Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O>ClCCl>[CH3:16][CH:15]([CH3:17])[CH2:14][C:13]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: CC(C)CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
3-Aminoquinoline-4-thiol (4.6 g) was added to polyphosphoric acid (80 g). Isovaleric acid (3.5 mL) was added and the reaction mixture was heated at 140° C. for 2 hours. The reaction mixture was poured into a mixture of ice and water (300 mL). The mixture was filtered through a layer of Celite® filter aid to remove some insoluble material. The filtrate was made alkaline with 50% sodium hydroxide while cooling with ice and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel and eluted with 1:1 ethyl acetate:hexanes. The eluant was concentrated under vacuum to provide 2-(2-methylpropyl)thiazolo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[CH2:14]=O.Cl>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:8])[O:7][CH2:14]2
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: C=O
Agent: Cl
Product: COc1cc2c(cc1OC)C(=O)OC2
Temperature: 60 °C
Yield: 58.4 %

Procedure:
A suspension of 3,4-dimethoxy-benzoic acid (353.5 g, 1.94 moles) in HCHO (1.7 l, 24.5 moles) under stirring was prepared and cooled in ice, saturated with gaseous HCl (340 g, 9.32 moles), then gradually warmed to 60° C. After one night the temperature was cooled to the room value and further HCl (300 g) was bubbled in, then the temperature was brought again to 60° C. for one night. The mixture was partially evaporated, taken up in water (1 l), neutralised with 28% NH4OH (1.5 l) and kept at cold for 2 hours, then filtered. The filtrate was washed with water up to neutrality, then crystallised from methanol (2 l) and dried under vacuum at 60° C. to give 220 g of the title compound (yield: 58.65%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:34]([O:41][C@H:42]1[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:45][C@H:44]([CH2:65][P:66]([O:71][CH2:72][CH3:73])(=[O:70])[O:67][CH2:68][CH3:69])[C@@H:43]1O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.P([N:91]=[N+:92]=[N-:93])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1>[N:91]([C@H:43]1[C@@H:42]([O:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:45][C@@H:44]1[CH2:65][P:66]([O:71][CH2:72][CH3:73])(=[O:70])[O:67][CH2:68][CH3:69])=[N+:92]=[N-:93]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O)OCC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
DIAD (2.4 mL, 12.4 mmol) was added dropwise to a cooled (−5° C.) solution of Ph3P (3.1 g, 11.7 mmol) in THF (50 mL). After 30 min, a solution of 2 (5.57 g, 9.5 mmol) in THF (20 mL) was added. After an additional 10 min, diphenyl phosphorazidate (DPPA; 2.4 mL, 11.31 mmol) was added and the reaction mixture was allowed to attain rt. After stirring overnight, the solvent was evaporated and the residue was purified by silica gel chromatography to give 3 (5.0 g, 8.2 mmol, 86%) as a colorless oil. 13C-NMR (CDCl3) 138.17, 137.92, 137.38, 128.6-127.7, 78.2, 74.3, 73.9, 73.7, 73.5, 72.4, 69.5, 68.8, 62.2, 62.1, 62.0, 61.9, 61.0, 60.9, 27.9 (d, J=141 Hz), 16.5, 16.4; 31P-NMR (CDCl3) 27.9.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]4[N:27](C5CCCCO5)[N:28]=[CH:29][C:22]=34)=[CH:16][CH:15]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>CCOCC>[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]4[NH:27][N:28]=[CH:29][C:22]=34)=[CH:18][CH:19]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]ncc23)cc1
Yield: 100.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 2-phenyl-N-{[(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)amino]-carbonothioyl}acetamide (0.070 g, 0.14 mmol, 1.0 eq.) and 4M HCl/Dioxane (5 ml). After 5 minutes ether was added. The resulting solid was filtered and washed twice with ether. The solid was further dried under vacuum to give 2-phenyl-N-({[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)acetamide (0.057 g, 96% yield). 1H NMR (400 MHz, DMSO): 12.40 (s, 1H), 11.79 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.71 (d, 2H), 7.33 (m, 8H), 3.83 (s, 2H); MS (ESI) for C20H16N6O2S: 403 (MH+).
Reaction SMILES: [Cl:1]C1C=C(C=C(Cl)C=1)C(C)=C.S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20](O)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20]([Cl:1])=[O:21]
Reactant: C=C(C)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1

Procedure:
It has been known that 3,5-dichloro-α-methylstyrene can be produced by reacting thionyl chloride with 3,5-dichlorobenzoic acid to obtain 3,5-dichlorobenzoyl chloride and then reacting methanol with 3,5-dichlorobenzoyl chloride to obtain methyl-3,5-dichlorobenzoate and reacting methylmagnesium chloride with methyl-3,5-dichlorobenzoate in ether and then, hydrolyzing the product with a diluted hydrochloric acid and dehydrating the product over sodium bisulfate, in for example, Journal of the American Chemical Society 73 January 1951, page 455-456. However, this process is not advantageous as an industrial process because many reaction steps are needed for producing methyl3,5-dichlorobenzoate and a complicated reaction step is included in these steps for producing the starting material and the hydrolysis and the dehydration should be separately carried out.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)(=O)C(Cl)=O.C[N:32](C)C=O.N>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([NH2:32])=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CN(C)C=O
Reactant: CC1(CCCC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(CCCC(N)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 3 h

Procedure:
To a very fine suspension of 0.4 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-10-yl)butyric acid in 20 ml of chloroform is added, at a temperature in the region of 20° C., 0.13 g of oxalyl chloride followed by a solution of 0.5 ml of dimethylformamide in 5 ml of chloroform, and the stirring is continued for 3 hours. 2 ml of a 5.6N solution of ammonia in methanol are then added and the stirring is continued for 18 hours. The reaction mixture is concentrated on a rotary evaporator and the evaporation residue is stirred for 2 hours with 30 ml of distilled water. The solid is filtered off and purified by chromatography on a column of silica (25 g), eluting under a pressure of 0.5 bar with a mixture of dichloromethane and methanol (9/1 by volume). 0.045 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)butyramide is obtained in the form of a light-beige-coloured solid melting above 260° C. (1H NMR spectrum: (300 MHz; (CD3)2SO-d6 ; δ in ppm): 0.65 (mt, 2H: CH2); 1.53 (s, 3H: CH3); 1.80 (t, J=7.5 Hz, 2H: CH2CON); 2.10 and 2.28 (2 mts, 1H each: hetero-CH2); 6.58 and 7.10 (2 broad s, 1H each: CONH2); 7.27 and 7.33 (2 t, J=7.5 Hz, 1H each: H 7 and H 8); 7.42 and 7.92 (2 broad s, 1H each: H of the imidazole); 7.50 and 7.68 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccco2)cc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccco2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-nitrophenyl)furan (0.378 g, 2 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951) in ethanol (20 mL) was heated to 70° C. and added stannous chloride dihydrate (2.26 g, 10 mmol) and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), the whole was extracted with ethyl acetate (30 mL×2). The organic layer was dried over Na2SO4, filtered through celite and concentrated to give the crude subtitle compound (0.35 g). MS (EI): m/z 159 (M+)
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15].[O:16]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17]1>O1CCCC1.O>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH2:17][C:18]2([OH:16])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:12]=1
Reactant: COc1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 ml) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 ml) in anhydrous tetrahydrofuran (400 ml) at 30° C. under nitrogen. After a further 16 hours at 30° C., copper(I) bromide dimethyl sulphide complex (0.4 g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2 g) in anhydrous tetrahydrofuran (I 10 ml). After a further 3 hours at 30° C., the solution was cooled to 20° C., diluted with water (600 ml) and extracted with tert.-butyl methyl ether (600 ml) then ethyl acetate (600 ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid.
Reaction SMILES: [NH2:1][C:2](=[O:34])[C@H:3]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:4][C:5]1[N:6]=[N:7][N:8]([C@@H:10]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:20](O)=[O:21])[CH:13]=[CH:12][C:11]2=3)[CH:9]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[OH:21][CH2:20][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([N:8]1[CH:9]=[C:5]([CH2:4][C@@H:3]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])[C:2]([NH2:1])=[O:34])[N:6]=[N:7]1)[CH2:19][CH2:18][CH2:17]2
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C(=O)O)ccc43)nn2)C(N)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CO)ccc43)nn2)C(N)=O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-5-(4-((R)-3-amino-2-(4-methylbenzenesulfonamido)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1.63 g, 3.28 mmol) in 40 mL toluene was added a solution of 1.5M DIBAL-H in toluene. The reaction mixture was stirred for 3 h and then cooled to 0° C. The reaction mixture was quenched by the slow addition of 10% HCl and extracted with EtOAc (3×). The extracts were dried over MgSO4, concentrated and purified by Sio2 (5% MeOH/CH2Cl2) to afford a light yellow solid. MS (m/z): 470.4 (m+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>CC(O)C>[N:31]1[CH:32]=[CH:33][C:28]([N:15]2[CH2:16][CH2:17][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[CH:29][CH:30]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)CC2)C1
Temperature: 90 °C

Procedure:
tert-Butyl-2,8-diazaspiro[4.5]decane-2-carboxylate (10.403 mmol, 1 equiv.) and N-ethyl-diisopropylamine (41.608 mmol, 4 equiv.) were placed in 2-propanol (20 ml). 4-Chloropyridine (31.206 mmol, 3 equiv.) was added, and the mixture was heated for 16 hours at 90° C. Saturated sodium hydrogen carbonate solution (50 ml) was then added, and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×50 ml), and the combined organic phases were washed with saturated NaCl solution (50 ml) and dried over magnesium sulfate. After purification by column chromatography (ethyl acetate/DCM/methanol/ammonia (25% aq), 100:100:25:1), the desired product was obtained in the form of a yellow oil. Yield: 1.8 g (55%)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:8]1[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncccc1C#C[Si](C)(C)C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
First, 2-methylpyridin-3-yl trifluoromethanesulfonate (34.3 g, 142 mmol), trimethylsilylacetylene (30 ml, 212 mmol), bis(triphenylphosphine)palladium (II) chloride (10.0 g, 14.2 mmol), and copper (I) iodide (2.75 g, 14.4 mmol) were dissolved in N,N-dimethyl formamide (150 ml). Thereafter, triethylamine (43 ml, 309 mmol) was added in a nitrogen atmosphere at room temperature to the mixture. The mixture was then stirred for 3 hours (exothermic reaction took place). The reaction mixture was separated by ethyl acetate and a saturated aqueous ammonium chloride solution and insoluble substance was removed by filtration. The organic layer of the filtrate was washed twice with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (22.6 g, yield: 84.1%) as brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: COc1ccccc1[Mg]Br
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 1.0 M 2-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][O:21][CH2:22][CH3:23])[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[C:14]1[CH2:20][O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19]
Reactant: OB(O)c1cccnc1
Reactant: CCCCn1c(COCC)nc2c(N)nc3ccc(Br)cc3c21
Product: CCCCn1c(COCC)nc2c(N)nc3ccc(-c4cccnc4)cc3c21

Procedure:
8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (8%-10% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol (3×) and chromatography as above afforded 1-butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 220-222° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:30])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 68 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 25 (205 mg, yield 68%) as a red solid.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][C:5]([CH2:10][Br:11])([CH2:8][Br:9])[CH2:6][OH:7].[CH2:12](Br)[CH:13]=[CH2:14]>>[Br:3][CH2:4][C:5]([CH2:10][Br:11])([CH2:8][Br:9])[CH2:6][O:7][CH2:14][CH:13]=[CH2:12]
Reactant: OCC(CBr)(CBr)CBr
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCOCC(CBr)(CBr)CBr
Temperature: 22 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Sodium hydride (1.67 g, 42 mmol) was added carefully to 3-bromo-2,2-bis(bromomethyl)propanol (9.75 g, 30 mmol) and allyl bromide (12.9 ml, 150 mmol) in dry and degassed DMF (40 ml) under nitrogen at 0° C. The temperature was then increased to room temperature (22° C.) and the reaction mixture was stirred for another 3 h. The reaction mixture was then carefully added to an aqueous saturated NH4Cl (50 ml). The H2O-phase was then extracted with diethyl ether (2×50 ml) and the combined organic phases were washed with H2O (5×50 ml) and then brine (50 ml). The organic phase was dried with Na2SO4 followed by filtration. The volatile materials were removed at reduced pressure to give a pale yellow oil (9.7 g). Column chromatography on silica (heptane:EtOAc 9:1) gave 6.6 g (62%) of the product as a clear oil. 1H-NMR (CDCl3); 5.93 (m, 1H), 5.28 (m, 2H), 4.05 (d, 2H), 3.58 (s, 6H), 3.52 (s, 2H).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([S:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:43]2[CH:44]=[CH:45][C:40]([S:37]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)(=[O:38])=[O:39])=[CH:41][CH:42]=2)=[CH:7][CH:6]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2)CC1
Temperature: 85 °C
Yield: 87.7 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 250 mg) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine (177 mg) in acetonitrile (8 mL) was treated with aqueous sodium carbonate solution (2M, 0.483 mL) and then nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. under nitrogen for 18 h. The mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (70:10 to 100:0), then methanol/ethyl acetate (5:95) and then methanol/ethyl acetate/triethylamine (5:95:1) to afford the sub-titled compound (267 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH:29][CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.56 mmol; 680 mg) in DCM (10 mL) and add benzyl chloroformate (1.56 mmol; 0.23 mL) and DIPEA (3.11 mmol; 0.54 mL). Stir 15 min and evaporate. Purify the residue on 120 g silica gel with DCM to 20% EA/DCM to provide the title compound (741 mg; 83%). MS (ES): m/z=571 (M+H).
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.C([Li])(CC)C.[CH2:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:15][CH3:16].C(I)C>C1COCC1>[CH3:16][CH2:15][CH:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:3][CH3:4]
Reactant: CN(C)CCN(C)C
Reactant: CCCc1ccccc1C(=O)N(CC)CC
Agent: [Li]C(C)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC)c1ccccc1C(=O)N(CC)CC
Temperature: 25 °C
Yield: 25.1 %

Procedure:
To a solution of 9.3 ml (0.058 mol) of tetramethyl-ethylenediamine in 340 ml of THF at -78° C was added 52 ml of a 1.1M solution (0.057 mol) of s-butyl lithium in THF. The solution was then treated with a solution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75 ml of THF at -78° C. and the solution stirred for fifteen minutes and then treated with a solution of 8.3 ml of (0.104 mol) of ethyl iodide in THF. The solution was stirred for an hour and a half at -78° C. and then quenched by the addition of saturated ammonium chloride added dropwise at -78° C. The mixture was then allowed to warm to ambient temperature, diluted with diethyl ether, washed first with dilute hydrochloric acid, then with water, then with saturated sodium bicarbonate, then with brine dried and taken to dryness to give 12.91 g of crude product which was chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 3.23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide as a yellow oil.