Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.Br[C:7]12[CH2:14][CH2:13][C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.[CH:20]([OH:22])=[O:21]>S([O-])([O-])(=O)=O.[Ag+2]>[CH2:15]([C:10]12[CH2:13][CH2:14][C:7]([C:20]([OH:22])=[O:21])([CH2:12][CH2:11]1)[CH2:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=CO
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CCCCCC12CCC(C(=O)O)(CC1)CC2
Temperature: 5 °C

Procedure:
In another flask, 150 ml of concentrated sulfuric acid and 1.3 g of silver sulfate (Ag2SO4) were mixed and cooled to 5° C., and 5 ml of a solution of 3 g of the aforesaid 1-bromo-4-pentylbicyclo(2,2,2)octane in n--C6H14 was added. Subsequently, 1 ml of 98% HCOOH was gradually added thereto. After the evolution of gas ceased, the reaction solution was added to 600 ml of ice water to deposit crystals. The crystals were collected by filtration to obtain 4-pentylbicyclo[2,2,2]octanecarboxylic acid.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[O:38]1[CH2:43][CH2:42][N:41]([C:44]2[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:47]4[CH:48]=[N:49][C:44]([N:41]5[CH2:42][CH2:43][O:38][CH2:39][CH2:40]5)=[CH:45][CH:46]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(N3CCOCC3)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (6-morpholinopyridin-3-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=583, obsd.=583).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](/[CH:12]=[CH:13]/[CH:14]=[O:15])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][CH:14]=[O:15])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(/C=C/C=O)cc(C(C)(C)C)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CCC=O)cc(C(C)(C)C)c1
Reaction time: 6 h
Yield: 590.8 %

Procedure:
To 1.2 g (5.7 mmole) of (E)-3-(3-tert-butyl-5-methylphenyl)-2-propenal in ethanol (20 ml) there were added 5% Pd/C (0.12 g) and sodium acetate (0.12 g, 1.4 mmole). The mixture was hydrogenated at room temperature and atmospheric pressure during 6 h. After filtration of the catalyst, the solvent was evaporated (1.2 g). The raw product was dissolved in CH2Cl2 (20 ml) and a suspension of PCC (0.62 g, 2.8 ml) in CH2Cl2 (20 ml) was added thereto at room temperature. After 2 h, the mixture was diluted in ether (100 ml) filtered on a FLORISIL® column (Fluka) and concentrated (1.2 g). Bulb-to-bulb distillation (80°/10 Pa) provided 3-(3-tert-butyl-5-methylphenyl)propanal (6.88 g, purity>95%, yield 70%).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCC=CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.8 g of 3-hexenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.10 g of the desired Compound No. 7 in the form of pale yellow powdery crystals melting at 197.5°-198.5° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)(=[O:18])=[O:17])[CH3:14])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][CH2:12][CH:13]([NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)(=[O:18])=[O:17])[CH3:14]
Reactant: [H][H]
Reactant: CC(CNC(=O)OCc1ccccc1)NS(=O)(=O)c1cccc2cnccc12
Agent: [Pd]
Solvent: CCO
Product: CC(CN)NS(=O)(=O)c1cccc2cnccc12
Yield: 97.9 %

Procedure:
In 50 ml of ethanol was dissolved 2.0 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide obtained above, and to the solution was added 0.1 g of 5% palladium-carbon. Then the solution was stirred at a temperature of 15° C.~25° C. in a hydrogen (0.7 to 1.40 kg/cm2) for 3 hours. The palladium-carbon was separated from the reaction solution by filtration under the reduced pressure. After the methanol was distilled therefrom, the reaction solution was concentrated to dryness to give 1.30 g of N-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 98%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:11])[CH:9]=[O:10].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH:13]1C(O)=O>C(Cl)(Cl)Cl>[CH3:7][N:8]([CH3:11])[C:9]([CH:18]1[CH2:19][CH2:20][C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.94 mL of oxalyl chloride and 0.026 mL of N,N-dimethylformamide were added to a chloroform (20 mL) solution of 3 g of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, and stirred at room temperature for 1 hour. The reaction liquid was concentrated, and the residue was dissolved in 20 mL of tetrahydrofuran, and 22.13 mL of 2 M dimethylamine/tetrahydrofuran solution was added thereto. Water was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away to obtain 3.53 g of the entitled compound as a crude product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][C:30]#[N:31]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (150 mg, 0.55 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (202 mg, 1.46 mmol) and 4-chlorobutyronitrile (152 mg, 1.46 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (71 mg, yield 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 10.9 g. of p-n-octylbenzaldehyde in 100 ml. of benzene is treated with 150 ml. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 16.5 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-octylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.5°-32.8° C. and a clearing point of 68.8° C. Up to 54.4° C. the compound is smectic. UV (ethanol): ε280 = 24200 (shoulder at 312 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:29]([NH:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Solvent: CC(C)=O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)Nc4ccccc4)nc3cc21
Yield: 63.3 %

Procedure:
A solution of D5 (172 mg) and phenyl isocyanate (72 mg; 0.6 mmol) in acetone (3 ml) is stirred at RT for 3 days. Acetone is evaporated and the residue is purified by flash chromatography on silica gel eluted with CH2Cl2/MeOH (20:1) to give the desired compound (154 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]2[C:15](=O)[O:14][C:13](=[O:18])[C:12]=2[C:11]([O:19][CH2:20][CH3:21])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=1[F:35]>C(O)(=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:20]([O:19][C:11]1[C:12]2[C:13](=[O:18])[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=3[F:35])[C:15](=[O:14])[C:16]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12)[CH3:21]
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 120 °C
Yield: 68.6 %

Procedure:
4,9-Bis(ethyloxy)naphtho[2,3-c]furan-1,3-dione (0.100 g, 0.35 mmol) in acetic acid (5 ml) was treated with DMAP (0.013 g, 0.11 mmol) then ethyl (4-amino-3-fluorophenyl)acetate (0.138 g, 0.70 mmol) and heated to reflux (120° C.) under argon overnight. The reaction mixture was cooled to room temperature and the solvent evaporated to afford a brown/orange oil which was diluted in DCM and washed with saturated NaHCO3 and then 2N HCl. The organics were dried over MgSO4 and evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-20%) in hexane over 30 minutes. The evaporated fractions were triturated with hexane to give the title compound as a solid (0.110 g, 0.24 mmol, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:53])[C:3]([O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2([CH2:28][C:29]3[N:30]=[CH:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:33]=3)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl>CO>[CH3:53][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2([CH2:28][C:29]3[N:30]=[CH:31][NH:32][CH:33]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3c[nH]cn3)CCNCC2)c1
Temperature: 60 °C
Yield: 89.7 %

Procedure:
To a solution of tert-butyl 4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)-4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-1-carboxylate from step C (180 mg) in MeOH (5 mL) was added HCl (1 N in dioxane, 1 mL). The reaction was heated at 60° C. for 1 hour, and then concentrated under vacuum. The residue was dissolved in EtOAc (5 mL), washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum to produce the title compound (84 mg, 93%). MS (ES+) [M+H]+=372.2.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cnc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-Hydroxynicotinic acid was added portionwise to sulfuric acid (50 mL) at 0° C. After complete dissolution, nitric acid (3 mL) was added dropwise to the cooled solution. After the addition was complete, the bath was removed and the solution stirred overnight at ambient temperature. The solution was then heated at 50°-70° C. for one and a half hours. The solution was cooled to ambient temperature and poured onto ice (100 g). The pale yellow solid which resulted was collected by filtration and dried in vacuo at 50° C. to give 7.3 g (87% yield) of the title compound which was used without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (d, 1H,J=3), 9.01 (d,2H,J=3).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O.N1C=CC=CC=1>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (32 mg) was dissolved in a mixture of N,N-dimethylformamide (1.0 ml) and pyridine (1.0 ml). To the solution was added octanoyl chloride (17 μl) with stirring under nitrogen atmosphere in an ice-water bath. The mixture was stirred for 2 hours under nitrogen atmosphere in an ice-water bath and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography and development was carried out with a mixture of chloroform and methanol to afford 4-formyl-6,9-dihydroxy-11-octanoyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (33 mg).
Reaction SMILES: Cl.[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:28][CH3:29])[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:28][CH3:29])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
Ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-ethylaminopropionate hydrochloride, which is the product of Example 177(b), is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:25][C:12]2([CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>N1C=CC=CC=1>[CH2:27]([O:29][N:30]=[C:21]1[CH2:20][CH2:19][CH:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:25]3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1)[CH3:28]
Reactant: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC(=O)CC3)CC2)C1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C1CCC(N2CCC3(CC2)CN(C(C)=O)Cc2ccccc23)CC1
Temperature: 60 °C

Procedure:
4-(2-Acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)cyclohexanone 6e (100 mg; 0.29 mmol) was dissolved in pyridine (1 mL) and treated with O-ethyl hydroxyamine hydrochloride (34 mg; 0.35 mmol). The vial was sealed and heated to 60° C. for 1 hr. The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (2 mL) and purified by LC/MS (10-99% CH3CN—H2O gradient, with 0.05% TFA, 9 min) to provide 1-(1′-(4-(ethoxyimino)cyclohexyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)ethanone. LC/MS m/z [M+H]+ 384.4 retention time 1.80 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, CDCl3) δ7.69 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.19-7.15 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 4.63 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.79 (dd, J=13.4, 18.1 Hz, 2H), 3.41 (d, J=13.0 Hz, 1H), 3.33 (d, J=9.3 Hz, 2H), 3.17 (m, 2H), 3.04-2.98 (m, 2H), 2.59-2.47 (m, 4H), 2.14 (s, 3H), 1.76-1.69 (m, 6H), 1.21-1.14 (t, J=7 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCCCCC2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (10 g, 43.47 mmol) is added under argon to a mixture of azepane (4.9 ml, 43.47 mmol) and potassium carbonate (6 g, 43.47 mmol) in 100 ml of DMF. After stirring over night at room temperature, the mixture is filtered and evaporated under high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave 9.1 g (84%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:7]=[O:8].[I:15]I.C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[OH:14][C:5]1[C:4]([I:15])=[C:3]([O:2][CH3:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(O)c(C=O)cc1[N+](=O)[O-]
Reactant: II
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c([N+](=O)[O-])cc(C=O)c(O)c1I
Reaction time: 15 h
Yield: 73 %

Procedure:
To the stirred solution of 2.0 g (10.2 mmol) (1.52 mmol) of 4-methoxy-5-nitrosalicylaldehyde and 2.58 g (10.2 mmol) of iodine in 60 ml of carbon tetrachloride, 4.8 g (11.2) mmol) of [bistrifluoroacetoxyl) iodo]benzene was added slowly and then the reaction mixture was stirred for 15 hrs. at RT. To this reaction mixture, 60 ml of hexanes was added and then the formed solid was collected by filtration, washed with hexanes, dilute HCl, water, and dried to give 2.4 g of D. (Yield: 73%): 1H NMR (CDC13) δ12.48 (s, 1H), 9.81 (s, 1H), 8.35 (s, 1H), 4.07 (s, 3H); MS (70 eV) m/e (% relative intensity) M+2 =325 (1.78), M+1 =324 (11) M=323 (100), 293 (41), 276 (51), 262 (11), 120 (8.5), 119 (8.6), 108 (38), 107 (22), 92 (23), 80 (10) 79 (18), 77 (18), 64 (12), 63 (10), 62 (10), 61 (10), 51 (14), 49 (23); IR (nujol) 1660, 1608, 1557, 1512, 1467, 1376, 1312, 1080, 970, 725 cm-1
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1)=[CH2:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution containing 600.0 mg (2.25 mmol) of 2,3-dihydro-6-(2-trimethylsilylethynyl)-(4H)-1-benzothiopyran-4-one and 100.0 mg (0.72 mmol) K2CO3 in 15 ml MeOH was stirred at room temperature for 20 hours. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as an orange solid. 1H NMR (CDCl3): δ 8.17 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.19 (1H, d, J=8.2 Hz), 3.22 (2H, t, J=6.3 Hz), 3.08 (1H, s) 2.94 (2H, t, J=6.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12]([O-])(=O)=O.[Na+].Br>>[Br:12][CH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: Br
Agent: [Na+]
Product: Cc1cccc(CBr)c1C(=O)O

Procedure:
It has now been found that the reaction of 2,6-dimethyl-benzoic acid (II) with sodium bromate and hydrobromic acid in the presence of light gives 2-bromomethyl-6-methyl benzoic acid (I) in high yield and purity.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:8][C:9]([OH:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(O)CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To ethyl 3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate (6.7 g, 29.2 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (5.2 ml, 43.8 mmol) dropwise, followed by K2CO3 (12 g, 87.6 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 7 g product (75%). [M+H] calc'd for C19H29NO3, 320; found 320.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8](/[CH:11]=[CH:12]/[C:23]2[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Yield: 28 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl sulfonylacetic acid (4.5 g, 15.5 mmol) in 30 mL of glacial acetic acid was added 2,4,6-trimethoxybenzaldehyde (3.05 g, 15.5 mmol) and a catalytic amount of benzylamine (0.6 mL). The resulting mixture was heated at reflux temperature for 6 h. The reaction mixture was then concentrated under reduced pressure to yield a gummy material. The gum was triturated with 2-propanol to yield a solid product. The solid product was recrystallized from a mixture of acetic acid and 2-propanol to provide the 2((E)-2-(4-methoxy-3-nitrobenzylsulfonyl)vinyl)-1,3,5-trimethoxybenzene product in 28% yield. m.p. 186-187° C.