Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH3:11].C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[S:6][C:5]2=[N:7][C:10]([CH3:11])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nnc(Br)s1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cn2nc(Br)sc2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
5-bromo-1,3,4-thiadiazol-2-amine (1 g, 5.55 mmol, 1 eq) and chloroacetone (1.327 mL, 16.665 mmol, 3 eq) in water (24 mL) was stirred at reflux temperature overnight. More chloroacetone (1.106 mL, 13.887 mmol, 2.5 eq) was added, and heating was continued over the weekend. The reaction mixture was cooled to RT, poured into NaHCO3 (sat. sol., 43 mL) and extracted with DCM. The organic extracts were dried (MgSO4), filtered and concentrated to give a dark brown residue that was purified by flash chromatography (SiO2, DCM) affording the desired product (white solid, 0.613 g, 50%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.7 mL/min): tR=4.81 min, [M+H]+ m/z 217.9; 1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:18])[N:15]([CH3:17])[N:16]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CO>C1COCC1>[CH2:26]([CH:13]1[NH:12][N:11]2[C:14](=[O:18])[N:15]([CH3:17])[N:16]=[C:10]2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc2n(c1=O)NC(Cc1ccccc1)C(c1ccc(Cl)cc1)=C2c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-2-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (50 mg, 0.135 mmol), prepared as described in Example 474, in THF (1 mL) at −20° C. was added benzyl magnesium bromide (0.34 mL, 0.675 mmol, 2.0 M in THF). The reaction was stirred at −20° C. for 30 min. After this time MeOH (5 mL) was added to quench the reaction. The reaction was allowed to warm to RT and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an automated system eluting with a gradient of (0% to 80% EtOAc for 20 min. and holds at 80% for 20 min.) to give the title compound, 6-benzyl-7,8-bis(4-chlorophenyl)-2-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (29 mg, 46%) as a beige solid. HPLC retention time: 4.10 min; MS [M+H]+: found 463. 1H NMR (CDCl3, 400 MHz) δ 7.30-6.90 (m, 13H), 4.22 (t, 1H), 3.36 (s, 3H), 2.90-2.75 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>[Ni].C(O)(C)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[NH2:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [Ni]
Solvent: CC(C)O
Product: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Into an autoclave, 1.05 g of Raney Nickel catalyst (10 wt %) and 100 ml of isopropanol were introduced, and 10.0 g of 2,5-bis(trifluoromethyl)nitrobenzene was added thereto in small amounts. Hydrogen gas was blown until 5 kg/cm2 with stirring, and the temperature was increased to 70° C. Reaction was carried out at from 70 to 90° C. for 8 hours. After the temperature was recovered to room temperature, hydrogen gas was evacuated, and the Raney Nickel was subjected to filtration and washed with isopropanol. The solvent was concentrated to obtain 2,5-bis(trifluoromethyl)aniline (6.42 g, yield 73%, purity by GC 99.4%). As a result of analysis by GC-Mass, 1H-NMR and 19F-NMR, the product was confirmed to be 2,5-bis(trifluoromethyl)aniline.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[CH2:11][O:12][C:8]=2[C:7]=1[CH2:16][CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[CH3:22][C:21]1[C:17]([CH2:16][C:7]2[C:8]3[O:12][CH2:11][C:10](=[O:13])[C:9]=3[CH:14]=[CH:15][C:6]=2[O:5][CH3:4])=[C:18]([CH3:19])[NH:3][N:2]=1
Reactant: COc1ccc2c(c1CC(C(C)=O)C(C)=O)OCC2=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1Cc1c(C)n[nH]c1C)OCC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A solution of hydrazine monohydrate (0.0102 g, 0.203 mmol) in water (1.25 mL) was cooled to 0° C., and added with a solution of 3-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]pentane-2,4-dione (0.0533 g, 0.193 mmol) in acetic acid (2 mL), and the mixture was stirred for 18 hours with warming it to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, thereby made basic, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-methoxybenzofuran-3(2H)-one (0.0427 g, 81%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>N1C=CC=CC=1>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:5]([O:4][CH2:3][CH2:2][F:1])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCF
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a 0° C. solution of 2-fluoroethanol (1.0 g, 15.6 mmol) in pyridine (15 mL) was added tosyl chloride (6.5 g, 34.1 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 4 h and quenched by adding ice-cold water and EtOAc. The layers separated and the organic layer was washed successively with water, 1M HCl (5×), saturated Na2CO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (12 g) using 5% to 40% EtOAc in hexane as the eluant to obtain fluorotosylate 20 (3.2 g, 95%) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=10.0 Hz, 1H), 7.38 (d, J=10.0 Hz, 2H), 4.59 (dt, J=50.0 & 5.0 Hz, 2H), 4.28 (dt, J=30.0 & 5.0 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:26])[CH3:25]
Reactant: N#Cc1cccc(N)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1cccc(C#N)c1)[Si](C)(C)C
Yield: 96.8 %

Procedure:
About 5.87 g of 3-aminobenzonitrile, 11.57 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.41 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 12 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 3-[bis(trimethylsilyl)amino]benzonitrile (3-BTMSABZN) as a brown oil (12.62 g, 97% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (multiplet, 1H, aromatic proton), 6.81 (multiplet, 1H, aromatic proton), 6.67 (multiplet, 1H, aromatic proton), 6.59 (multiplet, 1H, aromatic proton), −0.10 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 12.5 °C
Yield: 84.3 %

Procedure:
Stearyl alcohol (2.7 g, 0.01 mol), and triphosgene (0.99 g, 0.0067 mol) were dissolved in 20 ml methylene chloride, stirred and cooled to 10-15° C. Anhydrous pyridine (0.8 g of, 0.02 mol) was added dropwise into the pre-cooled solution over a 1 hr period. The reaction mixture was stirred for an additional 1 h, then heated in a water bath at 65° C. for 15 min until all the methylene chloride evaporated. The residue was washed 3 times with cold water, dried over Na2SO4 and evaporated to give stearyl chloroformate (1.88 g, 83% yield), also known as octadecyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](OCC)=[O:11].O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)Cc1cccc(C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCO)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
LiAIH4 (3.1 g, 0.083 mol) was suspended in dry tetrahydrofuran (100 ml) in argon atmosphere. Ethyl 2-(2-bromo-3-methylphenyl)acetate (8.5 g, 0.033 mol) solved in dry tetrahydrofuran (50 ml) was added and the mixture was stirred at room temperature for 4 h. The mixture was cooled on ice and 3.1 ml of water was added dropwise, followed by 3.1 ml of 15% sodium hydroxide and then 9.3 ml of water. After 15 h. the solids were removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate was removed under reduced pressure. Purification of the residue by filtrating through silica gel using methylene chloride:methanol (9:1) as eluent gave 7.0 g (98.6%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)NCc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and isopropylsulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.82 Hz, 6H), 3.23-3.32 (m, 1H), 3.83 (s, 3H), 4.45 (s, 2H), 6.70 (s, 1H), 7.09-7.17 (m, 1H), 7.27 (ddd, J=7.6, 1.14 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 344.1431 [(M+H)+ Calcd for C18H22N3O2S: 344.1433].
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=2[C:16]#[N:17])[CH2:8][CH2:7]1)=[O:5].C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:15]=2[C:16]([NH2:17])=[N:33][C:32]([NH2:34])=[N:31]3)[CH2:10][CH2:11]1)=[O:5]
Reactant: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2Cl)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccccc4Cl)CC3)cccc2n1
Yield: 29 %

Procedure:
The cyclization of 2-[1-(2-chlorobenzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile (219 mg, 0.6 mmol) and guanidine carbonate was carried out using Method Z to afford 70.6 mg of title compound (29% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.52 (m, 1H), 7.43 (m, 3H), 7.36 (t, J=8.4 Hz, 1H), 7.2 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.57 (t, J=7.2 Hz, 1H), 6.0 (br s, 2H), 4.56 (br d, J=12 Hz, 1H), 4.03 (d, J=6 Hz, 2H), 3.28 (m, 1H), 3.05 (m, 1H), 2.85 (t, J=12.8 Hz, 1H), 2.23 (m, 1H), 1.91 (m, 1H), 1.72 (t, J=13.6 Hz, 1H), 1.33 (m, 2H). MS m/z (ESI) 412 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: OCc1ccccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCc4ccccn4)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-hydroxymethylpyridine in dioxane. ES-MS m/e (%): 500 (M+Na+, 23), 478 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:24])[CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:23])[CH3:24])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7yl)oxy]acetate (4.2 gm., 0.011 mole) is added to a solution composed of 20% aqueous sodium hydroxide solution (4.32 ml., 0.022 mole) and methanol (45 ml.). The mixture is stirred and heated at reflux for two hours and then concentrated in vacuo at 50° C. The residue is dissolved in water (50 ml.) and made acid to Congo red paper with 6 normal hydrochloric acid. The solid that separates is removed by filtration, washed with water, then with a little methanol and finally with a little ether. After drying, the product is recrystallized from acetic acid to give pure [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3Hfluoren-7-yl)oxy]acetic acid. Using a procedure similar to that described in Example 25, except that in Step A there is substituted for the [(6,7-dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid, an equimolar amount of:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]=[C:34]=S.C(Cl)CCl>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:34]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCCN=C=S
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: CCO
Solvent: ClCCCl
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (35 mg, 0.093 mmol) was dissolved in ethanol (5 ml) and 2-methoxyethyl isothiocyanate (22 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo. The residue was dissolved in THF (5.0 ml) and EDC (35.7 mg, 0.186 mmol) was added, then the solution was heated at 60° C. for 3 h, cooled and evaporated in vacuo and the residue purified by MDAP (formate) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-amine (25 mg, 0.055 mmol, 58.5% yield) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][N:5]2[N:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:4]2[CH2:3]1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1([CH3:12])[CH2:11][N:5]2[N:6]=[C:7]([CH:9]=[O:10])[CH:8]=[C:4]2[CH2:3]1
Reactant: CC1(C)Cc2cc(CO)nn2C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC1(C)Cc2cc(C=O)nn2C1

Procedure:
To 3.19 g of the crude (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) methanol in 222 mL of CHCl3 was added activated MnO2 (18.5 g) under a nitrogen atmosphere at room temperature, and then refluxed for 1 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, and then the column was eluted with hexane-AcOEt (3:1). The titled compound was obtained as a brown solid (2.48 g, 68.0% from the ester).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=3[N:6]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 2-chloro-benzooxazole-5-carbonitrile (5.0 g, 28.0 mmol, 1.0 equiv; prepared as described in A. Batista-Parra, S. Venkitachalam, W. D. Wilson, D. W. Boykin Heterocycles 2003, 60, 1367-1376) in acetonitrile (65 mL) was added N-ethyl diisopropylamine (36.0 mL, 27.1 g, 210.0 mmol, 7.5 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.61 g, 28.0 mmol, 1.0 equiv). The reaction mixture was stirred at rt for 18 h under Ar, poured on crashed ice and the pH adjusted by addition of a solution of 37% HCl to pH 3.0. The reaction mixture was extracted with ethyl acetate (3×100 mL), the combined organic phases washed with water and dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) to give 7.31 g (76%) of the title compound. MS (ESI): 343.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][C:21]1[C:26]([OH:27])=[C:25]([CH:28]=O)[CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[OH:27][C:26]1[C:21]([O:20][CH3:19])=[CH:22][CH:23]=[CH:24][C:25]=1/[CH:28]=[CH:1]/[C:2]1[N:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:12])[C:5]2[CH:11]=[N:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1cccc(C=O)c1O
Reactant: Cc1nc2ccncc2c(=O)n1-c1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(/C=C/c2nc3ccncc3c(=O)n2-c2ccccc2)c1O
Yield: 9.5 %

Procedure:
The crude compound 18 (0.436 mg, 1.84 mmol) was mixed with o-vaniline (0.60 g, 4.0 mmol) in 5 mL of glacial acetic acid. The reaction mixture was heated in a microwave for 2 h keeping temperature constant at 150° C. The reaction mixture was concentrated in vacuo, co-evaporated several times with toluene and purified by flash chromatography (CH2Cl2/EtOAc) to give 65 mg of the target compound 19 (8% yield for two last steps). MS: m/z+372.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:1][C:2]1[NH:3][N:4]=[C:5]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(SCc2ccccc2)n[nH]1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
3-Amino-5-mercapto-1,2,4-triazole (40.36 g) was treated at room temperature with sodium hydroxide (13.9 g) in ethanol (450 ml), and benzyl chloride (44.3 g) was added. The mixture was stirred overnight, and was then filtered. The ethanol was evaporated off, and the residue was recrystallised from ethyl acetate to give 64.97 g of the desired product, mp 104° C.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1>C1COCC1.O>[Br:2][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCO)c2c1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCBr)c2c1
Reaction time: 3.5 h

Procedure:
Phosphorus tribromide (0.03 ml) was added dropwise to a solution of N-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]methanesulphonamide (0.18 g) in dry THF (20 ml) stirred in an ice bath. There was an immediate reddish colour produced. The solution was stirred for 2 h and then at room temperature for a further 3.5 h, then again chilled in ice, diluted with water (40 ml) and extracted with ether (2×50 ml, 3×25 ml) combined extracts were washed with brine (3×20 ml) and dried (Na2SO4). Removal of the solvent by rotary evaporation at 35°-40° afforded the title compound as a viscous pink oil (0.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][S@@](C(C)(C)C)=O)([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH2:15])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(C)C[C@](C)(N[S@](=O)C(C)(C)C)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)C[C@](C)(N)c1ccc(F)c(Br)c1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a solution of (R)-N-((S)-2-(3-bromo-4-fluorophenyl)-4-methylpent-4-en-2-yl)-2-methylpropane-2-sulfinamide (1.8 g, 5.1 mmoles, 1 equiv) in 1,4-dioxane (6 mL) is added hydrogen chloride (4.0 M in 1,4-dioxane, 15 mL). The reaction is stirred for 5 minutes and the solvent is removed under reduced pressure. To the residue is added saturated aqueous sodium bicarbonate and the mixture is extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (97% yield): 1H NMR (CDCl3, 400 MHz) δ 7.66 (dd, 1H, J=6.40, J=2.80 Hz), 7.37-7.33 (m, 1H), 7.02 (t, 1H, J=8.40 Hz), 4.83 (s, 1H), 4.62 (s, 1H), 2.47 (d, 1H, J=13.2 Hz), 2.35 (d, 1H, J=13.2 Hz), 1.44 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:25]CC1>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH:2]=[O:25])=[CH:4][CH:5]=3)[O:10][C:9](=[O:13])[CH:8]=2)=[CH:15][CH:16]=1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2o1
Reactant: C[N+]1([O-])CCOCC1
Solvent: C1COCCO1
Product: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one can be prepared as described in Example 1A; its preparation is also described in U.S. Pat. No. 5,552,437. 7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one (11.42 g, 34.3 mmol) and NMO (13.9 g, 102.8 mmol) in 110 mL of dioxane were heated to reflux for 6 h. The solution was cooled to rt and the solvent removed. The crude compound was diluted in EtOAc and washed with NH4Claq, water, brine and dried over MgSO4. The solvent was removed to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.20 (1H, s), 7.95 (1H, s), 7.85 (1H, m), 7.68 (3H, m), 7.38 (2H, m) and 6.51 (1H, s).