Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:10](=[O:30])[N:11]([CH2:13][C:14]3[CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[CH:17]=[CH:18][C:19]=3[CH2:20][OH:21])[N:12]=2)=[CH:4][CH:3]=1.ClS([N:42]=[C:43]=[O:44])(=O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[C:43](=[O:44])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])=[CH:15][C:14]=1[CH2:13][N:11]1[C:10](=[O:30])[N:9]([CH2:31][C@H:32]([OH:37])[C:33]([F:34])([F:36])[F:35])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1)[NH2:42]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=c1n(Cc2cc(-c3cccc(Cl)c3Cl)ccc2CO)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)OCc1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
65 mg (0.11 mmol) of the compound from Example 137 were dissolved in 3 ml of dichloromethane, and the mixture was cooled to 0° C. 14 μl (0.16 mmol) of chlorosulfonyl isocyanate were added, and the mixture was stirred at RT for 18 h. 1.5 ml of water were then added, and the mixture was stirred at 60° C. for a further 18 h. For work-up, 3 ml of saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 30 mg (43% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.Cl.[CH:16]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[CH:16]1([CH2:21][NH:22][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: NCC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (1.0 g, ex Maybridge) in dichloromethane (7 ml) at −2° was added a dropwise a solution of cyclopentanemethanamine hydrochloride (0.55 g) and triethylamine (1.4 ml) in dichloromethane (13 ml) and the solution stirred at 0° for 1 hour. Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed with 2N hydrochloric acid (3×15 ml), dried (MgSO4), evaporated and triturated with isohexane to afford 2-chloro trifluoromethyl-pyrimidin-5-carboxylic acid (cyclopentylmethyl)-amide (838 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](I)[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2].[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([F:11])=[C:8]([B:19]([OH:22])[OH:20])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(I)c(F)cc1OC
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 64D (324 mg, 1.1 mmol) in THF (5 mL) at −78° C. was slowly added n-BuLi (1.6 M in hexanes, 1.40 mL, 2.2 mmol). The reaction mixture was stirred at −78° C. for 20 min, followed by addition of trimethyl borate (0.31 mL, 2.8 mmol). The mixture was stirred at −78° C. for 3.0 h and then warmed up to rt over 18 h. It was quenched by addition of 1.0 N HCl (2.0 mL). After extraction with EtOAc, washing with a solution of Na2S2O3, brine and drying over Na2SO4, the crude product was purified by silica gel chromatography (eluting with 5% methanol in CH2Cl2) to give 64E (210 mg, 80% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.36 (t, J=6.81 Hz, 3H) 3.86 (s, 3H) 4.00 (q, J=7.03 Hz, 2H) 6.72 (d, J=10.11 Hz, 1H) 6.89 (d, J=5.27 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[CH:20]1([C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(O)[CH3:24])[CH2:22][CH2:21]1>ClCCl>[CH:20]1([C:23]([C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(C)(O)C2CC2)cc1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(C)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 ml (3.00 mmol) of trifluoroacetic acid was added to 885 mg (4.99 mmol) of the compound from Example 8A and 440 mg (2.50 mmol) of the compound from Example 137A in 44 ml of dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 87.4 mg (10% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)nc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(O)c2ccc(N)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-5-methylpyridine (3.0 g) and sodium azide (4.97 g) in DMSO (60 ml) was stirred for 24 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (3.39 g) in THF (40 ml) was added dropwise to a suspension of aluminum lithium hydride (1.06 g) in THF (40 ml) at 0° C. The mixture was stirred at room temperature for 1 hour, and water (1.06 ml), 15% aqueous solution of sodium hydroxide (1.06 ml) and water (3.18 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred for 64 hours at room temperature, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized, to give (4-aminophenyl)(5-methylpyridin-2-yl)methanol (2.07 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O1CCCC1>[CH2:23]([NH:31][C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)=[O:8])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A solution of 10 g of 6-chloro-nicotinic acid in 80 ml of N,N-dimethylformamide and 160 ml of tetrahydrofuran was treated with 10.75 g of 1,1'-carbonyldiimidazole and stirred at room temperature for 4 h. Thereafter, the reaction mixture was treated with 8.76 g of phenethylamine and stirred at 70° C. for a further 2 h. The mixture was cooled to room temperature, evaporated to dryness and the residue was taken up in 200 ml of dichloromethane. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from isopropanol yielded 11.9 g of 6-chloro-pyridine-3-carboxylic acid phenethyl-amide as a colorless product, m.p. 115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[NH:11][N:12]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>C(O)C>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]=[N:16][NH:15][C:13]([C:10]2[NH:11][N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=2)=[O:14])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1O
Reactant: NNC(=O)c1cc(-c2ccccc2Cl)n[nH]1
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2cc(-c3ccccc3Cl)n[nH]2)cc1O
Yield: 68.1 %

Procedure:
In ethanol (3 ml), 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide (30 mg) prepared in the Step 22-1-3 and 3-hydroxy-4-methoxybenzaldehyde (25 mg) was heated under reflux for 24 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration and dried to give the title compound (32 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])C(=O)OC(C)(C)C)=[CH:17][N:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][NH:20][CH2:28][CH2:29][O:30][CH3:31])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 47 (400 mg, 0.568 mmol) in toluene (10 mL) was added TFA (0.874 mL, 11.35 mmol) and the reaction mixture was stirred at RT overnight. The mixture was concentrated to dryness and the residue was purified by Gilson Reverse Phase HPLC (Aquasil C18, elient a linear gradient of 35% MeOH in water to 95% MeOH in water with 0.05% of formic acid, 60 min run) to afford 48 as a white solid, (305 mg, 65% yield) as the TFA salt. MS (m/z): 605.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:18]=[O:19]
Reactant: CSc1cc(N)c(Br)cc1Cl
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CSc1cc(N=C=O)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-chloro-5-methylsulfanyl-phenylamine (0.10 g, 0.396 mmol) in toluene (3 ml) was added pyridine (0.042 ml, 0.515 mmol), DMAP (0.048 g, 0.396 mmol) and 20% phosgene in toluene (0.225 ml, 0.436 mmol). The mixture was stirred at room temperature for two hours, then filtered. The filtrate was concentrated to dryness to give 1-bromo-5-chloro-2-isocyanato-4-methylsulfanyl-benzene (0.095 g) as a white solid that was used directly in the next step.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4-dichloro-benzenesulfonamide. LC: Tr 0.98 min, MS: 317.0 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45 (t, 1H), 6.11 (d, 1H), 6.72 (d, 1H), 6.92 (t, 1H), 7.59 (dd, 1H), 7.80 (d, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:34])[NH2:14])=[CH:8]2
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=S)cc3c2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a solution of 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (1.86 g) in tetrahydrofuran (40 mL) was added Lawesson's reagent (2.3 g), and the mixture was stirred at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70 to 90/10, volume ratio) to give the title compound (2.04 g, 100%) as a yellow amorphous solid. MS 344 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of methyl 3-cyano-4-methoxy-benzoate (1.5 g, 7.9 mmol) in CH3OH/H2O (25 mL; 1:1), was added LiOH (2.5 g, 60.0 mmol). The reaction mixture was refluxed for 2 h, cooled at rt and 6M HCl was added dropwise until pH 2 was obtained. The precipitate was collected, washed with H2O (3×20 mL), dried in vacuo to afford 3-cyano-4-methoxy-benzoic acid. MS (ESI) 178 (M+H)+. To a 100 mL round-bottom flask with 3-cyano-4-methoxy-benzoic acid (1.4 g, 7.8 mmol), was added SOCl2 (15 mL) dropwise. The reaction was refluxed for 1 h and was cooled to rt. The excess of SOCl2 was removed in vacuo and the oily acid chloride was dissolved in THF (15 mL). The resulting solution was added dropwise to a mixture of 2-aminophenol (1.3 g, 11.7 mmol), triethylamine (1.3 g, 11.7 mmol) and THF (30 mL) at 0° C. The reaction was warmed up to rt and stirred an additional 3 h. The precipitate was removed by filtration and the filtrate was concentrated and dried in vacuo. The dark brown solid residue was dissolved in toluene (20 mL) and p-toluenesulfonic acid (6.0 g, 46.8 mmol) was added. The reaction was refluxed overnight, cooled to rt, and EtOAc (300 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CHCl3:CH3OH 8:1) to afford 5-(1,3-benzoxazol-2-yl)-2-methoxy benzonitrile. MS ESI) 251(M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[O-:32][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate (3.30 g, 10.6 mmol) by reaction with m-CPBA (4.63 g) to provide ethyl 3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate followed by reaction with p-toluenesulfonyl chloride (3.53 g, 18.6 mmol) and ammonium hydroxide solution (50 mL) to provide ethyl 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate as an off-white solid after recrystallization from aqueous methanol, mp 156-157° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:20])=[C:9]([NH2:19])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](O)(=O)[CH:22]([CH3:24])[OH:23].Cl>>[C:13]1([C:10]2[C:9]3[N:19]=[C:21]([CH:22]([OH:23])[CH3:24])[NH:20][C:8]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1c(-c2ccccc2)ccc(-c2ccccc2)c1N
Reactant: CC(O)C(=O)O
Agent: Cl
Product: CC(O)c1nc2c(-c3ccccc3)ccc(-c3ccccc3)c2[nH]1
Temperature: 140 °C
Yield: 82.8 %

Procedure:
A mixture of 1.25 g (4.8 mmol) 1,1′:4′,1″-terphenyl-2′,3′-diamine, 0.75 ml (8.6 mmol) 85% aq. lactic acid and 4.8 ml 4N HCl were stirred at reflux for 6 hours and then the volatile materials evaporated over 1 hour. The oily residue was heated to 140° C. and stirred for 15 min. After cooling to room temperature 10 ml water were added and the mixture triturated for 30 min. Addition of conc. NH4OH to pH˜7.5–8 followed by filtration, washing with water (4×10 ml) and drying under vacuum at 60° C. gave 1.25 g (82.8%) of the desired product. 1H NMR (250 MHz, CDCl3), δ, ppm: 1.58 (d, JHH=6.7 Hz, 3H), 3.64 (br.s, 1H), 5.07 (q, 1H), 7.37–7.76 (m, 12 H), 9.53 (br. s, 1H).
Reaction SMILES: O[CH2:2][C@@H:3]([NH:6][C:7]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=1[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])[CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:48]CCCl>C(Cl)(Cl)(Cl)Cl>[Cl:48][CH2:2][C@@H:3]([NH:6][C:7]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=1[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])[CH2:4][CH3:5]
Reactant: ClCCCl
Reactant: CC[C@@H](CO)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@@H](CCl)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2

Procedure:
To a solution of (S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (127 mg) in 1,2-dichloroethane (4 mL) and carbontetrachloride (2 mL) was added triphenylphosphine (215 mg), and the mixture was stirred for an hour under reflux. The solvent was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-2-[1-(chloromethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (71 mg) as a solid substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-methanesulfonylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:8]=3[N:7]([CH3:16])[C:6]2=[O:17])[CH2:4][CH2:3][CH2:2]1.CS([Cl:22])(=O)=O>ClCCl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>[Cl:22][CH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[C:6](=[O:17])[N:7]([CH3:16])[C:8]=2[CH:13]=1
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCC2)c2ccc(CCl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (13.79 g, 59.4 mmol) was diluted with dichloromethane (300 mL) and triethylamine (12.4 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (6.9 mL, 89.1 mmol) was added. The mixture was stirred for 1 hour at 0° C. then was diluted with saturated sodium bicarbonate and extraced into dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The resulting oil was filtered through silica gel using ethyl acetate containing 1% triethylamine as eluent to give 11.92 g of 5-Chloromethyl-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([O:25][CH3:26])=[CH:17][C:16]=2[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:21]([C:19]1[C:18]([O:25][CH3:26])=[CH:17][C:16]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:20]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CNC(=O)Cc1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)Cc1cc(OC)c(C(C)(C)C)cc1-c1ccc[nH]c1=O
Reaction time: 0.5 h

Procedure:
step 2—A mixture of 57 (55 mg) and 10% Pd/C (10 mg) in MeOH (5 mL) at RT was stirred under 1 atmosphere of H2 for 0.5 h. The catalyst was filtered off and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC developed with 10% MeOH/DCM to afford 45 mg of I-10 as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:15]3[CH:14]=[CH:13][C:11]4[N:12]=[C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:9][C:10]=4[CH:16]=3)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c3c(N)ncnn23)CC1
Yield: 54.8 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and acetyl chloride as starting material, 27 mg (54.8%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.04 (d, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.59 (d, 1H), 7.41-7.29 (m, 5H), 7.56 (s, 1H), 4.76-4.68 (m, 1H), 4.44 (s, 2H), 3.96-3.90 (m, 1H), 3.56-3.44 (m, 1H), 3.30-3.24 (m, 1H), 2.70-2.80 (m, 1H), 2.22-2.12 (m, 2H), 2.10 (s, 3H), 1.76-1.60 (m, 2H) LC-MS m/z [M+H]+ 483.3, RT 2.76 min.
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH2:12][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:25]([NH2:27])[CH3:26].Cl>>[CH2:25]([NH:27][C:14]([C:11]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:9][N:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]1)=[O:16])[CH3:26]
Reactant: CCN
Reactant: CCCCCCN1CCC(C(=O)OCC)(c2ccccc2)CC1
Agent: Cl
Product: CCCCCCN1CCC(C(=O)NCC)(c2ccccc2)CC1

Procedure:
This compound was prepared as above from ethyl 1-hexyl-4-phenyl-4-piperidinecarboxylate hydrochloride (3.54 g, 10 mmol) and ethylamine (2.25 g, 50 mmol). Reaction time 2 days. The crude product (1.0 g) was recrystallized from disopropyl ether, yielding 0.81 g with m.p. 92°-94° C. Hydrochloride m.p. 221°-223° C. (from 2% aqueous acetone).