Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cccc(O)c1

Procedure:
A solution of 3-Hydroxyphenylacetic acid (25 g, 164.31 mmol) and p-Toluenesulfonic acid monohydrate (3.49 g, 18.3 mmol) in abs ethanol (250 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A mixture of 4-(trifluoromethyl)phenylboronic acid (495 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 mL), and powdered 4A MS (1.5 g) in DMF (10 ml) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (45 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]12[O:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][CH2:10]2.[Cl:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[N:21]=[C:20]([CH3:28])[N:19]=1.Cl>O1CCOCC1.C(OCC)C>[ClH:17].[CH:25]1([NH:24][C:22]2[N:21]=[C:20]([CH3:28])[N:19]=[C:18]([N:11]3[CH2:10][CH:9]4[O:16][CH:13]([CH2:14][CH2:15]4)[CH2:12]3)[N:23]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(Cl)nc(NC2CC2)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Yield: 63 %

Procedure:
2 equivalents of triethylamine dissolved in dioxane are added to one equivalent of 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride suspended in the same solvent. 1 equivalent of 2-chloro-4-cyclopropylamino-6-methyl-1,3,5-triazine dissolved in dioxane is then added. The mixture is heated under reflux for some hours. It is cooled to room temperature and the precipitate which has formed is filtered off. The filtrate is evaporated under reduced pressure and the residue is redissolved in dichloromethane. The solution is washed with water. The organic phase is separated off and dried over sodium sulfate, and the solvent is then evaporated under reduced pressure. The residue thus obtained is purified by chromatography on silica (eluent: 98:2 (v/v) dichloromethane-ethanol). 2-cyclopropylamino-4-methyl-6-(8-oxa-3-azabicyclo[3,2,1]oct-3-yl)-1,3,5-triazine hydrochloride is prepared by addition of one equivalent of hydrochloric acid to the free base in diethyl ether. Yield: 63%. M.P.: 220°-223° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]1([CH2:23][CH2:24][C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(CCc1ccccc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 3-phenylpropanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.46 (m, 1H), 8.15 (td, J=7.7, 1.4 Hz, 1H), 7.99-8.09 (m, 2H), 7.28-7.34 (m, 4H), 7.20-7.25 (m, 1H), 2.94 (t, J=7.7 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H); MS (ESI−) M/Z 360 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[CH3:50][OH:51].CN([CH:55]=[O:56])C>C(O[Pd]OC(=O)C)(=O)C>[F:13][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])([CH3:12])[CH3:10])[C:50]([O:56][CH3:55])=[O:51]
Reactant: CO
Reactant: CC(C)(O)Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(C)(C)O)c(F)c1
Temperature: 80 °C
Yield: 85 %

Procedure:
1-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g, 9.51 mmol), diacetoxypalladium (214 mg, 0.951 mmol), 3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.951 mmol), and Et3N (4.24 mL, 30.4 mmol) in DMF (26 mL) were treated with MeOH (20.0 mL, 495 mmol). The vessel was charged to 50 psi with CO (266 mg, 9.51 mmol) and then vented. This operation was repeated twice. The reaction was charged to 50 psi and heated at 80° C. for 15 h. The reaction mixture was allowed to cool, vented and partitioned between EtOAc/brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed twice with brine, dried over Na2SO4, filtered and concentrated to an orange oil. The residue was purified by silica gel flash column chromatography using 0-30% EtOAc in hexanes to yield methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.83 g, 85%) ESI-MS m/z calc. 226.1, found 227.5 (M+1)+; Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J=7.9, 1.7 Hz, 1H), 7.71 (dd, J=10.3, 1.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 2.88 (d, J=1.3 Hz, 2H), 1.26 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O>O1CCOCC1.C(OCC)(=O)C>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[S:12][C:11]([N:13]4[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]4)=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[N:30]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(N)c3)s2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a solution of ethyl 1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (42 mg, 0.13 mmol) in dioxane (1.3 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (23 mg, 1.3 mmol) and 4-methylbenzenesulfonic acid (24 mg, 0.127 mmol), resulting in the instant formation of a suspension. The mixture was heated to 100° C. and N,N-dimethylformamide (0.5 mL) was added to afford a homogenous mixture. The solution was heated at 100° C. for an additional 2 hours. Thus the mixture was the cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL). The aqueous fractions were further extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by CombiFlash (30-100% ethyl acetate:hexanes) provided 22 mg (0.046 mmol, 36% yield) of ethyl 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+](CC)([O-])=O.FC1C=CC=C[C:17]=1[CH:18]=[O:19].[N+](CCC)([O-])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:18](=[O:19])[CH3:17]
Reactant: O=Cc1ccccc1F
Reactant: O=Cc1ccccc1Cl
Solvent: CCC[N+](=O)[O-]
Solvent: CC[N+](=O)[O-]
Product: CC(=O)Cc1ccccc1Cl
Yield: 27 %

Procedure:
Following a procedure similar to that described in Preparation 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitroethane were used in place of the 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a brown oil in a yield of 27%.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Li+].[Cl-].COC([C:17]1[C:22]([C:23]([C:25]2[C:26]([CH:31](OC)[C:32]3[CH:37]=[CH:36]C=CC=3)=NC=NC=2)=[O:24])=[CH:21][N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.C1C[O:43][CH2:42]C1>[Cl-].[Cl-].[Zn+2]>[CH3:42][O:43][C:32]1[CH:31]=[CH:26][C:25]([C:23]([OH:24])([C:22]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:1]2[CH2:3][CH2:2]2)=[CH:36][CH:37]=1
Reactant: C1CCOC1
Reactant: COC(c1ccccc1)c1ncncc1C(=O)c1cncnc1C(OC)c1ccccc1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [Zn+2]
Product: COc1ccc(C(O)(c2cncnc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To a solution of cyclopropylmagnesium bromide (0.5 M in THF, 9 mL, 4.5 mmol) was added ZnCl2 (612 mg, 4.5 mmol) and LiCl (0.189 mg, 4.5 mmol). To this clear yellow solution was added 18 (1.00 g, 4.5 mmol) in THF and the mixture was stirred for 4 h at rt before being washed with sat. NH4Cl. The organic layer was diluted with EtOAc and washed with sat. NaHCO3 before being dried and evaporated to a brown gum, which was dissolved in toluene and poured over a plug of silica gel (20 g). The plug was washed with hexane-EtOAc (100 mL). The eluants were evaporated to a yellow oil that solidified upon trituration with hexanes. The solid was filtered and dried to afford 374 mg (31%) of 15 as a white solid. Mp=108-110° C.; 1H NMR (300 MHz, CDCl3) δ ppm 9.06 (s, 1H), 8.48 (s, 2H), 7.82 (d, 2H), 7.03 (d, 2H), 3.99 (s, 3H), 1.08 (m, 1H), 0.50-0.31 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc2[nH]c(=O)n(C3=CCN(Cc4ccccc4)CC3)c2cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(=O)n(C3=CCNCC3)c2cc1C

Procedure:
A solution of 5,6-dimethyl-1-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (D99) (1.05 mmol, 350 mg) in ethanol (10 mL) and acetic acid (2 mL) was treated with 10% palladium on charcoal (0.25 eq wt, 90 mg) then shaken under 50 PSI of hydrogen pressure for 24 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the acetate salt of the title compound also containing some saturated analogue (reduction of the C═C double bond in the piperidine core) as a beige solid (1.2 mmol, 370 mg, >100% yield) M+H 246.2, M−H 242.3.
Reaction SMILES: [N:1]([O-])=O.[Na+].S(=O)(=O)(O)O.[NH2:10][C:11]1[S:12][C:13]([CH:17]=[O:18])=[C:14]([Cl:16])[N:15]=1.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24])[CH3:20]>C(O)(=O)CC.C(O)(=O)C.O>[Cl:16][C:14]1[N:15]=[C:11](/[N:10]=[N:1]/[C:28]2[CH:29]=[CH:30][C:25]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][OH:24])=[CH:26][CH:27]=2)[S:12][C:13]=1[CH:17]=[O:18]
Reactant: CCN(CCO)c1ccccc1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)c(C=O)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=O)s2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.3 g (18.56 mmol) sodium nitrite was added in small portions to 13.2 g conc. sulphuric acid and cooled to 0° C. and diluted with 4.8 ml propionic acid and 19.2 ml acetic acid. 3.0 g (18.45 mmol) 2-amino-4-chloro-1,3-thiazole-5-carbaldehyde were then added in small portions. The viscous reaction mixture was stirred for 2 hours at 0° C. This mixture was then added slowly to a solution of 3.2 g (18.56 mmol) 2-[ethyl(phenyl)amino]ethanol in 180 ml water, containing 6 ml sulphuric acid. After stirring for another 2 hours at room temperature, the obtained precipitate was filtered off, washed with water and dried at 40° C. in vacuum.
Reaction SMILES: [CH2:1]([NH:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N:24]1[C:31](Cl)=[N:30][C:28](Cl)=[N:27][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:26][C:25]1[N:24]=[C:31]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[NH:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[N:30]=[C:28]([N:13]([CH:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:27]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN(c1nc(Cl)nc(N(CCCCCCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 1.5 h

Procedure:
A solution of 35.7 g of 4-dodecylamino-2,2,6,6-tetramethylpiperidine in 50 ml of xylene was added dropwise at 20°-25° C. to a solution of 9.2 g of cyanuric chloride in 250 ml of xylene. The mixture was stirred for 1.5 hours at the same temperature and then for 5 hours at 50°-55° C. At the end of this time, the reaction mixture was neutralised with an aqueous solution of potassium carbonate, and the xylene layer was separated and dried over anhydrous potassium carbonate. The xylene was distilled off and the resulting oil was purified by column chromatography through silica gel eluted with a 20:20:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine to give the title compound as an oil. The Rf value of this compound on thin layer chromatography was 0.28, using silica gel and using, as developing solvent, a 20:20:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:10]=1
Reactant: CCCC(C)OC(=O)c1ccc(OC(C)=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: NCc1ccccc1
Product: CCCC(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Two grams of the crude compound (2) was dissolved in 50 ml of ethanol and 4 g of benzylamine was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with 500 ml of chloroform, washed with dilute hydrochloric acid and water in this order, and dried with magnesium sulfate. After the solvent was evaporated, the residue was subjected to isolation and purification by silica gel column chromatography to obtain 1.6 g of a final compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:30])[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:30][N:15]([CH3:14])[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[N:17]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: COc1cc(N(C)C)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N(C)C)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 104.7 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9 g), 1-(4-dimethylamino-6-methoxypyrimidin-2-yl)piperazine (1.1 g) and potassium carbonate (1.0 g) in dimethylformamide (10 ml) was stirred at 80° C. for 8.5 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (1.9 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a yellow oil (1.6 g). The obtained yellow oil was crystallized from ethyl acetate/hexane (1:1, 20 ml) to give the title compound (1.0 g) as pale-yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Br[C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(CN1P2N(CC(C)C)CCN(CCN2CC(C)C)CC1)C>C1(C)C=CC=CC=1>[CH3:28][C:23]1[C:22]([N:1]2[CH2:2][CH2:3][C:4](=[N:7][O:8][CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH2:5][CH2:6]2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ncccc1Br
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ncccc1N1CCC(=NOC2CCN(C(=O)OC(C)C)CC2)CC1
Temperature: 80 °C

Procedure:
Compound 2d (30 mg, 0.11 mmol), 3-bromo-2-methyl-pyridine (0.16 mmol), cesium carbonate (72 mg, 0.22 mmol), PddppfCl2 (10 mg), and triisobutylphosphatrane (15 μL) were combined in toluene (0.5 mL). The mixture was heated at 80° C. for 20 h. The mixture was concentrated under a stream of nitrogen and the residue was partitioned between DCM and water. The DCM layer was concentrated and taken up in methanol and purified by preparative HPLC to afford 4-1: LC-MS 375.4 (MH+), tR=7.88 (Method 6). EC50: 4804 nM.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: C=Cc1ncc(C(=O)OCC)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)o1
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time=1.09 minutes (condition A); MS (m+1)=170.3; 1 H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.6 Hz, 3 H) 1.36 (t, J=7.2 Hz, 3 H) 2.87 (q, J=7.7 Hz, 2 H) 4.35 (q, J=7.2 Hz, 2 H) 7.71 (s, 1 H)
Reaction SMILES: O=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5]C=CC=2)[N:3]1C1CCN(C(OC(C)(C)C)=O)CC1.BrN1[C:29](=O)[CH2:28][CH2:27][C:26]1=[O:31].[C:32](#[N:34])C>ClCCl.O>[O:31]1[CH2:26][CH2:27][CH:28]([N:34]2[CH2:5][CH:4]3[NH:3][CH:2]([CH2:10][CH2:9]3)[CH2:32]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Reactant: CC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: C1CC(N2CC3CCC(C2)N3)CO1
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Tert-butyl 4-(2-oxoindolin-1-yl)piperidine-1-carboxylate (100 mg, 0.32 mmol) in ACN is cooled down to −10° C., N-bromosuccinimide (56.47 mg, 0.32 mmol) is added and stirred at −10° C. for 2 h. The reaction mixture is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is used for the next step without further purification. Yield 99%, m/z 395 [M+H]+, rt 1.126 min, LC-MS Method Z020_S01.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH:40]1[O:45][C:44]2[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=2[O:42][CH2:41]1>CN(C)C=O>[O:45]1[CH:40]([CH2:39][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[CH2:41][O:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]1=2
Reactant: BrCC1COc2ccccc2O1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CC4COc5ccccc5O4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.23 g, 0.55 mmol) and potassium carbonate (0.114 g, 0.83 mmol) in N,N-dimethylformamide (5 mL), was added 2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (0.082 mL, 0.55 mmol, d=1.533). After stirring at 55° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (7% methanol/dichloromethane) to obtain the title compound (0.17 g, 54%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.63 (d, 2H, J=12 Hz), 2.54-2.60 (m, 2H), 2.65 (d, 2H, J=6 Hz), 2.81-2.93 (m, 6H), 3.99-4.04 (m, 1H), 4.37 (dt, 2H, J=10.4 and 2.4 Hz), 4.60 (d, 2H, J=11.2 Hz), 6.76-6.88 (m, 7H), 7.23 (t, 2H, J=8.8 Hz), 7.48-7.55 (m, 2H), 7.79 (m, 1H), 7.83 (dt, 1H, J=7.2 and 2 Hz); MS for C34H39N3O5 m/z 570.12 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][S:6][C:5]1=[NH:9])[CH:2]=[CH2:3].C(=O)([O-])O.[Na+].O1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl[C:21]([O:23][CH3:24])=[O:22]>O>[CH2:1]([N:4]1[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[S:6][C:5]1=[N:9][C:21]([O:23][CH3:24])=[O:22])[CH:2]=[CH2:3]
Reactant: COC(=O)Cl
Reactant: C=CCn1ccsc1=N
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCn1c(=NC(=O)OC)sc2ccccc21
Reaction time: 2 h
Yield: 91 %

Procedure:
To a mixture comprising 3.8 g of 3-allyl-2-iminothiazole, 3.4 g of sodium hydrogencarbonate and 50 ml of tetrahydrofuran was added 1.9 g of methyl chloroformate dropwise at room temperature under stirring. After reacting for two hours, the reaction mixture was poured into approximately 200 ml of water. The crystals precipitated were collected by filtering to thereby obtain 4.5 g of the objective compound.