Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[C:18]2[O:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[N:8]=[C:7]([NH2:19])[N:6]=1)(=O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>COCCO>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:5]2[C:18]3[O:17][CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc2c1OCc1ccccc1-2
Solvent: COCCO
Product: CN1CCN(c2nc(N)nc3c2OCc2ccccc2-3)CC1

Procedure:
A mixture of Example 41C, 1-methyl-piperazine (0.5 mL) and 2-methoxy-ethanol (1 mL) was heated at 110° C. for 60 hours, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of 2, 3.5 and 5% (9:1 MeOH: saturated aqueous NH4OH) to provide the title compound. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.52 (t, J=4.75 Hz, 4H), 3.83 (t, J=4.75 Hz, 4H), 4.61 (s, 2H), 5.06 (s, 2H), 7.12 (m, 1H), 7.34-7.44 (m, 2H), 8.05 (m, 1H); MS (M+H)+ m/z 298.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(=O)CC(C)=O)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=[O:27])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(=O)CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h
Yield: 65 %

Procedure:
0.48 g (1.2 mmol) of t-butyl 4-hydroxy-3-{[4-(trifluoromethyl)benzoyl]amino}piperidin-1-carboxylate (product of step 1) was dissolved in 10 mL of methylene chloride, and 5.24 g (1.9 mmol) of Dess-Martin periodinane was dropwise added thereto. After stirring for 5 hours, 50 mL of ethylacetoacetate was dropwise added thereto, and the resulting solution was washed with water. An organic layer dried over anhydrous magnesium sulfate. The reaction solution was filtered off and distilled off under reduced pressure, then the residue was purified by column chromatography to give 0.30 g (0.78 mmol) of the title compound in a total yield of 65%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: CNCC=O
Reactant: Cc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product dimethyl acetal of 2-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1>C(O)C.[C].[Pd]>[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Product: Cc1nccc2c(N)cccc12

Procedure:
A solution of 1-methyl-5-nitroisoquinoline in ethanol was hydrogenated in the presence of 10% palladium carbon at 60 psi for 4 hours. Reaction mixture was filtered through celite bed. Filtrate was concentrated under vacuum to afford the desired compound as pale white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][N+:13]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH2:13]
Reactant: COc1ccc(C=C[N+](=O)[O-])c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN)c(OC)c1
Reaction time: 1.5 h

Procedure:
The ethylene compound in 500 ml of tetrahydrofuran was added to 36.7 g of lithium aluminum hydride in 500 ml of ether. After a reflux period of 1.5 hours, the mixture was combined with 184 ml of lN sodium hydroxide solution. The resulting cake was separated by filtration and washed with 200 ml of hot tetrahydrofuran. The ethereal extracts and mother liquors were stripped. The residual oil was taken into chloroform, dried and stripped to give 94.9 g of 2,4-dimethoxyphenethylamine as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
N-(4-(methylthio)phenyl)methanesulfonamide (200 mg, 0.920 mmol) was dissolved in DMF (3 ml). K2CO3 (254 mg, 1.841 mmol) and tert-butyl 2-bromoacetate (359 mg, 1.841 mmol) were added, and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water and filtered. The precipitate was dissolved in EtOAc and extracted with water and HCl 1M, dried over Na2SO4 and concentrated under vacuum to give tert-butyl 2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetate (220 mg, 72.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:15]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[H][H]>O1CCCC1.[C].[Pd]>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(OC)cc1OC

Procedure:
A 4.00 g portion of methyl 2,4-dimethoxy-5-nitrobenzoate was dissolved in 200 ml of tetrahydrofuran, and 0.40 g of 10% palladium-carbon was added, followed by stirring for 12 hours at room temperature under normal pressure in an atmosphere of hydrogen. After removing insoluble matter by filtration, the solvent was evaporated under a reduced pressure to give 3.6 g of methyl 5-amino-2,4-dimethoxybenzoate.
Reaction SMILES: O1CCCC1.[CH:6]1([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]3[C:23]([O:56]C(OCC)C)([CH3:55])[CH2:24][CH2:25][CH:26]([OH:54])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:53])=[CH:37]/[CH:38]=[CH:39]/[C:40]([OH:52])([CH3:51])[CH2:41][CH:42]4[O:50][CH:43]4[CH:44]([CH3:49])[CH:45]([OH:48])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]3)=[O:29])=[O:20])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>COC(C)(C)C.COC(C)(C)C.O1CCCC1.C(O)(C)(C)C>[CH:6]1([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]3[C:23]([OH:56])([CH3:55])[CH2:24][CH2:25][CH:26]([OH:54])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:53])=[CH:37]/[CH:38]=[CH:39]/[C:40]([OH:52])([CH3:51])[CH2:41][CH:42]4[O:50][CH:43]4[CH:44]([CH3:49])[CH:45]([OH:48])[CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]3)=[O:29])=[O:20])[CH2:15][CH2:14]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(C)OC1(C)CCC(O)CC(=O)OC(/C(C)=C/C=C/C(C)(O)CC2OC2C(C)C(O)CC)C(C)C=CC1OC(=O)N1CCN(C2CCCCCC2)CC1
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCN(C3CCCCCC3)CC2)/C=C/C1C
Agent: CCOC(C)OC1(C)CCC(O)CC(=O)OC(/C(C)=C/C=C/C(C)(O)CC2OC2C(C)C(O)CC)C(C)/C=C/C1OC(=O)N1CCN(C2CCCCCC2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: COC(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCN(C3CCCCCC3)CC2)C=CC1C
Reaction time: 3 h

Procedure:
At an outside temperature of 25° C., tetrahydrofuran (145 mL) and t-butanol (62.1 mL) were added to a t-butyl methyl ether/tetrahydrofuran solution of the (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide obtained in Example 5, following which 11.8 g (46.9 mmol) of pyridinium p-toluenesulfonate was added and stirring was carried out for 3 hours. Next, t-butyl methyl ether (104 mL) and a saturated aqueous solution of sodium bicarbonate (104 mL) were added to the reaction mixture, following which the organic phase was separated and washed with a 4% saline solution (104 mL), then evaporated, yielding 50.6 g (content: 20.2%; by weight, 10.2 g) of a crude form (yellow oily substance) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[S:4][N:3]=1.Cl>N>[CH2:12]([C:11]1[NH:9][C:7](=[O:8])[C:6]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[N:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1nsc(NC(=O)CC(C)C)c1C(N)=O
Agent: Cl
Agent: N
Product: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Temperature: 140 °C
Yield: 25.9 %

Procedure:
The 3-methyl-5-(3-methyl-butyrylamino)-isothiazole-4-carboxylic acid amide (method 25) (45.8 g, 190 mmol) was suspended in 700 ml of 30% NH3 and then was heated to 140° C. for 5 h in a pressure reactor. The mixture was poured into a 4 L beaker and cooled in an ice bath. To the cold solution con HCl (560 ml) was added dropwise to pH 7.5 and a white precipitate was formed. The precipitated product was filtered off, washed with water (100 ml) and dried under vacuum overnight. 6-Isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (11 g, 26%) was isolated as an off-white powder. 1H NMR (300 MHz) δ 1.05 (d, 6H), 2.32 (m, 1H), 2.69 (d, 2H), 2.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:29][CH2:30][NH2:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH2:29][CH2:30][NH:31][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCCCC1CCNCc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 2-(2-Amino-ethyl)-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 431.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]3[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:2]=3[CH3:1])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1cccc(C)c1CNc1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C23H23ClN6O2, 450.9
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=O)(=O)[CH3:2].[CH:9]1([NH:15][C:16](=[O:21])[CH2:17]C(C)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH:9]1([NH:15][C:16]([C:17]2[CH:6]=[C:5]([CH3:8])[O:4][C:1]=2[CH3:2])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)OC(C)C=O
Reactant: CC(=O)CC(=O)NC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)NC2CCCCC2)c(C)o1
Temperature: 25 °C

Procedure:
24 parts (by weight) of α-acetoxypropionaldehyde is stirred with 36.6 parts of acetoacetic cyclohexylamide and 1 part of concentrated H2SO4 in 100 parts of toluene for 3 hours at 50° C. After the mixture has been cooled to room temperature it is washed with sodium hydrogen carbonate. The organic phase is dried with Na2SO4 and concentrated to dryness. There is obtained 41 parts of 2,5-dimethylfuran-3-carboxylic cyclohexylamide having a melting point of 111° to 113° C. After recrystallization from cyclohexane the compound melts at 114° to 115° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:28][CH2:29][CH:30]([OH:36])[CH2:31][C:32](OC)=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[C:21]1([C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:28][CH2:29][CH:30]([OH:36])[CH2:31][C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
125 mL of THF and 24 g of diisopropylamine were charged and cooled to −15° C. 168 mL of 1.2 N n-BuLi was added at −15 to −5° C. and was stirred for 30 minutes. 21.56 g of tert-butyl acetate in 45 mL of THF, which was pre-cooled to −45° C., was added maintaining the temperature between −45 to −25° C. for 60 minutes. The reaction mixture was cooled to −45° C. and 30 g of methyl 4-triphenylmethyloxy-3-hydroxybutyrate in THF was added over a period of 20 minutes and the stirring was continued at −25° C. for 90 minutes. Water was added and the layers were separated. The aqueous layer was extracted using EtOAc and the combined organic layers were washed with brine, water, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]1([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)[CH:32]=[O:33]>C1COCC1>[F:29][C:24]1[C:23]([O:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:27]=[CH:26][C:25]=1[CH:32]=[O:33]
Reactant: Fc1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Oc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Cool a solution of 2,2,6,6-tetramethylpiperidine (5.1 mL, 30.0 mmol) in THF (40 mL) to −78° C. Add dropwise n-Butyllithium (18.7 mL, 30.0 mmol, 1.6M in hexanes) and stir for 10 min at −78° C. Add dropwise 2-fluorophenyl phenyl ether (4.7 g, 25.0 mmol), stir 2 h at −78° C. Add N,N-dimethylformamide (2.3 mL, 30.0 mmol) dropwise over 15 min. Stir the resulting mixture for 3 h at −78° C. and allow to warm to ambient temperature over 16 h. Quench the reaction mixture with water (50 mL), extract with ethyl acetate, dry over Na2SO4, filter and concentrate under reduced pressure to give an oil. Crystallize the oil with hexanes to give a solid, collect and recrystallize from hexanes/ethyl acetate/methylene chloride to give the title compound: mp 75-77° C.; MS (m/e): 216 (M+); Calculated for C13H9FO2: Calcd: C, 72.22; H, 4.20. Found: C, 72.41; H, 4.23. Purification of the mother liquors by silica gel chromatography (2-3% ethyl acetate/hexanes) gives an additional amount of the title compound: MS (m/e): 216 (M+).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([B:18]([OH:20])[OH:19])=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1

Procedure:
A solution of (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (10 g, Example 11) in methanol (150 ml) was stirred for 16 hours at room temperature and 2M hydrochloric acid (25 ml). The solution was concentrated to give an acidic aqueous residue which was washed with diethyl ether. The aqueous layer was basified with saturated sodium bicarbonate, the product was extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as a foam. (6.97 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH3:35]>>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:15]2[S:16][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:35])[CH:7]=4)=[N:13][C:12]=3[CH:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: N
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(F)c4)nc(N4CCOCC4)c3s2)CC1
Agent: [OH-]
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(N)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(2-Fluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (107 mg) was heated in ammonia hydroxide (90 ml) in a sealed stainless steel pressurized vessel at 150° C. for 5 days. Extraction into chloroform and purification on silica afforded 418 (57 mg). NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.55 (2H, br s), 7.36 (1H, s), 7.54 (1H, s), 7.65 (1H, d, J=5.3), 8.21 (1H, d, J=5.3) MS (ESI+): MH+490.16 (74%)
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1>[CH2:10]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([O:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[C:20]=2[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC1CCCCC1
Reactant: Clc1ncnc2c1ccn2Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2ccc3c(OC4CCCCC4)ncnc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a flame dried flask under nitrogen was charged 84 mg (2.10 mmol) of 60% sodium hydride in mineral oil and 3.0 mL of THF and the mixture cooled to 0° C. Cyclohexanol (0.18 mL/0.70 mmol) was added and the reaction mixture stirred for 5 min. A solution of 102 mg (0.419 mmol) of the product from Method L in 1.0 mL of THF was added and the mixture heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2 N HCl and concentrated in vacuo. The resulting residue was then slurried in ethyl acetate, filtered and the filtrate concentrated in vacuo to provide 76 mg (59%) of the title compound as an oil. LRMS: 308 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CC(C)c1csc(N)n1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(C(C)C)cs1
Yield: 48 %

Procedure:
The title compound was prepared from 4-isopropyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, white foam, 80 mg (48% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0257).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.[CH:30]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)([CH3:32])[CH3:31].C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:11]2[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH:30]([CH3:32])[CH3:31])[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CC(C)Oc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
To toluene 1.6 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added ethanol 0.60 mL, water 0.30 mL, 2-isopropoxyphenylboronic acid 0.048 mL, sodium hydrogen carbonate 48 mg and tetrakis(triphenylphosphine)palladium(0) 11 mg at room temperature, and it was heated and refluxed for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 2-(4-fluoroanilino)-4-(2-isopropoxyphenyl)benzoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CO>ClCCl>[CH3:14][N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=1)[CH2:6][C:2]1[N:3]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:4]=[CH:5][N:1]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
The compound (281 mg) obtained in Example 84-5 was dissolved in dichloromethane (6.0 ml) and added with diisopropylethylamine (310 μl) at room temperature under a nitrogen atmosphere. The solution was added with tritylchloride (310 mg) under ice-cooling and the whole was stirred at room temperature for 4 hours. After completion of the reaction, methanol was added thereto. The solvent was distilled off under reduced pressure and the residue was diluted with chloroform and added with water. The aqueous layer was subjected to extraction with chloroform. The combined organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and evaporated to dryness under reduced pressure and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (217 mg) as a yellow oily substance.