Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.C([C:17]1[CH:26]=[CH:25][C:20]([C:21](OC)=O)=[CH:19][CH:18]=1)=O.[C:27]([O-])(=O)[CH3:28].[K+].II>C(OC(=O)C)(=O)C.CO>[C:27]1([CH:28]=[CH:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:13]=[C:12]([CH:14]=[CH:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:26][CH:25]=4)[CH:11]=[CH:10][N:9]=3)[CH:3]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)[O-]
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Agent: II
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: C(=Cc1ccnc(-c2cc(C=Cc3ccccc3)ccn2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4,4′-Dimethyl-2,2′-bipyridine and methyl 4-formylbenzoate were purchased from Aldrich and Fluka respectively. 4,4′-Di(phenylethenyl)-2,2′-bipyridine 3 was prepared by hydrolysis of the styryl ester 2, which was synthesized from 4,4′-Dimethyl-2,2′-bipyridine 1 by a modified version of the previously described procedure (see Klein et al., 2005 below) as follows: 4,4′-Dimethyl-2,2′-bipyridine (11.054 g, 0.06 mol) and methyl 4-formylbenzoate (29.549 g, 0.18 mol) were dispersed in acetic anhydride (16 mL) then dry potassium acetate (5.889, 0.06 mol) and iodine (50 mg, 2×10−4 mol) were added. The resulting mixture was heated under reflux for 48 h. After cooling, methanol (200 mL) was added and the resulting fine off-white crystals were filtered off. The solid was stirred for 5 minutes with boiling methoxyethanol (400 mL), the mixture allowed to cool to RT, and the crystalline product filtered off and dried to give pure styryl ester (19.449 g, 72%). The compound gave spectroscopic data identical to that previously reported. 4,4′-Dicarboxy(phenylethenyl)-2,2′-bipyridine 3 was then obtained in quantitative yield from the styryl ester according to the literature procedure. (Engineering of a Novel Ruthenium Sensitizer and its Application in Dye-Sensitized Solar Cells for Conversion of Sunlight into Electricity, C. Klein, Md. K. Nazeeruddin P. Liska, Davide Di Censo, N. Hirata, E. Palomares, J. R. Durrant and M. Grätzel, Inorg. Chem. 44, 178-180, 2005).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([C:8]#N)[CH:7]=1.C(O)=[O:12]>O.C1(C)C=CC=CC=1.[Ni].[Al]>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH:8]=[O:12])[CH:7]=1
Reactant: O=CO
Reactant: N#Cc1cnc(Cl)c(Br)c1
Agent: [Ni]
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cnc(Cl)c(Br)c1
Reaction time: 48 h

Procedure:
3-Bromo-2-chloro-5-cyanopyridine (8.6 g) in 90% formic acid (40 ml) and water (10 ml) were treated with Raney nickel/aluminum alloy (8.0 g) and the mixture stirred and heated to 55°-60° for 6 hours. The mixture was left to stand for two days, and then filtered. The filtrate was diluted to 500 ml with water and extracted with ether (2×250 ml). The ether extract was washed with aqueous sodium carbonate, dried, and evaporated to give an oil. The oil was diluted with toluene which was then removed under reduced pressure. The residue was diluted with a little ether, the solution filtered, and the filtrate evaporated to give an oil identified as the required aldehyde.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:38][N:3]1[CH2:4][CH:5]=[C:6]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[CH:18]=2)=[O:12])[CH2:7][CH2:8]1
Reactant: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1nnc(C(=O)NCC2=CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride (30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.47 mmol, 0.1 g) was added and stirred at room temperature for 2 h. The reaction was diluted with DCM (5 mL), and the DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM-6% (NH3 in MeOH, 2M) in DCM to provide 6-Butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1-methyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide, which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and solid was dried under high vacuum (38 mg). LCMS: m/z 464.1 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.38 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 5.71 (1H, s), 4.40-4.50 (1H, m), 4.11 (2H, s) 3.88 (1H, d), 3.55-3.70 (2H, m), 3.17-3.28 (3H, m), 2.94 (3H, s), 2.52-2.66 (1H, m), 2.44 (1H, d), 1.97-2.10 (2H, m), 1.75-1.88 (2H, m), 1.25-1.70 (10H, m), 0.84 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7]CC)=O.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[C:29](#[N:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:4]=1[C:5](=[O:7])[NH:38][C:29]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[CH:14]2
Reactant: COc1ccc(C#N)cc1
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1ccc(-c2cc3cccc(OC)c3c(=O)[nH]2)cc1
Reaction time: 0.75 h
Yield: 13.7 %

Procedure:
Ethyl 2-methoxy-6-methylbenzoate (5.011 g) was dissolved in tetrahydrofuran (20 ml), followed by the addition of 1.5M lithium diisopropylamide/cyclohexane solution (19 ml) in nitrogen atmosphere at −70° C. The resulting mixture was stirred for 45 min. Anisonitrile (3.462 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture. The cooling bath was removed, and then the mixture was stirred for 100 min. An aqueous solution of saturated ammonium chloride and ethyl acetate were added to the reaction solution, and the mixture was stirred for 30 min. The resulting insoluble matters were collected by filtration, and then washed with ethyl acetate and water, to give the title compound as a pale yellow solid (991 mg, yield; 13%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc([C@@H](N)CO)cc1
Reactant: CC(C)(C)N=C=S
Solvent: O
Solvent: CCO
Product: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 5.78 g of (2R)-2-amino-2-(4-methoxyphenyl)-1-ethanol and 6.48 cm3 of tert-butyl isothiocyanate in 73 cm3 of ethanol for 17 h 30 minutes at a temperature in the region of 20° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the solid residue obtained is then ground in 45 cm3 of water, filtered and washed with twice 20 cm3 of water and twice 25 cm3 of diethyl ether. The crystals are dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 45° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)2-hydroxyethyl]-thiourea are obtained in the form of a white solid. (Rf=0.60 in ethyl acetate, on a Merck 60F254R silica plate).
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[P:19]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:2][P+:19]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Product: C[P+](Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 91 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (2.755 g; 8.7 mmol) is added at room temperature to triphenyl phosphite, P(OC6H5)3, (2.075 g; 6.7 mmol) in a 10 ml glass flask. The two-phase reaction mixture is warmed and stirred at 60° C. for 5.5 h. A cloudy and colourless reaction mixture forms, that is stirred at RT for 16 h and at 60° C. for 5 h. Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (0.380 g; 1.2 mmol) is added again, and the mixture is again stirred at 60° C. for 5.5 h. Methyltriphenoxyphosphonium bis(pentafluoroethyl)phosphinate, [(C6H5O)3PCH3]-[(C2F5)2P(O)O], can be isolated as white and crystalline solid (3.827 g; 6.1 mmol) in a yield of 91% and a purity of 89% by purification in vacuo (10−3 mbar) at 80° C.
Reaction SMILES: NC1N(CC2C=CC=CC=2)N=NC=1C(N)=O.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C.[CH2:30]([N:37]1[C:41]([NH:42][C:43](=O)[C:44]([CH3:47])([CH3:46])[CH3:45])=[C:40]([C:49]([NH2:51])=[O:50])[N:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.O>[CH2:30]([N:37]1[C:41]2[NH:42][C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[N:51][C:49](=[O:50])[C:40]=2[N:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)C(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: NC(=O)c1nnn(Cc2ccccc2)c1N
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-amino-1-benzyl-1H-1,2,3-triazole-4-carboxamide (150 g, 691 mmol, Eq: 1.00) was suspended in N,N-dimethylacetamide (512 g, 550 ml). Pyridine (82.1 g, 83.5 ml, 1.04 mol, Eq: 1.5) was added followed by pivaloyl chloride (126 g, 129 ml, 1.04 mol, Eq: 1.5) and the reaction mixture was heated to Tj=80° C. After complete acylation (ca 1 h30), KHCO3 (347 g, 3.45 mol, Eq: 5.00) was added and the suspension was heated to Tj=155° C. to convert the 1-benzyl-5-(2,2-dimethylpropanoylamino)triazole-4-carboxamide intermediate to the product. After 18 h30 at 155° C., the reaction mixture was cooled to RT and water (3.48 kg, 3.48 l) was added dropwise within 30 Min. The light yellow suspension was stirred for 30 min at RT, 2 h at 0° C. and filtered. The filter cake was washed with cold (0-5° C.) water (600 g, 600 ml) and dried at 50° C./5 mbar to give 161.3 g of the title compound as an off-white powder. MS(m/e): 284.0 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 64-68° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.7, 1.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.07 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.76-6.72 (m, 1H), 6.50 (s, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.5 Hz, 1H), 4.89 (d, J=16.5 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (d, J=267 Hz), 112.8 (d, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH:1]1([C:7](=[O:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:1]1([C:7](=[O:18])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH2:32][CH2:31]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCC(C(=O)C1CCCCC1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a solution of 0.84 g of Compound 5c and 1.19 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of dichloromethane, 1.48 g of sodium triacetoxyborohydride and 0.98 ml of acetic acid were added and the resulting mixture was stirred at r.t. for 5 h. After overnight resting, the organic layer was washed with excess of 1M NaOH then with water, dried (Na2SO4) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography eluting with petroleum ether-EtOAc 7:3 to give 1.45 g (99%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][CH2:15][NH:4][C:3]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(O)ccc1N
Reactant: C=Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(O)ccc1NCCc1ccccn1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A mixture of 50.0 g (0.4 mole) of 2-methyl-4-hydroxyaniline, 2.4 g of glacial acetic acid and 125.0 ml of anhydrous methyl alcohol was heated to reflux with stirring and 63.1 g (0.6 mole) of 2-vinylpyridine was added dropwise to the mixture. The resultant reaction mixture was maintained at reflux for approximately forty-eight hours, cooled to ambient temperature and added to a mixture of aqueous sodium bicarbonate and toluene. The water layer was separated from to toluene layer and the water layer was extracted a second time with toluene. The two toluene layers were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid, which crystallized from the toluene upon standing, was collected by filtration, washed with hexane and dried to obtain 23.6 g of N-[2-(2-pyridyl)ethyl]-2-methyl-4-hydroxyaniline (Formula VI: R1 =R9 =H; R2 =CH3 ; R11 =OH), a pale beige-colored solid which melted at 137.5°-139.5° C. after recrystallization from toluene. Significant infrared maxima appeared at 3200 cm-1 (OH;m) and 1601 cm-1 (C=C;m). The nuclear magnetic resonance spectrum was in accord with the assigned structure.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(OC)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
To a DMF (50 mL) solution of 1-benzhydryl-3-ethylazetidin-3-ol (2.18 g, 8.15 mmol), methyl iodide (0.51 mL, 8.15 mmol) and 60% sodium hydride (0.65 g, 16.31 mmol) were added at 0° C. under a nitrogen stream, and the mixture was stirred for 1.5 hours at the same temperature. This reaction liquor was poured onto ice water, and the mixture was extracted with ethyl acetate. The extract was washed with ice water and saturated brine in this order, and then dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, ethyl acetate/n-hexane=1/9-4/6), to obtain the title compound (1.18 g, 52%) as an oily matter.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:17]1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 =ml) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was then washed once with water, and the organic portion was separated. The aqueous portion was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g (27%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)C>[C:24]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=3)=[N:8]2)=[CH:18][CH:17]=1)(=[O:26])[CH3:25]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: CC(=O)Oc1ccc(C=C2N=C(c3ccc(Cl)cc3)OC2=O)cc1

Procedure:
A mixture of 60 g of N-(p-chlorobenzoyl)glycine, 34.5 g of p-hydroxybenzaldehyde, 23 g of fused sodium acetate and 170 ml of acetic anhydride was heated under reflux for 1 hour. The reaction mixture was cooled slightly and 400 ml of ethanol was added. A solid precipitated on cooling and was filtered and washed with cold ethanol and cold water. An analytical sample was made by recrystallization from CCL4 /EtOH/AcOH, m.p. 185-186.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[N+:5]([O-:14])=[C:4]([NH:15]C(OCC)=O)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)C.[OH-].[K+]>O>[NH2:15][C:4]1[CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([NH2:8])[N+:5]=1[O-:14]
Reactant: C1COCCN1
Reactant: CCOC(=O)Nc1cc(Cl)cc(NC(=O)OCC)[n+]1[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide (10.0 g., 0.03 mole) and 60 ml. of morpholine is refluxed with stirring under a nitrogen atmosphere for a period of 24 hrs. and concentrated to dryness. The residual material thus obtained is taken up in 200 ml. of absolute ethanol and 24.0 g. (0.36 mole) of 85% potassium hydroxide. After stirring at reflux temperature for a period of 16 hr., 200 ml. of absolute ethanol is added and reflux continued for an additional period of 30 hr. Concentration of the basic solution to dryness provides a residue which on stirring with water affords 4.4 g. (69% yield) of 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide as the free base, m.p. 315°-325° C. (dec.). The free base is taken up in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ethyl acetate to the acidified ethanolic solution and cooling affords the product which is collected and crystallized from absolute ethanol to provide 2.8 g. of analytically pure 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide hydrochloride hydrate, m.p. 203.5°-206.5° C. (dec.) (corr.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26]([OH:28])=O.[N-:29]1C=CN=[CH:30]1.CN>ClCCl>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26](=[O:28])[NH:29][CH3:30]
Reactant: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: c1c[n-]cn1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C)OCO3
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A mixture of 2.17 g (5.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3dioxolo[4,5-h][2,3]benzodiazepine-7-carboxylic acid-imidazolide, 75 ml of dichloro methane and 15 ml of a 33% ethanolic methyl amine solution is stirred for 3 hours. The reaction mixture is evaporated in vacuo and the residue is suspended in 75 ml of water. The crude product is filtered off, washed with 25 ml of water, dried and recrystallized from 25 ml of ethanol. Thus 1.68 g of the desired compound are obtained, yield 85%, mp.: 221–229° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[CH:19]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.C(OCC)(=O)C>[C:20]([C:11]1[C:12]2[O:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]=2[CH:19]=[C:9]([Br:8])[CH:10]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)COc2c(C(=O)c3ccccc3)cc(Br)cc21

Procedure:
Following General Procedure I and using aluminum chloride (1.76 g, 13.2 mmol), 20 mL of anhydrous dichloromethane, 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 1.5 g, 6.61 mmol) and benzoyl chloride (1.53 mL, 13.2 mmol) followed by flash column chromatography on silica gel (230-1400 mesh) using 7% ethyl acetate in hexane as the eluent, the title compound was obtained (2.15 g, 99%).