Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5](=[O:18])[N:4]=1
Reactant: COc1nsnc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC1=NS(=O)N=C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole (35.2 g; 24.1 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2749 (1975)] in 100 ml of chloroform was added over a period of 3 minutes to a stirred solution of m-chloroperbenzoic acid (50.7 g; 25.0 mmoles; 85% assay) in 900 ml of chloroform at 20°, using a cooling bath to keep the exothermic reaction from rising above 32°. After stirring for 3 hours at ambient temperature, the excess peracid was reacted with an additional 2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole and stirred for 1 hours.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=2)[C:17]2[CH:46]=[C:47]([CH3:54])[C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:16]1=2)=O)(C)(C)C>C(Cl)Cl>[F:44][C:42]([F:43])([F:45])[C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=1)[CH2:31][N:22]([C@H:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:49]=[C:48]([C:50]([F:51])([F:52])[F:53])[C:47]([CH3:54])=[CH:46][C:17]1=2)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Add trifluoroacetic acid (2 mL) to a solution of (S)-5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino}-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.0650 g, 0.0952 mmol) in methylene chloride (2 mL) at room temperature, stir for 1 h. Evaporate solvents and partition the residue between saturated aqueous sodium bicarbonate solution (10 mL). Extract the mixture with methylene chloride (10 mL). Separate two layers and dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as a colorless oil (0.0340 g, 62%). MS (ES+): 583 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(C)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(C)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(4-methylphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])[C:3]=1[CH3:10]
Reactant: Cc1c(F)cccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c(F)cccc1/C=C/[N+](=O)[O-]
Yield: 89 %

Procedure:
A Knoevenagel condensation was carried out by stirring 3-fluoro-2-methyl-benzaldehyde (20.721 g, 150 mmol), nitromethane (48.75 ml, 900 mmol) and ammonium acetate (34.687 g, 450 mmol) in 300 ml of acetic acid at 115° C. for 3.5 h. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 250 ml of EA. The solution was washed with water (250 ml), three times with a 1 N sodium hydroxide solution (125 ml) and with brine (125 ml), dried over magnesium sulfate, filtered and evaporated to dryness. 24.18 g of the title compound were obtained as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16]>C(O)C.O.[OH-].[Na+]>[CH3:18][C:17]([CH3:20])([CH3:19])[C:15](=[O:16])[CH:14]=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc(C2OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(C2OCCO2)cc1
Reaction time: 1 h
Yield: 38.8 %

Procedure:
100 g (0.5612 mol) of 4-(1,3-dioxolan-2-yl)-benzaldehyde and 56.1 g (0.56 mol) of pinacoline are dissolved in a mixture of 280 ml of ethanol and 56 ml of water, and 17 ml of 10% strength sodium hydroxide solution are added at room temperature. The mixture is subsequently stirred for 1 hour, 0.56 g of solid sodium hydroxide are added and the mixture is subsequently stirred for 2 days. Thereafter, the precipitate is filtered off with suction, washed with 200 ml of ethanol/water (1:1) and then with water, dried and recrystallized twice from ethanol. 56.5 g (39% of theory) of 4,4-dimethyl-1-[4-(1,3-dioxolan-2-yl)-phenyl]-1-penten-3-one of melting point 79°-81° C. are obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[N:42]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN1C(=O)CCC1>[CH:41]1([NH:42][C:25](=[O:26])[C:21]2[CH:20]=[C:19]([O:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:24]=[CH:23][N:22]=2)[CH2:39][CH2:40]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NC1CC1)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5.9 %

Procedure:
To the reaction solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (5 mg, 39 μmol), HATU (15 mg, 39 μmol) and DIPEA (14 μL, 78 μmol) in 1 ml of NMP was added cyclopropylamine (7 ul mg, 30 μmol). The reaction solution was stirred at room temperature for 12 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give N-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide (1 mg, 2.3 μmol) as white powder. ES/MS m/z 425.2 (MH+).
Reaction SMILES: I[C:2]1[C:3]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][O:5][C:6]=1[CH3:7].C([Mg]Br)(C)C.[O:18]1COC[O:20][CH2:19]1.C(=O)=O>C1COCC1.O>[CH2:9]([O:8][C:3]1[C:2]([C:19]([OH:20])=[O:18])=[C:6]([CH3:7])[O:5][N:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: C1OCOCO1
Reactant: Cc1onc(OCC(C)C)c1I
Agent: CC(C)[Mg]Br
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(OCC(C)C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a stirred solution of 4-iodo-3-isobutoxy-5-methyl-isoxazole (669 mg, 2.38) in THF (10 mL) at −30° C. and under argon was added isopropylmagnesium bromide (1.49 mL of a 2.0 M solution in THF) dropwise. The reaction mixture was warmed to 0° C. and stirred for 1 h, then 1,3,5-trioxane (429 mg, 4.76 mmol) in THF (1 mL) was added and the reaction mixture warmed to 50° C. After 1.5 h to the reaction mixture was added further 1,3,5-trioxane (860 mg, 9.52 mmol) and the reaction mixture heated at 70° C. After 2 h the mixture was cooled to 0° C. and solid CO2 (˜10 g) added. After 1 h the reaction mixture was diluted with water (15 mL) then extracted with diethylether. The aqueous phase was acidified with HCl (1 N, 10 mL), then the resultant precipitate filtered off and washed with water (5 mL), then dried under vacuum (60° C.) to afford the title compound (152 mg, 32%) as a white solid. MS: m/e=198.4 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[O:28]=[S:29]1(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([N:30]3[CH2:31][CH2:32][CH2:33][S:29]3(=[O:34])=[O:28])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=S1(=O)CCCN1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Product: Cn1cc(-c2nc(N3CCCS3(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O

Procedure:
The title compound of Example 152, step 5 was treated with 1,1-dioxidoisothiazolidine instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 3.93-3.91 (m, 4H), 3.59 (s, 3H), 2.38-2.31 (m, 2H), 1.06-1.01 (m, 1H), 0.44-0.39 (m, 2H), 0.20-0.16 (m, 2H). LCMS: 427.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cc(-c2ocnc2C(=O)O)ccc1C
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COc1cc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)ccc1C

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-4-methyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:45]=[N+:46]=[N-:47].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:47][N:46]=[N:45][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.17 g (0.34 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethoxy}-3,5-dimethyl-benzonitrile in 4 ml o-xylene, were added 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide and the solution was heated at 150° C. (oil bath temperature) for 19.5 h. Another 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide were added and the reaction mixture was heated for an additional 4 h, then stirred for 3 days at room temperature. The reaction mixture was poured onto aqueous 1M hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in acetonitrile, filtered and washed with acetonitrile. The obtained crude material was purified on a preparative HPLC (Zorbax column) eluting with a gradient of acetonitrile and water containing 0.5% formic acid. White solid (18%). MS (Turbo Spray): m/z=549.199 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methyl 4-hydroxybenzoate (609 mg, 4.00 mmol), 1-(4-bromophenyl)-3-methylbutan-1-ol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1 M HCl (3×100 mL) and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-(4-bromophenyl)-3-methylbutoxy)benzoate (1.4 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.89-7.83 (m, 2H), 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 6.83-6.78 (m, 2H), 5.16 (dd, J=9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.75 (m, 1H), 1.58-1.51 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[K].C(O[C:18]([S-])=[S:19])C.Cl>N1C=CC=CC=1>[Cl:13][C:9]1[CH:10]=[C:11]2[O:12][C:18](=[S:19])[NH:1][C:2]2=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1cc(Cl)cc(O)c1N
Agent: Cl
Agent: [K]
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)cc2oc(=S)[nH]c12
Temperature: 125 °C
Yield: 99.3 %

Procedure:
To a mixture of methyl 2-amino-5-chloro-3-hydroxybenzoate (4.00 g, 19.84 mmol) in anhydrous pyridine (30 mL) was added potassium-O-ethylxanthate (3.50 g, 21.82 mmol), and the reaction mixture heated to 125° C. for 3 h under nitrogen atmosphere. The warm solution was poured into a mixture of concentrated HCl (12 mL) and ice (120 mL), the resulting precipitate filtered, and dried under vacuum to provide methyl 6-chloro-2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (4.80 g, 99%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 4.01 (s, 3H); MS (ESI+) m/z 244 (M+H).
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:21][CH:22]=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.B(Br)(Br)Br>CCCCCC>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH:21][CH:22]=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(Cc2ccc(F)cc2)NC=O)cc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CNC(Cc1ccc(F)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a -20° C. CH2Cl2 (100 mL) solution of N-[1-(4-methoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (1.6 g, 5.86 mmol) (for preparation see step A of Example 48) was added 11 mL of 1N BBr3 in hexane. After warming to 0° C. and stirring for one hour, an additional 5 mL of BBr3 solution was added. After 40 minutes, the reaction was complete by HPLC analysis. The reaction was quenched upon transferal into a stirred 4° C. aqueous NaHCO3 solution and extracted with CH2Cl2 (3×). The organic phases were washed with pH 4 NaH2PO4, brine, dried over Na2SO4 and concentrated to yield 1.4 g of N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide as a yellow solid. To a 50° C. DMF (10 mL) containing benzyl bromide (400 mg, 2.3 mmol) and N-[1-(4-hydroxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (450 mg, 1.7 mmol) under N2 was added 60% NaH (200 mg, 5 mmol). After one hour the reaction was quenched with H2O, extracted with EtOAc (3×). The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 1 g of crude product. Flash chromatography on silica gel using 1:1 EtOAc/hexane eluted 300 mg of N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide. A 1:1 ETOH/H2O solution (10 mL) containing N-[1-(4-phenylmethoxyphenyl)-2-(4-fluorophenyl)ethyl]formamide (300 mg, 0.86 mmol) and NaOH (200 mg, 5 mmol) was refluxed for 40 hours, diluted with H2O and extracted 3× with EtOAc. The organic phases were washed with H2O (3×), brine, dried over Na2SO4 and concentrated to yield 290 mg of α-(4-phenylmethoxyphenyl)-4-fluorobenzeneethanamine.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[OH-].[K+]>[Cu].C1C2C(CCCC2)CCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Product: Brc1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 25.1 %

Procedure:
A mixture of 9.2 g (38 mmol) of 9H-tribenz[b,d,f]azepine (synthesized in accordance with J. Org. Chem., vol. 56, p. 3906 (1991)), 44.8 g (190 mmol) of 1,4-dibromobenzene, 5.6 g (100 mmol) of potassium hydroxide, 1.6 g (25 mmol) of copper powder, and 50 ml of decalin was heated at an external temperature of 200° C. for 36 hours in a nitrogen stream while stirring. The reaction mixture was worked up in the same manner as in Example 1, and the resulting crude product was purified by silica gel column chromatography to give 3.8 g (25%) of 9-(4-bromophenyl)-9H-tribenz[b,d,f]azepine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:21])=[S:20]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:21]=[CH:19][S:20][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: NC=S
Solvent: CCO
Product: c1ccc(COc2ccc(-c3cscn3)cc2)cc1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
A mixture of 4'-benzyloxy-2-bromoacetophenone (3.0 g) and thioformamide (0.63 g) in ethanol (50 ml) was refluxed under heating for 30 minutes. The reaction mixture was poured into ice-water, and the precipitating crystals were collected by filtration, extracted with diethyl ether and purified by column chromatography on silica gel [eluting solvent: methylene chloride-hexane (1:9)] to give 4-(4-benzyloxyphenyl) thiazole (720 mg, 27.7%), which was further purified by recrystallization from diethyl ether-hexane. m.p. 109°-110° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])([OH:14])=[O:12]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of methyl E-4-[5-[2-(t-butoxycarbonyl)-1-propenyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (6.4 g) in a small volume of methylene chloride (10 ml) cooled in an ice-bath. After 1.5 hr, the solution was evaporated (at approximately room temperature), and the residue was crystallized from methanol to give methyl E-4-[5-(2-carboxy-1-propenyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g, 75%) as a white powder: mp 182°-183° C.: partial NMR (250 MHz, DMSO-d6): 2.03(s, 3H, CCH3), 3.75(s, 3H), 3.83(s, 3H), 3.90 (s, 3H), 4.06(s, 2H, ArCH2Ar').
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4cccc([N+](=O)[O-])c4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (40 mg, 0.1 18 mmol) (from Example 5 supra) and Et3N (33 μL , 0.237 mmol) in 3 mL of chloroform was cooled to −78° C. and then treated with 3-nitrobenzoyl chloride (24 mg, 0.129 mmol) (Aldrich). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 7 h. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was dissolved in ethanol, and re-precipitated by the addition of distilled water to yield pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-nitrobenzamide (yield: 50 mg, 94%) as a yellow solid (mp 265-266° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:15])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Clc1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.3 mg). Calcd for C21H18C12 N2O2: 400.0745, found 400.0750.