Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].ClC(OCC(C)C)=O.[CH3:40][N:41]1CCOCC1.CN>CN(C)C(=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:41][CH3:40])=[O:14])[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(C)c(-n2c(NC)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 27 %

Procedure:
To a cooled (0° C.) solution of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.18 g, 0.38 mmol) in N, N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.60 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.46 mmol) and 4-methylmorpholine (0.55 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.50 mmol). Stirred at 0° C. for 35 min. Added methylamine (0.29 mL of 2M solution in THF, 0.57 mmol). After 1 h, distilled DMA and purified the crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) 67.86 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H, J=8.0 Hz), 6.98 (m, 2H), 5.52 (q, 2H, J=12.8 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 2.09 (s, 3H). ESHRMS m/z 493.0659 (M+H calculated for C21H20BrF2N4O3 requires 493.0681).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:6]([CH2:5][C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ccccc1CNCc1ccccn1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 1 (0.3 g, 1.3 mmol) was dissolved in 10 mL CH3CN and 1,6-dibromohexane (4.85 g, 19 mmol), and potassium carbonate (0.37 g, 2.6 mmol) was added. The reaction mixture stirred overnight at room temperature. The solvent was evaporated to a minimum volume and purified by silica gel chromatography eluting with 100% CH2Cl2 twice and several times with 0.5% methanolic NH3 (7 M NH3 in methanol)/99.5% CH. The organic layers were combined and rotovaped (61.5%). 1H NMR (CDCl3) δ 8.480 (d, 1H, Ar), 7.612 (t, 1H, Ar), 7.553 (d, 1H, Ar), 7.474 (d, 1H, Ar), 7.192 (t, 1H, Ar), 7.097 (t, 1H, Ar), 6.923 (t, 1H, Ar), 6.824 (d, 1H, Ar), 3.776 (overlapped s, 5H, —CH2—, —OCH3), 3.671 (s, 2H, —CH2—), 3.328 (m, 2H, —CH2—), 2.488 (ddd, 2H, —CH2—), 1.783 (p, 2H, —CH2—), 1.531 (m, 2H, —CH2—), 1.331 (p, 2H, —CH2—), 1.271 (p, 2H, —CH2—). Mass Spect=391.14 (M+H)+.
Reaction SMILES: C(O)(=O)C.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:10]#[C:11][CH2:12][OH:13].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>N1C=CC=CC=1>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCC#Cc1nccs1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: OCCCc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Glacial acetic acid (16 ml) was added dropwise during 0.25 h to a stirred solution of 3-(2-thiazolyl)-2-propynol (2.4 g) and dipotassium azodicarboxylate (50 g) in pyridine (200 ml). The mixture was stirred at room temperature for 1 h and additional glacial acetic acid (40 ml) added during 0.5 h. The mixture was stirred at room temperature for 2 days. The solvent was removed by azeotropic distillation with toluene (2×100 ml) and the residue partitioned between (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined extracts dried and evaporated to leave a brown oil. This was purified by FCC eluting with toluene:ethyl acetate:triethylamine (50:50:1) to give the title compound as an orange oil (1.45 g), t.l.c. (toluene:ethyl acetate:triethylamine 50:50:1) Rf 0.15.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)/C=C/c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of the product of Step 2 (20 g) in 300 mL of DMF was added 30 g of BrCH2CO2-t-Bu and 65 g of Cs2CO3. The reaction mixture was stirred at 60° C. for 24 h, and was then diluted with 300 ml of acetone and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with 1:2 EtOAc/hexane to give 30 g of the title compound as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12]C.[CH3:14][Li].Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:14])[CH2:6][C:5]2=[O:12]
Reactant: [Li]C
Reactant: COc1ccnc2ccc(F)cc12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CC(=O)c2cc(F)ccc2N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A stirred solution of 25.8 g (0.146 mole) of 6-fluoro-4-methoxyquinoline from example 3 in 300 ml of tetrahydrofuran was heated under a nitrogen atmosphere to its reflux temperature and then cooled to -20° C. To the cold solution was added 90 ml of 182 M methyl lithium in diethyl ether over a period of 0.5 hour. After adding 40 ml of the solution, the reaction temperature was allowed to rise to 0° C. After the addition of methyl lithium was completed, the reaction temperature was allowed to rise to 15° C. The solution was then poured into 1200 ml of a mixture of ice water and hydrochloric acid. After stirring for 0.5 hour the mixture was extracted with about 1200 ml of diethyl ether. The organic layer was dried, filtered and evaporated in vacuo to provide a yellow solid. The product was recrystallized from carbon tetrachloride to give 9.5 g. (37% yield) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CC(C)=O.O1CCOCC1.[Pd]>[C:28]([N:12]1[CH2:13][CH2:14][C:8]2[C:9](=[N:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[N:7]=2)[CH2:11]1)(=[O:30])[CH3:29]
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c(NC(C)C)nc2C1
Temperature: 45 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
To a pressure reactor charged with a red-orange solution of tert-butyl 4-(3-(isopropylamino)pyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (2.0 g, 5.37 mmol) in acetone (100 mL) and dioxane (100 mL) was added palladium, 10 wt % on activated carbon (0.229 g, 2.148 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (5.04 mL, 53.7 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 17 hr at 45° C. The reaction mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using 10% to 100% gradient of EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.068 g, 47.5%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) 6 ppm 1.16-1.21 (m, 6H), 1.42 (s, 9H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.58 (t, J=5.9 Hz, 0.9H), 2.70 (t, J=5.6 Hz, 1.1H), 2.87-2.98 (m, 4H), 3.51 (br s, 4H), 3.67-3.75 (m, 2H), 4.06-4.15 (m, 1H), 4.41 (s, 1.1H), 4.44 (s, 0.9H), 5.50 (d, J=7.8 Hz, 1H), 5.53 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 419.0.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>CC#N>[CH:13]1([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[O:18][CH3:19])[N:3]=[C:2]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[N:11]=[CH:10]3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc2nc(Cl)ncc2cc1OC1CCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CC#N
Product: COc1cc2nc(N[C@H]3CC[C@H](O)CC3)ncc2cc1OC1CCCC1
Temperature: 60 °C

Procedure:
To a suspension of 2-chloro-6-(cyclopentyloxy)-7-methoxyquinazoline (100.0 mg, 0.36 mmol) (obtained from the company compound collection) in 20 ml of CH3CN at room temperature was added the trans-4-aminocyclohexanol (207.0 mg, 1.79 mmol). The resulting mixture was heated to 60° C. for 5 hours. The reaction was cooled and partitioned with EA and water. The organics layer was washed with water (2×20 mL) and brine (20 mL), combined and dried over MgSO4, Removal of the solvent provided a yellow solid. The crude material was purified using silica gel eluting with 95/5 EA/MeOH to afford 45.9 mg of the desired product with 35.9% yield. 1H NMR (400 MHz, DMSO-d6) ppm 1.14-1.40 (m, 4H), 1.51-2.06 (m, 12H), 3.36-3.52 (m, 1H), 3.66-3.80 (m, 1H), 3.82-3.95 (m, 3H), 4.54 (s, 1H), 4.75-4.88 (m, 1H), 6.74 (d, J=8.06 Hz, 1H), 6.83 (s, 1H), 7.12 (s, 1H), 8.80 (s, 1H). HRMS: m/z 358.21218 [M+H]+), calc. 358.21252. MS m/z, (APCI); 358.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
6-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3940 g, 0.0019 mol) is added to a slurry of pentane-washed NaH (0.0966 g, 0.0024 mol) in DMF (3 mL) and after stirring for 10 min, p-fluorobenzyl bromide (0.29 mL, 0.0023 mol) is added. After stirring for 4 h at room temperature, the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using methanol/dichloromethane (0.5/99.5) to give 0.5678 g (94%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 182.5-183° C.; MS (ESI+) for C19H15F2NO m/z 312.2 (M+H)+; IR (drift) 1631, 1511, 1483, 1466, 1449, 1256, 1228, 1218, 1137, 1094, 867, 836, 813, 808, 802 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.28, 6.94, 7.13, 7.96. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.27; H, 4.92; N, 4.54.
Reaction SMILES: C(N1C(=O)[C:12](Cl)=[C:11]([O:16]C)[CH:10]=N1)C1C=CC=CC=1.CSC1C=CC(B(O)O)=CC=1.[CH2:29]([N:36]1[C:41](=[O:42])[C:40](Cl)=[C:39]([C:44]2[CH:49]=[CH:48][C:47]([S:50][CH3:51])=[CH:46]C=2)[CH:38]=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(O)C.CC(C)([O-])C.[K+]>>[CH2:29]([N:36]1[C:41](=[O:42])[C:40]([O:16][CH:11]([CH3:12])[CH3:10])=[C:39]([CH2:44][CH2:49][CH2:48][CH:47]([S:50][CH3:51])[CH3:46])[CH:38]=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: CSc1ccc(B(O)O)cc1
Agent: [K+]
Solvent: CC(C)O
Product: CSC(C)CCCc1cnn(Cc2ccccc2)c(=O)c1OC(C)C

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-trifluoromethylsulfonyloxy-analog following the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid according to the method of Example 9 provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This 4-chloro-intermediate thus prepared was treated with 2-propanol (20 mL, 261 mmol) and potassium t-butoxide (110 mg, 0.98 mmol) at reflux for 45 minutes furnished 2-benzyl-4-(2-propoxy)-5-[4-(methylthio)pentyl]-3(2H)-pyridazinone. This methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 180 mg, 80%). mp 109-111° C. 1H NMR (300 MHz, CDCl3) δ 1.18 (d, J=6 Hz, 6H), 3.12 (s, 3H), 5.36 (s, 2H), 5.49 (h, J=6 Hz, 1H), 7.35 (m, 3H), 7.47 (dd, J=9 Hz, 3 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 399 (M+H)+. Anal. calc. for C21H22N2O4S: C, 63.29; H, 5.56; N, 7.03. Found: C, 63.17; H, 5.57; N, 6.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([C:21](O)=[O:22])[C:17]([F:20])=[C:18]([F:19])[C:12]=2[N:11]=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(OCC)(=O)C.C(#N)C>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:21]([C:16]2[C:17]([F:20])=[C:18]([F:19])[C:12]3[N:11]=[C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:14][C:13]=3[CH:15]=2)=[O:22])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1ccc(Br)cc1)c1cc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c(F)c1F

Procedure:
2-(2,6-Dichlorophenylamino)-4,5-difluoro-1H-benzimidazole-6-carboxylic acid (150 mg 0.42 mmol), TEA (0.15 mL, 1.05 mmol), 4-bromoaniline (70 mg, 0.42 mmol) and 50% solution of PPA (0.3 mL 0.5 mmol) in ethyl acetate in 10 mL acetonitrile was stirred for a weekend at ambient temperature. Then the solvent was removed i.vac. The residue was purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1.S(Cl)(Cl)(=O)=O>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:40])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2nccc(Cl)c12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(Cl)ccnc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) in THF (418 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (120 μl, 0.120 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-chloro-5-methylquinoline-7-sulfonyl chloride (30 mg, 0.109 mmol) in THF (0.6 ml). After 30 min LC/MS indicated desired product and methanolysis of the sulfonyl chloride (about 1:1). Additional solid N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) was added with stirring at room temperature. After 15 min, no further conversion had occurred. Additional LHMDS (0.5 eq) was added after cooling back to 0° C. and stirring continued. After 20 min, LC/MS indicated consumption of sulfonyl chloride (methanolysis) with product visible as a minor species. To the orange/brown solution was added acetic acid (300 μl) and the mixture dried under reduced pressure. The crude material was purified with a 25 g (25 μm spherical) silica column ramping EtOAc in heptane (0-50%, 5% DCM throughout) to provide 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol, 12.01% yield) as a white solid. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: OCC(CC1(O)CC1)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CC1(O)CC1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.0 g, 4.63 mmol) and triethylamine (1 mL, 7.4 mmol, Shantou Xilong chemical factory) in 30 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.64 g, 5.6 mmol, Shanghai Haiqu chemical Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 1 hr and then quenched with 5 mL of ice-water. The resulted mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to furnish 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate as yellow oil (used in the next step immediately without further purification).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([NH:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([N:12]([CH2:13][CH2:14][OH:15])[C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Acetyl chloride (0.858 g, 10.8 mmol) was added drop by drop to a solution of N-benzyl ethanol amine (1.5 g, 9.9 mmol) and triethylamine (1.5 g, 14.9 mmol) in dry dichloromethane (20 ml) at 0° C. under nitrogen atmosphere and stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, 10% aq. NaHCO3, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 5% methanol in dichloromethane as eluent afforded 0.68 g of the desired product as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:21])=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c(N)c(N)n(C)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the stirring solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (1.13 g, 4.0 mmol) in glacial acetic acid (22.5 ml) and water (7.5 ml) at 65° C. was added sodium nitrite (345 mg, 5.0 mmol) in portions. The pink mixture was stirred at 65° C. for 1 hour and then cooled to 0-5° C. After filtration, the violet solid was washed with water (2×10 ml) and then suspended in water (20 ml) and heated at 65° C. while sodium hydrosulfite (2.78 g, 16.0 mmol) was added in portions. The pale yellow solution was stirred at 65° C. for an additional 1 hour, cooled to room temperature and extracted with chloroform (3×25 ml). The combined extracts were dried over magnesium sulfate and filtered to provide crude (R)-3-(5-acetoxyhexyl)-5,6-diamino-1-methyluracil in chloroform. To this clear solution was added 1,1′-carbonyldiimidazole (650 mg, 4.0 mmol). After stirring overnight at room temperature, the mixture was washed with water (2×25 ml), with 1 N aqueous hydrochloric acid (2×25 ml), with water (2×25 ml), with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-methyluric acid (280 mg) as a beige solid which was dissolved in 20 ml of ethanol. To this solution was added hydrogen chloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). After refluxing overnight, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyluric acid (210 mg, 19% yield) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Li].[CH3:16][Si:17]([CH3:20])(Cl)[Cl:18]>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Si:17]([CH3:20])([CH3:16])[Cl:18]
Reactant: [Li]C1=C(C)Cc2ccc3ccccc3c21
Reactant: C[Si](C)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C([Si](C)(C)Cl)c2c(ccc3ccccc23)C1
Temperature: 0 °C
Yield: 100 %

Procedure:
The thus-obtained white solid (2-methylbenzo[e]indenyllithium, 0.94 g, 5.1 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (40 ml, 1/1 v/v). On the other hand, dimethyldichlorosilane (2.60 g, 20.2 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (20 ml, 1/1 v/v), and the resulting solution was dropwise added to the previously-prepared 2-methylbenzo[e]indenyllithium solution at −5° C., over 1 hour. After the addition, this was immediately warmed up to 0° C. with stirring, and further stirred at room temperature for 2 hours. The solvent was removed from the pale yellow suspension under reduced pressure to obtain a yellow paste. The paste was extracted with dry diethyl ether (10 ml×3), and the resulting solution was filtered through a cannula. The filtrate was collected, the solvent was removed under reduced pressure, and this was dried under reduced pressure until it had a constant weight. The thus-obtained viscous yellow oil is 2-methylbenzo[e]indenyldimethylchorosilane (1.35 g, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 59%).