Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]2[C:13]([F:24])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[N:18][CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cn1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc(Cl)cn3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidineamine gave N4-(5-chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.80 (bs, 1H), 9.77 (bs, 1H), 8.45 (bd, 1H), 8.26 (d, 1H, J=3.9 Hz), 8.15 (d, 1H, J=8.7 Hz), 7.85 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (m, 3H), 6.43 (bd, 1H, J=7.2 Hz); LCMS: purity: 97%; MS (m/e): 332 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH3:15]>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: Cc1ccc2[nH]nc(I)c2c1
Reactant: CCCBr
Product: CCCn1nc(I)c2cc(C)ccc21
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 3-iodo-5-methyl-indazole and 1-bromopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J=7.2 Hz), 1.90-1.96 (2H, m), 4.32 (2H, t, J=7.2 Hz), 7.22-7.28 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:29])[C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
In 25 ml of dry N,N-dimethylformamide was dissolved 11.0 g (25.1 mmol) of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b), followed by addition of 5.2 g (38 mmol) of potassium carbonate powder. Then, 3.90 g (27.7 mmol) of methyl iodide was further added and the mixture was stirred at room temperature for 8 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and dried over magnisium sulfate. The solvent was distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). From the first fraction, 1.7 g (yield 15%) of the objective position isomer (17b') was obtained as oil. From the subsequent fraction, 9.14 g (yield 80%) of the objective 5-(3,5-dichlorophenylthio)-1-methyl-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17b) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH:18]([CH2:21][CH3:22])[CH2:17][NH:16][C:15](=[O:23])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:21]([CH:18]1[CH2:17][NH:16][C:15](=[O:23])[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:11]=[CH:10]4)[NH:20][C:19]1=2)[CH3:22]
Reactant: CCC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CCC1CNC(=O)c2cc(-c3cccc4ccc(Nc5ccccc5)nc34)[nH]c21
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(2-chloroquinolin-8-yl)-7-ethyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 22; 0.075 g, 0.230 mmol) and aniline (0.105 ml, 1.151 mmol) was treated with LHMDS (1.0 M in THF; 1.151 ml, 1.151 mmol) at RT. After 2 h, the reaction was concentrated, then dissolved in DMSO and treated with TFA (0.089 ml, 1.151 mmol). This material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.055 mmol, 23.85% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (1H, br. s), 9.53 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.96 (1H, dt, J=7.5, 0.6 Hz), 7.53-7.67 (3H, m), 7.39 (2H, t, J=7.8 Hz), 7.29 (1H, t, J=7.6 Hz), 7.03-7.15 (2H, m), 6.86-6.95 (2H, m), 3.46-3.61 (1H, m), 3.06-3.21 (1H, m), 2.58-2.71 (1H, m), 1.15-1.32 (2H, m), 0.66 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 383.0 (M+H)+. A portion of this material was resolved by chiral SFC (Chiralpak IC (21×250 mm, 5 μm); additive in supercritical fluid CO2 was 50% MeOH with 20 mM NH3; 60 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers (R)-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 25) and (S)-7-ethyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one. (Example 26).
Reaction SMILES: [C:1]1([N:10]=[C:11]=[S:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[S:9])=[CH:3][CH:2]=1.[CH:13]([NH:16][CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(#N)C>[C:4]1([NH:7][C:8]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:9])[CH:3]=[CH:2][C:1]([NH:10][C:11]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:12])=[CH:6][CH:5]=1
Reactant: CC(C)NC(C)C
Reactant: S=C=Nc1ccc(N=C=S)cc1
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(NC(=S)N(C(C)C)C(C)C)cc1)C(C)C

Procedure:
To a solution of 1.92 g. of 1,4-phenylenediisothiocyanate in 100 ml. of acetonitrile is added 2.5 g. of diisopropylamine. On standing, a precipitate forms which is filtered off and crystallized from acetone-cyclohexane to yield 2.7 g. of the title compound, melting point 185° C.
Reaction SMILES: [OH-].[K+].COC([C:7]1([O:29][CH3:30])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[C:9]([C:15]([C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[O:16])=[C:8]1[OH:28])=O>O1CCOCC1.O>[OH:28][C:8]1[CH:7]([O:29][CH3:30])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[C:9]=1[C:15]([C:17]1[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC1CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 3 h

Procedure:
0.586 g of potassium hydroxide is added to 1.4 g of 2-hydroxy-1-methoxy-5-methyl-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-4-oxo-cyclohex-2-enecarboxylic acid methyl ester in dioxane/water (5:3) and the batch is stirred for 3 hours. The batch is then acidified (pH 3) and extracted with fresh ethyl acetate. The crude product is purified by chromatography analogously to Example P7. 3-Hydroxy-4-methoxy-6-methyl-2-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-cyclohex-2-enone is obtained in the form of a viscous oil (as a mixture of 3 tautomeric forms, according to 1H-NMR).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C(OC)=O)=[CH:8][C:7]=1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CO>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[C:7]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1
Reactant: CCOC(=O)CCc1cc(OC(=O)OC)ccc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCc1cc(O)ccc1OC
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of sodium methoxide (227 mg) in methanol (10 ml) was added ethyl 3-(2-methoxy-5-(methoxycarbonyloxy)phenyl)propanoate (1.00 g), and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (730 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C:16]#[C:17][CH3:18]>CN(C=O)C>[CH3:18][C:17]1[C:16]([C:15]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 1-aminopyridinium iodide (19 g, 86 mmol) and potassium carbonate (12 g, 86 mmol) in DMF (100 mL) was added ethyl 2-butynoate (8.0 g, 71 mmol) and the reaction stirred overnight. The DMF was removed by rotary evaporation and the resulting solid was taken up in EtOAc (200 ml) and water (200 ml), partitioned and the aqueous phase extracted with 2×150 ml EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([O-:8])=[O:7]>O1CCCC1>[CH:12]([C:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:16]=[CH:15][CH:14]=1)=[CH:4][CH2:3][CH2:2][CH2:1][CH2:15][CH2:16][CH2:9][CH2:10][CH3:11]
Reactant: [Li]CCCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) and triphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500 ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexane solution) over not less than 1 hour at 0° C. After the dropwise addition, the reaction mixture was stirred at said temperature for 30 minutes and at room temperature for 1 hour, and a solution of 3-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwise added thereto at 0° C. over 1 hour. The reaction mixture was stirred at room temperature for 10 hours and filtered. The residue was washed with ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100:1) to give 57.3 g of 3-(1-decenyl)nitrobenzene (cis/trans=7:3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([NH2:27])=[S:26]>C(#N)C.CO>[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]1[S:26][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:27]=1
Reactant: NC(=S)COc1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CO
Solvent: CC#N
Product: CSc1ccc(-c2sc(COc3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone (2.05 g, 6.04 mmol) (Example 1, Step 3) and 2-chlorophenoxy thioacetamide (1.21 g, 6.0 mmol) in 30 mL of acetonitrile was heated to reflux for 3 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration. The crude solid was further purified by flash chromatography over silica gel and the appropriate fractions were combined, concentrated in vacuo and crystallized from methanol to provide 2.60 g (98%) of pure 4-2- ((2 -chlorophenoxy) methyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl) thiazole: mp 126°-129° C., 1H NMR (CDCl3) 300 MHz 7.55-7.39 (m, 4H), 7.28-6.90 (m, 8H), 5.44 (s, 2H), 2.49 (s, 3H). 19F NMR (CDCl3) -114.00 (m). Mass spectrum M+H+ =442.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1Br.[CH3:12][N:13](C)C=O.O>ClCCl>[C:8]([C:5]1[CH:4]=[C:3]([C:12]#[N:13])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Br)c1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(N)c(C#N)c1
Reaction time: 0.33 h

Procedure:
A stirred mixture of 35.5 g of 4'-amino-3'bromoacetophenone, 17.8 g of cuprous cyanide and 180 ml of dry dimethylformamide was heated at reflux, under nitrogen for 6 hours. After cooling, the mixture was treated with 180 ml of a solution of ferric chloride (prepared from 400 g of ferric chloride hexahydrate, 100 ml of concentrated hydrochloric acid and 600 ml of water) and stirred for 20 minutes at 60°-70° C. A 500 ml portion of water and 400 ml of dichloromethane were added. To facilitate phase separation, the mixture was filtered and then the filtrate was extracted with two 400 ml portions of dichlorometbane. The organic extracts were combined, washed with 200 ml of water and 200 ml of saturated sodium bicarbonate solution and the solvent removed in vacuo at 80° C. The residue was evaporated twice from 100 ml portions of toluene, giving a yellow solid, which was crystallized from ethanol, giving 14.35 g of the desired compound, mp 155°-159° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1NS(=O)(=O)c1ccc(COC2CCCCO2)cc1
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
4-Hydroxymethyl-N-(2-methoxyphenyl)benzenesulfonamide (99.6 mg, 0.34 mmol) was dissolved in methylene chloride (3 ml) to which, with cooling in an ice bath, were subsequently added 3,4-dihydro-2H-pyrane (48 μl, 0.51 mmol) and a catalytically effective amount of p-toluenesulfonic acid monohydrate. After 90 minutes of stirring at the same temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution (5 ml) and extracted with ether. The resulting organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate, and the solvent was removed by evaporation. Thereafter, the thus obtained light yellow oily material was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain 117 mg (91.2%) of the title compound in the form of colorless solid.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9]1)C1C=CC=CC=1.[C:29]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O>>[Si:22]([O:21][CH2:20][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:12][N:8]([C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: Cc1ccccc1[C@H]1CN(Cc2ccccc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2C)C1

Procedure:
Using the (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-methylphenyl)pyrrolidine obtained in Reference Example 127 which is described later, the elimination of benzyl group and amidation with monoethyl adipate were carried out in that order in the same manner as in Reference Example 16 and Reference Example 50 to produce ethyl 6-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-methylphenyl)pyrrolidin-1-yl]-6-oxohexanoate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Cl)ccc1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (step 1, 300 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.11 mmol) in 1,2-dimethoxyethane (6 mL) was stirred at 50° C. under nitrogen for 30 min. Then 3-fluorophenylboronic acid (191 mg, 1.37 mmol) and 2 M sodium carbonate solution (2.28 mL, 4.55 mmol) was added, and the resulting mixture was heated at 90° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated sodium hydrogen carbonate aqueous (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by TLC [hexane/ethyl acetate (8:1)] to give 107 mg (34%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=8.4, 2.4 Hz), 7.26–7.14 (2H, m), 6.91–6.79 (3H, m), 4.34 (2H, s), 3.84 (3H, s).
Reaction SMILES: [NH:1]1[C:6](=O)[CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.B.CSC>O1CCCC1>[NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cnccc2N1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: c1cc2c(cn1)OCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred solution of 1H-pyrido-[3,4-b][1,4]oxazine-2-(3H)one (3 g, 21 mmol) in tetrahydrofuran (150 ml) was added rapidly a borane/dimethyl sulfide solution (52 ml of a 2M solution in THF, 5 eq) at 25° C. over 15 minutes. The reaction mixture was stirred at 25° C. for 2 hours and quenched with 5 ml of water. The solvent was removed in vacuo using a rotary evaporator and the residue treated with aqueous 1M HCl with stirring. The water was removed and the residue chromatographed on silica gel using CH2Cl2 /MeOH/NH4OH (90/10/1) to give 2 g (70%) of titled product. m.p. 167°-169° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1CCCC1=O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 39.5 %

Procedure:
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride (972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC indicated that the reaction was complete, the reaction solution was poured into distilled water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. A solid was isolated by filtration, rinsed with water and then dried in a vacuum oven. This material was stirred with chloroform (500 mL) and then filtered. The filtrate was loaded onto a silica gel column. The column was eluted with 1-5% methanol in chloroform. The purified material was dried in a vacuum oven to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a solid, m.p. 189.4-190.0° C. Analysis: Calculated for C24H27N5O. 0.82H2O: % C, 69.25; % H, 6.93; % N, 16.82; Found: % C, 69.50; % H, 7.15; % N, 17.02.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[N:18]2)=[CH:13][CH:12]=1)C.[OH-].[Li+].CO>O>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17]3[N:16]=[CH:15][C:14]4=[CH:13][CH:12]=[C:11]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:4]([OH:34])=[O:3])[N:19]4[N:18]=3)=[CH:26][CH:25]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5C(=O)O)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
Into a 8-dram vial, 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzoic acid ethyl ester (0.250 g, 0.548 mmol), Lithium hydroxide (0.0262 g, 1.10 mmol), Methanol (15 mg), and Water (3.0 mL) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The solid was acidified with 1N HCl. The reaction was partitioned DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzoic acid as a solid (180 mg, 76%). The solid was used as is without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12]Cl)([O-:3])=[O:2].[CH2:15]([NH:19][CH3:20])[CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12][N:19]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:20])([O-:3])=[O:2]
Reactant: CCCCNC
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: CCCCN(C)CC(=O)Nc1ccccc1[N+](=O)[O-]

Procedure:
N-(2-Nitrophenyl)-2-chloroacetamide (32.2 g) was dissolved in benzene (350 ml) and N-n-butylmethylamine (26.1 g) added. The mixture was boiled under reflux for 22 hours, the benzene evaporated off, and water (300 ml) added. The mixture was extracted with diethyl ether (3 × 200 ml), the extract dried with magnesium sulphate, filtered, and the ether evaporated off to give N-(2-nitrophenyl)-2-(N-n-butyl-N-methylamino)acetamide as a yellow oil which was used in the next stage without purification.