Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27](OCC)=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1.Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOCC>[F:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Temperature: 75 °C
Reaction time: 17 h
Yield: 65.4 %

Procedure:
DIPEA (0.693 mL, 3.98 mmol, 1.5 eq) was added to a mixture of ethyl 7-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (850 mg, 2.65 mmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (0.534 g, 3.18 mmol, 1.2 eq) in dioxane (20 mL). The reaction mixture was stirred at 75° C. for 17 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the title compound as an off-white solid (703 mg). MS (m/e)=406.2 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[OH2:3].Cl[C:5]([CH3:28])([CH3:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:26])[C:22](Cl)([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:7].Cl>CO.C1(C)C=CC=CC=1>[OH:1][C:5]([CH3:28])([CH3:27])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:26])[C:22]([OH:3])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:7]
Reactant: O
Reactant: [OH-]
Reactant: CC(C)(Cl)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(O)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1
Temperature: 50 °C

Procedure:
208.0 g (1.56 mol) of 30% NaOH and 208 ml of deionised water and 205.7 g of methanol are combined. The temperature rises to approximately 36° C. The mixture is then heated to 50° C. using an oil bath. While stirring well, 249.5 g (0.65 mol tq) of the crude product bis[4-(2-chloro-2-methyl-propionyl)-phenyl] ether from the chlorination reaction, dissolved while warm with 230 ml of toluene and with 102.8 g of methanol, are then added dropwise in the course of approximately one hour. The internal temperature slowly rises to 55-60° C. The alkaline mixture (approximately pH 12) is then stirred for approximately from two to three hours at 55-60° C. The conversion is checked using a GC sample and using a 1H-NMR sample. The mixture is then cooled to 50° C. and adjusted to a pH of approximately 1-2 by the dropwise addition of approximately 68 g of 16% hydrochloric acid. The colour of the emulsion changes from a strong yellow to yellow. The mixture is subsequently stirred for approximately 30-60 minutes. When the hydrolysis is complete, the reaction mixture is rendered neutral with a small amount of dilute sodium hydroxide solution. The two phases are separated at approximately 50° C. in a separating funnel. 200 ml of water are added to the organic phase, which is stirred and separated off again. The warm organic phase is partially concentrated (approximately 100 ml) using a rotary evaporator in order to remove residual methanol and water. It is then diluted with 660 ml of warm toluene. The solution is seeded at 45° C. and is cooled later, after crystallisation. The thick suspension is filtered and washed with toluene. The white crystals, bis[4-(2-hydroxy-2-methyl-propionyl)-phenyl] ether, are dried in vacuo. 190.5 g of white crystals, which melt at 97.2-97.6° C., are obtained. In the 1H-NMR spectrum, the product 1,2-bis[4-(2-hydroxy-2-methyl-propionyl)-phenyl] ether is isomerically pure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(C)nc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)[n+]([O-])c1

Procedure:
Following a literature procedure (Koncewicz, J. and Skrowaezewska, Z., Politec. Wroclaw Rocz. Chem., 1968, 42, 1873-85 (Chem. Ab., 70. 114972u (1968))) 2,5-dimethylpyridine was dissolved in 400 ml glacial acetic acid and 30% hydrogen peroxide (55 mL) was added slowly. The mixture was heated to 70° C. for 48 hours, with addition of more hydrogen peroxide (55 mL) at 5 hours and 20 hours. The reaction mixture was cooled, diluted with water, and the solvents removed to give 141 g of crude 2,5-dimethylpyridine-N oxide as a pale yellow liquid.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[C:27]([Cl:42])[C:6]=1[C:7]([NH:9][C@H:10]([C:23]([O:25]C)=[O:24])[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:21])[CH:15]=1)=[O:8]>O.O1CCCC1.CO>[Cl:4][C:5]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[C:27]([Cl:42])[C:6]=1[C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([OH:20])[CH:19]=1)=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cc(O)cc(O)c2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of lithium hydroxide monohydrate (160 mg, 3.8 mmol) in water (10 mL) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dihydroxybenzoylamino)L-alanine, methyl ester (490 mg, 0.85 mmol) in tetrahydrofuran/methanol (3:1; 40 mL). The solution was stirred at room temperature overnight and then the solvent was evaporated. Tetrahydrofuran and water (75 mL each) were added followed by 1 M HCl (10 mL). The cloudy white solution was heated at approx. 50° C. for 10 min and then allowed to stand overnight at room temperature. The solvents were evaporated and the residue was dissolved in methanol/water (1:4; 60 mL) and purified by HPLC in 10 mL portions. Fractions homogeneous for the product were pooled and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine (308.5 mg, 65%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous piperidine. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitated 1-(4-acetylbenzenesulfonyl)piperidine removed by filtration, washed with water and dried; m.p. 113°-114° C. after crystallization from 2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(-c2nc(C3CCNCC3)co2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)N1CCC(c2coc(-c3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]piperidine (220 mg, 0.90 mmol) in DCM (20 mL) was treated with DIEA (0.31 mL, 1.8 mmol) and allowed to stir at rt for 15 min. Methanesulfonyl chloride (0.2 mL, 2.7 mmol) was slowly added to the solution and the resulting mixture was stirred at rt for 2 hr. Upon completion of the reaction, DCM (20 mL) and water (40 mL) was added to the mixture and the two layers were partitioned. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC to afford the title compound (100 mg). LC/MS: m/e 325.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OC2CCCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 66.6E (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 mL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1:1:2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The crude material was purified on silica gel (0-10% EtOAc in hexanes) to yield a white solid. The product was recrystallized from MeOH to provide 66.6F (yield 90%). 1H NMR (400 MHz, CDCl3) δ ppm 8.24 (1H, d, J=2.0 Hz), 7.93 (1H, dd, J=8.6, 2.0 Hz), 7.17 (1H, d, J=8.6 Hz), 5.62 (1H, t, J=2.5 Hz), 3.90 (3H, s), 3.83 (1H, td, J=11.1, 2.9 Hz), 3.66 (1H, m), 2.18 (1H, m), 2.04 (1H, m), 1.94 (1H, m), 1.79 (2H, m), 1.67 (1H, m).)
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:29])[CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:30][Mg]Br.CCOCC.[Cl-:38].[NH4+]>O1CCCC1>[ClH:38].[ClH:38].[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([OH:29])([CH3:30])[CH3:28])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCN1CCN(c2nc(-c3ccc(CCC(C)=O)cc3)cc3ccccc23)CC1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(CCC(C)(C)O)cc3)cc3ccccc23)CC1
Product: Cl

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-[4-(3-oxobutyl)phenyl]isoquinoline (0.50 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was stirred under ice-cooling, to which was then added 3.0M methylmagnesium bromide/ether solution (860 μl). The resulting mixture was stirred for 30 min. Then, 3.0M methylmagnesium bromide/ethyl ether solution (860 μl) was additionally added thereto, and the resulting mixture was stirred for 2 hr. An aqueous solution of saturated ammonium chloride was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 0.21 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH:16]([CH2:18]OS(C)(=O)=O)[CH2:15][CH:14]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH:14]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:15][CH:16]([CH2:18][N:1]=[N+:2]=[N-:3])[CH2:17]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1onc2c1c(=O)n(C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CC(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 60 °C
Yield: 83.3 %

Procedure:
Add NaN3 (0.33 g, 5.1 mmol) to a solution of 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-5-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 1.7 mmol) in DMF (20 mL). Heat 24 H at 60° C., cool to 0° C. and quench with water. Concentrate to dryness. Partition between 20% iPrOH/CHCl3 and water. Extract 3×CHCl3. Wash the combined organics 2× with brine, dry over Na2SO4, filter and concentrate to dryness to afford the title compound (0.67 g, 84%) as a white foam as a mixture of cis isomers. MS(IS) 473.2 (M+); TLC (50% EtOAc/hexanes) Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[C:23](C)[CH:24]=[C:25](C)[N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.[Cl:40]C1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.CC1C=NC2N(N=C(C=O)N=2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[CH:23][C:24]([Cl:40])=[CH:25][N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:36][CH2:37]1
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cnc2nc(C=O)nn2c1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(O)=C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2Cl)CC1

Procedure:
The title compound was prepared analogously to Example B(97), 1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione in that example and 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (400 MHz, CDCl3) δ: 1.16–1.18 (m, 2H), 1.19–1.5 (m, 8H), 1.51–1.53 (m, 2H), 1.86–1.89 (m, 2H)), 2.16–2.29 (m, 1H), 2.35–2.47 (m, 3H), 2.59 (d, J=17 Hz, 1H), 3.56 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.08 (d, J=7.8, 1 Hz, 1H), 7.20–7.23 (m, 2H), 8.70 (d, J=2.5 Hz, 1H), 9.41 (d, J=2.5, 1.1 Hz, 1H), 10.7 (s, 1H). C28H27Cl2N5O3.0.25: C, 60.38; H, 4.98; N, 12.57. Found: C, 60.30; H, 4.80; N, 12.53. MS (ESI): 552.2(M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]2[NH:22][N:23]=[CH:24][CH:25]=2)[CH:14]=1)=[O:11].[Br:26]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:26][C:25]1[CH:24]=[N:23][NH:22][C:21]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1[nH]ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a cooled and stirred solution of 1-(2,4-Difluoro-phenyl)-3-[4-methoxy-3-(2H-pyrazol-3-yl)-phenyl]-urea (0.6 g, 1.74 mmole) in DMF (15 mL) was added N-bromosuccinimide (0.37 g, 2.09 mmole) over a period of 15 minutes. The reaction mixture was warmed slowly to ambient temperature and stirred for another 2 hrs. The reaction mixture was poured into well-stirred ice water containing NaHCO3/Na2S2O3. The resulting solid was filtered and washed with ice water (50 mL). The solid was dried in vacuo to afford off-white solid (0.68 g, 92%). LCMS m/z (%)=425 (M+H, 79Br, 100), 427 (M+H, 81 Br, 99). 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 8.96 (bs, 1H), 8.44 (bs, 1H), 8.02-8.08 (m, 1H), 7.48 (bs, 2H), 7.27-7.32 (m, 1 h), 6.99-7.08 (m, 2H), 3.73 (s, 3H) (major tautomer).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1)#[N:2].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][C:1]#[N:2])[CH2:6][CH2:7]1.[C:21]([OH:23])([C:20]([F:25])([F:24])[F:19])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC[C@H]1CC[C@H](N)CC1

Procedure:
A mixture of tert-butyl {trans-4-[2-cyanovinyl]cyclohexyl}carbamate (0.13 g, 0.52 mmol) and 10% palladium on carbon (52 mg) in ethanol (2 mL) was hydrogenated under balloon pressure of H2 over weekend. The mixture was filtered, and the filtrate was concentrated to give tert-butyl [trans-4-(2-Cyanoethyl)cyclohexyl]carbamate. LCMS calculated for C10H17N2O2 (M-tBu+H)+: m/z=197.1. Found: 197.1. This carbamate intermediate was treated with trifluoroacetic acid (0.4 mL, 5 mmol) in methylene chloride (1 mL) at room temperature for 1 h, and then the solvent removed to give the desired product as TFA salt. LCMS calculated for C9H17N2 (M+H)+: m/z=153.1. Found: 153.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([O:14][CH3:20])=[O:13])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2
Reactant: CO
Reactant: COc1ccc(C(=O)O)c2ccoc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c2occc12

Procedure:
7-Methoxybenzofuran-4-carboxylic acid (0.50 g) was dissolved in methanol (10 ml), and sulfuric acid (0.6 ml) was dropwise added thereto under ice-cooling, followed by heating under reflux for one hour. Sulfuric acid (0.2 ml) was further added to the mixture followed by heating under reflux for 30 minutes. After being allowed to stand for cooling, the solvent was distilled off, and the residue was poured into a 1N aqueous solution of sodium hydroxide. The precipitate was collected by filtration and dried to give Compound IIw-a (0.53 g, 99%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].N1C=CC=CC=1.[C:11]([C:14]1[CH:39]=[CH:38][C:17]([CH2:18][NH:19][C:20]2[C:30]3[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][C:21]=2[Cl:37])=[CH:16][CH:15]=1)(=O)[CH3:12]>C(O)C>[Cl:37][C:21]1[CH:22]=[CH:23][C:24]2[CH2:25][CH2:26][N:27]([C:31](=[O:36])[C:32]([F:35])([F:33])[F:34])[CH2:28][CH2:29][C:30]=2[C:20]=1[NH:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:11](=[N:4][O:3][CH3:2])[CH3:12])=[CH:39][CH:38]=1
Reactant: CON
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 82.6 %

Procedure:
Add O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) and pyridine (0.02 mL, 0.24 mmol) to a solution of 6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50 mg, 0.12 mmol) in ethanol (10 mL). Heat the mixture to reflux for 1.5 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (45 mg, 83%). MS (ES+) m/z: 454 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:26])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(NCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)C=Cc2ccc(NCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(4-methoxyphenyl)-3-(4-phenylmethylaminophenyl)-1-oxoprop-2-ene (13.7 g, 0.04 mol) was dispersed in methanol (100 ml). Sodium borohydride (4.1 g, 0.11 mol) was added slowly at ambient temperature under vigorous stirring. After completion of the addition of sodium borohydride, the reaction mixture was kept stirred at ambient temperature for 20 hours. When the reaction was complete, the reaction mixture was poured into water (500 ml), and extracted with toluene. The toluene was removed using a rotary evaporator leaving an oily residue. The crude product was purified from petroleum ether : toluene (9:1 v/v) to give 1-(4-methoxyphenyl)-3-(4-phenylmethylaminophenyl)prop-2-en-1-ol as an amorphous solid in a yield of 12.3 g (89.1% of theory).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)=[O:20].[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32].[NH4+].[Cl-]>O1CCCC1>[F:29][C:30]([F:35])([F:34])[C:31]([OH:32])([CH3:33])[C:28]#[C:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(C(=O)c2ccccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccn2)cc1)C(F)(F)F
Reaction time: 0.42 h
Yield: 1.1 %

Procedure:
To 150 mL tetrahydrofuran was added diisopropylamine (2.4 g), and the mixture was then cooled to -78° C. n-Butyl-lithium was added (8.1 mL, 2.5 molar solution in hexanes). To this mixture was added a solution which had been prepared by dissolving 4-(2-pyridylcarbonyl) phenyl ethyne (3.5 g) in a few mL tetrahydrofuran. The mixture was allowed to stir for 25 minutes. 1,1,1-trifluoroacetone (4.76 g) was added in one portion and the mixture was stirred for 15 minutes. The reaction mixture was then poured into 30 mL aqueous saturated NH4Cl. The ensuing mixture was extracted with 3×300 mL diethyl ether. The organic layers were combined, dried over MgSO4, filtered and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with 80/20 hexane/ethyl acetate. The appropriate fractions were combined and evaporated to dryness. The remaining solid was recrystallized from diethyl ether-hexanes to yield 60 mg of the title compound; mp 116°-118° C.; (300 MHz, (CDCl3): 1.74 (s,3, methyl), 2.79 (s,1, OH), 7.49-7.53 (m,2, aromatic), 7.54-7.58 (d,2, aromatic), 7.89-7.95 (t,1, aromatic), 8.06-8.09 (d,2, aromatic), 8.71-8.73 (d,1, aromatic); Analysis for C17H12F3O2N: Calculated: C, 63.95; H, 3.79; N, 4.39; Found: C, 63.96; H, 3.97; N, 4.38.