Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([NH:19][C:11]([C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:14][CH3:15])=[N:8][CH:9]=1)=[O:12])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCNC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a 0° C. suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride in 10 mL of tetrahydrofuran is added 3.5 mL (46.2 mmol) of allylamine and 20 mL of tetrahydrofuran. The reaction suspension is allowed to warm briefly to room temperature, then stored at 0° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 2.1 g (51%) of the title compound:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[CH:7]=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>CC(C)=O>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([C:10]([OH:25])=[O:11])=[C:8]([O:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(OC)nc(Oc2cccc(OC(F)F)c2C=O)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2cccc(OC(F)F)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-difluoromethoxy-2-(4,6-dimethoxypyrimidin-2-yl)oxybenzaldehyde (3 g) was dissolved in acetone (30 ml). Then, an equimolar amount of an aqueous potassium permanganate solution (10 ml) was dropwise added thereto. The mixture was stirred at room temperature for 3 hours. Then, the precipitate was filtered. A large amount of water was added to the filtrate, and unreacted material was removed by extraction with ethyl ether. The aqueous phase was acidified with a 5% hydrochloric acid aqueous solution, and extracted with ethyl ether. The extract was washed with water and dried. Then, ethyl ether was distilled off under reduced pressure to obtain the above identified compound as white crystals (1.9 g). Melting point: 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:36]C(=O)C)=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:41])[C:5]([CH3:40])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH:35]=2)[C:18]([NH:20][C:21]2[CH:22]=[C:23]([C:31]([F:33])([F:34])[F:32])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Yield: 41.5 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,5-bistrifluoromethylaniline (0.130 g, 0.222 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.0921 mmol, 41%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cl
Reactant: Nc1nccs1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nccs1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a stirred solution of 15.1 g (151 mmole) of 2-aminothiazole in 200 ml of dry pyridine is added slowly 18.8 g (173 mmole) of ethyl chloroformate. After approximately 1 day, insolubles are removed by filtration and discarded and the filtrate is concentrated at reduced pressure. The resultant gum is dissolved in aqueous ethanol and redried in vacuo to a sticky solid. The crude product is dissolved in a boiling mixture of 100 ml of ethanol and 25 ml of water, clarified by filtration, and allowed to cool. The resultant crystalline solid is collected and washed thoroughly with water, giving 11.3 g (65.6 mmole) of 2-carbethoxyaminothiazole as a tlc-homogeneous (ethyl acetate eluent on silica gel plates) substance. Structure assignment is supported by the nmr spectrum.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCCCN1CCN(c2ccccc2)CC1
Yield: 71.7 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), N-phenyl piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-phenylpiperazine (1.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH:11]1(I)[CH2:15][CH2:14][CH2:13][CH2:12]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCCC2)cn1
Temperature: 120 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min cyclopentyl iodide (2.2 eq.) is added and the reaction solution is stirred 3 days at 120° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-cyclopentyloxy-pyridine is obtained after column chromatography (heptane/ethylacetate) as yellow oil in a yield of 45%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (259 mg, 0.930 mM), morpholine (162 μL, 1.86 mM) was added to the resulting solution and then the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (274 mg, yield: 90%).
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C1N2CCN(CC2)C1.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]([CH3:22])([NH:1][S:38]([CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:40])=[O:39])[C:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:4])=[CH:14][CH:15]=1)[CH3:21]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOc1ccc(OCC(C)(N)C(=O)N2CCOCC2)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CCOc1ccc(OCC(C)(NS(=O)(=O)Cc2ccccc2)C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.370 g 2-Amino-3-(4-ethoxy-phenoxy)-2methyl-1-morpholin-4-yl-propan-1-one and 0.276 g DABCO are dissolved in 8 ml tetrahydrofurane. After addition of 0.274 phenyl-methane sulfonyl chloride the mixture is stirred for 20 h at room temperature. This mixture is then subjected to flash chromatography without further work-up to yield 260 mg of a white solid. M.p. 109-111° C.
Reaction SMILES: OS(O)(=O)=O.C[C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][NH:9][C:8]=1[C:15]([OH:17])=[O:16].O.[CH3:19]O>>[CH3:19][O:17][C:15]([C:8]1[NH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:16]
Reactant: Cc1c([N+](=O)[O-])c[nH]c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c[nH]1

Procedure:
A solution of H2SO4 (0.8 mL) in MeOH (8 mL) was added to Py-1 (0.77 g, 4.53 mmol) and the mixture heated at reflux for 24 hr. Water was added and the mixture extracted with DCM. The organic solvent was dried using MgSO4, and solvent evaporated under vacuum to yield the product as a crystalline solid. Yield 0.55 g, 66%). 1H NMR (DMSO): δ 7.57 (d, 1H, J=2.1 Hz); 7.40 (d, 1H, J=2.0 Hz); 3.99 (s, 3H); 3.86 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](N1C=CN=C1)([N:41]1C=CN=[CH:42]1)=O.Cl.CNC.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31](=[O:33])[N:41]([CH3:42])[CH3:39])=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(-c5nnn[nH]5)c5cc(OCC(=O)O)ccc54)ccc3o2)n1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)COc1ccc2c(c1)c(-c1nnn[nH]1)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.7 %

Procedure:
A mixture of 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(carboxymethoxy)indol-3-yl}-1H-tetrazole (60 mg) and 1,1'-carbonyldiimidazole (60 mg) in dichloromethane (2 ml) was stirred at room temperature for 5 hours. And then, dimethylamine hydrochloride (16.5 mg) and triethylamine (0.5 ml) were added to the mixture successively. After being stirred for 18 hours, the mixture was concentrated under reduced pressure. The resulting residue was acidified with diluted hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform, ethyl acetate and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N,N-dimethylcarbamoylmethoxy)indol-3-yl}-1H-tetrazole (30.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[CH2:11]([O:13][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:12].[ClH:10]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(Br)cc1

Procedure:
A solution of 4-bromo-benzonitrile (58 mmol) in ethanol (200 mL) at 0° C. was bubbled through with HCl gas for 30 min and the resulting solution was stirred from 0° C. to room temperature over the weekend. After the reaction mixture was concentrated in vacuo, the residue was suspended in ether and the solid was filtered to give of 4-bromo-benzimidic acid ethyl ester as HCl salt (47 mmol).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 3-methylphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 326.0 (M+H)+, retention time 1.55 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[CH:25])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[C:25][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-methylpyridine (Apollo; 355 mg; 2.06 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (82 mg; 0.11 mmol), copper(I) iodide (21 mg; 0.11 mmol) was degassed during two minutes under nitrogen then THF (7.5 mL) and triethylamine (520 μL; 3.75 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvents were removed under vacuum affording a dark brown residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark brown sticky solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28]C(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].[C:33](OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:21]1)(=[O:28])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Reaction time: 1 h

Procedure:
A suspension of (S)-6-phenyl-4-(piperidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydrochloride salt (Example 44, 12.2 mg, 0.033 mmol) in CH2Cl2 (0.3 mL) was added acetic anhydride (3.72 μL, 0.04 mmol) followed by DIPEA (0.017 mL, 0.1 mmol). The reaction was stirred for 1 h at which time the starting material had been consumed as judged by HPLC. The solvents were removed and the product purified via reverse phase preparative HPLC. LCMS: 378 (M+H)+; HPLC (conditions E): retention time=7.41 min; 1H NMR (MeOD, 400 MHz) δ 8.17 (d, J=13 Hz, 1H), 7.97 (dd, J=1.7, 12.3 Hz, 1H), 7.75 (m, 3H), 7.40 (m, 3H), 7.27 (m, 1H), 4.38 (m, 1H), 3.83-3.94 (m, 2H), 3.42 (m, 2H), 2.21 (s, 3H), 1.98 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:15]=1.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:29][C:6]1[C:5]2[N:15]=[C:2]([CH3:1])[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (11.21 g, 29.0 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (5.53 g, 29.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature and treated with 75 mL of CH2Cl2 and 75 mL of water. The organic portion was then washed with 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated and triturated in ether to yield 7.13 g of tert-butyl 2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light green solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH3:27][C:28]([O:31][C:32]([NH:34][C@H:35]([C:39](O)=[O:40])[CH2:36][C:37]#[CH:38])=[O:33])([CH3:30])[CH3:29].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:28]([O:31][C:32]([NH:34][C@@H:35]([CH2:36][C:37]#[CH:38])[C:39]([NH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:40])=[O:33])([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN)c2)CC1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.59 g, 1.6 mmol), Boc-L-propargylglycine (0.35 g, 1.6 mmol), N-ethyldiisopropylamine (0.73 ml, 4.1 mmol) in DMF (20 ml) was added HBTU (0.81 g, 2.1 mmol). The resulting solution was stirred at room temperature overnight. (S)-tert-Butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)pent-4-ynamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate was isolated and purified over Gilson HPLC as a colorless oil. MH+ 554.44
Reaction SMILES: [CH:1]1(/[C:4](=[N:6]/[S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])/[CH3:5])[CH2:3][CH2:2]1.[CH3:13][Al](C)C.[Li]C>C1(C)C=CC=CC=1>[CH:1]1([C:4]([NH:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])([CH3:13])[CH3:5])[CH2:3][CH2:2]1
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Reactant: C[Al](C)C
Agent: [Li]C
Solvent: Cc1ccccc1
Product: CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
To a stirred solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (0.6 g, 3.2 mmol) in 30 mL of toluene at −78° C. was added Me3Al (1.76 mL, 3.5 mmol, 2M in toluene) under nitrogen atmosphere. After stirred 20 minutes at −78° C., MeLi (2.3 mL, 7 mmol, 3M in dimethoxymethane) was added drop-wise and the mixture stirred at −78° C. for 4 hours. The reaction was quenched by adding 2 mL of water. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give N-(2-cyclopropylpropan-2-yl)-2-methylpropane-2-sulfinamide (0.18 g, 28%) as a yellow oil. MS: (M+H)+=204.1; 1H NMR (300 MHz, CDCl3): δ 3.03 (brs, 1H), 1.17 (s, 3H), 1.16 (s, 9H), 1.12 (s, 3H), 0.98-0.95 (m, 1H), 0.43-0.29 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[S:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:29]3[CH2:30][CH2:31][S:27][CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: C1CSCN1
Product: O=C(c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
120 mg (0.31 mmol) of the compound of Example 36A is reacted analogously to the synthesis of the compound of Example 3 with 30 mg (0.34 mmol) of thiazolidine. 86 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:16]1[CH2:19][N:18]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1)(=O)=O>CN(C=O)C>[C:21]1([C:20]([N:18]2[CH2:19][CH:16]([O:7][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[CH3:8])[CH2:17]2)=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccccc1O
Reactant: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1CN(C(=O)c2ccccc2)C1
Temperature: 60 °C
Yield: 34.7 %

Procedure:
To a stirred solution of o-cresol (0.16 g, 1.51 mmol) in DMF (10 ml) was added 60% sodium hydride (0.063 g, 1.59 mmol) at room temperature. After 10 min 1-benzoylazetidin-3-yl methanesulfonate (0.50 g, 1.96 mmol) was added and the resulting reaction mixture was heated at 60° C. for 16 h. After this reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80:20 to 50:50, heptane/ethyl acetate) to provide a white solid. Trituration of the solid with heptane/ethyl acetate and collection of the resulting solids by filtration provided phenyl(3-(o-tolyloxy)azetidin-1-yl)methanone (0.14 g, 35%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-(2-quinolinylmethyloxy)benzaldehyde.