Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:38])[CH2:36][CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:26])[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=[CH:12][C:13]=2[N:14]2[CH2:15][CH2:16][N:17]([CH2:34][C:35](=[O:38])[CH2:36][CH3:37])[CH2:18][CH2:19]2)[CH2:6][CH2:7]1
Reactant: CCC(=O)CBr
Reactant: CC1(C)CCC(c2cc(N3CCOCC3)ccc2N2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)CN1CCN(c2ccc(N3CCOCC3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[3-(4,4-dimethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (20 mg, 0.052 mmol) produced in Example (84b) in dimethylformamide (1 mL) were added potassium carbonate (11 mg, 0.078 mmol) and 1-bromo-2-butanone (9.4 mg, 0.063 mmol), followed by stirring for 2 hours and 5 minutes at an external temperature of 80° C. After air-cooling, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and then filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4-[2-(4,4-dimethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-one. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.020 mL, 0.080 mmol) was added. The solution was concentrated under reduced pressure, and then hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The obtained solid residue was dried under reduced pressure to give 25 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH2:34][CH3:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:19].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH2:34][CH3:35])[C:26]5[C:31]([C:32]=4[CH:33]=3)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:19])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCBr)ccc21
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCN3CCC(O)(c4ccc(Cl)cc4)CC3)ccc21
Yield: 81.1 %

Procedure:
4-(4-Chlorophenyl)-4-hydroxypiperidine (229 mg, 1.1 mmol, 1.5 equiv) was added in one portion to a solution of 3-bromo-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (250 mg, 0.72 mmol, 1 equiv) and triethylamine (0.301 mL, 219 mg, 2.2 mmol) in DMF (2 mL). The resultant solution was maintained at room temperature for 21 hours and then diluted with ethyl acetate (25 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride (2×25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (5% MeOH/CH2Cl2) to afford 3-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (278 mg, 81%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.C1COCC1.CC(O)=O.C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:15]([NH:14][C:12](=[O:13])[NH:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)ccc2s1
Temperature: 60 °C
Yield: 38.3 %

Procedure:
1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid (16 mg) was dissolved in EtOH (5 mL), THF (1 mL) and AcOH (0.5 mL) and 10% palladium on carbon (3 mg) was added followed by ammonium formate (78 mg). The mixture was degassed and heated at 60° C. for four days then cooled to rt. The mixture was filtered through a syringe filter and the filtrate concentrated in vacuo. The material was purified by preperative HPLC (Gilson, 40-60%, water/MeCN+0.1% formic acid). The relevant fractions were combined and freeze-dried overnight to give Compound 46 as a white solid (5.2 mg). 1H NMR ((CD3)2SO): δ 1.09 (3H, t, J=7.2 Hz), 1.13 (3H, s), 1.29 (2H, m), 2.03 (2H, br d, J=13.5 Hz), 3.17 (4H, m), 4.1 (1H, br s), 4.23 (2H, br dt, J=13.5 and 4.7 Hz), 7.43 (1H, dd, J=8.2 and 1.5 Hz), 7.6 (1H, br s), 7.83 (1H, d, J=1.5 Hz), 7.88 (1H, d, J=8.2 Hz), 8.71 (2H, s), 11.5 (1H, br s). m/z: 441 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].S(Cl)([Cl:10])=O.[CH2:12](O)[CH3:13]>C(Cl)Cl>[ClH:10].[CH2:12]([O:5][C:4](=[O:6])[CH:3]([CH3:7])[CH2:2][NH2:1])[CH3:13]
Reactant: CC(CN)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)CN
Product: Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
3-Aminoisobutyric acid (1.00 g, 9.7 mmol) was stirred in DCM under nitrogen and thionyl chloride (1.4 ml, 19.4 mmol) was added at room temperature. The reaction was heated to 50° C. for 2 h. The solvent and any excess thionyl chloride were removed under reduced pressure and the oil obtained was dissolved in ethanol (20 ml) stirring at room temperature for 18 h. The solvent was removed under reduced pressure to give 3-aminoisobutyric acid ethyl ester hydrochloride as a viscous, cloudy oil (1.47 g, 90%).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.Cl.Cl.[CH3:32][N:33]1[CH2:40][CH2:39][CH2:38][C:34]21[CH2:37][NH:36][CH2:35]2.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([N:36]2[CH2:37][C:34]3([N:33]([CH3:32])[CH2:40][CH2:39][CH2:38]3)[CH2:35]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CN1CCCC12CNC2
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 55 %

Procedure:
A mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 300 mg, 0.76 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol), DIPEA (0.158 mL, 0.92 mmol) and DMA (4 mL) was heated at 100° C. for 1 h. The mixture was then absorbed onto an SCX column, and the column was washed with CH3OH. The column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% CH3OH in CH2Cl2 gave the title compound (209 mg, 55%) as an orange solid; 1H NMR: 1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H, d), 3.88 (3H, s), 3.96 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H, t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34 (2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES+ MH+ 500.6.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[C:26](OC)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CO>[CH:10]1([N:15]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]2[CH2:26][OH:27])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1cc2cnc(SC)nc2n1C1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc2cc(CO)n(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
DIBAL-H (1.0 M in toluene) (33.8 mL, 33.8 mmol) was added dropwise to a solution of compound 227 (4.93 g, 16.9 mmol) in dichloromethane (85 mL) at −78° C. The reaction was stirred for 20 minutes, then warmed to 0° C. and quenched with 400 mL of 0.5 M Rochelle's salt saturated with NaCl. The mixture was stirred for 3 h then extracted with ethyl acetate (4×250 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to provide 4.36 g of crude. The crude material was taken up in dichloromethane and methanol, plated onto silica gel, and flashed through a plug of silica using 30% ethyl acetate in hexanes, then switching to 10% methanol in DCM to provide compound 228 (3.37 g, 75.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 1H) 6.29 (s, 1H) 4.83-4.95 (m, J=17.30, 8.59, 8.59 Hz, 1 H) 4.79 (d, J=5.87 Hz, 2 H) 2.62 (s, 3 H) 2.47-2.58 (m, 2 H) 1.97-2.15 (m, 5 H) 1.67-1.81 (m, 2 H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:39]([C:40]([F:41])([F:43])[F:42])[C:32]=2[F:31])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: Fc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2F)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.7 g, 0.002 mol) in DMF (10 mL), was added 2-fluoro-3-(trifluoromethyl)benzyl bromide (0.5 g, 0.002 mol) and powdered potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.84 g in 72% yield. 1H NMR (CDCl3) δ 7.35 (t, 1H), 7.17 (m, 12H), 6.85 (t, 2H), 6.63 (s, 1H), 6.59 (t, 1H), 4.16 (t, 1H), 3.69 (s, 3H), 3.68 (s, 2H), 3.63 (t, 2H), 3.57 (d, 2H), 3.10 (d, 2H), 2.67 (t, 2H), 1.82 (t, 2H). 13C NMR (CDCl3) δ 173.4, 160.4, 144.8, 136.6, 130.8, 130.8, 129.7, 129.6, 129.4, 127.7, 126.8, 124.9, 123.1, 122.8, 116.8, 114.5, 66.3, 61.4, 53.5, 52.4, 51.8, 51.1, 42.7, 28.3.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3.[O-:22][CH2:23][CH3:24].[Na+]>C(O)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1=[N:4][N:3]=[C:2]([O:22][CH2:23][CH3:24])[N:6]1[N:7]=[C:8]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nn1c(Cl)nnc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nnc2c3ccc(Cl)cc3c(-c3ccccc3)nn12
Temperature: 100 °C

Procedure:
A mixture of 3,8-dichloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5 g), sodium ethoxide (1.3 g) and absolute ethanol (40 ml) is poured into a steel bomb and heated to 100° C. for 8 hours. Then the mixture is cooled and concentrated to dryness. The obtained residue is triturated with water, filtered and crystallized from ethanol/chloroform yielding 3.3 g of the compound of the title. M.p. 226°-28° C.
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[CH3:12][I:13]>CO>[I-:13].[CH3:12][N+:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][CH:2]([OH:1])[CH2:10][CH3:11])[CH:9]=1
Reactant: CCC(O)Cc1cnccn1
Reactant: CI
Solvent: CO
Product: CCC(O)Cc1c[n+](C)ccn1
Product: [I-]

Procedure:
3.1 g of 2-(2-hydroxybutyl)pyrazine (3300) was dissolved in 30 ml of methanol, 10 ml of methyl iodide added and the solution refluxed for 3 days. It was then concentrated, taken up in water and extracted with chloroform. The aqueous solution was concentrated and chromatographed (Biogel P-2/water). Freeze-drying gave 4.6 g of product (3400) as a yellow solid. It was recrystallized from ethyl acetate/ethanol, m.p. 108°-9°. UV H2O max: 227 (4.11), 282 (3.85). 13C NMR: 163.30, S (C3); 150.63, D (C5); 138.77, D, 136.12, D (C2, C6); 72.66, D (CHOH); 49.93, Q (NCH3); 43.02, T, 30.11, T (--CH2 --); 9.97, Q (CH3). 1H NMR: 9.35, D, T (H6); 8.95, S (H2); 8.85, D (H5); 4.49, S (NCH3); 4.11, M (CHOH); 3.39-3.14, M (ArCH2); 1.75-1.52, M (--CH2 --); 0.99, T (CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[N:34][OH:35])[NH2:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]3[NH:33][C:36](=[O:37])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidi n-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (408 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (146 mg, 0.90 mmol) dissolved in acetonitrile (8.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.488 mL, 3.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H29ClFN7O2 [M+H]+ 526. found 526. 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.83 (s, 1H), 4.67-4.42 (m, 3H), 3.91-3.81 (m, 1H), 3.79-3.64 (m, 2H), 3.53-3.45 (m, 1H), 2.20-2.12 (broad, 1H), 2.06-1.98 (broad, 1H), 1.94-1.78 (m, 2H), 1.40-1.31 (broad, 2H), 1.17-1.07 (broad, 1H), 1.06-0.96 (broad, 1H), 0.89 (d, J=12.5, 1H), 0.67 (d, J=6.4, 3H), 0.63-0.36 (m, 5H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:21].[K+].II.[N:25]([O:27]C(C)(C)C)=[O:26]>C(#N)C.[Cu](I)I>[I:21][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)(C)ON=O
Reactant: COc1cc(-c2ccc(N)c3c2CNC3=O)ccc1O
Reactant: [I-]
Agent: I[Cu]I
Agent: II
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2ccc(I)c3c2CNC3=O)cc([N+](=O)[O-])c1O
Yield: 31.4 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-(4-hydroxy-3-methoxyphenyl)isoindolinone (202 mg, 0.747 mmol) was dissolved in acetonitrile (10.1 mL), and the solution was treated with potassium iodide (149 mg, 0.896 mmol), copper iodide (171 mg, 0.896 mmol), iodine (228 mg, 0.896 mmol) and tert-butyl nitrite (0.266 mL, 0.896 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1) to obtain 7-iodo-4-(4-hydroxy-3-methoxy-5-nitrophenyl)isoindolinone (100 mg, yield 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:33])=[C:16]2[N:15]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 1-fluoro-4-isocyanatobenzene (13 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 90 minutes before it was concentrated and directly purified by column chromatography on silica, eluting with 3:1 EtOAc/hexanes to yield the final product as a solid (30 mg, 84% yield). MS (apci) m/z=453.2 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[C:14](=[O:15])[N:13]3[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][OH:18]>>[CH3:17][O:18][C:14]([CH:7]([CH:8]1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C1C(c2ccccc2)C2CCCCN12
Reactant: CO
Agent: Cl
Product: COC(=O)C(c1ccccc1)C1CCCCN1

Procedure:
reacting the 7-phenyl-1-azabicyclo[4.2.0]octan-8-one obtained in step (i) with a solution of hydrogen chloride in methanol to give methylphenidate;
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C:7]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[O:6][CH2:5][C:4]1=[O:21])[CH3:2].C(O)(C(F)(F)[F:25])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38]>ClCCl.O>[Br:48][C:45]1[CH:46]=[CH:47][C:42]([CH:36]([N:11]2[CH2:12][CH2:13][C:7]3([O:6][CH2:5][C:4](=[O:21])[N:3]([CH2:1][CH3:2])[CH2:8]3)[CH2:9][CH2:10]2)[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:43]([F:25])[CH:44]=1
Reactant: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1=O
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(CC)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1 g, 3.35 mmol) in dichloromethane (10 mL) was added TFA (0.775 mL, 10.05 mmol). The reaction mixture was stirred at room temperature overnight, at which point the deprotection had proceeded to completion. The reaction mixture was concentrated in vacuo, dichloromethane was added, and the solution was concentrated in vacuo again. The residue was dissolved with N,N-dimethylformamide (12 mL). To this solution was added potassium carbonate (0.463 g, 3.35 mmol) and ethyl 2-bromo-2-(4-bromophenyl)acetate (1.079 g, 3.35 mmol). The reaction mixture was stirred at 40° C. for overnight, at which point the reaction had proceeded to completion. The reaction mixture was poured into water (120 mL) and was extracted with ethyl acetate (80 mL×3). The combined organic layers were dried and concentrated in vacuo. Crude ethyl 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate was obtained (590 mg) and was used directly in the next step. MS(ES)+ m/e 457 [M+H]+.
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([OH:17])[CH:9]([OH:16])[CH:10]([OH:15])[CH:11]([OH:14])[CH:12]=[O:13]>>[CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[O:13]=[CH:12][C@@H:11]([C@H:10]([C@@H:9]([CH2:8][OH:17])[OH:16])[OH:15])[OH:14]
Reactant: O=CC(O)C(O)C(O)CO
Solvent: O=Cc1ccco1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
In a process disclosed by David J. Medeiros et al. in U.S. Pat. No. 4,533,743, aqueous pentose solution was reacted at high temperature and pressure in the presence of a mineral acid catalyst to maximize furfural yield and selectivity. The process utilized a plug flow reactor and a combination of four conditions: The concentration of pentose in the pentose-aqueous feed solution before entry into the reactor was between 1 and 10 percent by weight of the aqueous solution before the addition of acid; the concentration of the mineral acid in the reactor was between 0.05 and 0.2 normality before entry into the reactor; the reactor was operated at a temperature between 220° C. and 300° C.; and the residence time of the pentose in the reactor was between 0.5 and 100 seconds. The reactor pressure was high enough to prevent vaporization of the aqueous solutions at the high temperatures used, between about 1000 and 2000 psi (6.895 and 13.79 MPa). In one configuration of the process, furfural produced from a xylose stream was separated with a water immiscible extraction solvent. The yield of furfural was 66% after one pass. Because incomplete conversion of the xylose took place, the aqueous solution could be recycled for additional yield. The selectivity of the xylose converted was 73%. Faster flow rates increased selectivity at the expense of lowered conversion, suggesting that maximum yields using multiple cycles would reach 80-85%. In a second configuration, the aqueous xylose solution was mixed with an immiscible solvent, toluene, before reaction. The conversion was 98% and the yield was 71%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([CH2:25]Cl)[CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:27])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([CH2:25][NH:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:27])=[CH:11][CH:10]=1
Reactant: NCc1ccccn1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNCc3ccccn3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Aminomethylpyridine (0.372 g) was added to a solution of 0.597 g of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole and 0.350 g of potassium carbonate in 3 ml of N,N-dimethylformamide, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was extracted with water and with ethyl acetate. The organic layer was washed twice with water, and the solvent was distilled off under reduced pressure. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 9:1), and was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.300 g of 1-(biphenyl-4-ylmethyl)-2-methyl-6-[2-pyridylmethyl)aminomethyl]benzimidazole (265).