Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[N:13]=[C:14]=[O:15].[CH3:16][C:17]([CH3:28])([CH3:27])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14]([NH:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:17]([CH3:28])([CH3:27])[CH3:16])=[CH:26][CH:25]=1)=[O:15]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CC(C)(C)Cc1ccc(CN)cc1
Solvent: ClCCl
Product: CCCCCCCN(C(=O)NCc1ccc(CC(C)(C)C)cc1)c1c(OC)cc(OC)cc1OC
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure of Example 97, but using 760 mg (3.63 mmole) 2,4,6-trimethoxyphenylisocyanate, 1.0 g (3.63 mmole) 4-(2,2-dimethylpropyl)benzylamine, and 20 ml methylene chloride. There was obtained 1.25 g product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH3:30])(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH2:28][CH2:29][CH3:30])=[O:32])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCCSCCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)CCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(3-propylthiopropoxy)quinoline (200 mg, 0.47 mmol) was dissolved in 5 ml methylene chloride. A solution of sodium bicarbonate (80 mg, 0.95 mmol) in 5 ml water was added. The mixture was cooled to 2°-4° C. A solution of 70% m-CPBA (115mg, 0.47 mmol) in 5 ml methylene chloride was added dropwise during 10 min. The temperature was allowed to rise and the mixture was stirred for 30 min at room temperature. The methylene chloride layer was separated and washed with water. The organic layer was then dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (methylene chloride: ethanol 95:5). 160 mg (77%) of the title compound was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:22][CH2:21][C:15]2([NH:19][CH:18]=[N:17][C:16]2=[O:20])[CH2:14][CH2:13]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:22][CH2:21][C:15]2([N:19]([C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:18][NH:17][C:16]2=[O:20])[CH2:14][CH2:13]1
Reactant: O=C1N=CNC12CCN(CC1=Cc3ccccc3CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3ccccc3CC1)CC2
Reaction time: 0.5 h

Procedure:
A solution of 8-[(3,4-dihydro-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]dec-2-en-4-one (5.0 g) in dry tetrahydrofuran (30 ml) is added dropwise to a slurry of lithium aluminum hydride (0.5 g) in tetrahydrofuran (60 ml). The resulting mixture is refluxed under nitrogen for 16 hours. The reaction mixture is cooled and treated, in order, with water (0.6 ml), 15% sodium hydroxide solution (0.6 ml), and water (1.8 ml). The resulting mixture is stirred for 30 minutes. The mixture is filtered and the solids washed with chloroform. The filtrate is washed with brine, dried over sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].C([O-])(O)=O.[Na+].[CH:31]([N:34]1[CH:38]=[C:37]([CH2:39][CH2:40]OS(C)(=O)=O)[CH:36]=[N:35]1)([CH3:33])[CH3:32]>CN(C=O)C>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:40][CH2:39][C:37]3[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=3)[CH2:18][CH2:19]2)[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CC(C)n1cc(CCOS(C)(=O)=O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(CCN2CCC(Oc3cccc(NC(=O)c4c(F)cc(F)cc4F)n3)CC2)cn1
Yield: 27.7 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), NaHCO3 (96 mg, 1.14 mmol), KI (24 mg, 0.14 mmol) and DMF (5 mL). Add methanesulfonic acid 2-(isopropyl-1H-pyrazol-4-yl)-ethyl ester (214 mg, 0.92 mmol) dropwise to the above mixture and then beat at 80° C. overnight. Quench the reaction with 0.1N NaOH solution, extract with ether/ethylacetate (8:1) three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3-4% methanol in methylene dichloride provides 96 mg (28%) of the title compound as a white solid: mass spectrum (ion spray): m/z=488.1 (M+1); 1H NMR (CDCl3, ppm): 8.04 (s, br, 1H), 7.86 (d, br, 1H), 7.65 (t, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 6.81 (m, 2H), 6.55 (d, 1H), 4.98 (m, 1H), 4.45 (hept, 1H), 2.81 (m 2H), 2.68 (m, 2H), 2.59 (m, 2H), 2.04 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H), 1.49 (d, 6H). Hydrochloride salt: Anal calcd for C25H28F3N5O2.HCl.0.5H2O: C, 56.34; H, 5.67; N, 13.14. Found: C, 56.35; H, 5.58; N, 12.96.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:2]1.[CH2:16]1CCN2C(=NCCC2)C[CH2:17]1.C(Br)C>C1C=CC=CC=1>[CH2:16]([O:13][C:12](=[O:14])[C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:15])[CH3:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Solvent: c1ccccc1
Solvent: CCBr
Product: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Yield: 70 %

Procedure:
Following the same method as previously described, 1,0 g 3-indole-pyruvic acid were reacted with 1,5 ml DBU and 790 microliters ethylbromide. In this case the benzene solution appeared red orange. After flash chromatography purification the ethyl ester was obtained with a yield of about 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH3:44])[C@@H:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]([CH3:44])[C@H:36]([OH:43])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: C[C@H](NS(=O)(=O)c1ccccc1Br)[C@@H](O)c1ccccc1
Product: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1)[C@H](O)c1ccccc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C25H23FN4O3S, 478.15; m/z found, 479.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.12-8.05 (m, 2H), 7.89-7.83 (m, 1H), 7.67-7.62 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.34 (m, 1H), 7.27-7.12 (m, 7H), 4.60 (t, J=4.4, 1H), 3.42-3.34 (m, 1H), 0.91-0.84 (m, 3H).
Reaction SMILES: [C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2].C([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(N)C=CC1=2)(=O)C>>[C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([NH2:42])=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cc(C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(N)cc(C)cc21

Procedure:
This compound prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylate following the procedure of Example 26, Steps 1-2 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 546 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:38])[CH:10]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=1)C1C=CC=CC=1.[OH-].[K+].C1COCC1>CO.O>[C:34]([O:33][C:31]([NH:30][C@H:10]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=1)[C:9]([OH:38])=[O:8])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(CC=Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CC=Cc2ccccc2)c2ccccc12)C(=O)O
Reaction time: 8 h

Procedure:
To 2-tert-butoxycarbonylamino-3-[1-(3-phenyl-allyl)-1H-indol-3-yl]-propionic acid benzyl ester (6.483 g. 12.71 mmol) in MeOH (25 mL) was added KOH (2.4 g, 42.86 mmol) in water (10 mL). THF (30 mL) was added until the solution became homogenous. The solution was stirred until completion (overnight). Volatile solvents were removed and the residue taken up into CH2Cl2 and water. The aqueous layer was carefully acidified with dilute aqueous HCl and extracted with-Et2O. The Et2O was washed with water and brine and then dried with MgSO4. The solution was filtered and the solvent removed to afford the required material without further purification (5.27 g, quantitative). ESMS 421 (M+H+) 1H NMR (DMSO-d6) δ 7.56-6.88 (11H, m), 6.47 (1H, d, 15.85 Hz), 6.40 (1H, dt, J=5.4, 15.85 Hz), 4.91 (2H, d, J=5Hz), 4.14 (1H, m), 3.15 (1H, m), 2.99 (1H, m), 1.29 (9H, s). 13C NMR (DMSO-d6) δ 173.8, 155.3, 136.1, 135.9, 131.4, 128.6, 127.9, 127.7, 126.8, 126.3, 125.8, 121.1, 118.6, 110.3, 109.9, 77.9, 54.6, 47.4, 28.1, 26. 8. ISMS: 421 (M+H),
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:27][S:26](=[O:29])(=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:8]=2[N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[N:10]=1)=[O:5])[CH3:2].[C:30]([NH:33][NH2:34])(=O)[CH3:31]>CCOC(C)=O>[CH3:31][C:30]1[O:16][C:14]([C:13]2[CH:12]=[C:11]([N:9]3[C:8]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[S:26](=[O:29])(=[O:28])[CH2:27][C:7]=4[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:10]3)[CH:19]=[CH:18][CH:17]=2)=[N:34][N:33]=1
Reactant: CCOC(=O)c1nn(-c2cccc(C(=O)O)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: CC(=O)NN
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cccc(-c3nnc(C)o3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 80 °C

Procedure:
To a solution of 3-[3-(ethoxycarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzoic acid (200 mg, 0.485 mmol) in EtOAc is added acetic hydrazide (35 mg, 0.485 mmol) under nitrogen. Then TEA (0.2 mL, 1.45 mmol) and propane phosphonic acid cyclic anhydride (0.7 mL, 1.2 mmol) is added to the reaction mixture at 0° C. under nitrogen. The reaction mixture is refluxed at 80° C. for 12 h after which it is diluted with EtOAC and washed with 10% aq. Na2CO3 solution. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure. The solid residue is purified by silica gel column chromatography over (1.5% MeOH in DCM to afford the title compound. MS (ESI+): 451.2.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:1](/[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)\[NH2:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C(N)=N/O)CC1
Temperature: 80 °C

Procedure:
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.5 g, 2.378 mmol) in ethanol (12 mL) was treated with hydroxylamine (50% in water, 0.51 mL, 8.32 mmol). The reaction was heated at 80° C. for 1.5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The concentrate was dried to constant weight in a vacuum oven at 60° C. to provide the title compound. DCI(+) m/z 244.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([Cl:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: N#CCc1cc(Cl)cc(CC#N)c1
Agent: Cl
Product: N#CCc1cc(Cl)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 27.8 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-chlorobenzene (650 mg, 3.4 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (735 mg, 3.4 mmol) and the resultant product was crystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2yl)methyl]-5-chlorophenylacetonitrile (333 mg, 28%) as a colorless powder.
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]([C:9]1(C(OC)=O)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[CH2:10]1)=[O:8].O.[Cl-].[Li+]>CCOCC>[Cl:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:7]([O:6][CH3:5])=[O:8])[CH2:17]2
Reactant: COC(=O)C1(C(=O)OC)Cc2ccc(Cl)cc2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1Cc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To 300 ml of dimethyl sulfoxide, were added successively 64.0 g of 2,2-dimethoxycarbonyl-5-chloroindane, 5 ml of water and 10 g of lithium chloride. The mixture was heated with stirring for 3 hours at 120° to 130° C. The reaction mixture was cooled to room temperature poured into 500 ml of ice water, and mixed with ether. After the ether layer was separated, the aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was distilled in vacuo to obtain 15.97 g of the purified intended product. Boiling point, 113°-131° C./0.3 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O>C(O)CCCCC>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:9][CH2:10][CH2:2][CH2:3][CH2:7][CH3:8])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)c1ccc(O)cc1O
Temperature: 60 °C

Procedure:
2,4-Dihydroxybenzoic acid (5 g) is added to 20 mL of n-hexanol. Concentrated sulfuric acid (5 mL) is added dropwise. The reaction mixture is heated at 60° C. for 6 days. Hexanol is removed under reduced pressure. The residue is recrystalized from methanol/water mixture. The crystals are collected, washed with cold methanol and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNC(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(CCNC(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}ethyl)-benzamide (0.13 g, 0.23 mmol) in 3 mL THF is added 0.7 mL of a 0.5M solution of TBAF in THF. The mixture is stirred at 50° C. for 2 h then is allowed to cool to RT. The mixture is poured into 1N HCl (20 mL) and extracted with EtOAc. The organic phase is washed with 1N HCl and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the resulting solid is triturated with ether/hexane to furnish the title compound.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC(Cc2ccccc2)CC1

Procedure:
A mixture of 7.15 g (0.031 mole) of 4-benzylidenecyclohexanone, ethylene ketal and 0.35 g of 10% palladium on carbon in 150 ml of ethyl acetate was shaken under hydrogen until the theoretical gas uptake had been observed (1 hour). The catalyst was then removed on a filter and the filtrate was concentrated in vacuo to give 4-benzylcyclohexanone, ethylene ketal as an oil, the nmr spectrum of which agreed with the structure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[CH3:26]>O>[CH3:25][O:24][C:21]1[CH:20]=[C:19]([CH3:26])[C:18]([O:17][CH3:16])=[CH:23][C:22]=1[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: COc1ccc(OC)c(C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(OC)cc1C
Reaction time: 0.83 h

Procedure:
A solution of 40 ml. phosphorous oxychloride (POCl3) and 45 ml. of N-methylformanilide is allowed to stand at ambient temperature for 50 minutes. There is then added 15.2 g. of 2,5-dimethoxytoluene and the resulting solution is heated on the steam bath for 140 minutes. The extremely dark viscous reaction mixture is added to 2 liters of water, and allowed to stir for several hours to complete the hydrolysis of the reaction intermediates. The solid product is removed by filtration, and after washing with water and air-drying yields 16.6 g of reddish crumbly crystals. This solid product is extracted with 2×125 ml. of boiling hexane, which on cooling deposits 12.1 g. of pale cream-colored crystals. Recrystallization from boiling hexane, yields a brilliant white product 2,5-dimethoxy-4-methylbenzaldehyde.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][C:9](=[O:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[C:1]1([CH:7]2[CH2:8][CH:9]([OH:11])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To the solution of 3-phenyl-cyclobutanone (100 mg) in THF (10 mL) was added LiAlH4 (0.2 mL, 2M in THF). The mixture was stirred at rt for 2 h, then 2M NaOH (1 mL) was added. The organic layer was concentrated and purified by PTLC providing the title compound (80 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:21])[CH2:15][C@@H:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH3:12].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:21])[CH2:15][C@@H:16]([NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:17][CH2:18][CH3:19])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC[C@H](N)CC(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC[C@@H](CC(=O)OCC)Nc1ccccc1[N+](=O)[O-]
Yield: 81 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (500 mg, 3.5 mmol) in DMF (150 mL) were added (S)-3-Amino-hexanoic acid ethyl ester (600 mg, 3.8 mmol) and diisopropyl ethylamine (0.65 mL, 3.8 mmol). The solution was heated to 90 C for 16 hours. The solution was cooled down and was water (300 mL) was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The mixture was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-(2-Nitro-phenylamino)-hexanoic acid ethyl ester (795 mg, 80%) as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH2:3]=[C:4]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.Cl>C(O)C>[CH2:3]=[C:4]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1
Reactant: C=C1C=Cc2cc(C(=O)OC)ccc2OC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C1C=Cc2cc(C(=O)O)ccc2OC1
Yield: 88.2 %

Procedure:
1.2 g of potassium hydroxide pellets are added to 4 g (18.5 mmol) of methyl 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 35, in solution in 20 ml of 80% aqueous ethanol. The medium is brought to reflux for 4 hours and then, after cooling, is treated with 1N hydrochloric acid until precipitation. The solid is filtered off and dried to give 3.3 g (88%) of 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylic acid in the form of a white solid; M.p.=188° C.