Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][NH:75][CH3:76]>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][N:75]([CH3:76])[C:32](=[O:34])[C:31]1[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[N:8]=3)=[CH:24][CH:23]=2)=[O:37])=[CH:29][CH:30]=1
Reactant: CNCCN(C)C
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 50.2 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with N1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to give N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:13][CH2:14][CH2:15][OH:16])=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H].[C:19](OC(=O)C)(=[O:21])[CH3:20].[OH-].[Na+]>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:13][CH2:14][CH2:15][OH:16])=[N:6][CH:7]=[C:8]([NH:10][C:19](=[O:21])[CH3:20])[CH:9]=1
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnc(OCCO)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1cnc(OCCO)c(N)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
8.5 g (37 mmol) of 2-(3,5-dinitro-2-pyridyloxy)ethanol was dissolved in 250 ml of degassified ethanol. The mixture was stirred in the presence of 400 mg of 5% palladium on carbon as a catalyst under 20 atm hydrogen pressure at room temperature for 2 days in an autoclave. The reaction mixture was filtered through Celite to remove the catalyst, and subsequently, 120 ml of ethanol and 74 ml of water were added to the filtrate. The temperature was maintained at about 10° C., and 3.7 ml of acetic anhydride (37 mmol) was added in approximately 0.2 ml portions, along with 5 drops of an aqueous 48% NaOH solution from a Pasteur pipette at intervals of 10 minutes, maintaining the pH at about 6-7. The mixture was stirred for an additional 30 minutes. The mixture was concentrated, then purified by silica gel column chromatography (Merck Co., Si60, ethyl acetate-methanol=10:1). Recrystallization from methanol yielded 4.6 g (22 mmol) of 2-(3-amino-5-acetamido-2-pyridyloxy)ethanol as a green solid (yield: 59%)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[C:23]1([CH:29]2[CH2:34][C:33](=O)[O:32][C:30]2=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([N:20]3[C:33](=[O:32])[CH2:34][CH:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:31])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)c(N4C(=O)CC(c5ccccc5)C4=O)c(C)c(C)c3OC2(C)C)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (2.95 g, 10 mmol) and phenylsuccinic anhydride (1.94 g, 11 mmol) in toluene was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A mixture of the residue and sodium acetate (0.86 g, 10.5 mmol) in acetic anhydride (60 ml) was stirred at 90° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and removed under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate−4/1) to obtain 2.27 g (yield 50%) of the title compound. mp. 130–131° C. low polarity product, 1H-NMR (CDCl3) δ: 1.00 (3H, s)=1.52 (3H, s), 1.64 (3H, s), 2.02 (3H, s), 2.16 (3H, s), 2.30 (3H, s), 3.00 (1H, dd, J=4.7, 18.5 Hz), 3.36 (1H, dd, J=9.5, 18.5 Hz), 4.15–4.25 (2H, m), 6.85 (2H, br), 7.06 (2H, brd, J=6.6 Hz), 7.30–7.47 (5H, m).
Reaction SMILES: COC(OC)CNCC1C=C(C)C=CC=1N.N#CBr.[NH2:20][C:21]1[N:30]([CH2:31][CH:32](OC)OC)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH3:37])[CH:27]=2)[N:22]=1.Cl>C(O)C>[CH3:37][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1=[N:20][CH:32]=[CH:31][N:30]1[CH2:29]2
Reactant: COC(CN1Cc2cc(C)ccc2N=C1N)OC
Agent: COC(CNCc1cc(C)ccc1N)OC
Agent: Cl
Agent: N#CBr
Solvent: CCO
Product: Cc1ccc2c(c1)Cn1ccnc1N2
Reaction time: 2 h

Procedure:
45 g of N-(2-amino-5-methylbenzyl)-aminoacetaldehydedimethylacetal obtained in step (d) and 25 g of cyanogen bromide are heated under reflux in 500 ml of 95% ethanol for 18 hours. After the mixture containing 2-amino-3-(2,2-dimethoxyethyl)-6-methyl-3,4-dihydroquinazoline is cooled, 200 ml of 5 N hydrochloric acid are added, and the solution is left to stand for 2 hours at room temperature. After the reaction solution is concentrated in a vacuum, it is made alkaline with dilute caustic soda, whereupon the title compound crystallizes out, and is recrystallised from methanol or ethanol. M.p. 265° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]4)[N:13]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].CN(C=O)C.Br[CH2:37][C:38]#[N:39]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]4)[N:13]=3)=[CH:8][N:9]2[CH2:37][C:38]#[N:39])=[CH:5][CH:4]=1
Reactant: N#CCBr
Reactant: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cn(CC#N)c2c1
Reaction time: 0.25 h

Procedure:
A solution of [4-(6-Methoxy-1H-indol-3-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (150 mg, 0.40 mmol) in 2 ml of THF was added to a suspension of sodium hydride (55.3 mg, 1.38 mmol, 60% mineral dispersion) in 2 ml of THF. 0.1 ml of DMF was added and stirring was continued for 15 minutes. Bromoacetonitrile (51.9 mg, 0.43 mmol) was then added and the solution was stirred for 5 hours. The solvent was removed and the residue was purified by flash chromatography on silicagel (EtOAc/MeOH/ammonia:5/1/0.05) to give the title compound. Yield: 142 mg (88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CCCCCC.CCOC(C)=O>CN(C)C=O>[C:15]1([CH2:14][O:10][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccc(OCc2cccc3ccccc23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-nitrophenol (200 mg) in 4.0 mL of dimethylformamide at 0° C. was added NaH. After 10 minutes, 1-bromomethylnaphthalene (480 mg) was added, and the cold bath was removed. After ca. 15 h, the solution was quenched by the addition of sat. NH4Cl solution, and concentrated to dryness in vacuo. The residue was diluted with ethyl acetate and washed with water, sat. aq. NaHCO3 solution, and brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to provide the crude product. Trituration with 9:1 hexane/EtOAc provided the titled compound as a light brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C@H:18]([CH2:21][CH3:22])[CH:19]=[CH2:20])[C:15](O)=[O:16])=[CH:10][CH:9]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([C@@H:18]([CH2:21][CH3:22])[CH:19]=[CH2:20])[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:16])=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: C=C[C@@H](CC)[C@H](C(=O)O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=C[C@H](CC)[C@H](C(=O)N1CCOCC1)c1ccc(Cl)cc1

Procedure:
Morpholine (0.107 ml, 1.23 mmol) and the intermediate I2 (239 mg, 1.12 mmol) were dissolved in 5 ml of DMF and cooled in an ice-bath. HOBT (188 mg, 1.23 mmol), triethylamine (0.309 ml, 2.24 mmol) and EDC (214 mg, 1.12 mmol) were added successively. The ice-bath was removed and stirring continued over night. The mixture was evaporated, redissolved in diethyl ether and extracted with 2N-HCl (twice), 5% sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give a pale yellow oil. Yield (crude): 320 mg (93%).
Reaction SMILES: ON1C=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](C)[CH2:3]1.[H-].[Na+].CI.[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[CH:18]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:3])[C:19]1=[O:20]
Reactant: CN(C)C=O
Reactant: CC1=CC([N+](=O)[O-])=CN(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1cc([N+](=O)[O-])cn(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1 g (6.49 mmol) 1-hydroxy-3-methyl-5-nitropyridine, 0.197 g (7.8 mmol) NaH and 0.61 ml (9.73 mmol) MeI in 20 ml DMF is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound as off-white crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1>C1C=CC=CC=1>[ClH:7].[NH2:3][CH2:4][CH2:5][O:6][C:11]1[N:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cl
Product: NCCOc1ccc(Cl)nn1
Yield: 54.2 %

Procedure:
To a suspension of 4.2 g of 61% sodium hydride in 100 ml of benzene was added dropwise 6.2 g of 2-aminoethanol at room temperature. Then, 15 g of 3,6-dichloropyridazine was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was washed with water, and dried over magnesium sulfate. After evaporating the solvent, the residue was treated with hydrogen chrolide-ether solution to give 5.73 g of 3-(2-aminoethoxy)-6-chloropyridazine hydrochloride as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:20]([CH2:19][CH3:18])[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(CC)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A mixture of 30 g of p-hydroxyacetophenone and 30 g of potassium carbonate was stirred in 500 ml of ethanol at 60° C. for 30 minutes. After cooling to room temperature, 521 g of ethyl 5-bromo-2,2-dimethylpentanoate was added to the reaction mixture. The resulting mixture was heated under reflux overnight while stirring. The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue. After stirring the mixture, the chloroform layer was fractionated and washed successively with water and then with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of chloroform by distillation gave a residual oily substance. The oily substance was subjected to silica gel column chromatography and eluted using chloroform as an eluant to give 42 g of ethyl p-acetylphenoxy-2,2-dimethylpentanoate as an oily substance. The thus obtained oily substance was dissolved in 1.6 l. of anhydrous methylene chloride and 24 g of bromine was dropwise added to the solution under ice cooling while stirring to allow to react for 3 hours. To the reaction mixture was added 1 liter of ice water. After thoroughly stirring, the organic layer was successively washed with water and with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of methylene chloride by distillation gave the desired product, ethyl 5-[p-(bromoacetyl)phenoxy]-2,2-dimethylpentanoate, as an oily substance.
Reaction SMILES: [CH2:1]([C:3]1([CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:12]=[CH:13][C:14]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37](=[O:40])[CH2:38][CH3:39].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:12]=[CH:13][C:14]=2[N:15]2[CH2:16][CH2:17][N:18]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH2:19][CH2:20]2)[CH2:5][CH2:4]1)[CH3:28]
Reactant: CCC1(CC)CCC(c2cc(N3CCOCC3)ccc2N2CCNCC2)CC1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)CN1CCN(c2ccc(N3CCOCC3)cc2C2CCC(CC)(CC)CC2)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[3-(4,4-diethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (20 mg, 0.052 mmol) produced in Example (84b) in dimethylformamide (1 mL) were added potassium carbonate (11 mg, 0.078 mmol) and 1-bromo-2-butanone (9.4 mg, 0.063 mmol), followed by stirring for 2 hours and 5 minutes at an external temperature of 80° C. After air-cooling, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and then filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4-[2-(4,4-diethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-one. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.020 mL, 0.080 mmol) was added. The solution was concentrated under reduced pressure, and then hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The obtained solid residue was dried under reduced pressure to give 25 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17]([OH:19])=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C(C)=CC=CC=1C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17](=[O:19])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)Nc1ccccc1)OC2
Reaction time: 72 h
Yield: 43.9 %

Procedure:
To a solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) in distilled dichloromethane (4 ml) under nitrogen was added aniline (32 μl, 0.34 mmol) followed by 2,6-lutidine (0.11 ml, 0.93 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 51 mg (45%) of 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=3[N:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc3c(n2)CC(C)(C)CC3=O)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.35 g, 1.67 mmol) and 4-methoxyphenylamine (0.267 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.22 g, 2.0 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.096 g, 19%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3F)c2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(S(C)=O)cc3F)c2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 0.45 g (1.0 mmol) of 2-propionyl-3-hydroxy-5-(3-(2-fluoro-4-(methylsulfinyl)phenoxy)-phenyl)cyclohex-2-en-1-one in 3 mL of methYlene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.14 g (1.5 mmol) of ethoxyamine hydrochloride and 0.12 g (1.5 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 30 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and the solvent evaporated off leaving the product as a yellow oil. Purification via flash chromatography (silica gel, methylene chloride/acetone) gave the above named product as a yellow oil in a yield of 0.33 g (66 percent of theoretical). 1H NMR (CDCl3): δ1.10-1.50 (m, 6H, both --CH2CH3 's), 2.60-3.55 (m includes s at 2.75 for CH3SO--, 10H), 4.21 (q, J=7 Hz, 2H, --OCH2), 6.80-7.56 (m, 7H, aromatics), 14.5-15.0 (very broad s, enol H) (Compound 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[Cl:8]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Nc1cc(Br)cnc1Cl
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N)c3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (1.73 g, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.836 g, 0.723 mmol) and potassium carbonate (2.20 g, 15.9 mmol) was suspended in 1,4-dioxane (25 ml) with water (2.5 ml). Argon was bubbled through the suspension for about 30 seconds. The flask was fitted with a reflux condenser and placed into a heat bath (100° C.). The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product. The mixture was allowed to cool to ambient temperature. The mixture was diluted with DCM and saturated sodium bicarbonate solution. The organic layer was extracted with DCM (3×25 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with ethyl acetate and the precipitate was collected by filtration. The precipitate was washed with hexanes to give N-(6-(5-amino-6-chloropyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.500 g, 32.5% yield) as a brown crystalline solid. MS (ESI pos. ion) m/z: 319 (MH+). Calc'd exact mass for C14H11ClN4OS: 318. 1H NMR (400 MHz, DMSO-d6): 2.22 (s, 3H), 5.66 (s, 2H), 7.42 (s, 1H), 7.65 (d, J=8.53 Hz, 1H), 7.81 (d, J=8.53 Hz, 1H), 7.94 (s, 1H), 8.24 (s, 1H), 12.41 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+](CCCCCC)([O-])=O.F[C:20]1[CH:27]=[CH:26][CH:25]=C[C:21]=1[CH:22]=[O:23].[N+](CCC)([O-])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:22](=[O:23])[CH2:21][CH2:20][CH2:27][CH2:26][CH3:25]
Reactant: O=Cc1ccccc1Cl
Reactant: O=Cc1ccccc1F
Agent: CCCCCC[N+](=O)[O-]
Solvent: CCC[N+](=O)[O-]
Product: CCCCCC(=O)Cc1ccccc1Cl
Yield: 17 %

Procedure:
Following a procedure similar to that described in Preparation 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitrohexane were used in place of the 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a pale yellow oil in a yield of 17%.