Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH3:21])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH3:21])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(Cc2ccc(Cl)cc2)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2)c1ccc(C(=O)O)cc1
Reaction time: 48 h
Yield: 143.4 %

Procedure:
To a solution of methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg) in THF (2.0 mL) and methanol (1.0 mL) was added a 1 M aqueous sodium hydroxide solution (1.0 mL) at room temperature, followed by stirring for 2 days. The reaction mixture was neutralized by adding 1 M hydrochloric acid (1.0 mL) at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate). The resulting product was dissolved in ethyl acetate (2.0 mL), and to the solution was added a 4 M hydrogen chloride ethyl acetate solution (2.0 mL) at room temperature, followed by stirring for 1 day. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration, and dried under reduced pressure to obtain 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoic acid hydrochloride (97 mg).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=Cc1ccc(F)cc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1ccc(F)cc1)C(=O)O

Procedure:
To p-fluoro-α-methylcinnamic acid (177.9 g, 0.987 mol) in 3.6 l ethanol is added 11.0 g of 5% Pd/C. The mixture is reduced at room temperature under a hydrogen pressure of 40 p.s.i. When hydrogen uptake ceases, the catalyst is filtered off, and the solvent is evaporated in vacuo to give the product, p-fluoro-α-methylhydrocinnamic acid, which was used directly in the next step.
Reaction SMILES: COC1C=CC(C2[O:14][CH2:13][C:12]([CH2:30][O:31][C:32]([C:41]([F:44])([F:43])[F:42])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])([CH2:15][O:16][C:17]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH2:11][O:10]2)=CC=1.C1(OC)C=CC=CC=1.[Al](Cl)(Cl)Cl>ClCCl>[F:19][C:18]([F:20])([F:21])[C:17]([C:26]([F:27])([F:28])[F:29])([C:22]([F:23])([F:24])[F:25])[O:16][CH2:15][C:12]([CH2:30][O:31][C:32]([C:33]([F:35])([F:36])[F:34])([C:37]([F:38])([F:39])[F:40])[C:41]([F:44])([F:43])[F:42])([CH2:11][OH:10])[CH2:13][OH:14]
Reactant: COc1ccc(C2OCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)CO2)cc1
Agent: Cl[Al](Cl)Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: OCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred mixture of compound 8 (33.1 g, 48.0 mmol) and anisole (20.7 g, 192.0 mmol) in dichloromethane (200 mL) at 0° C. was slowly added powdered aluminum chloride anhydrous (19.5 g, 144.0 mmol). After the addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 minutes. The reaction mixture was quenched by slowly addition of 1N HCl (100 mL) and the resulted mixture was extracted with ether (100 mL, 3 times). The combined organic layer was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=8/1) to give compound 9 as a clear oil (27.4 g, 99%). 1H NMR (400 MHz, CD3OD) δ 3.63 (s, 4H), 4.14 (s, 4H); 19F NMR (376 MHz, CD3OD) δ −71.14 (s); 13C NMR (100.7 MHz, CD3OD) δ 47.8, 60.4, 69.1, 80.9 (m), 121.8 (q, J=292.6 Hz); MS (CI) m/z 573 (M++1, 100); HRMS (CI) Calcd for C13H11F18O4: 573.0374, Found: 573.0374.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[OH-:21].[K+].Cl>C(O)C.CCOC(C)=O.O>[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[N:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cccc(F)c1F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)nc1Nc1cccc(F)c1F
Temperature: 120 °C
Yield: 26.7 %

Procedure:
2,6-Dichloro-3-nitropyridine (2.0 g, 10.4 mmol) and 2,3-difluoroaniline (2.5 g, 20.7 mmol) were taken up in ethanol (10.0 mL) and heated to 120° C. for 18 hours in a sealed tube. The solution was cooled in an ice bath, and the resulting precipitate was collected by vacuum filtration. The solid intermediate was dissolved in dioxane (12 mL) and 2 M aqueous potassium hydroxide solution (6.0 mL, 12.0 mmol) was added. The reaction mixture was heated to 80° C. for 18 h. After cooling to ambient temperature the mixture was diluted with EtOAc and H2O. The organic phase was discarded and the aqueous phase was acidified with 1 N HCl and extracted with EtOAc (2×). The organics were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (743 mg). 1H NMR (400 MHz, CDCl3) δ ppm 6.52 (d, J=9.2 Hz, 1H), 6.80 (m, 1H), 6.97 (q, J=8.2 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 10.09 (s, 1H).
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)C(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)O)C1C=CC=CC=1.[CH2:36]([C@H:43]1[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[N:44]1[C:50](=[O:70])[C:51]([C:53]1[O:57][C:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:60][CH:59]=2)=[CH:55][CH:54]=1)=[O:52])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH4-].[Na+]>>[CH2:36]([C@H:43]1[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[N:44]1[C:50](=[O:70])[CH:51]([C:53]1[O:57][C:56]([C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)=[CH:62][CH:63]=2)=[CH:55][CH:54]=1)[OH:52])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1

Procedure:
According to the procdure described in Example 13 for the preparation of 1-(4(S)-benzyl-2, 2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-2-hydroxy-ethanone, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-y-furan-5-yl)ethane-1, 2-dione was reduced with NaBH4 to give in quantitative yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-ethanone.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]#[N:17])[CH:15]=[C:10]2[N:9]=[CH:8]1.[NH2:31][OH:32]>C(O)C>[OH:32][N:31]=[C:16]([C:14]1[CH:15]=[C:10]2[N:9]=[CH:8][N:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)[C:11]2=[N:12][CH:13]=1)[NH2:17]
Reactant: NO
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C#N)cnc43)cc2OC)cn1
Solvent: CCO
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C(N)=NO)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (0.53 g, 1.32 mmol) in ethanol was added hydroxylamine solution (50% weight in water, 0.1 mL). The mixture was heated to 100° C. After 1 h, the mixture was concentrated to provide 0.66 g (>100%) of N′-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18]1OCCOCCOCCOCCOC1.IC>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 278 mg, 6.96 mmol) was suspended in THF (5 mL) and cooled to 0° C. trans-tert-Butoxy-N-(4-hydroxycyclohexyl) carboxamide (1 g, 4.64 mmol) and 15-crown-5 (0.965 mL, 4.88 mmol) were added and the reaction mixture was stirred at 0° C. for about 30 minutes. Iodomethane (0.289 mL, 4.64 mmol) was added and the reaction stirred at 0° C. for about 1 hour after which the LCMS showed it was complete. The reaction was quenched with methanol, the solvents removed in vacuo and the crude purified by column chromatography (SiO2, 8:2 n-hexanes/ethyl acetate) to afford 642 mg of the methyl ether. ES-MS: 230 (M+1).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4/[CH:43]=[CH:44]\[C:45]([O:47][CH3:48])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH3:48][O:47][C:45]([CH:44]1[CH2:7][CH:43]1[C:38]1[C:37]2[C:41](=[C:33]([C:30]3[N:29]=[C:28]([C:20]4[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:26])[CH3:27])=[C:18]([Cl:17])[CH:19]=4)[O:32][N:31]=3)[CH:34]=[CH:35][CH:36]=2)[N:40]([CH3:42])[CH:39]=1)=[O:46]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)/C=C\c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1CC1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C

Procedure:
To a suspension of trimethylsulfoxonium iodide (234 mg) in DMSO (3 mL) stirred under nitrogen at 20° C. was added NaHMDS (1.0 mol/L in THF, 1.0 mL) dropwise during 5 mins. The reaction mixture was stirred at this temperature for 15 mins. A solution of methyl (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D63) (120 mg) in DMSO was added dropwise. After addition was complete, the reaction was stirred at room temperature for 1.5 h, and then warmed to 50° C. for 4 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, aqueous HCl (2 M) and brine, dried over sodium sulphate and evaporated to afford methyl-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D65) (100 mg). MS (ES): C25H24ClN3O4 requires 465. found 466.2 (M+H+).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1>O.C1COCC1>[F:3][C:4]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Reaction time: 0.12 h
Yield: 83.4 %

Procedure:
Lithium hydroxide (13.3 mg, 0.554 mmol) in water (1 ml) was added into methyl 2-[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (149 mg, 0.277 mmol) dissolved in THF (2 ml). The mixture was then placed in microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 121 mg desired product, yield 83%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([CH3:16])[C:11]([C:12]#[N:13])=[C:10]([CH3:17])[CH:9]=1.Br[CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CC(C)=O>[CH:22]1([C:20](=[O:21])[CH2:19][O:7][C:8]2[CH:9]=[C:10]([CH3:17])[C:11]([C:12]#[N:13])=[C:14]([CH3:16])[CH:15]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(O)cc(C)c1C#N
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)C2CC2)cc(C)c1C#N
Yield: 94.1 %

Procedure:
Cesium carbonate (30.7 g, 111.16 mmol) was added to a solution of 4-hydroxy-2,6-dimethylbenzonitrile (15.27 g, 101.89 mmol), in acetone (377 ml). Then 2-bromo-1-cyclopropylethanone (15.1 g, 62.6 mmol), in acetone (100 ml), was added dropwise, over 5 minutes, to the suspension and the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between a saturated aqueous solution of potassium carbonate (300 ml) and dichloromethane (300 ml). The organic layer was separated and washed with brine (250 ml), dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:pentane (50:50 to 80:20, by volume) to provide the title compound (13.5 g, 64%) as a solid. 1H-NMR (400 MHz, CDCl3): δ=0.97-1.01 (m, 2H), 1.12-1.15 (m, 2H), 2.19 (m, 1H), 2.47 (s, 6H), 4.71 (s, 2H), 6.61 (s, 2H); LRMS: APCl−: 230 [MH+]
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:45])[C:27]([C:28]2[CH:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][C:29]=2[C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:26][CH2:25][CH2:24]1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:34][C:32]1[CH:31]=[CH:30][C:29]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[C:28]([C:27]2[C:23]([CH3:45])([CH3:22])[CH2:24][CH2:25][CH:26]=2)[CH:33]=1
Reactant: BrBr
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c(-c2ccc(CBr)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (0.13 g, 0.51 mmol) in DCM (1.0 mL), was slowly added bromine (0.081 g, 0.51 mmol, 0.25 mL, 2M in CCl4) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and then a mixture of compound T2.6 (0.15 g, 0.46 mmol) and anhydrous pyridine (0.041 mL, 0.51 mmol) in DCM (3.0 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. DCM (80 mL) was added, and the mixture was washed with water (20×2 mL), and dried over Na2SO4. The solvent was removed under reduced pressure to provide product T2.7. 1H NMR (400 MHz, CDCl3) δ ppm. 7.16-7.29 (m, 3H), 6.88 (t, 1H), 6.72 (m, 2H), 5.45 (s, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.16-2.19 (m, 2H), 1.59 (t, 2H), 0.78 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]=1)[NH2:12]
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cnc(C)c(NN)n1
Temperature: 50 °C
Yield: 27.9 %

Procedure:
A reaction flask was loaded with 2-chloro-3,6-dimethylpyrazine (10 g) and ethanol (15 ml), and heated up to 50° C. with stirring. To this, a mixture of hydrazine monohydrate (11.2 g) and ethanol (10 ml) was dropwise added in one hour. The temperature was raised to the reflux temperature, followed by stirring for six hours. The heating was stopped and the reaction mixture was condensed by an evaporator. The precipitated crystals were filtrated for collection and dried to give 2-hydrazino-3,6-dimethylpyrazine (2.7 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=O.O.[NH2:18]N.C[N:21]([CH3:24])C=O>C(O)C>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[N:18][NH:21][CH:24]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: CN(C)C=O
Reactant: NN
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Fc1ccccc1-c1cn[nH]c1
Temperature: 70 °C

Procedure:
11.08 ml of N,N-dimethylformamide was slowly added dropwise to 11.03 ml of POCl3 were at 0-5° C. while stirring and, after about 5 minutes a solution of 2-fluorophenylacetic acid (6 g, 38.9 mmol) in 20 ml of N,N-dimethylformamide was added dropwise. The mixture was then heated at 70° C. for about 17 hours. The mixture was subsequently quenched with ice-water and the mixture was made alkaline by adding NaOH. The resulting solid was filtered off, the solution was extracted with dichloromethane, and the organic phase was dried and concentrated. The oil obtained in this way was directly dissolved in 50 ml of ethanol. 7.3 ml of hydrazine hydrate were added, and the reaction mixture was heated at 55° C. for 3 hours. After the reaction was complete, the solvent was evaporated and the remaining solid was stirred with water and then dried. 2.65 g of 4-(2-fluorophenyl)-1H-pyrazole were obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:17]([NH:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4'-bromomethyl-2-cyanobiphenyl (10.0 g) in tetrahydrofuran (100 ml) was added butylamine (26.8 g). The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated and diluted with water, followed by extraction with chloroform. The extract was washed with water and dried. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow oil (10.7 g, quantitatively).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CC(N(C)C)=O.[C:21]1([NH:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DMA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21]C(=O)C)[CH:16]=1)([CH3:3])[CH3:2].C[O-].[Na+].O.C(OCC)(=O)C>CO>[CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2cc3cc[nH]c3cc2OC(C)C)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
N-(4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Production Example 17-5 (116 mg, 0.357 mmol) was dissolved in methanol (2.5 mL), 28% sodium methoxide (0.728 mL) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and then water and ethyl acetate were added for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off and the resultant was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-9:1), then the target fraction was concentrated under vacuum to obtain the title compound (66.3 mg, 66%).