Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[K+]>CCOCC>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:20][CH:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 5.3 mL, 10.53 mmol) in dry Et2O (10 mL), commercially available 4-cyclohexylbenzoic acid (0.5 g, 2.45 mmol) in dry Et2O (5.0 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.45 mL), 3.0 M KOH solution (0.45 mL) and H2O (2.0 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.46 g, quant.), which was used in the next step without any further purification. 1H NMR (CDCl3): δ 8.05-7.94 (m, 2H), 7.35-7.23 (m, 2H), 4.39 (q, 2H, J=7.12 Hz), 2.59 (tt, 1H J=11.41, 3.27 Hz), 1.97-1.73 (m, 5H), 1.53-1.34 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:15]([C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:13][C@@:11]1([CH3:12])[C@H:7]3[CH2:8][CH2:9][C@@H:10]1[OH:20]>CC(C)=O.S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[F:1][C:2]1[C:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:15]([C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:13][C@@:11]1([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]1=[O:20]
Reactant: C[C@]12CC[C@@H]3c4cccc(F)c4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4cccc(F)c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To a solution of 4-fluoroestra-1,3,5(10)-trien-17β-ol (100 mg, 0.36 mmol) in 1.5 ml of acetone at 0° C. was added, dropwise with stirring, a solution of 95 ml of 8N chromium trioxide in 8N sulfuric acid. After approximately 5 min. the reaction mixture was poured into 75 ml of ice water and the solids were collected. The filter cake was stirred with methanol. The inorganic salts were removed and the filtrate was evaporated to dryness to give the crude product, 4-fluoroestra-1,3,5-(10)-trien-17-one as a tan solid. The latter was crystallized from ether-petroleum ether (30°-60°) as a colorless solid (60 mg, 61% yield), mp 139°-141° C. Ir (KBr)cm-1 1724 (C17C=O), 1230 (aryl fluoride); 1H NMR δ 7.21-6.81 (m, 3, H1, H2, H3 aromatic) 2.91-1.54 (m, 15), 0.92 (s, 3, C18CH3).
Reaction SMILES: [NH2:1][C:2](=[O:18])[C@H:3]([NH:10]C(=O)OC(C)(C)C)[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:10][C@H:3]([CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:2]([NH2:1])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)Cc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solid (R)-tert-butyl 1-amino-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (448 mg) was dissolved in dioxane (4 mL), aq. 6N HCl (5 mL) was added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo to give (R)-2-amino-3-(thiophen-2-yl)propanamide hydrochloride as a solid (337 mg).
Reaction SMILES: [CH2:1]=[C:2]([CH2:7][C:8]([O:10]C)=O)[C:3]([O:5][CH3:6])=[O:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>CO>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:8](=[O:10])[CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:1]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of dimethyl 2-methylidenebutanedioate (47.5 g, 300 mmol) and 1-(4-methoxyphenyl)methanamine (41.2 g, 300 mmol) in 400 mL of MeOH was stirred at room temperature overnight. The resulting reaction mixture was concentrated in vacuo to remove methanol. The residual brown oil was stirred with 40 mL of EtOAc and 40 mL of PE vigorously. The precipitate was collected by filtration and washed with PE (40 mL×2) to afford methyl 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (68.0 g, yield: 86.1%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.NC(CC)(CO)CO.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Agent: CCC(N)(CO)CO
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Oc2ccc3nc(Cl)ncc3c2)c(F)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Compound (1G) (250 mg, 0.85 mmol) and 2-amino-2-ethyl-1,3-propanediol (298 mg, 2.5 mmol) in NMP (0.25 mL) were stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, CH2Cl2: MeOH, 95:5) to afford 150 mg of the above-titled compound (Example 1). Mp=110-112.9° C. MW (M+H)+=376.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:12]([NH:15][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:13][CH3:14]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCCNC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (2 g, 12.8 mmol), and propylamine (1.05 mL, 12.8 mmol), and sodium triacetoxyborohydride (8 g, 38 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:31]=1.CI.[NH4+].[Cl-]>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]([CH3:2])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCc1ccccc1
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
2.0 M LDA in heptane/THF/ethylbenzene (6.0 mL, 12 mmol) was slowly added to a solution of ethyl (4-bromophenyl)acetate (2.43 g, 10.0 mmol) in THF (20 mL) at −78° C. and then the mixture was stirred for 30 min. Methyl iodide (0.93 mL, 15 mmol) was added at −78° C. and then the reaction was stirred for an additional 30 min. Saturated NH4Cl aq. was added to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-10%) to afford the desired product (2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (3-bromo-4-methoxy-phenyl)-acetic acid (5.226 g, 21.32 mmol) in MeOH (52 mL) was added thionyl chloride (3.1 mL, 42.65 mmol), and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and then diluted with CH2Cl2 and aqueous 1N NaOH. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][CH:11]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:12]([O:14]CC1C=CC=CC=1)=[O:13]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH:11]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:12]([OH:14])=[O:13]
Reactant: Nc1ccccc1C=CCC(C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCCC(C(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of benzyl 5-(2-aminophenyl)-2-phthalimido-4-penteneoate (10.7 g) in ethanol (500 ml) is hydrogenated at atmospheric pressure with 10% palladium on charcoal (2 g) until uptake ceases. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The residue is triturated with ethyl acetate to give 5-(2-aminophenyl)-2-phthalimidopentanoic acid, mp 258°-260°, used without further purification in the next synthetic step.
Reaction SMILES: CCN(C(C)C)C(C)C.FC1C(C)=NC2C(N=1)=C([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)C=CC=2.CC1(N)CCCC1>CS(C)=O>[NH:29]1[C:28]2[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=2[CH:22]=[CH:21]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: CC1(N)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 1-methylcyclopentanamine (40.2 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-(1-methylcyclopentyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.21 (s, 1H), 7.83-7.91 (m, 1H), 7.53-7.61 (m, 1H), 7.30-7.39 (m, 1H), 7.07 (s, 1H), 6.95 (s, 1H), 6.18 (s, 1H), 3.40-3.48 (m, 2H), 2.85-2.94 (m, 2H), 2.55 (s, 3H), 2.37-2.48 (m, 2H), 1.67-1.85 (m, 6H), 1.64 (s, 3H). m/z (ESI, +ve) 376.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[C:11]1([C:17]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:9]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
The detailed preparation procedure is as follows: 3,6-dibromo-o-phenylene diamine (1.0 g, 3.7 mmol) was added to a solution of compound benzil (0.39 g, 1.84 mmol) in acetic acid (20 mL) at 120□, then the mixture was mixed uniformly. After refluxed for 12 hours, the fluid reactant was poured into water, and neutralized with sodium bicarbonate until neutral, then extracted with chloroform and washed with saturated brine, dried over anhydrous sodium sulfate, then it was vacuum evaporated to remove the solvent, and the resulting crude product was purified by column chromatography to give a white solid, and then it was purified by recrystallization from chloroform/n-hexane to give a white solid powder. The test result is: MS (EI) m/z: 440(M+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[F:16][C:17]1[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[CH2:1]([O:26][C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In N,N-dimethylformamide (70 mL), 3-fluoro-4-nitrophenol was dissolved, and benzyl bromide (6.53 g, 38.2 mmol) and potassium carbonate (6.59 g, 47.7 mmol) were added thereto and the mixture was stirred at room temperature for 18 hr. Water (100 mL) was added to the reaction mixture and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic layer was washed with 1 mol/L hydrochloric acid and brine. The mixture was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting solid was washed with hexane to afford 4-(benzyloxy)-2-fluoro-1-nitrobenzene as a yellow solid (7.47 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:2]([O:19][C:12]1[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([F:9])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Temperature: 55 °C

Procedure:
(Bromomethyl)benzene (10.9 g, 63.7 mmol) and 3-fluoro-4-nitrophenol (10 g, 63.7 mmol) were added to 150 mL acetone followed by potassium carbonate (8.8 g, 63.7 mmol) and sodium iodide (9.54 g, 63.7 mmol). The reaction mixture was heated at 55° C. overnight. The resulting mixture was filtered and concentrated. The crude material was recrystallized in ethyl acetate/hexane to give the title compound. MS (DCI+) m/z 264.9 (M+NH4)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][C:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:35])[N:17]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
3.1 g 4-(2-(3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 20 mL dichlormethane and 20 mL trifluoracetic acid was added. The reaction was stirred for 24 h at RT and the solvent was evaporated. Potassium carbonate solution (10%) was added to the residue, the precipate was filtered and crystallized from a mixture of acetonitrile and isopropylether to yield 2.3 g of the desired compound. (M+H)+: 384
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCCCC3)c21

Procedure:
Using Method C above, 1-(2-propynyl)-piperidine (41.3 mg, 0.34 mmol) (prepared according to Kano et al. supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(1-piperidinyl)-1-propynyl]-2H-indol-2-one. (Yield 15 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:45][S:46]([O:15][C@@H:14]1[C@@H:13]([CH3:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:10][C@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])(=[O:48])=[O:47]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of di-tert-butyl (4-{(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (500 mg, 0.957 mmol) in DCM (4.5 mL), triethylamine (0.227 mL, 1.63 mmol) was added followed by methanesulfonyl chloride (0.096 mL, 1.24 mmol). The capped solution was stirred at room temperature for 1 h. The reaction mixture was quenched with aq. NaHCO3, extracted with EtOAc. The organic layer was washed with brine, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a light yellow powder (574 mg, 100%). LCMS calc. for C27H45N4O9S (M+H)+: m/z=601.3. Found: 601.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>CCO.[Pt]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Yield: 98.4 %

Procedure:
According to Scheme 5 Step 2: A solution of tert-butyl 4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (2.50 mmol, 854 mg) in EtOH (450 mL) was passed through a Pt/C 5% column in an H-Cube equipment (mode: Full). Then the solution was concentrated under reduced pressure to yield tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46 mmol, 766 mg, 98%). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2o1
Temperature: 100 °C
Yield: 16.5 %

Procedure:
A solution of 35 g (0.263 mol) of 2-methyl-benzooxazole in CCl4 (300 mL) was treated with 47 g (0.263, 1 eq) of NBS and 1 g of benzoyl peroxide. The mixture was refluxed (100° C.) over night then cooled. Succinimide was filtered off and the mixture was evaporated to dryness. Column chromatography yielded 9.2 g (17%) of 2-bromomethyl-benzooxazole as a light yellow oil, MS: 210, 212 (MH+). (H. Uno, M. Kurokawa, Y. Masuda, Chem. Pharm. Bull., 1981, 29, 2359).
Reaction SMILES: N1C=CC(/C=C/C(O)=O)=C1.[C:11]([O:15][C:16](=[O:24])/[CH:17]=[CH:18]/[C:19]1[CH:23]=[CH:22][NH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>>[C:11]([O:15][C:16](=[O:24])/[CH:17]=[CH:18]/[C:19]1[CH:23]=[CH:22][N:21]([S:36]([C:34]2[S:35][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[CH:32][CH:33]=2)(=[O:37])=[O:38])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=C(O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tent-butyl ester (compound D1) and art-known 5-pyridin-2-yl-thiophene-2-sulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[O:15].[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1)=[O:26]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][N:37]1[CH2:38][CH2:39][CH:34]([C:30]2[CH:29]=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH3:40])[CH:33]=[CH:32][CH:31]=2)[CH2:35][CH2:36]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 5-chloro-1-(2-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])=[O:12]
Reactant: CC(=O)c1ccccc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (3.8 mL, 65 mmol) was added dropwise to a solution of 1-(2-chloro-phenyl)-ethanone (10. g, 65 mmol) in acetic acid (75 mL) at 0° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][N:6]=1>C1COCC1.[Ni]>[F:14][C:2]([F:1])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: CC(F)(F)COc1ncncc1C#N
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CN
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 4-(2,2-difluoropropoxyl)pyrimidine-5-carbonitrile (850 mg, 4.27 mmol) in THF (30 mL) was added Raney-nickel (600 mg). The mixture was de-gassed under vacuum for 10 minutes, and then hydrogenated under a fully-inflated balloon at room temperature overnight. The mixture was filtered through a pad of Celite and the cake was washed with ethyl acetate (200 mL). The filtrate was removed under vacuum and the residue was purified by preparative HPLC (5% to 60% acetonitrile in water) to give the product (260 mg, 1.28 mmol, 30% yield) as a yellow oil. MS (ESI) m/z 204.0 [M+H]+.