Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](C1NC=CN=1)(C1NC=CN=1)=[S:9].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl.C(OCC)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8]([N:23]1[CH2:24][CH2:25][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]1)=[S:9]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=S)Nc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
Part A: To a solution of 2-aminopyridine (9.41 g, 100 mmol) in methylene chloride (200 mL) at 25° C. was added thiocarbonyl diimidazole (18.75 g, 100 mmol), and the resulting mixture was stirred at 25° C. for 20 h. To the reaction mixture then was added tert-butyl piperazine-1-carboxylate (18.60 g, 100 mmol), and the resulting mixture was stirred at 25° C. for another 24 h. The mixture was diluted with diethyl ether, washed with water (×3) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% diethyl ether/methylene chloride) to afford tert-butyl 4-(pyridin-2-ylcarbamothioyl)piperazine-1-carboxylate (13.60 g) as a colorless solid, following crystallization from a mixture of 1-chlorobutane/hexane; 1H NMR (300 MHz, CDCl3) δ 7.97 (m, 1H), 7.64 (m, 2H), 6.88 (m, 1H), 4.00 (m, 4H), 3.51 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([OH:33])=[O:32])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=12.[CH2:34](OC(Cl)=O)[CH:35]([CH3:37])[CH3:36].[BH4-].[Na+]>C1COCC1.Cl>[Cl:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[N:22]=[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 1 h
Yield: 6.2 %

Procedure:
Triethylamine (535 μL, 3.8 mmol) was added to 2-(4-chloro-3,5-diphenyl-1Hpyrazolo[3,4-c]pyridazin-1-yl)acetic acid (700 mg, 1.92 mmol) in THF (20 mL) at 0° C., followed by the addition of isobutylchloroformate (342 mg, 2.9 mmol). The reaction mixture was stirred for 1 h. Sodium borohydride (220 mg, 5.8 mmol) was then added portionwise and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with 0.5 M HCl and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried (phase separator), and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:0), to provide Compound 12 as a solid (50 mg).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:15][CH3:16])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH3:16][O:15][C:10](=[O:14])[CH2:11][CH:12]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])[CH3:13]
Reactant: CNCc1ccccc1
Reactant: C/C=C/C(=O)OC
Product: COC(=O)CC(C)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.4 %

Procedure:
Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat to methyl crotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solution was stirred at room temperature for 72 h. The excess crotonic ester was removed in vacuo to yield the desired product (40.3 g, ˜100%) which was used without further purification; MS, m/z 222=M+1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:26][C:20]3[N:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O.C(O)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:20]3[N:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]=3[CH:18]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
After adding 0.381 g (1.3 equivalents) of sodium hydride (60% dispersion, Aldrich) to a solution of 2.46 g of the 6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-3 in dimethylformamide (30 ml), the mixture was stirred at room temperature for 40 minutes, 1.68 ml (1.3 equivalents) of 2-(chloromethoxy)ethyltrimethylsilane was added, the mixture was stirred at room temperature overnight, and then 20 ml of water and 1 ml of acetic acid were added and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (ethyl acetate) to obtain 2.83 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[CH3:2][C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:3]
Reactant: CC(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)NC1CNc2ccccc2C1

Procedure:
300 mg of the 3-(acetylamino)quinoline (Rf (D)=0.43) obtained by a single recrystallization from ethyl acetate/hexane are hydrogenated in 10 ml of ethanol in the presence of 60 mg of palladium-on-charcoal (10% of Pd) at 50° C. under normal pressure for 20 h. After the reaction mixture has been filtered over Celite® 545 and the crude product has been purified by chromatography over 25 g of silica gel (mobile phase P), 3(R,S)-methylcarbonylamino-1,2,3,4-tetrahydroquinoline is obtained: Rf (P)=0.49; MS: (M)+ =190.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF (5 mL) was added sodium hydride (85 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added ethyl bromoacetate (363 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-30% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 102.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (86.2% yield) of the titled compound. MS: m/z=603.2 (M+1).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])#[N:21]>C(O)C>[CH2:26]([NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C=CC=O)ccc1O
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccccc2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)benzylamide (34 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (50 mg, 75%). The product gave the following analytical data:
Reaction SMILES: [Cl-].C[O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CC[CH2:27][CH3:28].[C:29]([Si:33]([CH3:51])([CH3:50])[O:34][C@H:35]1[CH2:44][CH2:43][CH2:42][C@@:41]2([CH3:45])[C@H:36]1[CH2:37][CH2:38][CH:39]=[C:40]2[C@H:46]([CH3:49])C=O)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([Si:33]([CH3:51])([CH3:50])[O:34][C@H:35]1[CH2:44][CH2:43][CH2:42][C@@:41]2([CH3:45])[C@H:36]1[CH2:37][CH2:38][CH:39]=[C:40]2[C@H:46]([CH3:49])[CH2:28][CH:27]=[O:3])([CH3:31])([CH3:32])[CH3:30]
Reactant: [Li]CCCC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](C=O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@H](CC=O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 0.75 h

Procedure:
A suspension of 7.17 g of (methoxymethyl)triphenylphosphonium chloride in 50 ml of abs. THF was cooled to -20° and treated with 12.1 ml of nBuLi (1.55 M, hexane). 30 minutes later, the deep red ylide solution was cooled down to -78° and 3.525 g of (S)-2-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octa-hydronaphthalen-1-yl]-propionaldehyde dissolved in 21 ml of abs. THF, were slowly added and the reaction mixture kept for 45 minutes at that temperature. Partition between hexane and EtOH/H2O=8/2, washing of the upper layer with EtOH/H2O=8/2, drying over magnesium sulfate, evaporating i. V. and flash chromatography (SiO2, hexane/AcOEt=99/1) generated 2.590 g of an enolether intermediate as E/Z-mixture. This enolether was hydrolyzed by dissolving it in 30 ml of THF containing 10 ml of 25% aq. HCl. After 90 minutes at ambient temperature, the reaction mixture was poured onto crushed ice, extracted with ether, washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=98/2) yielded 2.424 g of (R)-3-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-yl]-butyraldehyde as yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH3:15][O:16][NH2:17].C(O)C>N1C=CC=CC=1>[CH3:15][O:16][N:17]=[C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: CON
Reactant: Cc1c(Br)ccc2c1C(=O)CCS2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCSc2ccc(Br)c(C)c21
Yield: 93.2 %

Procedure:
3.0 Grams (12 mmol) of 5-methyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvents were distilled off under reduced pressure, 50 ml of 5% hydrochloric acid was added, and a formed solid was recovered by filtration, washed with water and then dried to give 3.2 g (yield 93%) of 4-methoxyimino-5-methyl-6-bromothiochroman. (2) 1.1 Grams (46 mmol) of magnesium was dispersed in 10 ml of THF, and 2.2 g (20 mmol) of ethyl bromide was dropwise added under nitrogen current. The mixture was allowed to react for 10 minutes, and then a THF solution of 2.9 g (10 mmol) of the 4-methoxyimino-5-methyl-6-bromothiochroman obtained in the above (1) was gradually added at room temperature. The mixture was refluxed for 3 hours and then cooled to room temperature, and carbon dioxide gas was bubbled in for 1 hour. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ether. An ether layer was extracted with a 5% potassium carbonate aqueous solution, and an aqueous layer was neutralized with concentrated hydrochloric acid. The neutralization product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. The washed extract was dried over sodium sulfate, and then the solvent was distilled off to give 1.6 g (yield 63%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid.
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[C:12]1([O:22][CH2:23][C:24]([OH:26])=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.CN>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:24](=[O:26])[CH2:23][O:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)COc1cccc2ccccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)COc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (14.2 g, 74.2 mmol) was added to a solution of (1-naphthyloxy)acetic acid (15.0 g, 74.2 mmol) and 1-hydroxybenzotriazole (10.0 g, 74.2 mmol) in DCM (100 ml) and N,N-dimethylformamide (100 ml). The reaction mixture was stirred for 30 min at this temperature. A 8.0 M solution of methylamine (185 ml, 1.4 mol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (300 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (2×300 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane as eluent, to give 17.44 g of N-methyl-2-(1-naphthyloxy)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18]([OH:19])=[CH:13][CH:12]=[N:11]2
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc(OC)c2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.23 g, 30.0 mmol) in diphenyl ether was heated at 200° C. for 20 min., then cooled down to RT. Hexane was added and the mixture was stirred at RT for 30 mins. The solvent was removed to furnish 5,7-dimethoxyquinolin-4-ol as a light brown solid, which was used for next step without further purification. MS Found m/z=[M+H]+. 206.2 Calc'd for C11H11NO3: 205.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][C@H:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[C@H:46]([NH:45][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:20])=[N:12][C:11]=13)=[O:19])[CH2:47]2
Reactant: Cc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (51 mg, 0.26 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.11 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide (16 mg, 19%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.47 (d, J=7.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.20-8.10 (m, 2H), 7.83 (d, J=1.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.45-4.35 (m, 1H), 3.93 (s, 3H), 3.55-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.75 (m, 1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 396 (M+H); HPLC 99.0% (AUC), tR=14.57 min.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-:11].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:13]([NH:10][C:8](=[N:9][C:13](=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:7][CH3:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=N)N
Reactant: [OH-]
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=NC(=O)c1ccccc1)NC(=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
O-Methylisourea hydrogen sulfate (17.2 g, 0.1 mol) was suspended in water (100 mL) containing NaOH (20 g, 0.5 mol) and the mixture cooled to 5-10° C. The mixture was stirred vigorously as benzoyl chloride (35.15 g, 0.25 mol) was added at such a rate that the reaction temperature did not rise above 15° C. After the last addition, the mixture was stirred for 3 h and the resulting solid collected by vacuum filtration to give N,N′-dibenzoylcarbamimidoic acid, methyl ester.
Reaction SMILES: BrCCCC[C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[CH3:17][NH:18][CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+].[C:28]1([CH3:34])[CH:33]=[CH:32]C=CC=1>>[CH3:17][N:18]([CH2:19][C:20]#[CH:21])[CH2:32][CH2:33][CH2:28][CH2:34][N:11]1[C:12](=[O:13])[C:7]2[C:8](=[CH:14][CH:15]=[CH:16][CH:6]=2)[C:9]1=[O:10]
Reactant: Cc1ccccc1
Reactant: C#CCNC
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN(C)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of bromobutylphthalimide (31.98 g, 0.113 mol), N-methyl-N-propargyl amine (8.19 g, 10 ml, 0.119 mol), potassium carbonate (23.39 g, 0.170 mol), and toluene (140 ml) was refluxed for 8 hours followed by overnight stirring at ambient temperature. The insoluble material was filtered off and washed with toluene. The flitrate and washings are evaporated to dryness, and the residue is purified by flash chromatography (Merck 60 silica gel, step gradient from 0-5% methanol in CH2Cl2). The pure fractions were combined, evaporated and dried in vacuo to yield the title compound, which was used as such in the next step.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CN(C=O)C.I[CH2:19][C:20]1([CH3:32])[CH2:24][C:23]2[C:25]([CH3:31])=[CH:26][C:27]([CH3:30])=[C:28]([CH3:29])[C:22]=2[O:21]1.O>C(OCC)(=O)C>[CH3:19][C:20]1([CH2:32][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:24][C:23]2[C:25]([CH3:31])=[CH:26][C:27]([CH3:30])=[C:28]([CH3:29])[C:22]=2[O:21]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1C)OC(C)(CN1C(=O)c3ccccc3C1=O)C2
Temperature: 140 °C
Reaction time: 15 h
Yield: 68.9 %

Procedure:
Potassium phthalimide (702 mg, 3.79 mmol) was added to a solution of DMF (10 mL) containing 2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (1.00 g, 3.16 mmol) synthesized in Reference Example 126, and the mixture was stirred at 140° C. for 15 hours. After that, the reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-75:25) to give 730 mg of the title compound (yield: 69%)
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>>[F:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:6]3[C:7]4[C:12](=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=4)[CH:13]=[C:5]3[C:3]([OH:2])=[O:4])[C:19]=2[CH:26]=1
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: Fc1ccc2scc(CBr)c2c1
Product: COc1cccc2c1cc(C(=O)O)n2Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as yellow solid. MS: 354.0 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:6][C:5](=[O:7])[NH:4][CH2:3][C:2]1=[O:8].[C:9]([O-:12])(=O)[CH3:10].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:1]1[CH2:6][C:5](=[O:7])[N:4]([C:9](=[O:12])[CH3:10])[CH2:3][C:2]1=[O:8])(=[O:16])[CH3:15]
Reactant: O=C1CNC(=O)CN1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Temperature: 110 °C
Yield: 61 %

Procedure:
25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol) in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1.