Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.5 %

Procedure:
Ethyl 1 H-pyrazole-4-carboxylate (1.50 g, 10.7 mmol) was added in portions to a stirred suspension of sodium hydride (353 mg, 80% oil dispersion, 11.8 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen at room temperature. After 20 minutes, the mixture was cooled to 0° C. and trityl chloride (3.28 g, 11.8 mmol) was added. The mixture was stirred at 0° C. for 4 h and allowed to warm to room temperature overnight. The mixture was then heated at 50° C. for 3 h, cooled, and further portions of sodium hydride (321 mg, 10.7 mmol) and trityl chloride (1.0 g, 3.59 mmol) were added. The mixture was heated at 50° C. for 2 h, cooled, treated with water (50 ml) and concentrated under reduced pressure. The product was extracted into ethyl acetate (200 ml), the solution was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give ethyl 1 -(triphenylmethyl)-pyrazole-4-carboxylate (2.273 g, 56%), as a white solid.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:5][NH:4][N:3]=1.[OH2:15].[C:16]1(C)C=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>O1C=CCCC1.C(OCC)(=O)C>[I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:5][N:4]([CH:20]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CSc1nccc(-c2c[nH]nc2I)n1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2cn(C3CCCCO3)nc2I)n1

Procedure:
A solution of 4-(3-iodo-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (270 mg, 0.85 mmol) and p-toluenesulfonic acid monohydrate (32 mg, 0.17 mmol) in 3,4-dihydro-2H-pyran (1 ml) was heated at 60° C. for 5 h. The cooled mixture was diluted with ethyl acetate, and the mixture was washed with water and brine, and then dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (10% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z): 402.7 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C@H:10]2[C@@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CNCC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.37 mmol, 0.2 g) in DCM (2 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring for 1 h at room temperature. The volatiles were removed under reduced pressure; residue was dissolved in DCM, added hexanes to precipitate the desired HCl salt. Solvent was removed under reduced pressure and the solid was dried under high vacuum to provide (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:2].C1(C)C=CC=CC=1.C(O)C.Cl.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[S:49])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:26]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a stirred solution of 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (369 mg, 1.00 mmol) in 1:1 toluene/ethanol (5 mL) was added a solution of 4N HCl (0.375 mL, 1.50 mmol) in dioxane. Then 2-phenylethanoyl isothiocyanate (886 mg, 5.00 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (1 mL) all at once. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated. The residue was triturated with EtOAc (5 mL), and the resulting suspension was stirred for 1 hour to break up large chunks. The yellow suspension was filtered. The yellow solid was partitioned between EtOAc (15 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a Biotage Horizon system using a reverse phase C18 column (M25 size). The following gradient was utilized [solvent A=water, solvent B=CH3CN]: 15-30% B (100 mL), 30-70% B (300 mL), 70-95% B (100 mL), 95-100% B (100 mL), collecting in 96×9 mL tubes. Residual water/CH3CN was azeotroped with absolute EtOH (3×20 mL). The product was obtained as a white powder (170 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 12.51 (br s, 1H), 8.59 (br s, 1H), 8.51 (d, J=6 Hz, 1H), 7.94 (m, 1H), 7.59 (s, 1H), 7.41 (m, 4H), 7.32 (m 2H), 7.26 (m, 1H, overlaps chloroform), 6.54 (d, J=6 Hz, 1H), 3.76 (s, 2H), 3.74 (s, 2H), 2.67 (q, J=7 Hz, 4H), 1.15 (t, J=7 Hz, 6H). LRMS (APCI neg) m/e 545 (M−1). HPLC: 100% purity (220 nm).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CN.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: CNCc1cc2ccccc2n1C
Agent: CN
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 0.75 h

Procedure:
To a solution of 1-methyl-2-(methylaminomethyl)indole (0.96 g, 5.5 mmole), from Preparation 1, and methylamine (1.54 mL, 11.0 mmole) in CH2Cl2 (50 mL) at 5° C. was added acryloyl chloride (0.48 mL, 6.0 mmole). After 45 min, the reaction solution was poured onto H2O and the layers were separated. The organic phase was dried over Na2SO4 and concentrated to afford the title compound as a yellow oil. This was used directly without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:48][C@H:49]3[CH2:50][O:51]3)=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol (0.42 g, 1.0 mmol, 1.0 eq.) and Cs2CO3 (1.0 g, 3.0 mmol, 3.0 eq.) in DMF (3 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2R)-(−)-glycidyl tosylate (0.27 g, 1.2 mmol, 1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30-60 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1.O>C1COCC1>[CH3:1][N:2]([CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1)[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CCCn1ccnc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1ccnc1CN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
N-methyl-4-nitroaniline (2.3 g) was dissolved in THF (92 ml), 60% sodium hydride (1.85 g) was added to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. 2-chloromethyl-1-propylimidazole hydrochloride (3.54 g) was added to the mixture at room temperature and the mixture was stirred for 240 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give N-methyl-4-nitro-N-[(1-propylimidazol-2-yl)methyl]aniline (2.7 g).
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:3][O:4][CH2:5][CH:6]([OH:15])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(N([CH2:29][CH3:30])CC)C.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[O:47]=[C:31]([N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])[CH2:7][CH:6]([OH:15])[CH2:5][O:4][CH2:3][CH:2]([OH:1])[CH2:16][N:17]([C:31](=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNCC(O)COCC(O)CNCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N(CCCN(C)C)CC(O)COCC(O)CN(CCCN(C)C)C(=O)CCCCCCCCCCCCCCC
Yield: 20.1 %

Procedure:
Bis(2-hydroxy-8-methyl-4,8-diazanonyl)ether (10 g, 0.030 mol) synthesized using a known method, triethylamine (6.1 g, 0.060 mol), and methylene chloride (200 ml) were placed in a 500 ml four-necked round flask, and the mixture was cooled on ice. Hexadecanoylchloride (16.5 g, 0.060 mol) was added dropwise over 1 hour to the flask while the contents of the flask were stirred under nitrogen. The mixture was stirred for 24 more hours at room temperature. The solid which precipitated was removed by filtration, after which water was added for washing. Methylene chloride was removed from the organic phase under reduced pressure. The residue was purified by column chromatography (packed with Kieselgel 60 (product of Merck), eluent: chloroform/methanol=7:1 (v/v)) to obtain 4.9 g of bis(4-(1-oxohexadecyl)-2-hydroxy-8-methyl-4,8-diazanonyl)ether. Yield: 20 wt %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.C(=O)([O-])[O-:19].[Na+].[Na+].[I-].[K+].Cl[CH2:27][CH2:28][CH2:29][CH:30]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1>O.CC(C)CC(=O)C>[CH3:2][CH:17]([O-:19])[CH3:6].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH2:29][CH:30]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH2:15][CH2:16]3)[C:6]=2[CH:17]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(C)[O-]
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 20 h

Procedure:
A mixture of 5 parts of 6-chloro-1,3-dihydro-1-(4-piperidinyl)- 2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling for awhile, there are added 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane and stirring at reflux is continued for 20 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The oily residue is acidified with a diluted hydrochloric acid solution. After shaking thoroughly with toluene, the latter is decanted and discarded. The aqueous acid phase, together with the residual oil, is alkalized with ammonium hydroxide and the product is extracted with toluene. The extract is dried, filtered and evaporated. The oily residue is crystallized from 2-propanol, yielding 6-chloro-1{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one 2-propanolate; mp. 174.6° C.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:1]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=3[CH2:4][CH2:3][C:2]2=[O:12])=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1CCC2=C(CCCC2=O)N1
Product: O=C1CCCC2=C1CCC(=O)N2Cc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 29 from 3,4,7,8- tetrahydro-2,5(1H,6H)-quinolinedione and 4-chlorobenzyl- chloride.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH3:15])[CH2:12][O:13][CH:7]12)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:16]([CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([O:14][CH3:15])[CH2:12][O:13][CH:7]12)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1COC2C(OS(C)(=O)=O)COC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1COC2C(N=[N+]=[N-])COC12
Temperature: 140 °C
Yield: 99.8 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-yl methanesulfonate (1.1 g, 4.6 mmol) in anhydrous DMF (25 mL) was added sodium azide (1.66 g, 25.5 mmol). The reaction was heated to 140° C. for 12 h and then diluted with NaHCO3 (sat, 50 mL), and extracted with EtOAc (80 mL×3). The organic layers were washed with H2O (30 mL×5), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a light yellow solid (0.85 g, 99.4%).
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[CH:17][C:16]1=[O:40])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>CC#N.O>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[CH:17][C:16]1=[O:40])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 43.5 %

Procedure:
A solution of di-tert-butyl [4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (23) (35 mg, 0.05882 mmol) in CH3CN (700.0 μL), water (700.0 μL) and AcOH (0.7 mL, 12.31 mmol) was heated at 90° C. for 20 min then evaporated and co-evaporated with CH3CN (3×). The material was triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (13) (13 mg, 0.02558 mmol, 43.5%) as a white solid. ESI-MS m/z calc. 482.0446, found 483.4 (M+1)+; Retention time: 1.41 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.30 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J=2.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.44 (dd, J=7.6, 2.3 Hz, 1H), 5.51 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.15 (t, J=9.7 Hz) ppm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:17]=3[N:16]=[C:15]([NH2:25])[C:14]=2[N:13]=[C:12]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:25][C:15]1[C:14]2[N:13]=[C:12]([CH2:26][O:27][CH2:28][CH3:29])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:17]=2[N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNS(C)(=O)=O
Reaction time: 4 h
Yield: 120.6 %

Procedure:
Methanesulfonyl chloride (0.44 mL, 5.7 mmol) was added to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.04 g, 5.2 mmol) and triethylamine (0.94 mL, 6.8 mmol) in chloroform (100 mL), and the reaction was stirred for four hours. Water was added; a precipitate formed. The aqueous layer was adjusted to pH 10 with the addition of 50% aqueous sodium hydroxide. The precipitate was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel. Material from another run was added, and entire procedure was repeated to eliminate unreacted starting material. N-{4-[4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide (2.95 g) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][C:19]([F:18])([F:29])[F:30])=[CH:22][CH:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(OC(F)(F)F)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(OC(F)(F)F)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-(trifluoromethoxy)benzylamine in DME. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.[O:34]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][NH:36][C:35]1=[O:44].CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:41]3[CH2:40][CH2:39][C:38]4([O:34][C:35](=[O:44])[NH:36][CH2:37]4)[CH2:43][CH2:42]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20]
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(-c3ncc(CN4CCC5(CC4)CNC(=O)O5)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
A mixture of N-{2-[5(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), 1-oxa-3,8-diazaspiro[4.5]decan-2-one (110 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (82 mg, yield 43%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 224° C.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([C:9]([OH:11])=[O:10])[C:7]([CH3:13])([CH3:12])[S:6][C@H:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2].[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[O:10][C:9]([C@H:8]1[C:7]([CH3:13])([CH3:12])[S:6][C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])(=[O:22])[CH3:21]
Reactant: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)[C@@H]2N(C(C)=O)[C@H](c3ccccc3)SC2(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A solution of (2S,4S)-3-acetyl-5,5-dimethyl-2-phenyl-4-thiazolidinecarboxylic acid (102 g, 0.38 mol) in anhydrous DMF (500 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)benzothiazoline (127 g, 0.38 mol) in anhydrous DMF (500 ml) at room temperature. N,N-Dimethylaminopyridine (5.58 g, 45.7 mmol) was added thereto under a nitrogen atmosphere at room temperature with stirring. After ice-cooling, diethyl azodicarboxylate (87 g, 0.50 mol) was added thereto, and then the mixture was stirred under ice-cooling for 15 minutes, at room temperature for one hour and further at an internal temperature of about 40° C. for three days. The reaction mixture was concentrated under reduced pressure, a 10% aqueous citric acid solution (1,000 ml) was added to the residue, and the whole was extracted with ethyl acetate (1,000 ml). The organic layer was washed with water (1,000 ml) and saturated brine (1,000 ml) successively and dehydrated with magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, a mixed solvent (ethanol/diisopropyl ether=200 ml/1,000 ml) was added to the residue, the residue was dissolved by heating, and then the solution was allowed to stand at room temperature overnight. One precipitated diastereomer was filtered out, and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=1/1) to give 78.0 g (43%) of the target compound.