Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[OH:11][C:12]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([CH3:23])[O:17]2>CC(CC)=O.[I-].[K+]>[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH2:9][C:8]#[CH:7])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:23])([CH3:24])[O:17]2
Reactant: C#CCBr
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
In 60 ml of methyl-ethyl-ketone 4.2 g of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate, 0.2 g of potassium iodide, and 3.0 g (2.3 ml, 25 millimoles) of propargyl bromide are added and the reaction mixture is reflexed for 4 hours. The inorganic salt is filtered off, the residue is taken up in 100 ml of carbon tetrachloride and extracted twice with 25 ml of a 5% sodium hydroxide solution each. The aqueous-alkaline layer is cooled to 0° C. The aqueous-alkaline layer is cooled to 0° C. The precipitated sodium phenolate salt is filtered off, washed twice with 20 ml of acetone each, and suspended in 25% hydrochloric acid (50 ml). The mixture is stirred at 5° C. for an hour. The precipitated white product is filtered off, washed twice with 20 ml of water each and dried to constant weight. The crude product thus obtained can be directly subjected to further reactions. Thus 3.7 g of the desired compound are obtained, yield 75% Mp.: 122°-124° C.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[S:7])[CH:2]=1.[N:13]1([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[N:3]1([C:6]([N:16]2[CH2:17][CH2:18][N:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:30])[F:29])=[O:20])[CH2:14][CH2:15]2)=[S:7])[CH:2]=[CH:1][N:5]=[CH:4]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(C(=S)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
1,1-Thiocarbonyldiimidazole (2.14 g, 11.4 mmol) was added to the mixture of piperazin-1-yl-(2-trifluoromethylphenyl)methanone (3.36 g, 11.40 mmol) and triethyl amine (1.75 mL, 12.5 mmol) in 50 mL of dichloromethane at 0° C. The mixture was warmed up to room temperature and then stirred at room temperature overnight. The reaction mixture was washed with brine (2×15 mL), dried over anhydrous Na2SO4, concentrated to give the light yellow foam. The crude compound was triturated by anhydrous ether to afford [4-(imidazole-1-carbothioyl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone as a white solid in 96% yield (4.40 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=C(/C(O)=O)\C)[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:35]=[O+][O-].CSC>CO>[CH:26]([CH:25]([N:23]([CH3:24])[C:21]([CH:16]([NH:15][C:13](=[O:14])[CH:3]([NH:2][CH3:1])[C:4]([CH3:12])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:11])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH:32]([CH3:33])[CH3:34])=[O:35]
Reactant: O=[O+][O-]
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Solvent: CSC
Solvent: CO
Product: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (1.0 g) in methanol (20 mL) is added to 100 mL of methanol at −78° C. which had been treated with ozone until the solution is blue. The resulting colorless reaction mixture is treated with ozone at −78° C. until the blue color remained. After 5 min dimethylsulfide (2 mL) is added. The reaction mixture is allowed to warm to room temperature and then concentrated in vacuo to give the title compound as an oil. MS (ES): m/z 418.4 (M+H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](Cl)=[O:15].[OH-].[Na+]>O>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:15]
Reactant: C1CNCCNC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccco1)N1CCCNCC1

Procedure:
Homopiperazine (70 g., 0.70 mole) in 160 ml. water was treated with 6 N hydrochloric acid to adjust to pH 5.5 Furoyl chloride (79.5 g., 0.60 mole) and 25% (w/w) aqueous sodium hydroxide solution were added simultaneously to maintain a pH of 4.5-5.5. Then additional sodium hydroxide was added to bring the mixture to pH 9.5. The solution was extracted with chloroform, dried over anhydrous potassium carbonate and distilled to afford 63 g. of product, B.P. 124°-130° C. at 10 mm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[NH2:24]>C(O)(C)C>[CH3:19][N:15]([CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:21]([CH3:20])[CH:22]=1)=[N:3][CH:4]=[N:5]2)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Solvent: CC(C)O
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12

Procedure:
N-{2-[(4-Chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide (38 mg, 0.136 mmol) and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (obtained as described in Example 103, preparation of stating materials, 32 mg, 0.150 mmol) were dissolved in iso-propanol, and the mixture heated to reflux for 1 hour. The mixture was concentrated in vacuo, and the residue purified by chromatography, eluting with 0 to 5.5% (10:1 methanol/conc. NH3(aq)) in ethyl acetate. Evaporation of the appropriate fractions gave N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide as a dry film (24 mg, 39%); NMR Spectrum (DMSO-d6, 400 MHz), 373K 1.96 (s, 3H), 2.24 (s, 3H), 2.46 (s, 3H), 2.94 (s, 3H), 3.90 (t, 2H), 4.50 (t, 3H), 6.94 (d, 1H), 7.18 (d, 1H), 7.21 (m, 2H), 7.36 (d, 1H), 7.63 (dd, 1H), 7.68 (d, 1H), 7.71 (dd, 1H), 8.17 (dd, 1H), 8.47 (s, 1H), 9.76 (s, 1H); Mass spectrum MH+ 458.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][CH2:14][OH:15])[C:5]#[N:6]
Reactant: OCCCBr
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCO)c(Br)c1
Temperature: 50 °C
Reaction time: 0.59 h
Yield: 55.7 %

Procedure:
3-Bromo-4-hydroxy benzonitrile (10.0 g, 50.5 mmol) was dissolved in acetone and successively treated with 1-bromo-3-propanol (19.0 g, 138 mmol) and K2CO3 (20.9 g, 151 mmol) at ambient temperature. The resulting suspension was warmed to 50° C. and maintained 3 d. After cooling to ambient temperature, the solids were removed by filtration, exhaustively was with acetone and the filtrate concentrated. Purification by chromatography on SiO2 (A: hexanes; B: EtOAc; 0-100% B over 35.4 min; 200 mL/min; 330 g column) afforded a solid. Further purification by recrystallization from hot MTBE (131 mL) and pentane (130 mL), with cooling at −20° C. (12 h) to induce precipitation, afforded a solid (7.2 g, 58%). 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.56 (d, J=9 Hz, 1H), 6.94 (d, J=6 Hz, 1H), 4.23 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 2.08 (m, J=6 Hz, 2H).
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[CH2:22]1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[N:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:32])[CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]([OH:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Yield: 93.7 %

Procedure:
A solution of 2.8 g of (E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 30 ml of toluene were heated to reflux for 0.5 hr. Cooling and filtration yielded 4.12 g of (E)-2-[2-[3-[2-[4-(cyclohexyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 210°-211° C. from tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:28]=[O:29]>>[Si:13]([O:12][CH2:11][C:10]([N:9]1[CH2:8][CH:7]([CH2:6][O:5][C:4]2[CH:23]=[CH:24][CH:25]=[C:2]([Cl:1])[CH:3]=2)[O:22][C:28]1=[O:29])([CH3:20])[CH3:21])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NCC(O)COc1cccc(Cl)c1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 5.13 g of 1-(3-chlorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1,1-dimethylethylamino)ethanol (prepared as described in Preparation 105), 50 ml of anhydrous dimethylformamide and 2.59 g of N,N'-carbonyldiimidazole were used, to give 5.27 g of the title compound having an Rf value of 0.33 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[CH:21]=[C:20]1[OH:27])=[O:18].C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1([O:28][CH3:29])[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[C:21]([C:4]([C:3]2[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)=[O:5])=[C:20]1[OH:27])=[O:18]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 0.5 h

Procedure:
2.23 g of fresh 2-methyl-6-trifluoromethyl-nicotinoyl chloride are added to a mixture of 2.14 g of 2-hydroxy-1-methoxy-5-methyl-4-oxo-cyclohex-2-ene-carboxylic acid methyl ester and 2.02 g of triethylamine in 30 ml of acetonitrile. After about 30 minutes, 0.065 g of potassium cyanide is added and the batch is stirred for 18 hours. The batch is then extracted at pH 2 with water against ethyl acetate, dried over magnesium sulfate and concentrated by evaporation. By filtering over silica gel (mobile phase: ethyl acetate/methanol/triethylamine 85:10:5), pure 2-hydroxy-1-methoxy-5-methyl-3-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-4-oxo-cyclohex-2-enecarboxylic acid methyl ester is obtained in the form of a viscous oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (52 mg) in dry MeOH (5.7 mL) was added 4N HCl in 1,4-dioxane (0.971 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH7 with 2M sodium hydroxide solution and concentrated in vacuo to give a white solid. The solid was washed with water (20 mL) and was filtered under reduced pressure to give the title compound as an off-white solid (31 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:12][CH2:11][CH2:10][CH:7]1[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: OCCCC1COc2ccc(F)cc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc2c(c1)C(CCCCl)CO2
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared as described in EXAMPLE 11, (51 g) was dissolved in 300 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. During 20 min 50 ml of thionyl chloride was added dropwise followed by stirring for 3 h. Ice cold water was added, the organic phase separated, dried over magnesium sulfate and concentrated in vacuo giving 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9](O)=[O:10])=[C:6]([CH3:8])[N:7]=1.[Cl:14]C(OC(Cl)(Cl)Cl)=O>ClC1C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([C:9]([Cl:14])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)sc1C(=O)O
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(C(F)(F)F)sc1C(=O)Cl
Reaction time: 2 h
Yield: 98 %

Procedure:
In a similar apparatus to Example 1, 4.2 g (0.02 mole) of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of chlorobenzene, followed by the addition of 0.04 g of pyridine. Under heating and reflux, 9.9 g (0.05 mole) of trichloromethyl chloroformate were added dropwise over 5 hours. After completion of the dropwise addition, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 4.5 g of 2-trifluoromethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.7% and 98.0%, respectively.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[S:20]1[CH:24]=[CH:23][C:22]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:21]1=2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[S:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[C:22]=2[CH:23]=[CH:24]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1cccc2sccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2cccc3sccc23)nc(N2CCOCC2)cc1=O
Yield: 14.3 %

Procedure:
The product is prepared according to the procedure described in example 86, using 551 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 328 mg of benzo[b]thiophen-4-ylamine and 498 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 324 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 110 mg of N-(1-benzothiophen-4-yl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:68][O:69][C:70]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH3:80])[C:71]=1[NH2:72].C(N(CC)CC)C>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:72][C:71]2[C:73]([O:79][CH3:80])=[CH:74][C:75]([O:77][CH3:78])=[CH:76][C:70]=2[O:69][CH3:68])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Reaction time: 1.9 h

Procedure:
To a room temperature, stirred solution of 3-dodecyl-α-phenyl-5-isoxazole acetic acid and 5-dodecyl-α-phenyl-3-isoxazole acetic acid (48.42 g, 0.1303 mol) in dry tetrahydrofuran (1.4 L) was added in one portion 1,1'-carbonyldiimidazole (22.5 g, 0.139 mol), and the solution was stirred for 1.9 hours under nitrogen. To the mixture was added 2,4,6-trimethoxyaniline hydrochloride (28.5 g, 0.130 mol) and triethylamine (19 mL, 0.14 mol), and the mixture was stirred for 1.8 days under nitrogen. The mixture was rotoevaporated and partitioned between ethyl acetate and 1M HCl. The organic layer was washed (1M HCl; saturated NaCl), dried (MgSO4), and rotoevaporated to a tar. The tar was dissolved (THF) and repeatedly chromatographed on silica gel (230-400 mesh) using Heptane-ether-triethylamine-methanol (20:40:6:1) as eluent. Fractions containing pure compound were combined, rotoevaporated, dissolved in toluene, and reevaporated. The residue was crystallized from diisopropyl ether to give pure title compound; yield 17.6 g (25%); mp 107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[NH:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[NH:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (62.5 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 69 mg (59%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (br s, 1H, NH), 11.65 (br s, 1H, NH), 8.81 (br s, 1H, NH), 8.28 (s, 1H), 7.76 (s, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.38 (t, J=9.05 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 3.71 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2). MS 469 [M++1].
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].O1CCOCC1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2ccccc21

Procedure:
Saccharin (10 g) was treated sequentially with dioxane (40 mL), thionyl chloride (15 mL) and DMF (0.4 mL). The resulting suspension was heated to reflux for 24 hours. The reaction mixture was concentrated to dryness and recrystallized from 60 mL toluene to give 5.7 g of the sub-title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
87.5 g of 4-chlorobenzoyl chloride and a solution of 276 g of potassium carbonate in 552 ml of water cooled to 5° C. are added successively with stirring to a suspension of 80.6 g of powdered 4-piperidone hydrochloride hydrate in 1 l of tetrahydrofuran. The mixture is stirred at ambient temperature for a further 45 minutes. The organic phase is then separated off, the aqueous phase is extracted twice more with ethyl acetate, and the organic phases are combined, dried and evaporated down. The residue is dissolved in ethyl acetate and the solution is treated with petroleum ether. 88.6 g of the title compound of melting point 61°-63° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:42][N:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccnc1CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.11 mmol), 2-(chloromethyl)-1-methyl-1H-imidazole (22 mg, 0.13 mmol), KI (22 mg, 0.13 mmol), K2CO3 (76 mg, 0.55 mmol) in anhydrous DMF (1.2 mL) was heated at 50° C. for 100 minutes. Added 1.2 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI and heated for another 35 minutes. Added 2.4 equivalents each of 2-(chloromethyl)-1-methyl-1H-imidazole and KI along with 2.0 equivalents of K2CO3 and heated for 1 h. The solution was diluted with CH2Cl2 and washed with aqueous saturated NaCl (2×). The organic phase was dried under Na2SO4 and concentrated in vacuo to afford tert-butyl 5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.