccccc12
Reactant: CCCC1(N)Nc2cnc3cc(OCCCN)ccc3c2N1CC(C)C
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNS(=O)(=O)CCc4cccc5ccccc45)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolinamine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g of N-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide as white crystals, mp 164-168° C.