Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:17]=1)=[N:7][C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[CH:9][N:10]=2.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[C:6]3[N:17]=[C:2]([C:25]4[CH:26]=[CH:27][C:21]5[O:20][C:19]([NH2:18])=[N:23][C:22]=5[CH:24]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Clc1ccc2ncc(N3CCOCC3)nc2n1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
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: Nc1nc2cc(-c3ccc4ncc(N5CCOCC5)nc4n3)ccc2o1
Yield: 71.8 %

Procedure:
A mixture of 6-chloro-3-morpholinopyrido[2,3-b]pyrazine (E-29) (100 mg, 0.4 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (108 mg, 0.6 mmol, 1.5 eq), Pd(PPh3)4 (50 mg, 0.04 mmol, 0.1 eq), and Na2CO3 (0.22 g, 2.0 mmol, 5.0 eq),) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (5 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux temperature for 2 h. The reaction was complete based on TLC analysis. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (60:1:0.02 MeOH-DCM-NH3.H20) to afford 5-(3-morpholinopyrido[2,3-b]pyrazin-6-yl)benzo[d]oxazol-2-amine (2) (100 mg, 72% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.26 (m, 1H), 8.06 (m, 2H), 7.92 (m, 1H), 7.55 (bs, 2H), 7.47 (m, 1H), 3.82 (m, 8H); ESI-MS m/z: 349.14 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:13]([C:14](=O)[C:15]2SC=CC=2)=[CH:12][C:5]2CC(C(O)=O)O[C:4]=2[C:3]=1Cl.C(#[N:24])C>>[CH3:15][CH:14]([NH2:24])[C:13]1[CH:12]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Product: CC(N)c1ccccc1

Procedure:
By following substantially the procedure described in step A, the partially resolved 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylic acid (12.0 g., 0.035 mole); (obtained from the acetonitrile mother liquor of step A) and (+)-α-methylbenzylamine (4.3 g., 0.035 mole) are mixed in acetonitrile (1000 ml.). The resultant salt (14.5 g.) was thrice recrystallized from a minimum volume of acetonitrile and ethanol (10:1) to obtain 9.4 g. of the salt of the pure (-)-enantiomer which is converted to the acid by treatment of the salt with dilute hydrochloric acid and ether.
Reaction SMILES: C(O[CH2:6][CH2:7][O:8][CH2:9][CH:10]1[O:12][CH2:11]1)C1OC1>[OH-].[Na+]>[CH2:9]([O:8][CH:7]([O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[CH2:6][CH2:7][CH3:6])[CH:10]1[O:12][CH2:11]1
Reactant: C(COCC1CO1)OCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(OCC1CO1)OCC1CO1

Procedure:
Gels comprising agarose and ethyleneglycol diglycidylether prepared at different polymer/cross-linker ratios. A series of gel comprising 1% agarose polymer in 0.1M NaOH and 0.05, 0.1, 0.2, 0.4 and 0.6 ml of ethyleneglycol diglycidylether in 10 ml was prepared by incubation at room temperature for 4 days. Electrophoresis showed reduced migration distances with increasing cross-linker concentration. Resolution was inferior to that obtained with butanediol diglycidylether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][OH:13])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 110.4 %

Procedure:
A solution of 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.40 g) and triethylamine (2.07 g) in methylene chloride (25 ml) was cooled to 0° C. and treated with methanesulfonyl chloride (1.883 g). After being stirred for 1 hour at 0°-4° C., the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (50 ml). The separated organic layer was washed with 0.5N hydrochloric acid (50 ml), water (50 ml), aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml) successively, and dried over magnesium sulfate. The evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (3.742 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].[CH:15]1([CH2:20][NH:21][CH2:22][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][N:21]([CH2:22][CH3:23])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Reactant: CCNCC1CCCC1
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 100 °C
Reaction time: 8 h
Yield: 178.3 %

Procedure:
6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N-(cyclopentylmethyl)-N-ethylamine (11.70 g, 92.0 mmol) synthesized by the method described in International Patent Publication WO2006/073973 were mixed, and the mixture was stirred at 100° C. for 8 hours in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to obtain 6-[(cyclopentylmethyl)(ethyl)amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (9.96 g, 99%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C>ClCCCl>[CH2:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:19][CH:20]=1)[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCc1ccccc1
Reactant: Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(NCCc2ccccc2)cc1

Procedure:
A solution of 4-amino-N-quinolin-3-yl-benzamide (1.0 g, 3.8 mmol), phenylacetaldehyde (0.49 mL, 4.18 mmol), tetramethylammonium triacetoxyborohydride (2.0 g, 7.60 mmol) and acetic acid (a catalytic amount) in 1,2-dichloroethane (40 mL) was heated at reflux for approximately 18 hours. The resultant solution was cooled to room temperature and washed with a saturated solution of aqueous sodium bicarbonate. The solution was applied to a flash silica gel column, and the product was eluted with ethyl acetate (40% to 75%) in hexane to give the product, 0.67 g (48%), as a colorless solid. MS: m/z 368 (MH+). 1H NMR (DMSO-d6): δ 2.88 (t, 2 H), 3.35 (t, 2 H), 6.51 (br t, 1 H), 6.7 (d, 2 H), 7.20-7.27 (m, 1 H), 7.30-7.33 (m, 4 H), 7.55-7.67 (m, 2 H), 7.87 (d, 2 H), 7.95 (m, 2 H), 8.82 (d, J=2 Hz, 1 H), 9.15 (d, J=2 Hz, 1H) and 10.25 (s, 1 H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)(C)C>[C:7]1([CH:6]2[NH:3][N:2]=[CH:4][CH2:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NN
Solvent: CC(C)(C)O
Solvent: O
Product: C1=NNC(c2ccccc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (9.2 mL) was added to a solution of cinnamaldehyde (10.0 g) in t-BuOH (20 mL). The mixture was refluxed overnight, followed by concentration under reduced pressure. Water was added to the residue, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. This gave 10.46 g of a yellow oil containing 85% of the desired product, which was used in subsequent steps without further purification. 1H NMR (200 MHz, CDCl3) δ 2.61-2.80 (m, 1H), 3.04-3.23 (m, 1H), 4.72 (dd, J=8 and 10 Hz, 1H), 5.60-6.10 (br s, 1H), 6.77-6.87 (m, 1H), 7.18-7.47 (m, 5H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[O:15])=[CH:9][CH:8]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:14](=[O:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([S:6][CH3:5])=[CH:8][CH:9]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: CSc1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of fluorobenzene (181 mL) and aluminum chloride (18.5 g, 139 mmol) was treated with a solution of 4-methylthiophenyl acetic chloride (21.9 g, 120 mmol) in 37 mL of fluorobenzene. When the addition was completed, the mixture was stirred at 50° C. for 3 h. The reaction mixture was then poured into ice water and stirred for 1 h. It was extracted with chloroform and washed with 5% aqueous sodium bicarbonate solution and with brine. The organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated in vacuum to give 15.6 g (55%) of the desired compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1c2cccnc2c(Br)cn1Cc1ccccc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2cccnc12
Temperature: 95 °C
Yield: 66.2 %

Procedure:
A mixture of 6-benzyl-8-bromo-1,6-naphthyridin-5(6H)-one (0.260 g, 0.82 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.174 g, 1.24 mmol) and Na2CO3 (0.262 g, 2.47 mmol) in toluene (25 mL), ethanol (15 mL) and water (5 mL) was degassed. Pd(PPh3)4 (0.095 g, 0.08 mmol) was then added and the reaction heated at 95° C. for 17 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 ethyl acetate/methanol) to give 6-benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one (0.180 g, 66%) as a white solid: mp 192-195° C.; 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J=4.5, 1.9 Hz, 1H), 8.78 (dd, J=8.0, 1.9 Hz, 1H), 7.47 (dd, J=8.0, 4.5 Hz, 1H), 7.30-7.41 (m, 5H), 7.20 (s, 1H), 5.27 (s, 2H), 2.25 (s, 3H), 2.11 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([CH3:26])([OH:25])[CH3:24])[C:20]([CH2:27][OH:28])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:28][CH2:27][C:20]1[N:21]([CH2:22][C:23]([OH:25])([CH3:24])[CH3:26])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)Cn1c(CO)nc2cnc3cc(OCc4ccccc4)ccc3c21
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-[7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (39.0 g, 0.133 mol), pyridine (390 mL), and acetic anhydride (195 mL) was heated at 35±5° C. for one hour in a reaction flask fitted with a calcium chloride drying tube. The reaction mixture was poured into a mixture of ice (2.5 kg) and deionized water and stirred for approximately 15 minutes. A precipitate formed and was isolated by filtration, washed with deionized water (500 mL), and dried under vacuum at 50° C. to provide 41.8 g of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36]C(=O)C)[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:41][S:42](N[C@H](CC1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)(=[O:44])=[O:43]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 90 %

Procedure:
Using the procedure described in example 97f 0.140 g of 1-(2-(R)-methanesulfonylamino-3-phenyl-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.180 g (90%) of the title compound. (+)-APCI-MS: 496 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([OH:9])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][C:3]([C:2]([F:10])([F:11])[F:1])([OH:9])[CH3:8]
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC(C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid (1.81 g, 10.0 mmol) in methanol (10 ml) was added (trimethylsilyl)diazomethane (10 ml), dropwise. The reaction was then stirred at room temperature for 4 h. Removal of the solvent afforded the crude 3-(trifluoromethyl)-3-hydroxybutyric acid methyl ester as a yellow oil (1.92 g, 100%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH:5]1[CH3:18])(=[O:3])[CH3:2].[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCBr)C(C)N2C(C)=O
Reactant: C1=C(c2ccccc2)CCNC1
Product: COc1ccc2c(c1)C(CCN1CC=C(c3ccccc3)CC1)C(C)N2C(C)=O

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)-5-methoxy-2-methylindoline with 1,2,3,6-tetrahydro-4-phenylpyridine gives white crystals, m.p. 113°-115°C., after recrystallization from dilute methanol.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1.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>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:11]=[C:10]2[CH2:12][CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1ccc2nc(Cl)cc(CCNC(=O)C(F)(F)F)c2c1
Reactant: OB(O)Oc1ccccc1
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: O
Solvent: c1ccccc1
Product: COc1ccc2nc(-c3ccccc3)cc(CCNC(=O)C(F)(F)F)c2c1
Yield: 91713 %

Procedure:
A solution of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]-2,2,2-trifluoroacetamide (0.5 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and phenylboric acid (0.2 g, 1.65 mmol) in benzene (4.2 ml) was mixed with an aqueous solution (1.9 ml) of sodium carbonate (2 mol). This reaction mixture was heated under reflux in an atmosphere of argon for 64 hours. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:6) to obtain the title compound (515 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:17].Cl>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OC[C@H]1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: BrC[C@H]1CCCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Charge (R)-(1-benzylpiperidin-2-yl)methanol (30.0 g, 0.146 mol, ˜1.0 eq., crude) in 350 mL benzene and add a solution of phosphorus tribromide (20.6 mL, 0.219 mol, 1.5 eq) in benzene at 0° C. under nitrogen atmosphere. Heat the reaction mass at 70° C. for 16 h. After completion of reaction, quench the reaction with saturated solution of sodium carbonate (100 mL) and extract the compound in EA (3×100 mL). Wash the organic layer with brine and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and dissolve the solid residue in diethyl ether. Filter the dissolved portion and add slowly HCl (1.2 eq, 2 N in diethyl ether) and stir for 30 minutes at RT. Filter the precipitated salt and wash with EA followed by hexane. Dry under high vacuum to get 13.2 g of (R)-1-benzyl-2-(bromomethyl)piperidine as hydrochloride salt. MS(ES): m/z=268, 270 (M+H).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: C1CCNCC1
Product: CC(C)(CN1CCCCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with piperidine to provide the title compound: C13 NMR (100 MHz, CDCl3) 23.8, 25.6, 26.6, 57.0, 60.9, 69.2, 118.3, 134.4; MS m/z 253.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[O:14]=[C:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH2:21][CH3:22])([OH:14])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH3:20]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: CCOC(=O)C(=O)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)C(O)(CC)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) was added diisopropylamine (759 mg, 7.5 mmol) under nitrogen stream, and the solution was cooled to −78° C. To this solution was added a 1.58 M n-butyl lithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at −78° C. for 5 min and at 0° C. for 15 min. A solution of lithium diisopropylamide tetrahydrofuran thus obtained above was cooled to −78° C. To the solution, a solution of 3-phenylpropionic acid ethyl ester (891 mg, 5.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 1 h, and the reaction mixture was further stirred at −78° C. for 1 h. The cold solution of the enolate thus prepared above was added dropwise via a cannula to a solution of ethyl 2-ketobutyrate (781 mg, 6.0 mmol) in anhydrous tetrahydrofuran (5 mL) having been cooled to −78° C. After stirring at −78° C. for 2 h, the reaction mixture was quenched with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 1.12 g of 3-benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester as oil in the form of a diastereomer mixture (yield: 73%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[NH:30][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O=CO
Solvent: COC(OC)OC
Product: c1ccc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)nc2c1
Yield: 30.3 %

Procedure:
N-({4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)benzene-1,2-diamine (500 mg, 1.22 mmol), trimethylorthoformate (5 ml) and formic acid (0.5 ml) were stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between aqueous sodium carbonate (50 ml) and ethyl acetate (100 ml). The layers were separated and the organic phase washed with water (50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2 to 92:8:1 by volume). The relevant fractions were evaporated and the residue taken up in diethyl ether (20 ml). The unsoluble material was filtered off and the filtrate concentrated in vacuo to provide the title compound (150 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 1.83-1.85 (m, 4H), 1.98-2.06 (m, 4H), 2.23 (d, 2H), 2.62 (s, 4H), 2.69 (t, 2H), 3.42 (t, 2H), 3.82 (d, 2H), 4.00 (t, 2H), 4.33 (s, 2H), 6.84 (d, 2H), 7.06 (d, 2H), 7.14-7.18 (m, 3H), 7.26 (s, 1H), 7.55 (d, 1H). HRMS ESI+ m/z 420.2637 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[N:14]3[C:10]([S:11][CH:12]=[N:13]3)=[N:9][C:8]=2[C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]1([C:7]2[N:14]3[C:10]([S:11][CH:12]=[N:13]3)=[N:9][C:8]=2[C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nc3scnn3c2-c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(-c2nc3scnn3c2-c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
methyl 4-(5-phenylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzoate (0.25 g, 0.77 mM) is dissolved in 25 mL DCM. To this is added DIBAL (5 eq) at RT. The reaction mixture is stirred for 20 min. The reaction mixture is diluted with DCM and the organic layer is washed with water. The organic layer is dried and concentrated to obtain the desired compound as a white solid.