Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][O:27][NH2:28])[N:20]([CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.O>CN(C=O)C>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][O:27][NH:28][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[N:20]([CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CC(C)N=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)NOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Isopropyl isocyanate (0.234 mL, 2.39 mmol) was added to a stirred solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). After 5 minutes, a solid formed. The mixture was stirred for 1 hour and 45 minutes, then additional isopropyl isocyanate (0.234 mL) and DMF (2 mL) was added. The mixture was stirred at room temperature for 45 minutes. Water (40 mL) was added and a solid was isolated by filtration. The solid was washed with water and dried under vacuum to provide 272 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-N′-isopropylurea as a white solid. The filtrate was allowed to stand overnight at room temperature and crystals formed. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 60° C. to afford additional 38 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-N′-isopropylurea, as yellow crystals, mp 231-233° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1c(F)cc(C=O)cc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30.0 g (190 mmol) of 3,5-difluoro-4-hydroxybenzaldehyde [CAS 118276-06-5] are dissolved under argon in 600 ml of dichloromethane and, at 0° C., 44.7 g (417 mmol) of 2,6-lutidine are added. Then 87.2 g (284 mmol) of triisopropylsilyl trifluoromethanesulfonate are added dropwise, and the mixture is stirred at RT for 12 h. The solvent is distilled out in vacuo, and the residue is mixed with ammonium chloride solution and stirred for 5 min, and the organic phase is separated off. A further extraction with dichloromethane is carried out, and the organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and washed with dichloromethane, and the solvent is distilled off in vacuo. Chromatography on silica gel 60 (mobile phase: cyclohexane) results in 34.9 g (111 mmol, 58% of theory) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(-c3nsc(COS(C)(=O)=O)n3)cn(CC3CCCCC3)c12
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To a cooled solution (ice/methanol bath) of [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (2.3 g, 6.4 mmol) in dichloromethane (150 ml) was added methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) sequentially. The reaction was allowed to stir for 10 min and then poured into a separating funnel. The organics were washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford methanesulfonic acid 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (2.9 g, 6.7 mmol) which was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[Cl:34])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:34][C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3Cl)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3Cl)c[nH]c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
176 mg (2.70 mmol) of potassium cyanide and 8.2 mg (0.07 mmol) of 4-N,N-dimethylaminopyridine were added to 664 mg (1.35 mmol) of the compound from Example 108A in 29 ml of DMSO. The mixture was stirred at 120° C. for 1 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 460 mg (81% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:22].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:22])[C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cc(-c3cccc(F)c3)ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(-c3cccc(F)c3)ccc21
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one (48 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2 mL) was added 95% sodium hydride (10 mg, 0.40 mmol). The reaction mixture was stirred for 5 minutes, then warmed to 40° C. for 15 minutes under an atmosphere of dry N2. Iodomethane (142 mg, 1.00 mmol) was added, and the resulting mixture was stirred at room temperature for 15 hours. Methanol (2 mL) was added, and the mixture stirred for 10 minutes. Solvent was removed from the reaction mixture under reduced pressure, ethyl acetate (30 mL) and 30% ammonium chloride (10 mL) were added, the organic phase was washed with water (10 mL), 30% ammonium chloride (15 mL) and brine (15 mL), and the organic layer was concentrated under reduced pressure to give 6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. MS m/z 256.1 (M+H), anal HPLC 92% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (dd, J=8.6 Hz, 2.3 Hz, 1H); 7.30-7.42 (m, 3H); 7.25 (m, 1H); 6.98-7.10 (m, 2H); 3.39 (s, 3H); 2.97 (t, J=7.4 Hz, 2H); 2.70 (t, J=7.4 Hz, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]2COCC[Si](C)(C)C)=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[C:33]2[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccccc3Cl)ccc12
Yield: 18.9 %

Procedure:
2.9 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 900 mg of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 50 cm3 of ethyl acetate and the organic phase is washed successively with 2×30 cm3 of saturated sodium hydrogen carbonate solution, with 30 cm3 of water and with 30 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 120 mg of N-[6-(2-chlorophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a beige-coloured foam.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Yield: 35.2 %

Procedure:
In a manner similar to that described in part A of Example 1 hereinabove, 7.4 g (0.05 mole) of phthalic anhydride, 16.0 g (0.053 mole) of 76.5 percent active 1-n-octyl-2-methylindole, and 13.3 g (0.1 mole) of aluminum chloride were interacted in 50 ml of benzene to obtain 6.9 g of 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)7CH3), as a pink-colored powder which melted at 121°-123° C. The nuclear magnetic spectrum was in agreement with the structure and a significant maximum occurred at 1717 cm-1 (C=O; s).
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[NH:13][NH2:14]>C(O)C>[CH2:17]([O:16][C:12](=[O:15])[NH:13][N:14]=[CH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[NH:6][CH:7]=1)[CH3:18]
Reactant: CC(C)(C)c1nc(C=O)c[nH]1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(C(C)(C)C)n1

Procedure:
A 7.6 gm. portion of 2-tert-butyl-4-imidazolecarboxaldehyde and 5.2 gm. of ethyl carbazate in 100 ml. of ethanol are reacted as described in Example 32 giving the desired product, m.p. 194°-197° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]([Cl:17])=[N:10][C:11]2[C:12](=[CH:14][S:15][CH:16]=2)[N:13]=1>CCO>[Cl:17][C:9]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:13][C:12]2[C:11](=[CH:16][S:15][CH:14]=2)[N:10]=1
Reactant: Clc1nc2cscc2nc1Cl
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1nc2cscc2nc1N1CCNCC1
Yield: 29.1 %

Procedure:
Piperazine (92 mg, 1.07 mmol) was added to a stirred suspension of 2,3-dichlorothieno[3,4-b]pyrazine (110 mg, 0.54 mmol) in EtOH (5 mL) at room temperature. The mixture was stirred at reflux for 16 h and filtered. The solid was purified by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) to give 40 mg (29%) of the product as an orange solid. The material was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[CH:15]=[CH:14][N:13]=1)[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(C)cc2)ccn1
Yield: 88 %

Procedure:
Compound II (56 mg, 0.117 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), p-tolylboronic acid (32 mg, 0.235 mmol) and potassium carbonate (65 mg, 0.47 mmol) were stirred in toluene (3 mL) and water (1.5 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (30 mL) and extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 80:20) to furnish III as a colourless oil (43 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[O:4][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(O)cc1Cl

Procedure:
In ethanol, chlorohydroquinone was reacted with dodecylbromide in ethanol by using 1 equivalent of potassium hydroxide to obtain 3-chloro-4-dodecyloxyphenol. Then, 3.1 g of this 3-chloro-4-dodecyloxyphenol was reacted with 2.0 g of 2,4-acetoxybenzoic acid chloride in pyridine and the reaction mixture was treated by customary procedures to obtain 4 g of 3-chloro-4-dodecyloxyphenyl 4-acetoxybenzoate. This ester was dissolved in a THF/methanol liquid mixture and 1 equivalent of 1N LiOH was added to selectively isolate the acetoxy group, whereby 3-chloro-4-dodecyloxyphenyl 4-hydroxybenzoate was obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:5]2=[CH:4][C:3]=1I)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.[O:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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>[O:29]1[CH2:30][CH:31]=[C:32]([C:3]2[CH:4]=[C:5]3[C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:13]=4)[O:8][C:6]3=[N:7][C:2]=2[F:1])[CH2:33][CH2:34]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccnc3F)ccc1Oc1nc(F)c(C3=CCOCC3)cc12
Temperature: 120 °C

Procedure:
2-Fluoro-7-(2-fluoropyridin-3-yl)-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.151 g, 0.307 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.150 g, 0.71 mmol), tetrakis(triphenylphosphine)palladium (0.177 g, 0.153 mmol), and potassium phosphate (0.102 mL, 1.227 mmol) were suspended in dioxane (2 mL) and water (0.5 mL) and sealed in a microwave vessel under argon. The mixture was heated to 120° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between water (80 mL) and ethyl acetate (80 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (1-4% methanol in dichloromethane gradient) gave 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](=[N-])(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][S:23]2(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: [N-]=S(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Then, 590 mg of 1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine, 600 mg of sulfurylamide and 12 ml of pyridine are mixed and refluxed with heating for 2 hours. The reaction mixture is cooled to room temperature and poured into 50 ml of ice water. The white crystals deposited are separated by filtration, washed with 10 ml of water and dried to obtain 520 mg of the desired product as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][CH:19]=[CH:20][CH:21]=4)[N:26]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2cccnc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccccc3n2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.97-2.11 (m, 2H) 2.18-2.30 (m, 2H) 2.43 (s, 3H) 3.10-3.29 (m, 5H) 4.32 (s, 2H) 6.96-7.01 (m, 1H) 7.22 (s, 1H) 7.35 (d, J=8 Hz, 1H) 7.57 (d, J=8 Hz, 1H) 7.62-7.69 (m, 1H) 7.82 (ddd, J=8, 7, 1 Hz, 1H) 7.97-8.05 (m, 2H) 8.52 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]([S:12][CH3:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][S:2][C:4]([S:12][CH3:13])=[C:5]([Cl:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CSC(=Cc1ccccc1)S(C)=O
Solvent: ClCCl
Product: CSC(SC)=C(Cl)c1ccccc1

Procedure:
1-Methylsulfinyl-1-methylthio-2-phenylethylene (1.868 g) was dissolved in 10 ml of methylene chloride, and with stirring under ice cooling, a solution consisting of 0.71 ml of thionyl chloride and 6 ml of methylene chloride was added dropwise over the course of 30 minutes. Under ice cooling, the mixture was stirred for 1.5 hours, and concentrated under reduced pressure. The residue was chromatographed on a Florisil column using benzene/hexane as an eluant to afford 1.494 g of 1,1-bis(methylthio)-2-chloro-2-phenylethylene as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>[OH-].[Na+].O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: COCCCCl
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (800 mg, 4.9 mmol, 1.0 equiv) and 1-chloro-3-methoxypropane (528.97 mg, 4.9 mmol, 1.0 equiv) in 50% aqueous NaOH solution (10.0 mL) was stirred at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure to give 1-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (987.8 mg, 4.2 mmol) as yellow oil in 86% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.56 (s, 2 H), 4.02-4.04 (m, 2 H), 3.53-3.55 (m, 2 H), 3.36 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.02-2.04 (m, 3H); ESI-MS: m/z 237.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:21]=1
Reactant: FC(F)Oc1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(OC(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (2.5 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 100 mg (2.5 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.50 g (2.5 m mol) of 2,3-dichloro-5-difluoromethoxypyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reaction mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 1-(3-chloro-5-difluoromethoxypyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42]([CH3:44])[C:41]([O:45][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:40]([CH3:46])[CH:39]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate and a reaction time of 18 h. Light yellow solid (12%). MS (Turbo Spray): m/z=553.3 [M+H].