Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:40][OH:41].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([NH:40][OH:41])=[NH:24])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C(=N)NO
Temperature: 150 °C
Yield: 50.9 %

Procedure:
To a solution of 300 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-benzonitrile in 1.8 mL of tetrahydrofuran and 2 mL of methanol was added 387 mg of hydroxylamine hydrochloride followed by 0.62 mL of triethylamine. The resulting mixture was heated to 150° C. under microwave irradiation for 10 minutes. After allowing it to cool down to room temperature, the mixture was concentrated under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 50/ethyl acetate 50) to give 162 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-methoxy-benzamidine.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[C:1]([NH:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1cccc(C#N)c1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccc(C#N)c1)NC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 90.4 %

Procedure:
A suspension of methyl 2-(benzoylamino)-3-(3-cyanophenyl)2-propenoate (300 mg, 0.979 mmol) and 5% palladium/barium sulfate (60 mg) in tetrahydrofuran (3 mL) was stirred at 50° C. for 7.5 hours under a hydrogen flow. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and 5% palladium/barium sulfate (90 mg) was added to the solution. The mixture was stirred at 50° C. for 8 hours under a hydrogen flow. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (273 mg, 90%).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>>[NH2:23][C:19]1[CH:18]=[C:17]([CH:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(N)c1

Procedure:
Corresponding to Example 3b, 3 g of (4a) were reduced using tin-(II) dichloride. A white solid was obtained (yield: 2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH:14]([CH3:15])[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(CCC(O)C(C)C)cc1N
Product: COC(=O)c1sc(CCC(O)C(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-(3-hydroxy-4-methylpentyl)thiophene-2-carboxylic acid methyl ester was reacted with dimethoxymethyldimethylamine by method B. The product with the molecular weight of 312.43 (C15H24N2O3S) was obtained in this way; MS (ESI): 313 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[NH:18])OCC)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:26]([NH:28][NH2:29])=[O:27]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([NH:29][NH:28][CH:26]=[O:27])=[NH:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=N)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: NNC=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NNC=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 0.25 h

Procedure:
To a mixture of 120 g (0.42 mole) of ethyl 5-(4-chlorophenyl)-2-furimidate hydrochloride in 700 ml of absolute ethanol was added dropwise 62 ml (0.46 mole) of triethylamine at a temperature of 2°-4° while under a nitrogen atmosphere. To this stirring mixture was added portionwise 28 g (0.47 mole) of formic acid hydrazide while maintaining the temperature at 4°-7° by means of an ice bath. The mixture was kept at 5°-7° for 15 minutes, allowed to warm to 23° over a 21/2 hour period, cooled to 10°, filtered, and washed in stirring S.D.A #32 to yield 52 g (47%). An analytical sample was prepared by drying a sample in a vacuum pistol with refluxing chloroform, m.p. 155°-157° (Mel-Temp).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][C:17](OC)=[O:18].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:23][Si:2]([CH3:1])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][CH2:17][OH:18]
Reactant: COC(=O)C=C[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H](C=CCO)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -95 °C
Reaction time: 1 h

Procedure:
A 3.66 g amount of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml of hexane and 40 ml of toluene were then added to dissolve it. The solution was cooled to -95° C., then 12.2 ml of diisobutylaluminum hydride was slowly added and the solution stirred at the same temperature for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The consumption of the material was confirmed by thin layer chromatography, then the excess reducing agent was broken down by methanol and a saturated aqueous solution of sodium sulfate and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution of ammonia chloride were added for separation. Extraction was performed from the aqueous layer by 100 ml of ethyl acetate, then the organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 to 4/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l]-2-penten-1-ol in an amount of 3.31 g (98%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[O:15][CH2:16][C:17](O)=[O:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[NH2:39][OH:40].C[O-].[Na+]>O1CCCC1>[OH:40][NH:39][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)COc1cccc(NC(=O)C=Cc2ccccc2)c1
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: C[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(OCC(=O)NO)c1
Reaction time: 0.33 h
Yield: 28.8 %

Procedure:
To a solution of [3-(3-phenyl-acryloylamino)-phenoxy]-acetic acid (9) (0.297 g, 1.0 mmol) in tetrahydrofuran (3 ml) at 0÷5° C. temperature (ice bath) triethylamine (0.18 ml, 1.3 mmol) followed by iso-butyl chloroformate (0.15 ml, 1.15 mmol) were added. The reaction mixture was stirred for 20 min. In another vessel, a mixture of hydroxylamine hydrochloride (0.122 g, 1.7 mmol) and sodium methoxide (0.095 mg, 1.75 mmol) was prepared. The both mixtures were combined and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (20 ml) and the organic layer was washed successively with 1N KH2PO4, water, brine, and dried (Na2SO4). The solvent was partially removed until the formation of a precipitate started. The mixture was allowed to stand at room temperature for 6 hours. The precipitate was filtered and washed with diethyl ether to give the title compound (0.090 g, 30%). M.p. 163° C. (dec.). 1H NMR (DMSO-d6, HMDSO), δ: 4.45 (s, 2H); 6.60-6.73 (m, 1H); 6.83 (d, 1H, J=15.6 Hz); 7.18-7.30 (m, 2H); 7.36-7.51 (m, 4H); 7.53-7.68 (m, 3H); 8.98 (s, 1H); 10.23 (s,1H); 10.87 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities ˜1% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4, gradient from 50:50 to 100:0; detector UV 270 nm; sample concentration 0.7 mg/ml, flow rate 1.0 ml/min). Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16, N 8.97. Found: C, 65.09, H, 5.14, N, 8.73.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH:1]=[O:3])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC=O)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of acetic anhydride (0.33 mL, 3.57 mmol) and formic acid (0.17 mL, 4.46 mmol) was heated at 60° C. for 2 hours. The reaction mixture was cooled to 0° C., a solution of (4-amino-phenyl)-acetic acid ethyl ester (Preparation 267, 500 mg, 2.79 mmol) in THF (10 mL) was added slowly to the reaction mixture and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was neutralized with sat. aq. Na2CO3 solution and extracted with diethyl ether (2×25 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:MeOH 100:0 to 98:2) to afford the title compound as an oil in 93% yield, 500 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15])C.[OH-].[Na+]>CO>[CH3:1][O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15]
Reactant: CCOC(=O)CCCOc1ccccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCCOc1ccccc1I
Yield: 93.9 %

Procedure:
Under the conditions of example 5A, 1 g of 4-(2-iodophenoxy)-butyric acid ethyl ester in 10 ml of methanol and 10 ml of 1 n sodium hydroxide solution is saponified, worked up, and 900 mg of 4-(2-iodophenoxy)-butyric acid methyl ester with a melting point of 66.5°-67° C. is obtained.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:22]([C:25]1[C:26]([C:30]([OH:32])=O)=[N:27][NH:28][CH:29]=1)([O-:24])=[O:23].Cl.Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH2:46])[C:40]([NH2:45])=[CH:41][C:42]=1[O:43][CH3:44]>CN(C=O)C>[NH2:45][C:40]1[CH:41]=[C:42]([O:43][CH3:44])[C:37]([O:36][CH3:35])=[CH:38][C:39]=1[NH:46][C:30]([C:26]1[C:25]([N+:22]([O-:24])=[O:23])=[CH:29][NH:28][N:27]=1)=[O:32]
Reactant: COc1cc(N)c(N)cc1OC
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of EDC (4.81 g, 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-1H-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-1,2-diamine, dihydrochloride (5.06 g, 20.99 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between ethyl acetate (50 ml) and sodium bicarbonate (50 ml). A precipitate was formed and removed by filtration. This was washed with water followed by diethyl ether and then azeotroped with methanol and toluene to yield 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 36%).
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][C@H:2]1[O:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:3]1=[O:4]
Reactant: CC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1OC[C@@H](c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide from Step A (1.30 g, 5.71 mmol) in THF (100 mL) at 0° C. was added NaH (493 mg of a 60% dispersion in oil, 12.3 mmol) and the mixture was stirred at ambient temperature for 18 h. Saturated aqueous NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—75:25 to 0:100, to give the title compound. MS: m/z=192 (M+1).
Reaction SMILES: C1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])C=CC=CC=1.[CH2:15]([Ba:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(C1C=CC=CC=1)C.O1CCCC1>[C:24]1([C:23]([Ba:22][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(C[Ba]Cc2ccccc2)cc1
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CCC([Ba]C(CCc2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
2.50 ml (14.15 mmol) of 1,1-diphenylethylene were added at 25° C. to a suspension of 1.78 g (5.58 mmol) of dibenzylbarium in 70 ml of ethylbenzene and 10 ml of tetrahydrofuran (THF). Stirring for 14 hours resulted in a deep red solution. The solution was filtered off from small amounts of insoluble constituents and then evaporated to dryness. Solvent-free bis(1,1,3-triphenylpropyl)barium was firstly obtained as a very viscous, red-violet oil and, after prolonged drying, as a tough solid. The conversion was virtually quantitative.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=1>C(O)C.O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]2[CH:7]=[C:2]3[N:1]([CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:12][CH:11]=1
Reactant: Cc1ccccn1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc3ccccn3c2)cc1
Yield: 83.4 %

Procedure:
10 g of 2-picoline and 25 g of 4-methoxyphenacyl bromide in 35 ml of ethanol were refluxed for 18 hours. The reaction solution was concentrated under reduced pressure to give a solid, which was dissolved in 350 ml of water. After the aqueous solution was extracted with three 35 ml portions of ether, 35 g of sodium bicarbonate was added to the aqueous solution and was refluxed two hours. The cooled reaction mixture was filtered to give 20 g of product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:27][OH:28])[C:16]([N:19]3[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[C:17]([F:18])[C:12]=2[O:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([NH:8][C:9]1[C:13]2[CH:14]=[C:15]([CH:27]=[O:28])[C:16]([N:19]3[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[C:17]([F:18])[C:12]=2[O:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2c(CO)cc3c(NCc4ccccc4)noc3c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(NCc4ccccc4)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of {3-(benzylamino)-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazol-5-yl}methanol (Intermediate 504, 160 mg, 0.41 mmol) in acetonitrile (2 mL) was added NMO (73 mg, 1.5 mmol) followed TPAP (15 mg, 0.1 mmol) and mixture stirred for 2 hours at room temperature. The reaction mixture filtered thorough silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give title compound as a yellow solid. Yield: 75 mg, (47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.C(OC=C)=C>CN(C=O)C.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:30]([O:32][CH2:33][CH3:34])=[CH2:31])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=COC=C
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(OCc2ccccc2)cc2nc(NC(=O)NCC)sc12
Temperature: 100 °C

Procedure:
1-(5-benzyloxy-7-bromo-1,3-benzothiazol-2-yl)-3-ethyl-urea (1 g, 2.46 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (1.77 g, 4.92 mmol) were dissolved in DMF (30 mL) and the mixture deoxygenated by bubbling N2 through the solution for 20 min. Pd(PPh3)4, (284 mg, 0.246 mmol) was added and the reaction heated to 100° C. for 4 h under a N2 atmosphere, at the end of which time LCMS indicated clean formation of the vinyl ether. The reaction was concentrated under reduced pressure, diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:33])[CH2:22][C:23]4[CH:32]=[CH:31][C:26]5C(=O)OC[C:25]=5[CH:24]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNCC1.[N:55]1[O:56][N:57]=C2C=C(CC(=O)C)C=CC=12>>[N:55]1[O:56][N:57]=[C:25]2[CH:24]=[C:23]([CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][C:9]4[CH:10]=[CH:11][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)[CH2:20][CH2:19]3)[CH3:33])[CH:32]=[CH:31][C:26]=12
Reactant: CC(Cc1ccc2c(c1)COC2=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Reactant: CC(=O)Cc1ccc2nonc2c1
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Product: CC(Cc1ccc2nonc2c1)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1

Procedure:
1-{4-[1-(2,1,3-Benzoxadiazol-5-yl)propan-2-yl]piperazin-1-yl}-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone was prepared in an analogous fashion to that described above for the synthesis of 5-[2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)propyl]-2-benzofuran-1(3H)-one starting from 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride and 1-(2,1,3-benzoxadiazol-5-yl)propan-2-one. LC/MS: [(M+1)]+=433.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:18]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[OH-].[Na+]>ClC(Cl)C>[CH3:14][C:12]1[N:11]=[CH:10][N:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:15][C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:19]=4[N:20]=3)=[CH:4][C:3]=2[OH:2])[CH:13]=1
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2O)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
To a suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine (200 mg, 0.48 mmol) in dichloroethane (4.8 mL) was added under nitrogen at room temperature borontribromide (528 uL, 0.53 mmol) and the reaction was refluxed for 2 hours. The same amount of borontribromide was added and the reaction was refluxed for 2 hours, again the same amount of borontribromide was added and the reaction was refluxed for 1 hour, stirred at room temperature for 3 days. The reaction was set to pH 7 with aqueous sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol/concentrated aqueous ammonia (9:1:0.1 v/v/v) as eluent to yield the title compound (70 mg, 36%) as a beige solid. MS ISP (m/e): 403.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.06 (s, 2H), 7.64 (s, 1H), 7.25-7.31 (m, 2H), 7.17 (t, 1H), 7.00-7.11 (m, 6H), 4.04 (m, 1H), 2.71 (m, 2H), 2.19 (m, 1H), 2.13 (s, 3H), 1.66-1.85 (m, 3H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[S:10][C:11]=1[CH3:12].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCCl>[C:17]([C:8]1[C:7]([CH3:6])=[C:11]([CH3:12])[S:10][C:9]=1[NH:13][C:14](=[O:16])[CH3:15])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1cc(C)c(C)s1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)Nc1sc(C)c(C)c1C(=O)c1ccccc1
Yield: 82.4 %

Procedure:
General Method A. A solution of 1.71 M tin (IV) chloride (3.1 mL, 5.3 mmole) in 1,2-dichloroethane was added dropwise to a suspension of 9 (0.241 g, 1.42 mmole) and benzoyl chloride (0.31 mL, 2.66 mmole) in 1,2-dichloroethane and the mixture was refluxed for 10.5 hours. The reaction was quenched with ice and the organic phase was washed sequentially with 2N HCI, water and 2N NaOH. Drying over CaCl2 and evaporation gave a solid that was purified by chromatography on silica gel eluted with pet. ether-ethyl acetate 5:1. Recrystallization from water:gave 0.32 g of pure product as yellow crystals, 82%. 1H NMR (CDCl3) δ: 1.6 (s, 3H, CH3), 2.23.(s, 3H, CH3), 2.24 (s, 3H, CH3), 7.4–7.6 (m, 5H, C6H5), 11.1 (br s, 1H, NH.) 13C NMR (CDCl3) δ: 12.4, 14.8, 23.6, 122.4, 124.7, 127.6, 128.3, 128.4, 131.9, 140.3, 146.4, 167.4, 195.0.