Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](OB(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1)=[O:30]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Yield: 57.2 %

Procedure:
Under nitrogen atmosphere, 2-(2-{2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-5-iodobenzoic acid methyl ester (5.0 g) synthesized in Example 92-1 and 4-fluorophenylboric acid (1.5 g) were dissolved in dioxane (40 mL) and aqueous sodium carbonate solution (2 mol/L, 20 mL), tetrakis(triphenylphosphine)palladium (0.51 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.7 g) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0 g, 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydrous sodium acetate in isopropanol was refluxed for 2 hours. The reaction was stirred overnight (about 16 hours) at ambient temperature. The reaction was filtered and the filter cake was washed with ether and then dispersed into water. The water insoluble solid was collected and dried to yield 21.3 g of the product, mp 209°-211° C. Concentration of the filtrate afforded an oil which on standing one week partially solidified. The resultant mixture was triturated with CH3CN and an additional 7.5 g of the product 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.S(O)(O)(=O)=O.[NH2:60][C:61]1[NH:62][CH:63]=[CH:64][N:65]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncc[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 33 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 200 mg, 0.70 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (310 mg, 0.70 mmol), N,N-diisopropylethylamine (244 μL, 1.40 mmol), and 2-aminoimidazole sulfate (140 mg, 1.05 mmol) in dry N,N-dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide (81.4 mg, 33%) as a white solid: mp 58–60° C.; EI-HRMS m/e calcd for C17H19Cl2N3O (M+) 351.0905, found 351.0901.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:35])[C@H:12]([CH2:33]O)[NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:33][C@@H:12]([C:11]([O:10][CH3:9])=[O:35])[NH:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cn1ccnc1[N+](=O)[O-])NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.8 %

Procedure:
Di-isopropylazodicarboxylate (1.3 mL, 6.6 mmol) was added dropwise to a solution of 2-nitroimidazole (1.0 g, 9 mmol), N-trityl-L-serine methyl ester (2.0 g, 6 mmol) and triphenylphosphine (1.73 g, 6.6 mmol) in THF (100 mL). The reaction was stirred at ambient temperature for approximately 5 hours The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:19) to afford the title compound (1.2 g, 44%) as a white solid.
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH:6]3[CH:7]([CH:9]4[CH2:10][CH2:11]4)[CH2:8][NH:4][CH2:5]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Fc1ccc(C2CCN(CC3CNCC3C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.2 g (0.58 mmol) of 1-allyl-3-(RS)-(4-(4-fluoro phenyl)piperidinylmethyl)-4-(SR)-(cyclopropyl)pyrrolidine and 0.02 g (0.02 mmol) of Wilkinson's catalyst [Rh(PPh)3Cl] in 10 mL of an 90% solution of CH3CN and water in a Dean-Stark apparatus was heated at reflux and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH: NH3, 90: 10:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=1[Cl:34])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (2.1 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1 by volume) to afford title compound, 1.6 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[C:10]([F:28])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:10]1[C:9]2[O:8][C:5]3[C:4]([C:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[N:11]=1)=[CH:3][C:2]([C:35]1[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=1)=[CH:7][CH:6]=3
Reactant: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(Br)cc1C21COCC(N)=N1
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(-c3cccnc3F)cc1C21COCC(N)=N1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A sealable vial was charged with 7-bromo-1-fluoro-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (200 mg, 0.444 mmol), 2-fluoropyridin-3-ylboronic acid (125 mg, 0.888 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (31.4 mg, 0.044 mmol) and potassium phosphate (283 mg, 1.332 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was purged for 1 min with nitrogen. The vial was placed in a preheated oilbath (100° C.) for start 1.5 h. The reaction mixture was cooled to rt and water and EtOAc were added to the reaction mixture. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (1-10% MeOH in DCM) to obtain 1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a beige solid (185 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26].C(C1C2NC(CC)=NC=2C=CC=1)C>CN(C=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:25][CH3:26])[CH:13]=1
Reactant: CCI
Reactant: Oc1cccc(CCc2nc3ccccc3[nH]2)c1
Agent: CCc1nc2cccc(CC)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CCc2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 69 (2.00 g, 8.39 mmol), K2CO3 (1.74 g, 12.6 mmol), and DMF (20 mL). Ethyl iodide (1.44 g, 0.74 mL, 9.23 mmol) was added, and the mixture stirred at rt overnight. Analysis by HPLC showed a mixture of approximately 1:3:2 starting material:product:diethylbenzimidazole. The solids were filtered off and rinsed with EtOAc (60 mL). The filtrate was washed with saturated aqueous NH4Cl (2×50 mL), H2O (2×50 mL), 1% aqueous LiOH (4×50 mL), and brine (25 mL). The solution was filtered through phase separation paper and concentrated to 1.85 g of a yellow oil. The crude oil was chromatographed on silica gel with the product eluting with 25-35% EtOAc in hexanes. The product fractions were concentrated in vacuo to a white solid that was collected with hexanes. The material was dried to give 855 mg of 70 as a white solid (38%). 1H NMR (60 MHz, CDCl3): δ 7.8-7.5 (m, 2H), 7.5-7.0 (m, 3H), 6.9-6.6 (m, 3H), 3.8 (qt, 2H), 3.3-2.9 (m, 4H), 1.3 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 3.6 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH3:9])[CH2:3]1.O1CCOCC1.[OH-].[K+].[C:18]1([C:24](=[O:27])[CH:25]=[CH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]([CH3:9])([CH2:26][CH2:25][C:24](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1
Reactant: C=CC(=O)c1ccccc1
Reactant: CC1CN(C)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(=O)C(C)(CCC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.8 %

Procedure:
To a stirred solution of 1,3-dimethyl-piperidin-4-one (0.1 g, 0.787 mmol) in mixture of 1,4 dioxane (2 mL) and water (0.1 mL) was added crushed KOH (44 mg, 0.787 mmol). The reaction mixture was stirred at 25° C. for 10 min. To this was added 1-phenylprop-2-en-1-one (103 mg, 0.787 mmol) dropwise. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (10 mL) and EtOAc (20 mL), the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on neutral alumina (eluted with EtOAc:Hexanes, 1:99) to afford 1,3-dimethyl-3-(3-oxo-3-phenyl-propyl)-piperidin-4-one as an oil (22 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CNCCN1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (2.35 g) was dissolved in DMF (50 ml), and piperazine was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 10% MeOH/CHCl3) to obtain tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (1.8 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 427 [M+1]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16].[Na+].[Cl-]>C(Cl)Cl.ClCl>[CH2:13]([Cl:1])[CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: O=C1CCC(=O)N1Cl
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
N-Chlorosuccinimide (0.66 g, 4.95 mmol) was dissolved in 20 ml of dry CH2Cl2 under a nitrogen atmosphere. The solution was cooled to -30° C. and 0.37 ml dimethyl sulphide (5 mmol) was added. The mixture was allowed to warm to 0° C. before it was cooled to -40° C. Then farnesol (1 g, 4.5 mmol) dissolved in 2.5 ml CH2 Cl2 was added dropwise to the mixture over a period of 3 minutes. The reaction mixture was warmed to 0.C in 1 h, at which temperature it was maintained for another hour. After 15 minutes of stirring at room temperature the reaction mixture was poured into a separatory funnel which contained 12.5 ml of cold saturated NaCl. The aqueous layer was extracted with two 10 ml portions of pentane. The organic layers were combined with an additional 10 ml of pentane and washed with two 5 ml portions of cold saturated NaCl. The organic layer was dried over MgSO4 and concentrated to dryness in vacuo. Compound (b) was thus obtained in a yield of 89%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[CH3:27][C:28](=[CH:30][CH2:31][CH2:32]/[C:33](=[CH:35]/CO)/[CH3:34])[CH3:29].CO>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][C:3]([O:2][CH2:1]/[CH:35]=[C:33](/[CH2:32][CH2:31][CH:30]=[C:28]([CH3:27])[CH3:29])\[CH3:34])=[O:23])/[CH:27]=[C:28](/[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])\[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCCCCCCCCN(CC(=O)OC)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CC(=O)OC/C=C(\C)CCC=C(C)C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N-dodecyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester (6.59 g, 20 mmol, 1 eq) in toluene (80 ml) under argon was slowly added some sodium methoxide (0.27 g, 0.005 mol, 2*0.125 eq) and geraniol (7.3 ml, 42 mmol, 2*1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction was distilled with toluene over two hours after which the reaction appeared completed by 1H NMR. Any remaining toluene was evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N-dodecyl-N-(2-geranyloxy-2-oxoethyl)glycine geranyl ester as a light brown oil (quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)=[CH:3][C:4]=1[NH:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: CC(C)Nc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.67 h
Yield: 35 %

Procedure:
5-bromo-2-chloro-N-isopropylpyridin-3-amine (127.6 mg, 0.511 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (191.5 mg, 0.602 mmol), potassium carbonate (317.8 mg, 2.299 mmol), and Pd(dppf)C12-DCM complex (42.9 mg, 0.0526 mmol) were suspended in 1,2-dimethoxyethane (2.0 ml) and water (0.5 ml). Argon was bubbled through the suspension for about 15 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under argon for 100 minutes. The reaction was cooled to room temperature, concentrated, and treated with DCM and MeOH. These organic washings were decanted, concentrated, treated with water, and filtered. The solid was washed with water and the filtrate was discarded. Solid also washed with MeOH and Et2O, but the filtrate and solid contain product. The solid and filtrate were combined, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (64.5 mg, 35% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C17H17ClN4OS 360.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:14])[CH:12]=[CH2:13]>O1CCCC1>[C:4]1([CH:3]=[CH:2][CH2:1][NH:14][CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCN
Reactant: BrCC=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCNCC=Cc1ccccc1
Reaction time: 20 h
Yield: 82 %

Procedure:
A solution of cinnamyl bromide (10 g, 50.7 mmol) in 250 mL tetrahydrofuran was added dropwise to a solution of allyl amine (38 ml, 507 mmol) in 50 mL tetrahydrofuran at 0° C. the mixture was allowed to slowly come to room temperature then stirred 20 hours. The tetrahydrofuran was removed in-vacuo, and the residue was partitioned between 500 mL of ethyl acetate and 200 ml of water. The layers were separated, the organic phase was washed with water followed by brine, then dried over sodium sulfate and concentrated to an amber oil. The oil was purified by flash chromatography on an 8×15 cm silica column, eluting with 5% methanol/chloroform followed by 10% methanol/chloroform. Obtained 7.2 g of an amber oil as product. Yield=81%. NMR (300 MHz, CDCl3) δ 7.39-7.20 (m, 5H), 6.54 (d, 1H, J=16 Hz), 6.35-6.26 (m, 1H), 6.01-5.87 (m, 1H), 5.24-5.14 (m, 2H), 3.43 (d, 2H, J=7 Hz), 3.31 (d, 2H, J=6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O>O>[CH3:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: NC=O
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: O
Product: Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
8 g of 5-methyl 2-aminobenzoic acid and 15 ml formamide was heated at 170° C. 1.5 hour. Water was added and the solid filtered to give 7.3 g of 6-methyl 4-quinazolinone as a light brown-white solid, mp-268° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][NH:34][CH2:35][CH:36](C)[CH3:37])[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CC(C)CN>>[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[N:29]=[C:30]([CH2:33][N:34]5[CH2:2][CH2:37][CH2:36][CH2:35]5)[S:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNCC(C)C)n4)cc23)CC1
Solvent: CC(C)CN
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)n4)cc23)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (74 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 6.3 mg of the title compound (50%)