Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([OH:10])(=O)=[O:8])=[N+:2]=[N-:3].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][S:7]([Cl:13])(=[O:10])=[O:8])=[N+:2]=[N-:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: [N-]=[N+]=NCCCS(=O)(=O)O
Agent: [Na]
Solvent: c1ccccc1
Product: [N-]=[N+]=NCCCS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Azidopropanesulfonic acid, sodium salt 5 (1.87 g, 10.0 mmol) was suspended in dry benzene (20 mL), and PCl5 (2.3 g, 10.5 mmol) was added to the suspension. The mixture was stirred at room temperature for 30 minutes, then at gentle reflux for about 1 hour. The benzene and P(O)Cl3 were removed by evaporation under reduced pressure. Benzene was added to the crude mixture and the solvent was removed again under reduced pressure. The residue was dried in vacuo. The dried residue was dissolved in dichloromethane (anhydrous, 15 mL) and cooled at −10° C. using an ice/acetone bath.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]2)[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(Cl)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Cl)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-chlorophenyl)ethyl]pyrimidine-2-amine and 119 mg of 1-methanesulfonyl piperazine were dissolved in 3 ml of 1-butanol, and 0.23 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the objective compound as white powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C@@H:14]([CH3:52])[C@H:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)=[CH:20][CH:19]=1)[CH3:16]>C(OCC)(=O)C>[OH:13][C@@H:14]([CH3:52])[C@H:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)=[CH:20][CH:19]=1)[CH3:16]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogen carbonate (0.48 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C. for 30 min, 4′-{[4-(4-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}phenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.20 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.062 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.11 g, 47%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([C:23](=O)[CH3:24])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])[CH3:10].[CH3:26][N:27]([CH3:35])[N:28]1[C:32](=[O:33])[CH2:31][S:30][C:29]1=[S:34].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH2:23][CH:24]=[C:31]2[S:30][C:29](=[S:34])[N:28]([N:27]([CH3:35])[CH3:26])[C:32]2=[O:33])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:8])[CH3:10]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN(C)N1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)N1C(=O)C(=CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S

Procedure:
To 675 ml of toluene were added 20.9 g of 1-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]ethanone, 13.3 g of N-dimethylaminorhodanine 6.5 g of ammonium acetate and about 20 ml of acetic acid. The mixture was heated at reflux temperature and any aqueous layer generated was collected in a Dean-Stark trap. Over the following 52 hours an additional 39 g of ammonium acetate and about 100 ml of acetic acid were added in increments and a total of 89.2 ml of aqueous phase was drawn off. Following workup by conventional techniques, 17.1 g of the desired subtitled intermediate was recovered.
Reaction SMILES: [CH2:1](Cl)[CH3:2].[NH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:4][CH2:5][CH2:6][C:7]([O:9][CH2:1][CH3:2])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCl
Reactant: NCCC(=O)O
Reactant: BrCCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNCCCCCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of β-alanine ethyl hydrochloride (2.00 g) in N,N-dimethylformamide (65.0 mL), sodium hydride (60% dispersion in mineral oil, 1.15 g) was added and the mixture was stirred at room temperature for an hour. After adding (5-bromopentyl)benzene (2.52 mL), the mixture was stirred at 80° C. for 4 hours. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was separated off and dried over anhydrous magnesium sulfate; after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give the titled compound as a pale yellow oil (480 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Na]>C(Cl)Cl.CC(O)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(CN)cc(Oc2ccc(F)cc2)c1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 3-(aminomethyl)-5-(4-fluorophenoxy)benzylcarbamate (1.37 g, 3.96 mmol) in CH2Cl2 (15 mL) and 2-propanol (15 mL) was added 4-fluorobenzaldehyde (0.42 mL, 3.96 mmol). The reaction mixture was stirred at rt. under nitrogen for 40 min, and then treated with sodium triacetoxyhydroborate (1.76 g, 8.31 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer (clear solution) was washed with brine and dried over MgSO4. The filtrate was concentrated. The sample was purified by flash chromatography. Elution with 0-35% of ethyl acetate in CH2Cl2 gave the product as viscous oil (1.2 g, 67%). 1H NMR (CD3OD): δ 7.35-7.32 (m, 2H), 7.13-6.99 (m, 7H), 6.87 (s, 1H), 6.80 (s, 1H), 4.20 (s, 2H), 3.70 (s, 2H), 1.44 (s, 9H); MS (ESI): (M−H)−=513.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)([Cl:34])=[O:33]>ClCCl.C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:32]([Cl:34])=[O:33])[CH2:17][C:16]=3[CH:22]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: c1c[nH]c(-c2ccc(-c3ccc4c(c3)CNCCO4)cn2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine as obtained in step 3 was dissolved in dichloromethane (2 mL), diisopropylethylamine (0.12 mL, 0.65 mmol) was added, followed by addition of phosgene (0.07 mL of a 20% solution in toluene, 0.13 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated to afford crude 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O.CCOCC>C1COCC1>[C:14]([O:13][C:12](=[O:18])[NH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([Br:19])[CH:6]=2)[NH:1][CH2:2]1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Reaction time: 0.25 h
Yield: 1863.5 %

Procedure:
To a solution of 1A (2.7 g, 10.9 mmol) in THF (50 mL) at RT was added dropwise a solution of pyridinium tribromide (3.83 g, 0.41 mmol) in THF (50 mL). After addition, the reaction mixture was stirred for 15 min, then water (60 mL) and ether (60 mL) added. The aqueous layer was separated, and extracted with EtOAc (2×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 50%) in hexane to give the title compound (2.5 g, 70% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:6])([CH3:5])[CH2:3][NH2:4].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>C(O)CCC.C(OCC)(=O)C>[C:2]([OH:1])(=[O:11])[CH3:6].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:4][CH2:3][C:2]([OH:1])([CH3:6])[CH3:5])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]
Reactant: CC(C)(O)CN
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(=O)O
Product: CC(C)(O)CNCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Hydroxy-2-methyl-1-propylamine [prepared according to Journal American Chemical Society (1941), 63, p1034] (0.25 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in butan-1-ol (8 ml) and healed at 100° C. in a sealed tube for 24 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by solid phase extraction on SCX resin and preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) to give the title compound as the acetate salt (0.160 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:17](OC)(OC)[O:18]C.Cl(O)(=O)(=O)=O.[C:29]([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)([O:18][CH3:17])[O:7][CH3:29])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: COC(OC)OC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 27.5 °C

Procedure:
In a round bottom flask, (2 g) 4,4′-dichlorobenzophenone in 4 ml methanol was taken. (1.75 ml) (2 equiv.) tri-methyl orthoformate was added into the reaction mixture and stirred at 25-30° C. Then 0.04 ml perchloric acid (as a catalyst) was added and refluxed for 7.5 hrs. After completion of the reaction ethyl acetate and NaHCO3 solution were added and stirred for 10 min. Then layers were separated and washed the organic layer with water. Dry it over sodium sulfate. Concentrate it on rotavapor to obtain yellow colored liquid product
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[CH2:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[CH2:22]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:21])[CH:9]([CH2:10][C:11]13[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]1)[CH2:18]3)[CH2:22]2
Reactant: O=C(CCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1c2c(Cl)cccc2CC1CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
78.7 g (260 mmole) 1-(2-Chloro-phenyl)-3-(1-adamantyl)-propan-1-one, 77.5 g (2.1 eq.) urotropine and 72.6 g (2.7 eq.) of acetic anhydride were placed in a 500 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 100 ml water and 100 ml 2M NaOH were added and the mixture was extracted two times with 200 ml dichloromethane each. The organic layer was washed two times with 100 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 150 ml volume and the solution was added dropwise over a period of 2.5 h to 660 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 500 g of ice and extracted three times with 150 ml dichloromethane each. The organic layer was washed twice with 150 ml of a saturated sodium bicarbonate solution and once with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 5:1) to yield 58 g (71%) of the desired product as a slightly off-white glassy solid. 1H-NMR (400 MHz, CDCl3): δ=7.39 (t, 1H, aromatic), 7.27 (d, 1H, aromatic), 7.21 (d, 1H, aromatic), 3.37 (dd, 1H, COCH), 2.70 (m, 2H, benzylic), 1.36-1.18 (m, 17H, aliphatic) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[CH3:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH3:34])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CCCCC(=O)Cl
Agent: Cl
Product: CCCCC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and n-valeroyl chloride by using the same techniques as in Example 41.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@H:7]([CH2:17][CH:18]=[CH:19][CH3:20])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.Cl>O1CCCC1>[CH2:10]([O:9][CH2:8][C@H:7]([O:6][CH2:5][CH:4]=[O:3])[CH2:17][CH:18]=[CH:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CC=CC[C@H](COCc1ccccc1)OCC=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of ({[(2R)-2-(2,2-diethoxyethoxyl)hex-4-en-1-yl]oxy}methyl)benzene (C13) (350 g from the previous step, ≦0.64 mol) in tetrahydrofuran (1.4 L) was added aqueous hydrochloric acid (2 M, 700 mL), and the reaction mixture was stirred at 75° C. for 1 hour. Solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (2.0 L). The combined organic layers were washed with saturated aqueous sodium chloride solution (3×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a pale brown oil (210 g, ≦0.64 mol), which was taken directly to the following step.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 81.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.11 (s, 1 H), 7.05 (d, J=8 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 3.1-2.9 (m, 6 H), 2.71 (m, 1 H), 2.68 (bs, 1 H), 1.32 (d, J=8 Hz, 3 H). MS calculated for C11H14ClN+H: 196, observed: 196.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1.[OH-].[K+].C(O)(C(F)(F)F)=O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 50 °C

Procedure:
A solution of trans-methyl 4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexanecarboxylate (5 mg) in THF was treated with an aqueous solution of KOH (35 mg) in 2 mL of water. The mixture was heated at 50° C. for 12 hours. The mixture was acidified with TFA and concentrated. Silica gel chromatography (60:30:10 DCM:EtOAc:MeOH) provided 4.3 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.3 (dd, 1H), 8.1 (s, 1H), 7.7 (dd, 1H), 7.1 (td, 1H), 4.3 (m, 1H), 2.4 (m, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH:22]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:22]
Reactant: CCCCCCO
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCCOc1cc(Nc2nccs2)ccc1Cl
Reaction time: 1 h
Yield: 38 %

Procedure:
Following the procedure general for O-alkylation, Method C, 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol), 1-hexanol (0.024 ml, 0.23 mmol), Ph3P (60 mg, 0.23 mmol) were suspended in THF (0.07 mL). The reaction flask was lowered into a sonication bath and sonicated for several minutes giving a clear and highly viscous solution. While sonication, DEAD (0.045 mL, 0.23 mmol) was added slowly. The reaction mixture was stirred for 1 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 38% yield (23 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][CH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:5]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(O)c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCN(CCO)c1cccc(O)c1
Yield: 54 %

Procedure:
0.1 mol of 3-(n-butyl-amino)phenol in 100 ml of methanol is refluxed for 10 h with 0.11 mol of 2-bromoethanol and 0.1 mol of NaHCO3. After cooling, the mixture is filtered, the solvent is removed in vacuo and the residue is fractionated, to give 3-[N-(n-butyl)-N-(2-hydroxyethyl)amino]-phenol in a yield of 54%; b.p. 130-140° C. (5·10−5 torr), m.p. 45-47° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CO>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-fluoro-2-nitrophenol (4.05 g, 25.8 mmol) in MeOH (200 mL) was added tin(II) chloride dihydrate (17.47 g, 77.4 mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-fluorophenol as a grayish green solid. 1H NMR (CDCl3, 300 MHz) δ 6.64 (dd, 1H), 6.47 (dd, 1H), 6.33 (dt, 1H), 4.48 (br s, 1H), 3.78 (br s, 2H).