Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH2:29][CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]2)=[C:36]2[C:40]=1[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C@H:43]4[CH2:44][CH2:45][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:48]4)=[C:36]4[C:40]=3[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH2:29][CH3:30])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-ethoxybenzyl)phosphonate (Compound 244A, 29.84 mg, 0.064 mmol) and ethyl trans-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (22.2 mg, 0.070 mmol). 31.2 mg (65%) of the desired product was isolated after work-up/chromatography. 1H NMR (400 MHz, MeOD) δ ppm 8.48 (d, J=7.83 Hz, 1 H), 8.35 (s, 1 H), 7.87 (d, J=8.08 Hz, 1 H), 7.38 (d, J=8.84 Hz, 1 H), 7.05 (s, 1 H), 6.94 (dt, J=8.08, 2.27 Hz, 1 H), 4.52 (s, 2 H), 4.04-4.22 (m, 8 H), 3.28 (s, 2 H), 3.19 (s, 3 H), 2.63 (t, J=11.62 Hz, 1 H), 2.42-2.54 (m, 1 H), 2.13 (d, J=14.15 Hz, 2 H), 1.90-1.99 (m, 2 H), 1.54-1.77 (m, 4 H), 1.41 (t, J=6.95 Hz, 3 H), 1.24-1.33 (m, 9 H). MS (ES+): m/z 748.26/749.29 (100/98) [MH+]. HPLC: tR=1.80 min (Micromass TOF: polar—3 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH2:5][CH:6]1[CH2:8][O:7]1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1.O>CN(C)C=O>[OH:7][CH:6]([CH2:5][C:4]1[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([OH:12])=[C:2]([CH3:1])[CH:3]=1)[CH2:8][N:21]1[C:17](=[O:23])[CH2:18][CH2:19][C:20]1=[O:22]
Reactant: Cc1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: O=C1CCC(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CC(O)CN2C(=O)CCC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 6.6 g (0.03 mol) of 3-methyl-5-tert.-butyl-4-hydroxybenzyl-oxirane and 3 g (0.03 mol) of succinimide in 30 ml of dimethylformamide is stirred for 18 hours at a temperature of 150°-55° C whilst passing a slight stream of nitrogen through the mixture. After cooling to room temperature, the reaction mixture is poured into 150 ml of water and the oily reaction product which precipitates is dissolved in toluene. Successive extraction of the toluene phase with dilute hydrochloric acid, 5% strength aqueous sodium bicarbonate solution and water, drying over sodium sulphate and evaporation of the solvent gives the crude product. After recrystallisation from methylcellosolve, 6.5 g (68% of theory) of N-[2-hydroxy-3-(3-methyl-5-tert.-butyl-4-hydroxyphenyl)-propyl]-succinimide of melting point 217.5°-218° C are obtained in the form of colourless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1([CH:14]([CH3:24])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:26][CH2:27][CH2:28][C:29]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)OCC[O:30]1>CC(N(C)C)=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:11]2[CH2:12][CH2:13][C:8]([CH:14]([CH3:24])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])([OH:7])[CH2:9][CH2:10]2)=[CH:39][CH:38]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: CC(C(=O)Nc1ccccc1)C1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C(=O)Nc1ccccc1)C1(O)CCN(CCCC(=O)c2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
11.0 g of potassium carbonate are added to a solution of 11.0 g of crude 2-(4-hydroxy-4-piperidyl)-N-phenylpropionamide in 150 cc of dimethyl acetamide and the mixture is heated to 100° while stirring. A solution of 13.1 g of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3-dioxolane in 20 cc of dimethyl acetamide is subsequently added dropwise while stirring vigorously and the temperature is kept at 100° for 4 hours. The solution is subsequently cooled and the potassium carbonate is filtered off and the filtrate concentrated by evaporation at reduced pressure. The resulting compound is used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: COC[C@H]1CCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (R)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[N:11]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:12]3[CH:13]=[CH:14][NH:10][N:11]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1cc[nH]n1
Reactant: Nc1cc(Br)cnc1N
Product: Brc1cnc2[nH]c(-c3cc[nH]n3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and pyrazole-3-carbaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.070 g, 29% yield). LCMS: 557.40 (M+1)+; HPLC % 98.83 (@254 nm) (Rt; 4.303; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H, J=4 Hz), 7.56 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=8 Hz), 7.28 (s, 1H), 7.13 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.57 (m, 4H), 3.48 (s, 2H), 2.74 (t, 1H), 2.64 (s, 3H), 2.36 (m, 4H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69-1.71 (m, 3H), 1.53-1.56 (m, 2H), 1.41-1.44 (m, 2H), 1.10-1.23 (m, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:12]([S:19](Cl)(=[O:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[OH-].[Na+].O.CCOCC>[CH2:12]([S:19]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:21])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: On1nnc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(Cc1ccccc1)On1nnc2ccc(Cl)cc21
Yield: 56.5 %

Procedure:
In 1 N aqueous sodium hydroxide (13.0 ml) and water is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (2.23 g) and thereto is added dropwise a solution of benzylsulfonyl chloride (2.5 g) in ether (50 ml) under ice-cooling and stirring, and the mixture is stirred at the same temperature for 1.5 hours and further at room temperature for 1 hour. The reaction mixture is distilled to remove ether. To the resulting residue is added ethyl acetate. The ethyl acetate layer is dried and distilled to remove the solvent. The residue is recrystallized from benzene-n-hexane to give white needles of 1-benzylsulfonyloxy-6-chloro-1,2,3-benzotriazole (2.4 g), melting point: 126.5°-127.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:24]=1)[C:20]#[N:21]
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3cc(F)cc(C#N)c3)nc2)cs1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (30 mmol, 7.02 g) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (30 mmol, crude material, above procedure), dichlorobis(triphenylphosphine)palladium(II) (1.5 mmol, 1.05 g), and potassium carbonate (120 mmol, 16.6 g) were added to deoxygenated DME:water (1:1, 300 mL) at room temperature. The reaction was warmed to 80° C. and stirred overnight under nitrogen, then partitioned in a separatory funnel with EtOAc (500 mL) and water (300 mL). The organic layer was washed with one additional portion of water (100 mL) and the combined aqueous layers back extracted with EtOAc (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 30% EtOAc in hexanes, to afford the title compound as a tan solid. 1H-NMR (CDCl3, 500 MHz) δ 8.89 (m, 1H), 8.17 (dd, 1H), 8.04 (m, 1H), 7.98 (dd, 1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.42 (m, 1H), 2.79 (s, 3H). MS (ESI) 320.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])=[CH:17][CH:18]=3)[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].CO>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of 4-(3-cyano-5-benzyloxycarbonylindol-1-yl)benzoic acid ethyl ester (0.16 g) in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL) was added palladium-carbon powder (0.03 g) at 0° C. under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.057 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH:18]1([SH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([S:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: SC1CCCCC1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSC3CCCCC3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198°-199° C.) and cyclohexyl mercaptan.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(-c2onc3ccccc23)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2onc3ccccc23)cc1
Yield: 87.2 %

Procedure:
A solution of 24.5 g (0.11 mole) of 3-(4-ethylphenyl)-2,1-benzisoxazole in 330 ml of carbon tetrachloride was heated to reflux and treated with 19.6 g (0.11 mole) of N-bromosuccinimide and 10 mg of benzoyl peroxide. The mixture was maintained at reflux by illumination with a floodlamp for 20 min, at which time all insoluble material was floating. The mixture was cooled and filtered. The filtrate was washed with dilute sodium bicarbonate solution and the organic fraction was concentrated to a yellow solid. The solid was recrystallized from 200 ml of isopropanol to give 29.0 g (87%) of yellow crystals, m.p. 105.5°-8.0° C.
Reaction SMILES: [F:1][CH:2]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[CH2:13][CH:14]=C)[F:3].[O:16]=[O+][O-]>ClCCl>[F:1][CH:2]([F:3])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[CH2:13][CH:14]=[O:16]
Reactant: C=CCc1c(C)cc(C)cc1OC(F)F
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: Cc1cc(C)c(CC=O)c(OC(F)F)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
16.5 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenyl difluoromethyl ether were dissolved in 50 ml of dichloromethane and the solution was cooled to −70° C. Ozone was passed through the solution for one hour until the olefin was no longer detectable. The vessel was subsequently flushed with a stream of nitrogen, 13.7 g of dimethyl sulphide were added, and stirring of the mixture was continued for 30 minutes. The solution was warmed to room temperature and stirring was continued for a further 30 minutes. After the solution was free from peroxides, it was concentrated, and the residue was employed in the next reaction without further purification. 19.2 g of 2-difluoromethyloxy-4,6-dimethylphenylacetaldehyde were obtained as crude product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[N:3]1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])\[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Cn1ncc2c(O)cccc21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc2c1cnn2C
Yield: 74.2 %

Procedure:
A mixture of 1-methyl-1H-indazol-4-ol (0.130 g, 0.88 mmol), ethyl-2-butynoate (0.59 g, 5.26 mmol), a catalytic amount of 4-dimethylaminopyridine, and potassium carbonate (0.120 g, 0.88 mmol) in tetrahydrofuran (10 mL) in a sealed tube was heated at 80° C. for 14 h. The reaction mixture was then filtered. The solids were washed with a small amount of tetrahydrofuran and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 0% to 40% ethyl acetate/hexanes) which afforded (E)-3-(1-methyl-1H-indazol-4-yloxy)-but-2-enoic acid ethyl ester (0.170 g, 74%) as a viscous tan oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: COc1cccc(CCN2CCC[C@@H](Cl)C2)c1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Sixty-percent sodium hydride (0.30 g, 7.5 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 990 mg (5.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.4 g (5.5 mmols) of (R)-(-)-3-chloro-1-(3-methoxyphenethyl)piperidine [[α]D25 =-8.9° (c=1.2, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 45° C. for 2.5 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was then distilled off under reduced pressure. The thus-obtained residue was further subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was distilled off under reduced pressure to give 1.64 g of (S)-(-)-5,11-dihydro-5-[1-(3-methoxyphenethyl)-2-pyrrolidinylmethyl]-dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 79%.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(O)C>[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][CH:15]=3)[NH:1]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(OCCCl)cc1
Reactant: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(N2C(=O)c3cccc(OC)c3NC2c2ccc(OCCCl)cc2)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of 20.05 g (0.0736 mol) of 2-amino-N-(4-methoxy-phenyl)-3-methoxy-benzamide in 400 mL of ethanol was added 13.6 g (0.0736 mol) of p-(2-chloro-ethoxy)-benzaldehyde (Frinton Labs), and 10 mL of acetic acid. The reaction mixture was stirred and heated to a mild reflux overnight. After cooling to room temperature, the solvent was evaporated in a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate and washed with water (4×100 mL). The organic phase was removed, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The residual oil was placed under the vacuum pump, which yielded 26.0 g (mp 122-124° C.) of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(O)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)nn1C
Reaction time: 2.5 h
Yield: 17.4 %

Procedure:
To a solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (2.3 g, 16 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (5.27 g, 16 mmol) and methyl iodide (2.3 g, 1.0 mL, 16 mmol) and the resulting mixture stirred for 2.5 h. The mixture was then filtered off to afford the title compound (434 mg, 17%) as a white solid after trituration with ethyl acetate. MS: m/e=157.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Clc1nc2ccccc2o1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in toluene (25 mL) was added 2-chlorobenzoxazole (0.66 mL, 5.79 mmol). The purple solution was heated at reflux for 30 min and then at 100° C. for 17 h. The resulting white suspension/purple solution was cooled to room temperature and the precipitate was filtered. The filter cake was washed with five 2-mL portions of heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzoxazol-2-amine (1.480 g, 92%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=12.87 min, 97%; m/z 307 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH:9]1[CH2:17][CH2:16][CH:12]([C:13](O)=O)[CH2:11][CH2:10]1.[OH-].[Na+]>>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[CH:12]1[CH2:16][CH2:17][NH:9][CH2:10][CH2:11]1
Reactant: Nc1ccccc1O
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2oc(C3CCNCC3)nc2c1
Yield: 12.2 %

Procedure:
A mixture of 2-aminophenol (20 g, 183 mmol), isonipecotic acid (23.7 g, 1 mol. equiv.) and polyphosphoric acid (50 ml) was heated together for 2 hours with stirring. The reaction mixture was cooled, poured onto ice (400 g) and solid sodium hydroxide (85 g) added until the solution achieved pH8. The solid was filtered off, slurried in water (500 ml) and filtered to give the title compound (4.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[NH:12]1[CH:16]=[N:15][C:14]([SH:17])=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][C:14]2[N:15]=[CH:16][NH:12][N:13]=2)=[C:3]([NH2:9])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2nc[nH]n2)c(N)c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 1H-[1,2,4]Triazole-3-thiol (1.94 g, 19.2 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.1 g, 26%).