Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[CH:1]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (1.1553 g, 4.81 mmol) in ethyl acetate (10 mL) and methanol (10.00 mL) was treated with a 4M-solution hydrogen chloride in dioxane (1.669 mL, 48.07 mmol) was stirred at room temperature for 40 h under nitrogen. The reaction was incomplete so f 4M-solution hydrogen chloride in dioxane (10 mL) was added and the solution was stirred at room temperature for a further 2 h. The reaction mixture was evaporated to dryness to afford a solid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-cyclobutylpiperazine (0.571 g, 85%) as a yellow oil.
Reaction SMILES: [C:1]([CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)#[N:2].B.CO.[ClH:19]>O1CCCC1>[ClH:19].[NH2:2][CH2:1][CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(F)c(C(O)C#N)cc1OC
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c(C(O)CN)cc1OC

Procedure:
To a suspension of 3.24 g, α-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol obtained in Reference Example 1' in 20 ml tetrahydrofuran, was added dropwise 33 ml of 1M solution of borane in tetrahydrofuran with stirring in a methanol/ice bath under an argon gas atmosphere, and the resulting solution was heated under reflux for 3 hours. After cooling the reaction mixture in an ice bath, methanol was added until gas evolution was no longer observed, the resulting solution was stirred at room temperature for 1 hour, and hydrogen chloride gas was introduced until the pH fell below 1. The crystals which separated out were collected, affording 3.34 g of α-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol hydrochloride (m.p. 223°-226° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([NH:38][CH:39]3[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1.C(O)C(N)(CO)CO>CN(C=O)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([NH:38][C@@H:39]3[CH2:40][CH2:41][C@H:42]([NH:45][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:43][CH2:44]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: O=C(O)CCCCc1ccccc1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCc1ccccc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 8 h

Procedure:
31 mg (0.16 mmol) of 5-phenylvaleric acid, 112 mg (0.22 mmol) of PS-carbodiimide and 28 mg (0.18 mmol) HOBT in DMF (1 mL) were mixed for 15 min. 30 mg (0.11 mmol) of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine was added and the reaction was allowed to proceed overnight. 116 mg (0.54 mmol) of PS-trisamine was added and the reaction mixture was filtered after two hours. The solvent was evaporated and the product was purified by reverse phase HPLC to provide the titled compound. MS (ESI(+)) m/e 436 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 13.86 (brs, 1 H), 8.82 (d, 1 H), 8.72 (d, 1 H), 8.54 (d, 1 H), 7.94 (d, 1 H), 7.78 (dd, 1 H), 7.69 (d, 1 H), 7.21 (m, 5 H), 6.96 (d, 1 H), 3.89 (m, 1 H), 3.80 (m, 1 H), 2.58 (m, 2 H), 2.50 (m, 2 H), 2.16 (m, 2 H), 1.82 (m, 6 H), 1.47-1.70 (m, 6 H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[C@H:28]([CH2:44][N:45]3[CH:49]=[CH:48][N:47]=[CH:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH3:51][I:52]>O1CCCC1>[I-:52].[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[C@H:28]([CH2:44][N+:45]3[CH:49]=[CH:48][N:47]([CH3:51])[CH:46]=3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](Cn4ccnc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: CI
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[n+]4ccn(C)c4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Product: [I-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-nitrobenzyl (4R,5S,6S)-6-[(lR)-1-hydroxyethyl]-3-[(2S,4S) -2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.61 g) in tetrahydrofuran (3 ml) was added methyl iodide (2 ml) and stirred at ambient temperature for 15 hours. The mixture was concentrated under reduced pressure to give crude 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-(3-methyl-1-imidazolio)methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][NH:13][CH3:14].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cn(C)c2ccc(F)cc12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2ccc(F)cc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 39.8 %

Procedure:
According to the procedure of Example 24, except substituting 5-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.14 g, 41%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN1CCN(CCOc2ccc(CN(CC)c3cc(OC)ccc3C3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 18.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.2 mg) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33]O.C(N(CC)CC)C>CS(C)=O.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3CC(=O)O)cc2)c1
Reactant: CN(C)CCO
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a stirred solution of compound 38 (0.2 g, 0.471 mmol), 2-(dimethylamino)ethanol (0.14 mL, 1.41 mmol) and triethylamine (0.126 mL, 0.942 mmol) in DMSO (5 mL) at RT was added Pybop (0.360 g, 0.706 mmol) and the reaction mixture stirred overnight. The reaction was then diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over sodium sulphate and concentrated. The crude reaction mixture was purified by column chromatography using 3% methanol in dichloromethane to afford 39 (15 mg, 6%). LCMS: 496.25 (M+1)+; 1H NMR (CD3OD, 400 MHz) δ 8.23 (s, 1H), 8.05 (d, 1H, J=8 Hz), 8.01 (d, 1H, J=7.6 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.78 (t, 3H, J=8 Hz), 7.64 (d, 2H, J=8 Hz), 6.84 (s, 1H), 5.2 (s, 2H), 4.5 (t, 2H, J=4.8 Hz), 3.49 (d, 2H, J=4.8 Hz), 3.20 (s, 3H), 2.9 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[I-].[K+].F[C:10](F)(F)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)CCl.[CH:21]1[CH:26]=[CH:25]C=CC=1>>[CH2:11]1[CH2:12][CH2:13][CH2:16][CH2:17][CH2:18]1.[CH:11]([O:2][CH:26]([CH3:25])[CH3:21])([CH3:12])[CH3:10]
Reactant: c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [I-]
Agent: [K+]
Product: C1CCCCC1
Product: CC(C)OC(C)C
Yield: 63 %

Procedure:
The obtained intermediate 2-(4-piperidyl)-5-chloro-phthalimidine (15) (1.17 g, 0.00467 mol) was dissolved in 30 ml benzene. Potassium carbonate (1.93 g, 0.0140 mole) and potassium iodide (0.78 g, 0.00607 mole) was added whereupon 3-trifluoromethylbenzylchloride (1.18 g, 0.00607 mole) dissolved in benzene was added drop-wise at room temperature, and was then heated under reflux during three days. The inorganic salts were filtered off and the filtrate was evaporated to dryness in vacuum. The residue was re-crystallized with cyclohexane isopropylether (M.p. 115°-117° C., yield 63%).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>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[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc(I)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A mixture of (+) 3-ethynyl-3-hydroxyquinuclidine (180 mg), 4-butoxyiodobenzene (330 mg), bis(triphenylphosphine)-palladium (II) chloride (42 mg),copper (I) iodide (21 mg), triethylamine (2.5 ml) and dimethylformamide (5 ml) was stirred under argon at ambient temperature for 4 hours. The triethylamine and dimethylformamide were removed by evaporation. A solution of 2M sodium hydroxide (10 ml) was added and the mixture extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO4) and evaporated to a gum. This gum was further purified by flash column chromatography on silica gel using a mixture of 5% methanol in dichloromethane containing 1% ammonia (density, 0.88 g(cm3) as eluent, followed by crystallisation from ethyl acetate to give (+)-3-[2-(4-butoxyphenyl)ethynyl)-3-hydroxyquinuclidine (120 mg) as a solid, m.p. 115°-116° C.; microanalysis, found C, 75.4; H, 8.4; N, 4.5%; C19H25NO2 0.2H2O requires: C,75.35; H, 8.39, N, 4.63%; NMR: 0.86-0.99(3H,t), 1.2-1.5(3H,m), 1.5-1.71(3H,m), 1.72-1.97(3H,m), 2.6-2.72(4H,m), 2.75-2.85(1H,d), 3.0-3.1(1H,d), 3.9-4.01(2H,t), 5.15(1H,s), 6.85-6.95(2H,d), 7.27-7.37(2H,d); m/z 300(M+H) α=[+26.6]58921 (c=1; methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:19]([O:18][C:12](=[O:17])[C:13]([C:14](=[O:15])[CH3:16])=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccc(O)c(OC)c1)C(C)=O

Procedure:
Condensation of 3-methoxy-4-hydroxy benzaldehyde (vanillin) with ethyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[I-].[K+].[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47]Br>C1COCC1.O>[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([NH:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NC4CCCNC4)c23)cc1
Reactant: COC(=O)CCCBr
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN1CCCC(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1

Procedure:
Heat a mixture of 100 mg (0.25 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-N-piperidin-3-yl-furo[2,3-d]pyrimidin-4-amine (Example 39A), 65 μl (0.375 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of 4-bromobutyric acid methyl ester in 2 ml of THF under reflux for 1 h. After cooling, add the reaction mixture to water and extract three times with ethyl acetate. Wash the combined organic phases twice with buffer solution (pH 7) and saturated sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient), followed by chromatography on silica gel (eluent: dichloromethane→dichloromethane/methanol 50:1). After stirring the resulting product with methanol, the precipitate is filtered off with suction, washed with a little methanol and dried under high vacuum. 58 mg (46.4% of theory) of the target product are isolated.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[C:44]([CH3:50])=[CH:43][CH:42]=1>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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:50][C:44]1[C:45]2[N:46]([CH:47]=[CH:48][N:49]=2)[C:41]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:37])[CH3:38])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=2)=[CH:42][CH:43]=1
Reactant: Cc1ccc(Br)n2ccnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)sc3n2)n2ccnc12
Temperature: 150 °C
Yield: 87.5 %

Procedure:
A mixture of 2-[1-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (118 mg, 0.18 mmol), 5-bromo-8-methylimidazo[1,2-a]pyridine (45 mg, 0.21 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.035 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 244 as an off-white solid (80 mg, 89%). LCMS (Method G) RT 5.09 min; [M+H+ 508. 1H NMR (400 MHz, CHCl3-d): δ 9.22 (s, 1 H); 7.93 (d, J=7.4 Hz, 1 H); 7.75 (d, J=1.3 Hz, 1H); 7.14 (d, J=7.4 Hz, 1 H); 4.43 (m, 4 H); 3.90 (m, 4 H); 3.87 (s, 2 H); 3.10 (d, J=11.5 Hz, 2 H); 2.73 (s, 3 H); 2.23 (t, J=11.5 Hz, 2 H); 1.78 (m, 2 H); 1.55-1.41 (m, 2 H); 1.35 (m, 2 H); 1.22 (s, 6 H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CCNCC
Reactant: CN(c1ccc(OCCCCBr)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CCN(CC)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of N-[4-(4-Bromo-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide with diethylamine yielded N-[4-(4-Diethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][NH2:27])[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1.Cl.CN(C)CCCN=C=N[CH2:37][CH3:38].C(N(CC)C(C)C)(C)C.CN(C=[O:53])C>C(Cl)Cl.CC(O)=O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([CH2:26][NH:27][C:37](=[O:53])[CH3:38])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Reactant: CN(C)C=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine (100.00 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0798 g, 0.416 mmol), N,N-diisopropylethylamine (0.097 mL, 0.55 mmol), 1-hydroxbenzotriaxole Hydrate (0.0425 g, 0.277 mmol), and DMF (600 uL) in DCM (5 mL) was added AcOH (24 uL). The mixture was stirred at rt for 3 h under an atmosphere of nitrogen then diluted with DCM (20 mL), washed with saturated NaHCO3 (aq) (2×25 mL) and brine (2×25 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with DCM→2% 2M NH3 in MeOH/DCM to afford 0.02 g of the title compound. MS (ES+): m/z 403.31 [MH+]. 1H NMR (400 MHz, CDCl3): δ 1.12-1.31 (m, 3H), 1.79-1.86 (m, 2H), 1.94-1.97 (m, 2H), 2.02 (s, 3H), 2.04-2.09 (m, 2H), 2.91 (m, 1H), 3.20 (t, J=6.4 Hz, 2H), 5.51 (br, 1H), 5.66 (br, 2H), 6.79 (s, 1H), 7.10-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 9.07 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.[H-].[Na+].CN(C=O)C.BrC1C=C[C:26]2[C:31](=[O:32])[O:30][C:29](=O)NC=2C=1.IC>O>[Br:1][C:2]1[CH:14]=[C:6]2[C:5]([C:10]([OH:11])=[C:26]([C:31]([O:30][CH3:29])=[O:32])[C:8](=[O:12])[N:7]2[CH3:13])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reactant: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
7-Bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. Sodium hydride (0.47 g, 12 mmol) was added to a 3 neck 250 mL round bottom flask under nitrogen and then washed with hexanes. Once the hexanes were decanted, DMF (20.0 mL, 11 mmol) was added. The resulting mixture was cooled to 0° C. using an ice-water bath, and then 7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (2.7 g, 11 mmol) was added in one batch. After stirring at room temperature for 1 hour, iodomethane (0.70 mL, 11 mmol) was added dropwise to the yellow solution, and the reaction mixture was stirred for 16 hours. Water (50 mL) was added, and the resulting precipitate that formed was collected via filtration. The solid was washed with additional water (100 mL), followed by ether (100 mL). Drying in a vacuum oven overnight at 50° C. provided the title compound as an off-white solid (2.1 g, 74% yield).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH2:15][CH2:29][CH:28]=[CH2:27])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
20 mmol of 1-(4-(phenyl thio)phenyl)ethanone was dissolved in 100 mL of THF, and cooled at −78° C. To this, 22 mmol of lithium hexamethyldisilazide was added dropwise and stirred for 1 hour. Further, 20 mL of THF solution of 20 mmol of allyl bromide was added dropwise over 10 minutes and a solution temperature was slowly set back to room temperature, and further stirred for 1 hour. Then quenching was carried out with 100 mL of water. An organic layer was extracted with ethylacetate, and washed with an aqueous sodium chloride. Thereafter, the organic layer was concentrated. The thus-obtained mixture was purified by column chromatography (hexane/ethyl acetate=10/1). Thereby, 1-(4-(phenyl thio)phenyl)pent-4-en-1-one having the following structure was obtained with a yield of 52%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]([O:9]C)=[O:8])=[N:3]1.CO.[OH-].[K+]>O>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]([OH:9])=[O:8])=[N:3]1
Reactant: COC(=O)c1ncn(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cnc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate (280 mg) and methanol (1 ml) were added to potassium hydroxide (145 mg) in water (1 ml). The reaction was stirred for 3 h at RT. The solvent was evaporated and the residue was loaded onto an aminopropyl SPE cartridge (5 g) in DMF. The cartridge was washed with 10% methanol in DCM (3×15 ml), followed by 30% acetic acid in methanol. The appropriate fractions were combined, the solvent was evaporated and the residue dried at 50° C. under vacuum to give title compound (180 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10](OCC)(OCC)([O:13][CH2:14][CH3:15])[CH2:11][CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]([O:13][CH2:14][CH3:15])[CH2:11][CH3:12])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(CC)(OCC)OCC
Product: CCOC(CC)=Nc1cc(Cl)cc(Cl)c1

Procedure:
This is prepared by the reaction of equimolar amounts of 3,5-dichloroaniline and triethyl orthopropionate, as generally described in Chemical Reviews 61, 185 (1961), to give an 86% weight yield of product distilling at 89° C./0.15 mm.