Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([I:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:23])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:36]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37]1.N12CCCN=C1CCCCC2.Cl>O1CCCC1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([I:22])=[CH:20][C:16]([C:17]([NH:43][S:40]([N:36]4[CH2:39][CH2:38][CH2:37]4)(=[O:42])=[O:41])=[O:19])=[C:15]([F:23])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid (1.75 g, 4.07 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (1.31 g, 8.10 mmol). The resulting mixture was heated at 70° C. for 30 minutes and then cooled to ambient temperature. Azetidine-1-sulfonamide (1.10 g, 8.10 mmol) was added followed by 1,8-diazabicyclo-[5.4.0]undec-7-ene (1.72 mL, 12.20 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. After addition of 1 N hydrochloric acid (5 mL) and diluting the mixture with ethyl acetate (150 mL), the organic phase was washed with 1 N hydrochloride acid (5 mL) and brine (10 mL); dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes as eluent to afford the title compound as an off-white solid (0.48 g, 22%): 11H NMR (300 MHz, CDCl3) δ 8.51 (d, J=8.7 Hz, 1H), 6.56 (d, J=13.7 Hz, 1H), 3.90 (t, J=7.6 Hz, 4H), 3.59 (s, 2H), 2.35-2.15 (m, 2H), 2.12-1.99 (m, 3H), 1.83-1.63 (m, 12H); MS (ES−) m/z 547.1 (M−1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)=[O:29]>CCOC(C)=O>[Br-:26].[C:34]([C:33]1[CH:37]=[CH:38][C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)=[CH:31][CH:32]=1)([OH:36])=[O:35]
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (300 mg, 0.89 mmol) in EtOAc (5 ml), was added 4-(2-bromoacetyl)benzoic acid (238 mg, 0.98 mmol), and the reaction was stirred at r.t. for 15 hours. The precipitate was collected by suction filtration to obtain (R)-1-(2-(4-carboxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (500 mg, 97% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=1)[C:5]([NH:7][C:8]1[S:12][N:11]=[C:10]([CH3:13])[N:9]=1)=[O:6].[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31](Cl)=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:22]1([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:16]=3)[C:5]([NH:7][C:8]3[S:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[O:6])=[N:32][CH:33]=2)=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1nsc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)n1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Reaction time: 10 h
Yield: 17.7 %

Procedure:
A mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (237 mg, 0.77 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (151 mg, 0.77 mmol) and potassium carbonate (213 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and at 160° C. for 10 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (64 mg).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Yield: 69.7 %

Procedure:
The solution of tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 0.27 mmol) in dichloromethane: trifluoroacetic acid (4:1, 3 mL) was stirred overnight at room temperature. The solvent was evaporated in vacuo to give 4-(4-cyanophenoxy)benzoic acid (45 mg, 70%). LRMS (M+H+) m/z: calcd 239.06. found 239.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].[H][H]>CC(O)C.[Pt]=O>[C:22]([O:21][C:17]([NH:18][NH:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: [H][H]
Reactant: COC(=O)CCCC(=O)c1ccc(F)cc1
Agent: O=[Pt]
Solvent: CC(C)O
Product: COC(=O)CCCC(NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 5-(4-fluorophenyl)-5-oxopentanoate (CAS No. 149437-67-2, 116 mg) and tert-butyl carbazate (73 mg) in 2-propanol (3 mL) was heated under reflux for six hours. The reaction solution was left to cool to room temperature, and then platinum oxide (10 mg) was added to the reaction solution. The reaction solution was stirred at room temperature in an hydrogen atmosphere at 3.5 atm for eight hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=9:1→heptane:ethyl acetate=1:1) to obtain 81 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24]>C1COCC1.CO.O>[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
Lithium hydroxide monohydrate (2.29 g, 54.7 mmol) was added into a solution of methyl 2-(methoxymethyl)-2′-(trifluoromethyl)biphenyl-4-carboxylate (8.0 g, 27.3 mmol) in THF (100 mL), MeOH (30 mL) and water (30 mL). The resulting mixture was stirred at RT for 12 hours, and then the reaction mixture was concentrated under vacuum. The remaining aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. Then the organic layer was washed with water and brine, and then dried (Na2SO4) and concentrated under vacuum. The resulting solid was suspended in Et2O (30 mL), filtered and dried under vacuum to afford of the title compound as a pale yellow solid (6.2 g, 74%). LC/MS (Method B): 309.0 (M−H)−. 1H NMR (DMSO-d6, 400 MHz) δ 13.08 (1H, s), 8.06 (1H, s), 7.87 (2H, m), 7.73 (1H, m), 7.65 (1H, m), 7.35 (1H, d, J=7.5 Hz), 7.27 (1H, d, J=7.9 Hz), 4.11-4.03 (2H, m), 3.15 (3H, s).
Reaction SMILES: [C:1]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:2][NH:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl.ClCCl>[C:14]([O:13][C:1]([CH2:2][N:3]([CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:24])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)CCC(=O)O
Reaction time: 48 h
Yield: 72.6 %

Procedure:
Compound 14 (0.88 g, 3.59 mmol), succinic anhydride (0.377 g, 3.77 mmol), ethyldiisopropylamine (625 μL, 3.59 mmol) and 4-di(methylamino)pyridine (44 mg, 0.359 mmol) were dissolved in CHCl3 (15 mL) and stirred for 48 h. The mixture was diluted with dichloromethane (140 mL) and the organic layer was washed with H2O (2×75 mL) and saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80% EtOAc in hexanes) to give the compound 15 (0.9 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.47 (s, 9H), 2.62 (t, J=5.8, 2H), 2.69 (t, J=5.8, 2H), 4.02 (s, 2H), 4.06 (s, 2H). ESI-MS calculated for C16H27NO7, 345.59 found 368.1 (M+Na).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)=O.C([N:17](CC)CC)C.Cl.NO>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)#[N:17]
Reactant: O=Cc1ccn(-c2ccccc2O)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccn(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6 mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml), and the mixture is allowed to stir overnight at ambient temperature. The mixture is refluxed for 5 hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 min with 50 ml 2 M aqueous sodium hydroxide. After neutralisation with aqueous hydrochloric acid, and extraction with ethyl acetate, the organic layer is dried and concentrated. The residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-cyano-1-pyrrolyl)phenol (2.4 g, 92%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[I:20].[OH-].[Li+]>O.C1COCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][C:6]([I:20])=[C:5]([CH2:4][C:3]([OH:21])=[O:2])[CH:10]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the [5-(4-fluoro-benzyloxy)-2-iodo-phenyl]-acetic acid methyl ester (example 20c, 3 g, 7.49 mmol) and lithium hydroxide (215 mg, 8.99 mmol) in water and THF (1:1 v:v, 40 mL) was stirred at room temperature for 2 h. The THF was evaporated and the mixture acidified to pH 3-4 with 0.1N HCl. After extraction with ethyl acetate, drying of the organic layer with magnesium sulfate, filtration and evaporation a white solid was obtained (2.9 g, 100%). MS: m/e=384.9 (M−H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22](C4C=CC=CC=4)[CH3:23])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)=[O:4].N.ClCCl.[CH3:35][OH:36]>>[CH2:35]([O:36][C:14]1[CH:15]=[CH:16][C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[CH:12][CH:11]=4)[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:23][CH:13]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Agent: N
Solvent: ClCCl
Product: O=C(CCl)NCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1

Procedure:
This compound is synthesized using an analogous sequence as described for 2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (steps 40.4 to 40.6); Rf(dichloromethane/methanol/conc. ammonia 90:10:1)=0.40; MS-ES+: (M+H)+=498.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:26])[CH3:25])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(C)=O

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and acetic acid to yield (3aR,4S,7aR)-4-acetoxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); =6.041 min; LC-MS Method II
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=C)[C:13]([OH:15])=[O:14].CSC>ClCCl>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:1])[C:13]([OH:15])=[O:14]
Reactant: O=[O+][O-]
Reactant: C=C(C(=O)O)c1ccccc1OC
Solvent: ClCCl
Solvent: CSC
Product: COc1ccccc1C(=O)C(=O)O
Yield: 69 %

Procedure:
A stream of ozone is sparged at -75° C. for 3 hours 30 minutes into a solution of 1 g (5.62 mmol) of 2-(2-methoxyphenyl)acrylic acid, obtained under the conditions described in Example 38, in dichloromethane. 1.66 cm3 (22.5 mmol) of dimethyl sulphide are added and stirring is continued, the temperature being allowed to rise to the region of 20° C. After concentrating the reaction mixture to dryness, 0.7 g (69%) of (2-methoxyphenyl)oxoacetic acid is obtained in the form of crystals, the characteristics of which are as follows: mass spectrum (E.I.) M/Z=180 (M+)
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[C:29]1([C:35]2[CH:40]=[CH:39][C:38]([N+:41]#[N:42])=[C:37]([N+:43]([O-:45])=[O:44])[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C(C)=CC=CC=1>CO>[OH:23][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:14][C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])=[CH:12][C:11]=1[N:42]=[N:41][C:38]1[CH:39]=[CH:40][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:36][C:37]=1[N+:43]([O-:45])=[O:44]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Reactant: N#[N+]c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a solution of sodium hydroxide (12 g, 0.3 mol) and 2-phenyl-4-tert-octylphenol (14.1 g, 0.05 mol) in 150 mL of methanol maintained at 0-5° C. is added portionwise over 1.25 hours 4-phenyl-2-nitrobenzenediazonium hydrogen sulfate (30.6 g, 0.065 mol), prepared in (C) above. The reaction mixture is stirred for two hours at 0-5° C. Xylene (200 mL) is added to the reaction mixture. The organic phase is separated and extracted with water (4×200 mL). The organic phase is filtered and the solvent removed by distillation under an atmosphere of nitrogen. The residue is purified by flash chromatography (90:10 heptane:ethyl acetate eluent) to give 6.56 g of the title compound as a viscous dark red liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9](=[O:18])[C:8]=2[CH:19]=1)([O-])=O.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[NH:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9](=[O:18])[C:8]=2[CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CN1CCOc2ccc([N+](=O)[O-])cc2C1=O
Reactant: O=C=NCc1ccccc1
Product: O=C(O)CN1CCOc2ccc(NC(=O)NCc3ccccc3)cc2C1=O

Procedure:
Catalytic hydrogenation of (7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetic acid (Example 15 c) followed by treatment of the resulting amine with benzylisocyanate yielded [7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetic acid: mp. 60-70° C. (dec.); MS (ISP): 370 (M+1)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(COC)OC>[CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2ccccc2)CO1
Temperature: 50 °C
Reaction time: 7 h
Yield: 63.4 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.1 g of sodium hydroxide are added and, at 40° C., 4 g of benzyl chloride are metered in. The mixture is stirred at 50° C. for a further 7 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 5.6 g of 4-(dibenzylamino)furan-2(5H)-one are obtained (this corresponds to 68% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:12][C:9]2([CH2:11][CH2:10]2)[CH2:8][C@H:7]1[C:13](O)=[O:14])=[O:5])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[OH:14][CH2:13][CH:7]1[CH2:8][C:9]2([CH2:10][CH2:11]2)[CH2:12][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)[C@@H]1CC2(CC2)C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: CCOC(=O)C1CC2(CC2)CC1CO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
trans-6-(Ethoxycarbonyl)spiro[2.4]heptane-5-carboxylic acid (165 mg, 832 mmol) was placed in a 25 mL round bottom flask. After flushing the flask with nitrogen, tetrahydrofuran (1.6 mL) was added and the reaction mixture was cooled to −78° C. 4-Methylmorpholine (0.11 mL, 1.0 mmol) and isobutyl chloroformate (0.12 mL, 0.93 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 15 min., the reaction mixture was recooled to −78° C. and sodium borohydride (60 mg, 1.6 mmol) was added. Methanol (1.3 mL) was added and the reaction mixture was warmed to ambient temperature over 2 h and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with saturated aqueous sodium chloride solution and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on silica gel using 35:65 ethyl acetate:hexanes as eluent provided ethyl(5R/S,6R/S)-6-(hydroxymethyl)spiro[2.4]heptane-5-carboxylate as a colorless oil.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:10]([NH2:9])=[S:11])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzoyl isothiocyanate (8.8 mL, 64 mmol) was added dropwise to a solution of 4-chloro-3-methoxy-benzenamine (10 g, 63 mmol) in 160 mL THF. The mixture was stirred at room temperature for 40 minutes, volatiles were removed and the residue was dissolved in 400 mL methanol. A solution of potassium carbonate (26.3 g, 190 mmol) in 200 mL water was added and the mixture was stirred at room temperature for 90 minutes. The tide product (13.5 g, 98%) precipitated after removal of 450 mL of the solvents.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.COC1C=C(CCCC(=O)C=C)C=CC=1.[CH:36]([CH:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45])([CH3:38])[CH3:37]>>[CH:36]([C:39]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45])([CH3:38])[CH3:37]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Reactant: CC(C)C1C(=O)CCC1=O
Agent: C=CC(=O)CCCc1cccc(OC)c1
Product: COc1cccc(CCCC(=O)CCC2(C(C)C)C(=O)CCC2=O)c1
Yield: 97.7 %

Procedure:
Condense a mixture (6 g) of 1-diethylamino-6-(m-methoxyphenyl)hexan-3-one and 6-(m-methoxyphenyl)hex-1-en-3-one with 2-isopropylcyclopentane-1,3-dione (3 g) using a procedure similar to that described for the condensation of the 2-ethyl compound. Obtain the corresponding triketone, 2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2 g) as an uncrystallizable gum.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCNCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with 1-tert-butoxycarbonyl piperazine in N,N-dimethylacetamide at room temperature followed by treatment with trifluoroacetic acid at room temperature to yield trans-N-methyl-N-[4-(4-piperazin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 504 (MH+).