Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[C:3]([C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1C(=O)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone (26 mg, 0.11 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (28 mg, 0.10 mmol), DMAP (7.3 mg, 0.06 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 2 days. The reaction mixture was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 9.15 (s, 1H), 8.81-8.80 (m, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.29-8.26 (m, 1H), 8.20-8.18 (m, 2H), 7.98 (dd, J=8.4, 2.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51-7.48 (m, 1H). Mass spectrum m/z: 476.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[C:9](=[O:14])[CH2:10][CH2:11][C:12]=2[CH3:13])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CC1=C(c2ccccc2N)C(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2NS(=O)(=O)c2ccc(C)cc2)C(=O)CC1

Procedure:
0.815 g (4.35 mmol) of 2-(2-aminophenyl)-3-methyl-2-cyclopenten-1-one, pyridine 0.413 g (5.22 mmol), 0.829 g (5.22 mmol) of p-toluenesulfonyl chloride, and 4 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.330 g, 89%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2OC(=O)C)[CH3:10])[C:4](=[O:35])[CH2:3]1.[BrH:37]>C(O)(=O)C.C(Cl)Cl>[CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2[Br:37])[CH3:10])[C:4](=[O:35])[CH2:3]1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (100 mg, 0.19 mmol) and HBr in acetic acid (45%) (1.0 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with cold CH2Cl2 (10 ml), washed twice with cold H2O (30 ml), saturated NaHCO3 solution (20 ml) and with H2O again (20 ml). The organic phase was dried over MgSO4 and evaporated, giving 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranosyl bromide (3) (95 mg, 91%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:37])[CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH:18]=1)=[O:16].[ClH:38]>C(Cl)Cl>[ClH:38].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:37])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccnc(NC2CCNCC2)c1
Yield: 85.4 %

Procedure:
The mixture of (S)-tert-butyl 4-((4-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)pyridin-2-yl)amino)piperidine-1-carboxylate (510 g, 1.0 mol) in DCM (1000 mL) was dropped slowly into a stirred and cooled (−30° C.) solution of HCl (4M in EtOAc, 2000 mL). After addition, the mixture was stirred at −30° C. for 30 min. The resulting solid was then collected by filtration, washed with DCM and dried under reduced pressure to give the title compound (350 g yield: 85.4%, HCl salt) as a white solid. LCMS (m/z): 410.2 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (22.0 mmol) of 4-bromocinnamic acid, 6 mL of oxalyl chloride and 3 drops of DMF in 40 mL of CH2Cl2 was heated to gentle reflux until gas evolution ceased. The volatiles were removed in vacuo and the residue was taken up in 50 mL of CH2Cl2. Pyrrolidine (10 mL; 120 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and chromatographed to afford 5.36 g (19.1 mmol; 87%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][N:13]1C(OC)=O.Br>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][NH:13]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(C(F)(F)F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
(2R,4S)-Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.96 g, 2.47 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 19.48 mL, 111.25 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (687 mg, 84%). 1H NMR (600 MHz, dmso) δ 1.36 (q, 1H), 1.48 (dq, 1H), 1.84-1.92 (m, 1H), 1.94-2.02 (m, 1H), 2.75 (dt, 1H), 2.92 (tt, 1H), 3.08-3.15 (m, 1H), 4.00 (d, 1H), 5.73 (s, 1H), 7.53-7.62 (m, 2H), 7.78 (t, 1H). HRMS Calculated for [C15H14F4N2O2+H]+: 331.1070. Found: 331.1086
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15]C(=O)C)=[CH:10][C:9]=2Br)=[O:5])C.[ClH:20].[CH2:21]([OH:23])C>>[ClH:20].[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([O:23][CH3:21])[CH:10]=1)[NH:7][C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCO
Reactant: CCOC(=O)c1cc2cc(NC(C)=O)cc(Br)c2[nH]1
Agent: Cl
Product: COc1cc(N)cc2cc(C(=O)O)[nH]c12
Reaction time: 4.5 h

Procedure:
A mixture of 982 mg I.19 (5-acetylamino-7-bromo-1H-indole-2-carboxylic acid ethyl ester), 10 ml ethanol and 1.8 ml concentrated hydrochloric acid was stirred for 4.5 h at reflux. The reaction mixture was evaporated. The residue was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=2)=[O:20])=[CH:14][CH:13]=1>CN(C=O)C.CCCCCC.[Cu](Cl)Cl>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COc1cc(Br)nc(C(=O)Nc2ccc(C)cc2)c1
Reactant: Cc1cccc(O)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C)c2)nc(C(=O)Nc2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.45 g (0.0019×2.2 mol) of 3-methyl phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.15 g (ca. 60% in mineral oil; 0.0019×2.0 mol) of NaH and then with 0.60 g (0.0019 mol) of N-(4-methylphenyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.19 g (0.0019×1.0 mol) of copper chloride (I), the solution was stirred at about 100° C. for about 4 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31](=[O:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1>C1COCC1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:12])[N:7]=[CH:6][CH:5]=[CH:4]4)([OH:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Reactant: Fc1cc(F)c2cccnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reaction time: 1 h

Procedure:
A solution of 5,7-difluoro-quinoline (CAS 34522-72-0, 18.57 g, 112 mmol) in dry THF (120 mL) was added dropwise to a freshly prepared solution of LDA (n-BuLi 77 mL and diisopropylamine 18.94 mL, 123 mmol, in 500 mL THF) at −78° C. The solution was stirred at this temperature for 1 h, and then the solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethanone (CAS 90734-71-7, 20.0 g, 102 mmol) in 400 mL THF was added dropwise at −70° C. After stirring additional 45 min at −70 to −30° C. the RM was quenched with 1M NH4Cl, diluted with water, and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in DCM to afford the title compound as a beige solid (tR 2.94 min (conditions 1), MH+=361, 1H-NMR in DMSO-d6: 8.93 (d, 1H); 8.43 (d, 1H); 8.18 (d, 1H); 7.92 (s, 1H); 7.57 (m, 2H); 7.24 (d, 1H); 6.49 (s, 1H); 2.18 (s, 3H)).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=2)[O:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CC(C)(C)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of 2 g (10.53 mmol) of 2,2,4,4-tetramethylchroman (Compound 40) in 25 ml of nitromethane was added, under nitrogen, 941 mg (11.99 mmol) of acetyl chloride followed by 1.59 g (11.92) mmol) of aluminum chloride. The cooling bath was then removed and the mixture stirred at room temperature for 16 h. The mixture was then cooled again in an ice bath and treated with 25 ml of conc. HCl. The mixture was then filtered and the residue washed with methylene chloride. The filtrate was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 1.38 (6H, s), 1.39 (6H, s), 1.87 (2H, s), 2.56 (3H, s), 6.83 (1H, d, J~8.7 Hz), 7.71 (1H, dd, J~8.7 Hz, 2.1 Hz), 7.98 (1H, d, J~2.1 Hz) MS exact mass, m/e 232.1468 (calcd. for C13H20O2, 232.1464).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[S:12])#[N:2].[OH-].[Na+].[CH3:24]I>C(O)C>[CH3:8][C:7]1[C:3]2[C:1]([NH2:2])=[N:13][C:11]([S:12][CH3:24])=[N:10][C:4]=2[S:5][C:6]=1[CH3:9]
Reactant: CI
Reactant: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(N)c2c(C)c(C)sc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)-benzamide (Example 1a) (1.33 g, 4.22 mmol) in ethanol (25 mL) was added NaOH (2.0 N, 5.8 mL) at room temperature under nitrogen. After stirring at 100° C. under nitrogen for 0.5 h, the reaction mixture was cooled in an ice bath and MeI (0.8 mL) was added dropwise. After stirring for another 0.5 h, the resulting precipitate was collected by filtration, rinsed with water, 20% EtOH/H2O, and dried under vacuum to give the title compound (840 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 2.34 (s, 3H), 2.42 (s, 3H), 6.93 (bs, 2H). MS 226 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:34])=[C:6]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[S:20]([N:23]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH3:33])COC)(=[O:22])=[O:21])=[O:14])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2].Cl>C1COCC1>[C:1]([CH2:3][C:4]1[C:5]([CH3:34])=[C:6]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[S:20](=[O:22])(=[O:21])[NH:23][C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH3:33])=[O:14])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(CC#N)c1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c(C)c1CC#N
Temperature: 65 °C

Procedure:
To a solution of N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (2.29 g, 4.56 mmol) in THF (10 mL) was added concentrated hydrochloric acid (5 mL). The reaction was heated at 65° C. for 2 hours, then allowed to cool to room temperature. The mixture was poured into ice water (100 mL), extracted with ethyl acetate (3×100 mL), washed with saturated sodium chloride (150 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water). Acetonitrile was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with saturated sodium chloride (200 mL), then with saturated sodium bicarbonate (3×200 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water). Acetonitrile was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with saturated sodium chloride (200 mL), then with saturated sodium bicarbonate (3×200 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried (MgSO4), then concentrated. The residue was dissolved in water (300 mL) and lyophilized to give N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide, Na-salt (0.45 g, 21%) as a white powder, mp 153-173° C. 1H NMR (400 MHZ, DMSO-d6) δ7.69 (d, J=4.76 Hz, 1H), 7.35 (d, J=5.16 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 1.95 (s, 3H), 1.55 (s, 3H) ppm. IR (KBr) 3449, 2249, 1623, 1421, 1121 cm−1.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.Cl>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (1.00 g) and DMF (66 μL) in ethyl acetate (11 mL) was added oxalyl dichloride (1.11 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A small amount of 1N hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (929 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:35](CCCCSC2C=CC=CC=2)C2C3C=CC=CC=3N=C(SC3C=CC=CC=3)C=2N=1)CCC.N.C>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(Sc3ccccc3)nc3ccccc3c2n1CCCCSc1ccccc1
Reactant: CCCCc1nc2c(Cl)nc3ccccc3c2n1CCCCSc1ccccc1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCSc1ccccc1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A 3:1 mixture of 2-butyl-4-chloro-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline to 2-butyl-4-(phenylthio)-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline (1.38 g) and a solution of 7% ammonia in methanol (30 mL) were combined in a bomb and heated to 150° C. The reaction was judged to be complete after 5 hours. The volatiles were removed under reduced pressure and the resulting residue was stirred in water and made basic (pH 10) with solid sodium carbonate. The aqueous mixture was extracted with chloroform (3×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow crystalline solid. The solid (0.8 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.4 g) was added; the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 1.25 mmol) as white needles, m.p. 118-120° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2].[OH-].[Na+].[CH3:25]OS(OC)(=O)=O>CO.O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide (2.2 g, 6.6 mmol) in methanol (11 mL) is treated with a solution of sodium hydroxide (275 mg, 6.9 mmol) in water (2.4 mL). To this is added dimethylsulfate (0.64 mL, 6.8 mmol). The reaction is stirred at rt overnight, evaporated, and chromatographed on silica gel in 5% and 10% ethyl acetate-methylene chloride. The product fractions are further purified by crystallization from toluene-hexane to afford N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:4]=1.[H-].[Na+].Br[CH2:37][CH3:38].O>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:11]([CH2:37][CH3:38])[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[N:23]=[CH:24][O:25][C:26]=3[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[O:21])[CH:16]=[N:15]2)[N:6]=1
Reactant: CCBr
Reactant: COc1cc(OC)nc(NCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCn1cc(NC(=O)c2ncoc2-c2cccc(C)c2)cn1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of N-(1-(2-((4,6-dimethoxypyrimidin-2-yl)amino)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (80 mg, 0.178 mmol) in DMF (1 mL) was added NaH (12 mg, 0.27 mmol). The icebath was removed and the mixture was stirred for 40 min at rt, then 1-bromo ethane (20 uL, 0.25 mmol) was added and stirred for 18 h at rt. To the reaction mixture was added few drops of water and directly purified by prep. HPLC. LC-MS conditions D: tR=1.19 min, [M+H]+=478.3
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5]CC[CH2:2]1.[C:12]1(=O)CCC1.Cl.CNC>>[CH3:5][N:1]([CH3:2])[C:6]1([C:10]#[N:11])[CH2:7][CH2:12][CH2:9]1
Reactant: O=C1CCC1
Reactant: N#CC1(N2CCCC2)COC1
Agent: CNC
Agent: Cl
Product: CN(C)C1(C#N)CCC1

Procedure:
The title compound, colorless liquid, MS: m/e=125.1 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and dimethylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14].Br[CH2:22][CH2:23][C:24]([NH2:26])=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][CH2:22][CH2:23][C:24]([NH2:26])=[O:25])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: NC(=O)CCBr
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propan-1-amine (0.1 g, 0.34 mmol) and 3-bromopropionamide (0.052 g, 0.34 mmol) heated in a microwave tube at 120° C., 150 W for 30 minutes. Reaction purified by Prep HPLC using Basic 0A3 system, followed by silica column (Biotage SP4) eluting 0-10% MeOH in EtOAc to give 3-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]amino}propanamide (0.001 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]3[CH:25]=[C:24]([OH:26])[C:23]([O:27][CH3:28])=[CH:22][C:19]=3[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:29]#[N:30].C1(C)C=CC(S(O[CH2:41][CH2:42][CH2:43][Cl:44])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:44][CH2:43][CH2:42][CH2:41][O:26][C:24]1[C:23]([O:27][CH3:28])=[CH:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[CH:25]=1)[N:15]=[CH:14][C:13]([C:29]#[N:30])=[C:12]3[NH:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Yield: 23.3 %

Procedure:
Following the procedure of Example 16, 0.43 g (0.98 mmol) of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile is reacted with 0.31 g (1.25 mmol) of 3-chloropropyl p-toluene sulfonate and 0.48 g of (1.47 mmol) of cesium carbonate, then an additional 0.05 g (0.2 mmol) of 3-chloropropyl p-toluene sulfonate and 0.07 g (0.2 mmol) of cesium carbonate in 6 mL of dry dimethyl formamide. The crude product is purified by silica gel flash chromatography, utilizing a 99.5:0.5 to 99:1 gradient of methylene chloride/methanol to give 0.118 g of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 220-223° C.