Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A mixture of methyl 4-[3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (1.50 g), 1 M aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (10 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.31 g, yield 91%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 278–279° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([CH3:33])[CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.CO.CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([CH3:33])[CH:22]=2)(=[O:20])=[O:19])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NCC(C)C)c(C)c1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1OCCC(=O)O
Solvent: CS(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCC(=O)O)c(C)c2)c(C)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
To (4-butyl-2-methylphenyl)(2-methylpropyl)amine (21.94 mg, 0.100 mmol, prepared, for example, according to P2, Table 1) in pyridine (1 mL) was added 3-{[4-(chlorosulfonyl)-2-methylphenyl]oxy}propanoic acid (27.9 mg, 0.100 mmol) and left to stand at RT in air for 2 hours. The sample was dissolved in a 1:1 mixture of MeOH and DMSO and was purified by method A (see Table 8) using Waters Xbridge Shield RP18 column. Yield 37%. LCMS (M+1) 462, RT 1.46 mins.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22].[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)([CH:11]([CH3:13])[CH3:12])[C:9]([NH2:10])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)C(C#N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)C(C(N)=O)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile (2.21 g) was suspended in acetic acid (2 ml) and conc. sulphuric acid (2 ml) and heated to 130° C. for 1.5 hrs. The reaction mixture was poured onto ice/water and the pH adjusted to 9 with aq. ammonium hydroxide. The mixture was extracted with dichloromethane (3×), washed with water (2×) and brine, dried (MgSO4), filtered and concentrated. The product was taken up in dichloromethane and triturated with cold hexane to precipitate the title compound (50%; M.p. 142.3–147.0° C.).
Reaction SMILES: [Na:1].[CH2:2]1[C:6]2([O:11][CH2:10][CH:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][S:21]([C:23]4[NH:27][C:26]5[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=5[N:24]=4)=[O:22])[C:15]=3[CH3:32])[CH2:8][O:7]2)[CH2:5][CH2:4]C1.OCC(CO)CO.C1(=O)CCC1>>[Na:1].[CH2:2]1[C:6]2([O:11][CH2:10][CH:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][S:21]([C:23]4[NH:27][C:26]5[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=5[N:24]=4)=[O:22])[C:15]=3[CH3:32])[CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: Cc1c(OCC2COC3(CCCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C1CCC1
Agent: OCC(CO)CO
Agent: [Na]
Product: Cc1c(OCC2COC3(CCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 6.2 %

Procedure:
The same procedure as in the steps (21a) and (21b) of Example 21 was repeated using 2-(hydroxymethyl)-1,3-propanediol and cyclobutanone to obtain the title compound (265 mg, total yield: 6.2%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1ccc(F)cc1
Product: CNCC1Cc2cccc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.049 g, 21%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-fluorophenylboronic acid (0.173 g, 1.24 mmol). mp 209-211° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][NH:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:4]
Reactant: CNC(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)N[C@@H]1CCNC1
Temperature: 0 °C

Procedure:
tert-Butyl-(3R)-3-{[(methylamino)carbonyl]amino}pyrrolidine-1-carboxylate 6-3 (2.174 g, 8.93 mmol) was dissolved in 3 mL CH2Cl2 and the solution was cooled to 0° C. 4.0M HCl in dioxane (33.50 mL, 134.0 mmol) was added and the solution was allowed to warm to room temperature. After 4.5 hours the reaction was concentrated in vacuo to afford N-methyl-N′-[(3R)-pyrrolidin-3-yl]urea 6-4 as an off-white solid. HCl salt: 1H NMR (DMSO-d6) δ 9.13 (bs, 2H), 4.15 (m, 1H), 3.10-3.3.29 (m, 3H), 2.96-2.87 (m, 1H), 2.54 (s, 3H), 2.13-2.01 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=[CH:23]1.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>CC#N>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Add MeCN (2 ml) to a flask under N2 containing 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (50 mg, 0.152 mmol), 1H-pyrrolo[2,3-b]pyridine (18 mg, 0.152 mmol), 4-Pyrrolidin-1-yl-pyridine (2 mg, 0.167 mmol), and triethylamine (17 mg, 0.167 mmol). Heat reaction to 80° C. for 16 hours. Cool the solution to room temperature, remove MeCN on rotovap. Purify crude material on silica gel to give 45 mg (73% yield) of N-(4-Fluoro-benzyl)-4-(pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide. Mass Spectrum (m/e): 410.1 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:5]=1[C:6]([CH:8](C(=O)C)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C>[N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:5]=1[C:6](=[O:7])[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)c1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=C(CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1ccccc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of 2-(2-nitro4-trifluoromethylbenzoyl)-1-phenylbutan-1,3-dione (28.5 g) in ethanol (300 ml) was added to a mixture of concentrated sulphuric acid (225 ml) and ethanol (225 ml). The resultant solution was stirred and heated at 100° C. for 1 hour. The cooled solution was poured onto a mixture of ice and water (21) and extracted with dichloromethane (3×250 ml). The combined organic layers were washed with water (2×100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro4-trifluoromethylphenyl)-3-phenylpropan-1,3-dione (19.6 g) as an off-white solid mp 101°-103° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([N:13]1[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH2:15][CH2:14]1)=[O:12].Cl>C(Cl)Cl.O1CCOCC1>[N:13]1([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:36])[F:35])[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][NH:20][CH2:19]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CNCc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-tert-butyl 1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate (64 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added 4 M HCl in dioxane (2 mL). The mixture was stirred at rt for 2 h and concentrated to afford (E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one as its hydrochloride salt. LC-MS Method 1 tR=1.26, min, m/z=401.
Reaction SMILES: [CH3:1][O:2][Na].CO.Br[C:7]1[C:16]([OH:17])=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH3:18])=[N:14]2)=[CH:9][CH:8]=1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)(=O)C.O>[CH3:18][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:16]([OH:17])[C:7]([O:2][CH3:1])=[CH:8][CH:9]=2)[N:14]=1
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Reactant: CO[Na]
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ccc(C)nc2c1O
Reaction time: 0.17 h
Yield: 60 %

Procedure:
The protocol was established using works by: D. Planchenault et al. Tetrahedron 1995, 51, 5823-5830. A solution of CH3ONa (30% by weight) in CH3OH (8.04 ml; 42.2 mmol) is added to a solution of 7-bromo-2-methyl-8-hydroxyquinoline (1.00 g; 4.22 mmol) in DMF (60 ml). The mixture is stirred for 10 minutes under argon. CuCl2.2H2O (0.22 g; 1.27 mmol) is added and the reaction mixture is heated under reflux for 30 hours. After cooling, water (50 ml) and disodium EDTA dihydrate (10 g; 27 mmol) are added and the medium is stirred for 1 hour. The solution is lightly acidified with acetic acid (3 ml, pH=4-5) and subsequently rebasified gently with a saturated aqueous solution of NaHCO3 (3 ml). The aqueous phase is extracted with CH2Cl2 (3×100 ml). The combined organic phases are dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid obtained is purified by silica gel chromatography, eluted using a gradient of CH2Cl2/CH3OH/CH3COOH (94/4/2, v/v) to CH2Cl2/CH3OH/CH3COOH (94/5/1, v/v) then to CH2Cl2/CH3OH (94/6, v/v). Fractions containing the product are combined and washed with a saturated aqueous solution of NaHCO3 (3×100 ml). The organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield 2-methyl-7-(methyloxy)-8-quinolinol in the form of a white powder (480 mg; 2.54 mmol, yield=60%). NMR-1H (250 MHz, CDCl3) δ, ppm: 7.95 (d, 3J (H, H)=8.5 Hz, 1H); 7.26 (s, 2H); 7.15 (d, 3J (H, H)=8.5 Hz, 1H); 4.03 (s, 3H); 2.69 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.6 (Cq); 143.9 (Cq); 139.3 (Cq); 138.0 (Cq); 136.0 (CH); 121.7 (Cq); 120.6 (CH); 117.3 (CH); 115.2 (CH); 57.2 (CH3); 25.1 (CH3). MS (CID, NH3): m/z=190 (MH+). Analysis (%) for C11H11NO2: calculated C, 69.83. H, 5.86. N, 7.40. found C, 69.40. H, 5.85. N, 7.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(F)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(F)cc2)cc1

Procedure:
73 mg of solid yellow 3-{4-[3-(4-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-fluorophenyl isocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:21][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2N)CC1
Yield: 72.6 %

Procedure:
Using similar reaction conditions as described in step ii of Intermediate-27, tert-butyl 4-(4-bromo-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.17 mmol) was reduced using zinc dust (610 mg, 9.39 mmol) and ammonium chloride (1.0 g, 18.72 mmol) in THF/water 10/5 ml to afford 300 mg (72.4% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 30% ethyl acetate in hexane as eluent. MS: m/z=295.1 (M-Boc+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)cc2)c(O)c([N+](=O)[O-])c1
Yield: 75.5 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (100 mg, 0.51 mmol) and 4-benzyloxybenzaldehyde (100 mg, 0.47 mol) were reacted according to the same procedure as Preparation 1 to give 150 mg (Yield 75%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>C(Cl)(Cl)Cl>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNS(C)(=O)=O
Reaction time: 1.5 h
Yield: 26.8 %

Procedure:
A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) in chloroform (40 mL) was treated with triethylamine (1.62 mL, 11.6 mmol) and methanesulfonyl chloride (0.47 mL, 6.05 mmol). The reaction was stirred for 1.5 hours, and additional methanesulfonyl chloride (2 equivalents) was added. The reaction was stirred for 30 minutes, and then deionized water (15 mL) was added. A precipitate formed and was isolated by filtration, triturated once with methanol and twice with chloroform and 1% aqueous sodium carbonate, isolated by filtration, and dried overnight in an oven to provide 0.65 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}methanesulfonamide as a white solid, mp 233–235° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](B(CC)CC)[CH3:30].C1COCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:29][CH3:30])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Cl)ccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1ccc(Cl)c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C

Procedure:
Tetrakis-triphenylphosphine (0.083 g, 0.072 mmol) was added to a solution of 3,6-dichloro-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.25 g, 0.72 mmol) and potassium carbonate (0.2 g, 1.44 mmol) in DMF (4 mL). Triethylborane in THF (1 M, 0.79 mL, 0.79 mmol) was added via syringe under a nitrogen atmosphere and the reaction heated by microwave at 150° C. for 20 minutes. The reaction mixture was then cooled, filtered through celite and partitioned between DCM and water. The organics were separated, washed with 15% lithium chloride, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.086 g). LCMS m/z 241.3 [M+H]+. R.T.=5.20 min (Analytical Method 3).
Reaction SMILES: [N:1]1([C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:21]2[CH2:22][CH2:23][C@H:19]([O:18][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:17]4)[CH2:20]2)[CH2:28][CH2:27]1
Reactant: BrCC1CC1
Reactant: O=C(c1cc2cc(O[C@H]3CCNC3)ccc2[nH]1)N1CCOCC1
Product: O=C(c1cc2cc(O[C@H]3CCN(CC4CC4)C3)ccc2[nH]1)N1CCOCC1

Procedure:
According to the procedure described for the synthesis of [5-((S)-1-Isopropyl-pyrrolidin-3-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone the title compound was synthesized from Morpholin-4-yl-[5-((S)-pyrrolidin-3-yloxy)-1H-indol-2-yl]-methanone and bromomethyl-cyclopropane. The title compound was obtained as light yellow solid. MS (m/e): 370.3 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:18][S:15]([NH:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][N:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(SCc2ccccc2)s1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ncc(SCc2ccccc2)s1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
To a mixture of 2-amino-5-benzylthiothiazole (6.7 g.) and pyridine (50 ml.) was dropwise added mesyl chloride (10.3 g.) over 15 minutes under ice-cooling and stirring, and the mixture was stirred for 3.5 hours at room temperature. After the reaction, the reaction mixture was poured into ice-water (300 ml.), and the precipitates were collected by filtration and then washed with water. The precipitates were added to 1 N sodium hydroxide aqueous solution (50 ml.), and the mixture was heated at 60° C. to produce a solution. The solution was treated with activated carbon and then neutralized. The precipitates were collected by filtration, washed with water and then dried to give powder of 2-methanesulfonamido-5-benzylthiothiazole (7.7 g.), mp 159° to 162° C.
Reaction SMILES: [OH-].[K+].Br[C:4]1[CH:5]=[C:6]([C:10]2[N:14]([CH3:15])[C:13]([C:16]([CH3:28])([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=3[F:27])[CH3:17])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)(Cl)Cl.O.[CH3:34][N:35]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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>[CH3:15][N:14]1[C:13]([C:16]([CH3:28])([O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH3:17])=[N:12][N:11]=[C:10]1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:34]#[N:35]
Reactant: CN1CCCC1=O
Reactant: Cn1c(-c2cccc(Br)c2)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1c(-c2cccc(C#N)c2)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Zinc cyanide (118 mg), potassium hydroxide (75 mg) and tetrakis(triphenylphosphine)palladium (0) (290 mg) were sequentially added to a solution of 3-(3-bromophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazole (356 mg) in NMP (5 ml) under an argon atmosphere, followed by stirring at 100° C. for 3 hours. Chloroform and water were added to the reaction solution, the precipitated solid was separated by celite filtration, followed by extraction. The organic layer was washed with a 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 0:100), and the solvent was evaporated under reduced pressure. The residue was solidified with diisopropylether and washed under heating to obtain, as a colorless powdery solid, 3-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzonitrile (238 mg).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]Br.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:2]21[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]2=[O:8]
Reactant: O=C1CCCCCC1
Reactant: BrCc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCCC12Cc1ccccc1C2
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A solution of cycloheptanone (5.30 mL, 45.0 mmol) and 1,2-bis(bromomethyl)benzene (11.88 g, 45.0 mmol) in toluene (65 mL) was treated all at once with potassium tert-butoxide (10.10 g, 90 mmol). The reaction stirred for 20 hours at 85° C. After this time, the mixture was washed with 25 mL water and 65 mL of 15% HCl, then the aqueous washes were extracted three times with ether. The combined organics were washed with brine, dried over Na2SO4, and evaporated to a yellow oil, which was purified by chromatography on silica gel (93:7 to 85:15 EtOAc-hexane, eluant) to afford the title compound. 1H NMR (300 MHz, d6-DMSO) δ 7.09-7.18 (m, 4H), 3.26 (d, J=16.0 Hz, 2H), 2.75 (d, J=16.0, 2H), 2.59 (m, 2H), 1.84 (m, 2H), 1.57-1.66 (m, 4H), 1.47 (m, 2H). MS (DCI+) m/z 215 (M+H, 232 (M+NH4).