Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-L-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature, and the reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)[O:14]C1.O>C(O)COCCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1c(O)cccc1Cl

Procedure:
16.1 g (0.1 mol) of 2,6-dichlorotoluene, 19.8 g (0.3 mol) of potassium hydroxide (85%) and 0.3 g of dibenzo-18-crown-6 are heated in 30 ml of diethylene glycol at a bath temperature of 190° C. with reflux for 16 hours. The water released during the reaction is distilled off. After cooling, the reaction mixture is stirred with 100 ml of water until a solution is obtained and extracted three times with 50 ml of dichloromethane. The aqueous phase is admixed with 35 ml of 30% hydrochloric acid and extracted three times with 70 ml of dichloromethane. The organic phases are dried and concentrated under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (11.5 g, content by HPLC: 97%, 78% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].C(=O)=O.[Br:26]Br>ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([Br:26])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2cccc3ccsc23)c(F)c(N)c1Cl
Reactant: BrBr
Agent: O=C=O
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cccc3c(Br)csc23)c(F)c(N)c1Cl
Temperature: -5 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Methyl 4-amino-6-(benzo[b]thiophen-7-yl)-3-chloro-5-fluoropicolinate (0.500 g, 1.485 mmol) was dissolved in dichloromethane (9.90 mL) and cooled to −5° C. in a acetone bath to which was added a few pieces of dry ice. Bromine (114 mL, 2.227 mmol) was dissolved in dichloromethane (9.90 mL) and added dropwise. The reaction mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was dried and concentrated and the product purified by flash chromatography (SiO2, 5-40% ethyl acetate/hexane gradient) followed by a second purification by reverse phase chromatography to provide the title compound as a grey solid (0.278 g, 45).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:2]=1.C(N(CC)CC)C.[CH2:22]([O:24][C:25]([CH2:27][C:28](Cl)=[O:29])=[O:26])[CH3:23]>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:26])[CH2:27][C:28](=[O:29])[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH3:23]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)CCNCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of methyl 3-(3-pyridylmethylamino)propionate (28.72 g), triethylamine (22 ml) and methylene chloride (240 ml) is cooled to 5°-10° C., and thereto is added dropwise a solution of ethoxycarbonylacetyl chloride (23.38 g) in methylene chloride (60 ml). The mixture is stirred at room temperature for one hour. The mixture is filtered to remove precipitates (triethylamine hydrochloride). The filtrate is washed with water, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate) to give ethyl[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (35.22 g, 77.3%) as oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH2:10])=[O:9])=[C:4]([C:11]([NH2:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:21]1([C:27]#[C:28][C:2]2[S:6][C:5]([NH:7][C:8]([NH2:10])=[O:9])=[C:4]([C:11]([NH2:13])=[O:12])[CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1ccccc1
Reactant: NC(=O)Nc1sc(Br)cc1C(N)=O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1sc(C#Cc2ccccc2)cc1C(N)=O
Temperature: 100 °C
Yield: 18 %

Procedure:
5-Bromo-2-ureido-thiophene-3-carboxylic acid amide (0.264 g, 1.0 mmol), copper (I) iodide (0.005 g), triphenyl phosphene (0.030 g, 15 mole %), palladium acetate (0.010 g, 5% mole %), triethyl amine (1 mL) and phenylacetylene (0.1 g, 1.1 mmol) in DMF (4 mL) was added to a 9 mL reaction vial. The reaction vial was sealed and heated to 100° C. in a Smith Microwave Synthesizer for 20 min. Water (5 mL) and ethyl acetate (20 mL) were added to the reaction mixture, the organic phase was separated and then washed with brine (2×10 mL) and water (1×10 mL), and dried over anhydrous magneium sulfate. After filtration, the solvent was removed under vacuum and the crude residue was taken into DMSO (5 mL) and purified utilizing a Gilson preparative HPLC to give the above titled compound as a light brown solid (0.050 g, 0.18 mmol, 18% yield). LC-MS [M+H]+ m/z 286.
Reaction SMILES: Cl.Cl.[CH3:3][S:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[OH:22]O>>[CH3:3][S:4]([C:5]1[CH:6]=[C:7]([C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])=[O:22]
Reactant: COc1ccc(-c2nc3cnccc3[nH]2)cc1SC
Reactant: OO
Agent: Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)cc1S(C)=O

Procedure:
The compound obtained in Example 34, was oxidised using hydrogen peroxide (2 eq) in a manner analogous to that described in Example 21. The title compound was obtained as a white solid, m.p. 227°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH3:30][N:31]1[C:35]([C@H:36]2[CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:41])=[CH:34][CH:33]=[N:32]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C@H:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[C:35]2[N:31]([CH3:30])[N:32]=[CH:33][CH:34]=2)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8]
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 73.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (184 mg, 0.414 mmol) prepared in Example 15a, (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (68.7 mg, 0.414 mmol) prepared in Example 8a, sodium hydride (63%; 31.6 mg, 0.830 mol) and DMF (2.0 mL), to yield the title compound (180 mg, 73%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:18])([F:17])[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[C:9](F)[CH:8]=1.[F:19][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:19][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][C:25]=1[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:6]([F:18])([F:17])[F:5])=[CH:8][CH:9]=1)=[O:12]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
1.4 l of nitrobenzene were cooled in an ice bath and treated in succession at a maximum temperature of 6° C. with 492.6 g (3.656 mol) of aluminum chloride and 700 g (3.355 mol) of 4-trifluoromethyl-2-fluoro-benzoyl chloride in 350 ml of nitrobenzene. The mixture was stirred (15 min) and 427.5 g (3.388 mol) of 3-fluoroanisole were added slowly so that the temperature did not rise above 6° C. The solution was left to warm to room temperature, stirred 2 h at this temperature, poured on to ice-water (2.5 l) and extracted with methylene chloride. The organic phase was washed with water and concentrated. After crystallization from THF (1.2l)/hexane (4.2l), 237 g (24%) of (2-Fluoro-4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methanone were obtained, MS: 298 (M).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1)[CH3:30]>>[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1)[CH3:30]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCn1[nH]c2ccccc2c1=O
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-ethyl-1,2-dihydroindazol-3-one were reacted to give 252. LCMS m/z: 535.3 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30]Br)=[O:26])([CH3:23])([CH3:22])[CH3:21].[I-].[K+]>CN(C)C=O.O>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-methoxysalicylate (11.48 g, 63 mmol) in dimethylformamide (30 mL) was added solid K2CO3 (13.06 g, 94.5 mmol), 1-tert-butoxycarbonylamino-3-bromopropane (22.5 g, 94.5 mmol), and freshly ground potassium iodide (1.5 g). The resulting slurry was placed under a nitrogen atmosphere and stirred for 2.5 days. The slurry was diluted with water (250 mL), washed with 1 N NaOH (2×250 mL), water (250 mL), and brine (250 mL), then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified on a preparative (Waters Prep LC™) 500 A chromatography apparatus using two silica columns and a hexanes through 1:1 hexanes:EtOAc gradient to provide methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (19.93 g, 93.3%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=O.[P:7]([OH:10])([OH:9])[OH:8].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH2:3]([C:4]([P:7]([OH:10])([OH:9])=[O:8])([P:7]([OH:10])([OH:9])=[O:8])[OH:6])[CH2:2][NH2:1]
Reactant: NCCC(=O)O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of 3-aminopropionic acid (25 g, 0.280 mol) and phosphorous acid (34.5 g, 0.421 mol) in sulfolane (90 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (83 ml, 0.954 mol) while maintaining the temperature at 35-45° C. The mixture is heated to 63-67° C. for 3 hrs, whereby white solid results. It is then cooled to 0-5° C. and quenched by slow addition of water (250 ml) at 0-5° C. over a period of 1 hr. The resulting clear solution is charcoalized and is heated at 100° C. for 3 hrs, cooled to ambient temperature. Cooled the charcoalized solution and stirred for 4 hrs at 0-5° C. The crystallized product is filtered, washed sequentially with chilled water (100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C. until water content is less than 0.5% w/w. Yield 41.4 g, (62.7%), appearance: white crystalline solid, purity >99.0%.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:6])[CH:4]=[CH2:5].[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][N:2]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:6])[CH:4]=[CH2:5]
Reactant: CCCCCCCC(=O)Cl
Reactant: C=CC(=O)N(C)[Si](C)(C)C
Product: C=CC(=O)N(C)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 4.1 g (0.0252 mole) of N-methyl-N-trimethylsilylacrylamide was added dropwise 3.66 g of octanoyl chloride at 0° C. After the addition was completed, the mixture was allowed to stir for 45 minutes at room temperature. Complete conversion was indicated by IR after 2 hours and 45 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(=N\OCC(=O)N1CCCCC1)c1csc(N)n1
Yield: 58.2 %

Procedure:
83.8 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate, 94.4 g of N-chloroacetylpiperidine, 202.5 ml of N-ethyldiisopropylamine and 87.6 g of sodium iodide are stirred at room temperature for 12 hours in 1420 ml of acetonitrile. The mixture is diluted with 7 l of ethyl acetate, washed with water, dried over magnesium sulphate and concentrated to a small volume. The substance which crystallizes ot is filtered off and dried. There are obtained 77.2 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetate of melting point 151°-152° C.
Reaction SMILES: C1N2CCN(CC2)C1.[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]=[O:13].CN(C=O)C.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]([OH:13])[C:25](=[CH2:26])[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cc(F)ccc1Br
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C(=O)OC(C)(C)C)C(O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 114.4 %

Procedure:
Alternate Preparation. This procedure uses DABCO as a more economical substitute for (4s)-quinuclidin-3-ol. A 1 L flask was charged with 2-bromo-5-fluorobenzaldehyde (13.4 g, 66.0 mmol), DABCO (14.81 g, 132 mmol), DMF (53.6 mL) and water (13.4 mL). To this reaction mixture was added tert-butyl acrylate (12.68 g, 99.0 mmol). The mixture was then stirred at rt for 12 h. At this time TLC indicated consumption of starting material. The reaction mixture was diluted with 25 mL of water and then extracted with two 100 mL portions of MTBE. The combined organic phases were washed with 0.1N HCl, water and brine. It was then dried over MgSO4, filtered and concentrated to yield 25 g (>100%) of the product as a colorless oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C

Procedure:
In a sealed reaction flask 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) was dissolved in 3 mL of anhydrous DMF, to this solution tetrabutylammonium iodide (140 mg, 0.38 mmol) was added followed by N-methylpiperazine (0.127 mL, 1.14 mmol) and the reaction heated at 60° C. for 56 hours. At the end of this time 10 mL of water was added and the resulting solid removed by filtration. The solid was purified by reversed phase HPLC using a phenyl-hexyl reverse phase column with a 30-50% ACN/H2O gradient over 60 minutes. The appropriate peak was concentrated, basified with saturated sodium bicarbonate and extracted twice with ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea as a solid weighing 15.75 mg. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.4 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.47 (s, 1H), 4.2 (m, 2H), 3.99 (s, 3H), 2.5-2.2 (m, 9H), 2.11 (s, 3H), 1.99 (m, 2H), 1.27 (s, 9H). LC-MS (ESI) m/z 590 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: O=Cc1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: c1ccc(C2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzaldehyde (15.0 g, 141 mmol) in chloroform (150 mL), propane-1,3-dithiol (16.9 g, 155 mmol) and boron trifluoride etherate (26.1 g, 183 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 h, and was then poured into ice-cold aqueous sodium hydroxide (10%) and extracted with chloroform. The combined chloroform extracts were washed with water, dried over sodium sulfate, concentrated and purified by flash column chromatography using 1% ethyl acetate in hexane as eluent. Yield: 21.2 g, 77%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([C:9]([CH2:13][CH3:14])([CH3:12])[CH2:10][CH3:11])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:9]([CH2:13][CH3:14])([CH3:12])[CH2:10][CH3:11]
Reactant: CCC(C)(CC)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(CC)CC(=O)OC
Temperature: 170 °C
Yield: 67.7 %

Procedure:
Step B To a solution of 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester (3 g, 14 mmol) in DMSO (30 mL) was added LiCl (1.2 g, 28 mmol) and H2O (0.25 mL, 14 mmol). The reaction mixture was heated at 170° C. for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanoic acid methyl ester as a yellow oil (1.5 g, 68%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O

Procedure:
4-Hydrazinobenzenesulfonic acid (1.88 g, 10 mmol), 7-methyl-8-oxononanoic acid (2.8 g, 15 mmol) and glacial acetic acid (10 ml) were mixed and heated under reflux for 6 hrs. The solvent was then evaporated under vacuum and the residue triturated with diethyl ether until a solid was obtained. This was dried under vacuum to give crude product, 3.4 g (100%). This was purified by preparative HPLC as required (RPC18. Water+0.1% TFA→MeCN+0.1% TFA gradient). UV/Vis (Water+0.1% TFA): 274, 229, 204 nm. 1H-nmr (D2O) δ 0.6-0.9 (2H, broad m), 1.10-1.25 (2H, broad m), 1.35-1.50 (2H, m), 1.60 (3H, s), 2.10-2.40 (2H, broad m+2H, t), 7.77 (1H, d), 7.97 (1H, dd) and 8.06 (1H, d) MS (MALDI-TOF) MH+340.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)=[N:4][C:5]([NH:14][C:15]2[C:16]([O:21]C)=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl>O1CCOCC1>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH:14][C:15]2[C:16](=[O:21])[NH:17][CH:18]=[CH:19][CH:20]=2)=[N:4][C:3]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1
Reactant: COc1ncccc1Nc1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(F)c(N2CCOCC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cccc1Nc1nc(N[C@@H]2CCCNC2)c(F)c(N2CCOCC2)n1
Yield: 75.3 %

Procedure:
A mixture of (R)-tert-butyl 3-(5-fluoro-2-(2-methoxypyridin-3-ylamino)-6-morpholino pyrimidin-4-ylamino)piperidine-1-carboxylate (Preparation 24b, 0.099 g, 0.30 mmol) and a 4N solution of hydrogen chloride in 1,4-dioxane (70 mL) was stirred at ambient temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (×2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (0.088 g, 93%) as a yellow foam that was used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:17][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:16])OCC)[S:10][C:6]=2[CH:5]([Cl:18])[CH2:4]1)[CH3:2].[CH2:19]([NH:22][CH2:23][CH:24]=[O:25])[CH:20]=[CH2:21]>>[CH2:19]([N:22]([CH2:23][CH:24]=[O:25])[C:12]([NH:11][C:9]1[S:10][C:6]2[CH:5]([Cl:18])[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:17][C:7]=2[N:8]=1)=[O:16])[CH:20]=[CH2:21]
Reactant: C=CCNCC=O
Reactant: CCOC(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Product: C=CCN(CC=O)C(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Temperature: 125 °C

Procedure:
Ethyl N-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)-carbamate (0.08 mol) and the dimethyl acetal of 2-allylaminoacetaldehyde (30 ml.) are charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture is blanketed with nitrogen gas and is heated at 125° C. for a period of about 8 hours. After this time the reaction mixture is distilled to remove excess starting material. The residue is purified by elution chromatography using ethyl acetate as the eluant. The chromatographed solution is then stripped of solvent to yield the desired product dimethyl acetal of 2-[1-allyl-3-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde.