Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[K+].C[O-].[K+].O>OCC(CO)O>[C:16]1(=[O:17])[O:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)CCCCCSCCCCCCCCO
Agent: C[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCC(O)CO
Product: O=C1CCCCCSCCCCCCCCO1
Temperature: 153 °C

Procedure:
22 g of crude 15-hydroxy-7-thiapentadecanoic acid (9, n=3, m=7, R=H) was treated with 0.45 ml (4.0 mmol) of 50 percent potassium hydroxide solution and byproducts were distilled off at 180° C./20-23 mbar for 1 h. Thereupon, the reaction vessel was fitted with a condenser and separator and 1.2 g (17 mmol) of potassium methylate in 300 ml of anhydrous glycerol was added to the reaction mixture. The mixture was heated to reflux at 153° C./4-6 mbar over the separator for 2 d., with 1.2 g (17 mmol) of potassium methylate again being added after 14 h. The separated glycerol was poured into 800 ml of water and the crude product was extracted twice with 500 ml of MTBE each time and once with 500 ml of n-pentane. The combined organic extracts were dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. After flash chromatography (n-pentane/MTBE, 19:1, hRf=46) on silica gel, 2.9 g (11% overall yield) of 7-thia-pentadecanolide as a colorless wax-like solid with an intensive, linear musk odor accompanied by green-mossy aspects with a threshold value of 0.2 ng/l air was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Oc1cc2cccnc2nc1-c1ccccn1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
2-Pyridin-2-yl-[1,8]naphthyridin-3-ol (9 mg), 4-chloro-6,7-dimethoxyquinoline (27 mg), and 4-dimethylaminopyridine (16 mg) were suspended in o-dichlorobenzene (1.5 ml), and the mixture was stirred at 140° C. for 48 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 12%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].Cl.[NH2:18]O>CN1CCCC1=O.CCOCC>[C:9]([C:7]1[CH:6]=[C:5]([CH3:11])[C:4]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([CH2:1][CH3:2])[CH:8]=1)#[N:18]
Reactant: CCc1cc(C=O)cc(C)c1CCC(=O)O
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1cc(C#N)cc(C)c1CCC(=O)O
Yield: 94.1 %

Procedure:
A solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-propionic acid (1.67 g, 7.58 mmol) and hydroxylamine hydrochloride (780 mg, 11.36 mmol) in 1-methyl-2-pyrrolidone was heated to 80° C. for 30 min in the microwave (300 W, active cooling during irradiation). The reaction mixture was diluted with Et2O and washed with water and brine. The org. extract was dried over Na2SO4, filtered and evaporated to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid as a beige solid (1.55 g). LC-MS: tR=0.89 min, 1H NMR (D6-DMSO): δ 12.25 (s, 1H), 7.45 (s, 2H), 2.91-2.84 (m, 2H), 2.67-2.59 (m, 2H), 2.35-2.30 (m, 5H), 1.14 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH3:9])[C:5]([OH:8])=[C:6]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Cc1c(O)ccc(Cl)c1O
Reactant: COc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2cc(Cl)c(O)c(C)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-methyl-benzene-1,3-diol (1 eq) and p-methoxy phenyl acetic acid (1 eq) in boron trifluoride diethyl etherate (8 eq) was refluxed for 5 h, whilst stirring, under nitrogen. The solution was allowed to cool to room temperature, quenched with 10% NaOAc (aq) and left to stand overnight. The resultant precipitate was filtered, washed with water and dried to give 1-(5-chloro-2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone as a solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[N:6][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[N:8][CH:9]=1)=[O:3].Cl.[OH-].[Na+]>C(O)(C)C.C(O)C>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:6]=[C:5]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:4]([C:2]([NH2:1])=[O:3])=[CH:9][N:8]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)ncc2C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
1,1-Dimethylethyl [(3R,4R)-4-({5-(aminocarbonyl)-4-[(4-methylphenyl)amino]-2-pyrimidinyl}amino)tetrahydro-2H-pyran-3-yl]carbamate (52.2 g) was added to a mixture of hydrogen chloride in isopropanol (5M, 300 ml) and ethanol (400 ml). The mixture was heated to reflux while stirring and heating continued for 24 h with vigorous stirring. The mixture was allowed to cool to room temperature, filtered, the solid washed with ethanol (100 ml) and dried in vacuo. The crude product was suspended in water (900 ml) and heated to reflux, giving a clear solution. The solution was basified with sodium hydroxide solution (2M, 300 ml) and cooled in ice. The precipitated product was collected by filtration, washed with water (2×100 ml) and the beige solid dried in the vacuum oven at 40° C. for 2 h to give 2-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-4-[(4-methylphenyl)amino]-5-pyrimidinecarboxamide as beige solid (37.8 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc(-c2ccccc2)cc2ccccc12
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 1-methyl-3-phenylisoquinoline (21 g), N-bromosuccinimide (30.6 g) and benzoyl peroxide (1 g) in carbon tetrachloride (730 cc) is brought to boiling for 48 hours. After being cooled, the mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a toluene/methanol (98:2 by volume) mixture as eluant. After crystallization in isopropyl ether, 1-bromomethyl-3-phenylisoquinoline (11 g), m.p. 84° C., is obtained.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1N=CC=C2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(O)CCCCC1>CCOC(C)=O.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:37][CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:47]4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1cccc2cccnc12
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(OC3CCCCC3)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 120 °C
Yield: 50 %

Procedure:
A 10 mL flask was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (100 mg, 0.17 mmol, copper(I) iodide (1.7 mg, 0.009 mmol), 8-hydroxyquinoline (2.5 mg, 0.017 mmol) and potassium phosphate tribasic (74 mg, 0.34 mmol) under argon atmosphere. Cyclohexanol (1.82 mL, 17.3 mmol) was added and the reaction mixture was heated at 120° C. for 24 h. The reaction mixture was allowed to reach room temperature and then diluted with EtOAc (10 mL). The slurry was filtered over a celite pad and the filtrate was evaporated under vacuum. The crude residue was purified by preparative TLC (SiO2, Hex:EtOAc, 1:1×2) to give 52 mg (50%) of 2-cyclohexyloxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide. (M+Na)+=619.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[C:17]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:6]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC1CCCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
26.6 g of finely powdered aluminium chloride are added in portions to a solution of 10 g of 6-methoxy-1,2,3,4-tetrahydro-1-naphthyl-acetic acid ethyl ester in 50 ml of absolute methylene chloride whilst stirring at 5° C, and thereafter 16.9 g of benzoyl chloride are added sufficiently slowly that the reaction solution boils gently under reflux. After completion of the addition, the reaction mixture is allowed to boil for a further 30 minutes and is then allowed to cool to room temperature, after which it is poured onto 300 g of ice. The mixture is extracted with 3 times 100 ml of methylene chloride and the organic phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 500 g of silica gel, using methylene chloride as the eluting agent, gives 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-1-naphthylacetic acid ethyl ester of boiling point 190° C/0.04 mm Hg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=O)=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C[CH2:23][N:24]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CN>CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:24][CH3:23])=[O:21])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylic acid (116 mg, 0.404 mmol) in DMF (3 mL) was added EDCl (93 mg, 0.484 mmol), HOBt (60 mg, 0.444 mmol), NMM (0.111 mL, 1.01 mmol) followed by the methylamine solution (2 M in THF, 0.303 mL, 0.606 mmol) and the mixture stirred at ambient temperature for 16 hours. The solvents were removed in vacuo and the residue azeotroped with MeOH (10 mL). The resulting yellow gum was purified directly by Biotage 25M; loaded in 2% MeOH/DCM, and eluted with 2-7% MeOH/DCM over 520 mL. Product not fully eluted so continued over another 300 mL to 10% MeOH/DCM to give a solid that was then triturated with EtOAc, filtered and dried in vacuo to yield the title compound as a yellow solid, 78 mg, 65%. 1H NMR (400 MHz, DMSO-D6) □ ppm 9.11 (1H, s) 8.68 (1H, d, J=3.54 Hz) 7.90 (1H, s) 7.81 (1H, d, J=8.34 Hz) 7.57 (1H, d, J=8.34 Hz) 7.39 (1H, d, J=6.57 Hz) 4.56 (1H, d, J=4.29 Hz) 3.79 (1H, s) 3.36-3.50 (1H, m) 2.79 (3H, d, J=4.55 Hz) 1.80-2.03 (4H, m) 1.17-1.43 (4H, m); MS (API+) for C16H20N4O2 m/z 301.2 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.[CH:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([C:10]1[S:9][CH:13]=[CH:12][C:11]=1[C:14]([OH:16])=[O:15])=[O:22]
Reactant: CC(C)CC=O
Reactant: O=C(O)c1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(=O)c1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium diisopropylamide (86 mmol) in tetrahydrofuran (30 ml) was added at 0° C. to a solution of thiophene-3-carboxylic acid (5 g) in tetrahydrofuran (50 ml). Isovaleraldehyde (4.6 ml) was added as a solution in tetrahydrofuran (30 ml) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours and then water (100 ml) was added and the tetrahydrofuran was removed in vacuo. The aqueous residue obtained was extracted with ethyl acetate and the aqueous phase added to potassium permanganate (12.3 g) and warmed to 60° C. for 1.5 hours. The mixture was filtered, allowed to cool to ambient temperature, and then acidified with dilute hydrochloric acid. The acidic aqueous mixture was extracted with ethyl acetate and the organic extract dried and evaporated to give the sub-title compound as an oil (5.3 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>O>[Br:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Br)cn2cnnc12
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cn3cnnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A 100 mL round bottom flask was charged with 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (1.11 g, 4.73 mmol), tert-butyl piperazine-1-carboxylate (2.64 g, 14.2 mmol) and THF (50 mL). The resulting mixture was stirred at room temperature for 0.5 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.62 g (89%) of the product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)C)=O)[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([NH2:33])=[CH:28][N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Cl:18][C:17]1[C:4]2[N:3]=[C:2]3[N:33]([C:29]4[CH:28]=[N:27][C:26]([N:25]([CH3:24])[CH3:34])=[CH:31][C:30]=4[CH3:32])[C:8](=[O:10])[CH2:7][N:6]3[C:5]=2[C:14]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Reactant: Cc1cc(N(C)C)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1cnc(N(C)C)cc1C
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.62 g, 4.53 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (2.06 g, 4.85 mmol), p-toluenesulfonic acid monohydrate (922.9 mg, 4.85 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 days. After cooling, the reaction mixture was diluted with water and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with 1N hydrochloric acid (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give a mixture containing the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (49.7 mg, 0.121 mmol, 2.7%).
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: C=CCC(N)(CF)C(=O)OC
Agent: O=C1NC(=O)c2cccc1c2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(CF)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of methyl 2-fluoromethyl-2-amino-4-pentenoate (2.10 g, 13 mmol) and triethylamine (3 g) in dry dichloromethane, phthaloyl dichloride (2.37 g, 11.7 mmol) is added with ice cooling. After stirring overnight, at room temperature, the solution is washed with water and 1 N HCl. Drying and removal of solvent by evaporation gives a residue, consisting mainly of the iso-phthalimide. The residue is dissolved in dry dichloromethane, two equivalents of triethylamine are added, and the mixture is refluxed overnight. Work-up as described above gives the title compound as an oil (3.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Yield: 86.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.290 g; 0.76 mmol), LHMDS 1N in THF (0.84 mL; 0.84 mmol), 1-iodopropane (0.111 mL; 1.14 mmol) in DMF (3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.281 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3cccnc3)C2=O)cc1
Yield: 93 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and pyridin-3-yl-3-boronic acid instead of phenyl boronic acid to obtain the title compound (93%).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH:10]([OH:12])[CH2:9][CH2:8][CH2:7]1)=[O:2].CCN(CC)CC.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH:10]([O:12][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CCCCC1CCCC(O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(CCCC=O)O1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
In a 25 mL round bottomed flask was placed a solution of 6-(3-formylpropyl)-2-hydroxytetrahydropyran (153 mg, 0.89 mmol), DMAP (5 mg), and Et3N (0.4 mL) in CH2Cl2 (10 mL). The solution was cooled to 0° C., and tert-butyldimethylsilyl chloride (205 mg, 1.34 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight, and then the solvent was removed under reduced pressure. Ether was added and the organic layer was washed with saturated NH4Cl twice followed by brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was submitted to column chromatography on silica gel to afford 6-(3-formylpropyl)-2-(tert-butyldimethylsiloxy)tetrahydropyran as a clear yellow oil (206 mg, 90% yield): 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.10 (s, 3H), 0.89 (s, 9H), 1.19-1.73 (m, 10H), 2.43 (m, 2H), 3.34 (t, 1H, J=5.7 Hz), 4.63 (d, 1H, J=9 Hz), 9.74 (s, 1H); 13C NMR (CDCl3) δ -4.0, 18.14, 18.41, 22.21, 25.81, 30.61, 33.83, 35.25, 43.70, 75.70, 97.26, 202.63. HRMS [CI (CH4)] calcd for C15H29O3Si: 285.1886 (M-H,)+. Found: 285.1890 (Δ-1.4 ppm).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C)C=O>[C:20]([NH:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1)(=[O:22])[CH3:21]
Reactant: NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 36.3 %

Procedure:
A suspension of 4-[2-(2-aminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride (1.0 g), acetyl chloride (230 mg) and triethylamine (1.0 g) in N,N-dimethylformamide (30 ml) was stirred with cooling on an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with chloroform:methanol =10:11. Recrystallization from a mixture of methanol, ethyl acetate and diisopropyl ether afforded 4-[2-(2-acetylaminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.33 g).