Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][OH:33].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:31][CH2:32][OH:33])[C:23]4=[O:29])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)cn1)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cccc(OCCO)c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
A mixture of 5-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (30 mg, 0.070 mmol), 2-bromoethanol (0.020 mL, 0.28 mmol) and Cs2CO3 (90 mg, 0.28 mmol) in DMSO (1 mL) was stirred at 60° C. for 1 h. It was then purified by HPLC to give the titled compound (5 mg). MS 471.0 and 473.0 (M+H, Cl pattern).
Reaction SMILES: ONC(=O)C1C=CC(OCC[N:13]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[N:24][C:17]=3[O:16][C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]2=3)=CC=1.[OH-].[Na+].O>CN(C=O)C>[N:24]1[C:17]2[O:16][C:15]3[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=3[NH:13][C:19](=[O:20])[C:18]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NO)c1ccc(OCCN2C(=O)c3cccnc3Oc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2Oc2ncccc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Title compound 430 (3.65 g, 14.7 mmol) was dissolved in DMF (25.0 mL) and sodium hydroxide powder (0.706 g, 17.7 mmol) was added. The reaction mixture was stirred at 130° C. for 5 hours. The mixture was cooled down to room temperature and ice cooled water was added. The precipitate was filtered. The solid was triturated in ethanol to afford title compound 431 (1.798 g, 58%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.75 (s, 1H), 8.50 (dd, J=4.8, 2.1 Hz, 1H), 8.27 (dd, J=7.6, 2.0 Hz, 1H), 7.46 (dd, J=7.5, 4.8 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.25-7.14 (m, 3H). MS (m/z): 213.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2C(=O)CCC2CCC(=O)OCc2ccccc2)cc1
Temperature: 55 °C

Procedure:
A solution of 50 g of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester in 800 ml of tetrahydrofuran is treated with 28.3 g of 4-methoxybenzoyl chloride. The mixture is heated to 55° C. and a solution of 20 g of triethylamine in 400 ml of tetrahydrofuran is added dropwise over a two hour period. The mixture is stirred and heated at 55° C. for 16 hours. The warm mixture is filtered through filter aid to remove triethylamine hydrochloride and concentrated at reduced pressure. Chromatography over silica using a Waters Prep 500 HPLC apparatus yielded 1-(4-Methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid benzyl ester mp 80°-83° C. After concentration and crystallization.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:12]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)nc1

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (10 mmol) and p-toluenesulfonic acid monohydrate (2 mmol) in toluene (200 ml) is heated to reflux for 24 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude mixture is chromatographed on silica gel using mixtures of ethyl acetate and acetone as eluants to give the desired product.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O>C(OC(=O)C)(=O)C>[C:6]1([CH:4]2[N:3]=[CH:2][C:1](=[O:12])[O:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1C=NC(c2ccccc2)O1
Temperature: 70 °C
Yield: 34.7 %

Procedure:
A mixture of 80 g of hippuric acid and 400 ml of acetic anhydride is heated at 70° C. for two hours. The solution is then brought to ambient temperature and the acetic anhydride is evaporated off under vacuum. The residue is taken up into petroleum ether and crystallises. The crystals are filtered off with suction and washed with petroleum ether and with ethanol to give 25 g of 2-phenyl-5-oxazolone as crystals of melting point 90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:18]=4[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:25][C:12]1[N:11]=[C:10]([F:26])[C:9]2[O:8][C:5]3[C:4]([C@:15]4([C:19]5[CH:20]=[N:21][CH:22]=[CH:23][C:18]=5[C:17]([NH2:24])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:27]1[C:29]([F:32])=[N:11][CH:10]=[CH:9][CH:14]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (R)-7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine (14c-1) in step 3. MS m/z=447.5 [M+H]+. Calculated for C23H12ClF2N5OC2HF3O2: 561.85 (TFA salt) 1H NMR (400 MHz, MeOH) δ ppm 7.15 (s, 1H) 7.22 (t, J=1.66 Hz, 1H) 7.35 (ddd, J=7.24, 5.09, 1.76 Hz, 1H) 7.64 (d, J=8.61 Hz, 1H) 7.79 (d, J=8.80 Hz, 1H) 7.91 (ddd, J=9.93, 7.68, 1.76 Hz, 1H) 8.15 (d, J=4.70 Hz, 1H) 8.22 (dd, J=5.28, 0.98 Hz, 1H) 8.77 (s, 1H) 9.02 (d, J=5.28 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:89]1([NH2:94])[CH2:93]CC[CH2:90]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH:94][CH:89]([CH3:93])[CH3:90])=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3ccc(NC(C)C)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (100 mg, 0.24 mmol) in cyclopentylamine (50 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (71 mg, 0.11 mmol), cesium carbonate (155 mg, 0.48 mmol) and palladium (II) acetate (16 mg, 0.07 mmol). The resultant mixture was heated to 95° C. for 2 days at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ethyl acetate and the combined organics dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:2 hexanes:ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]N-isopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-5-amine (62 mg, 58%) as a yellow solid. 1H NMR (CDCl3) δ 8.13 (d, 1H), 7.91 (d, 1H), 7.50 (d, 2H), 7.44 (d, 1H), 6.93 (d, 2H), 6.25 (d, 1H), 6.19 (dd, 1H), 5.25 (d, 1H), 4.41 (m, 1H), 4.05 (d, 1H), 3.83 (s, 3H), 3.69 (m, 1H), 2.08–2.02 (m, 2H), 1.71–1.48 (m, 6H), 1.23 (d, 6H); MS m/z 443 (M+1).
Reaction SMILES: N[C:2](N)=[S:3].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CI)[CH2:23][CH2:24]2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[CH3:7]>O1CCCC1>[CH3:7][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:2][SH:3])[CH2:23][CH2:24]2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[CH3:5]
Reactant: NC(N)=S
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 86.5 %

Procedure:
Thiourea (7.5 g) is added to a solution of 6-(5-cholesten-3β-yloxy)hexyl iodide (15 g, 25.3 mmol) in tetrahydrofuran (200 ml) and the mixture is heated with stirring under reflux for 6 hours. The solution is concentrated to a residue which is triturated with anhydrous ether. The solid is filtered and dissolved in chloroform (100 ml). This solution is added to a solution of potassium metabisulfite (15 g) in water (100 ml). The mixture is heated under reflux in a nitrogen atmosphere for 20 minutes. The organic layer is washed with water, dried, and concentrated to dryness. The crude material is put on a silica gel column and eluted with 5% ethyl ether in peteroleum ether. The dried fractions are pooled and concentrated to give the title compound (11 g, 86% yield), m.p. 89°-90°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:52])([F:51])[F:50])[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[O:42][C:41]1[CH:40]=[CH:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]([F:50])([F:51])[F:52])=[CH:37][C:36]=1[C:33]1[CH:34]=[CH:35][N:30]=[N:31][CH:32]=1)#[N:2]
Reactant: Oc1ccc(-c2ccccc2C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 19, 206 mg, 0.474 mmol) and 3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-ol (Preparation 9, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The precipitate was collected by filtration and washed with water to afford the title compound as a solid (400 mg, 115%, contains residual dimethylsulfoxide). The material was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>[Pd].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(NCC)C>[F:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11]([CH3:14])([OH:15])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(I)cc1F
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: Cc1ccc(C#CC(C)(C)O)cc1F
Yield: 70 %

Procedure:
The mixture of 2-fluoro-4-iodotoluene (0.05 mol), 3-methyl-3-hydroxy-1-butyne (0.06 mol), tetrakis (triphenylphosphonium) palladium (0) 0.35 g, copper iodide 50 mg, and diethylamine 100 ml was refluxed for 5.5 hours. Diethylamine was distilled away under reduced pressure, the residue was extracted with diethylether, and the extract was washed with water. From the extract, diethylether was distilled away, the residue was purified by column chromatography (elution liquid: heptane-ethyl acetate) to obtain colorless oily 2-fluoro-4-(3-methyl-3-hydroxy-1-butynyl)toluene (0.035 mol).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:6]2[S:5][C:4](=[O:7])[NH:3][C:2]2=[NH:1])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(=O)N1
Solvent: CO
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3.5 parts of 4-imino-2-thiazolidinone, 4.4 parts of 1,3-diiminoisoindoline and 100 parts of methanol was stirred under an atmosphere of nitrogen at room temperature for three hours and then at reflux temperature for 2 hours. The reaction mixture was cooled to 25° C and the solid therein was collected by filtration, washed with fresh methanol and dried in varuo at 50° C to obtain 5.4 parts of 1-imino-3-(2-oxo-4-imino-5-thiazolidinylidene)isoindoline as a yellow powder melting at 346°-348° C (dec).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:20]2[O:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:11])[C:4]=3[C:2]=2[CH3:1])=[O:22])=[CH:15][CH:14]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cccc(O)c12
Yield: 17.4 %

Procedure:
A mixture of 2,6-dihydroxyacetophenone (4.5 g, 30 mmoles), p-chloro-ω-bromoacetophenone (6.9 g, 30 mmoles), potassium carbonate (4.1 g, 30 mmoles) and acetone (100 ml) was refluxed for 7 hours. The mixture was filtered and concentrated. The residue was partitioned between methylene chloride (250 ml) and in sodium hydroxide solution (100 ml). The aqueous phase was separated and acidified with 20% citric acid solution. The precipitated product was filtered and chromatographed to obtain 1.5 g of the title compound, m.p. 238°-241° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:5]=[CH:6][N:7]=1>S(=O)(=O)(O)O>[CH3:1][S:2][C:3]1[N:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)Cn1ccnc1SC
Agent: O=S(=O)(O)O
Product: CSc1nccn1CC(=O)O
Yield: 60.2 %

Procedure:
Ethyl (2-methylthio-imidazol-1-yl)-acetate (14.5 g.) in 4 N sulphuric acid (30 cc.) is heated under reflux for 1 hour. The sulphate ions are then removed by adding an aqueous solution of barium hydroxide and filtering off the precipitated barium sulphate. The filtrate is treated with decolorising charcoal and is then concentrated to dryness under reduced pressure (20 mm.Hg). The residue is taken up in benzene (80 cc.) and the mixture is again concentrated to dryness under reduced pressure (20 mm.Hg); this step is then repeated. Purification of the product by recrystallisation from dimethylformamide (30 cc.) yields (2-methylthio-imidazol-1-yl)-acetic acid (7.5 g.), m.p. 176° C.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1
Reactant: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Reactant: O=C(Cl)CCCc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCN(C(CN2CCN(C(=O)CCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.37 g of 4-Naphthalen-1-yl-butyric acid was dissolved in 5.0 ml of toluene, and 0.35 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by heating at 70° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude 4-naphthalen-1-yl-butyryl chloride. To the resulting crude 4-naphthalen-1-yl-butyryl chloride was added 2.3 ml of a toluene solution of 0.40 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine, followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 0.58 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyryl)piperazine as an oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.C(O)(=O)C(O)=O.[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(N(CC)CC)C>C(O)CC>[OH:33][CH2:34][CH:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: CC(CO)CCN
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Clc1ncnc2nc[nH]c12
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CC(CO)CCNc1ncnc2c1ncn2C1CCCCO1
Yield: 75 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2318 mg) 4-hydroxy-3-methylbutylamine oxalate, and 5 mL of triethylamine was refluxed in n-propanol for 3 hours and subsequently 24 hrs at laboratory temperature. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and partitioned into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of hexane. The solid residue was filtered off and the crude product crystallized from methanol. Yield 75%, white solid. TLC (CHCl3:methanol (4:1) (v:v): single spot; HPLC: purity >98%. 1H-NMR (400 MHz, DMSO): 0.88d (3H, J=6.6 Hz); 1.34m (1H); 1.56m (3H); 1.70m (1H); 1.71m (1H); 1.93m (2H); 1.94m (1H); 2.26m (1H); 3.25m (1H); 3.52bs (2H); 3.67m (1H); 4.0d (1H, J=11.3 Hz); 4.42t (1H, J=5.1 Hz); 5.61d (1H, J=10.6 Hz); 7.70bs (1H); 8.20s (1H); 8.30s (1H). MS (ES): [M+H]+=306 (100).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][S:21]([C:24]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][C:25]=1[NH2:26])(=[O:23])=[O:22].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CCOC(C)=O>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:26][C:25]1[CH:27]=[C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH:29]=[CH:30][C:24]=1[S:21]([CH3:20])(=[O:23])=[O:22])=[C:3]([CH3:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)cc1N
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A screw-cap vial was charged with 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline (50 mg, 0.18 mmol), 2-(methylsulfonyl)-5-morpholinoaniline (47.0 mg, 0.18 mmol), XPhos precatalyst (CAS 1028206-56-5; 27.1 mg, 0.037 mmol), sodium tert-butoxide (44.1 mg, 0.46 mmol), and toluene (1.8 mL). The mixture was stirred at 90° C. for 2 h, then cond. The crude residue was dissolved in EtOAc, washed with water, and the organic layer was dried over magnesium sulfate and cond. The crude product was purified by reverse-phase HPLC (0-70% acetonitrile in water), affording 5-fluoro-3-methyl-N-(2-(methylsulfonyl)-5-morpholinophenyl)-2-(pyridin-2-yl)quinolin-4-amine as an amorphous beige solid. Mass Spectrum (ESI) m/e=493.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (1H, br. s), 8.72 (1H, d, J=4.7 Hz), 8.14 (1H, br. s), 7.95 (2H, br. s.), 7.80 (1H, d, J=9.0 Hz), 7.64 (1H, m), 7.42 (1H, d, J=3.3 Hz), 7.20 (1H, m), 6.52 (1H, d, J=9.2 Hz), 6.04 (1H, s), 3.70-3.81 (4H, m), 3.18 (3H, s), 3.05-3.17 (4H, m), 2.30 (3H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([S:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[CH:13][CH:14]=3)[O:9][C:8](=[O:30])[CH:7]=2)=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(Cl)Cl>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([C:17]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[O:39])=[CH:13][CH:14]=3)[O:9][C:8](=[O:30])[CH:7]=2)=[CH:2]1
Reactant: O=c1cc(-c2ccoc2)c2ccc(Sc3cc(F)cc(-c4ccccc4)c3)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2ccoc2)c2ccc(S(=O)c3cc(F)cc(-c4ccccc4)c3)cc2o1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-furyl)-7-(5-phenyl-3-fluorophenylthio)coumarin (Example 17) (106 mg) in CHCl3 (3 mL) was added m-CPBA (88 mg; 50%). After 2 h, CH2Cl2 was added and the resulting solution was washed with 10% aq. NaHSO3, saturated aq. NaHCO3, dried (MgSO4) and concentrated. Chromatography of the residue (silica gel; hexane/EtOAc (7:3)) provided the title compound as a solid.