Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:15]=O)[CH2:11][O:12]2)=[CH:7][CH:6]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:15][N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18]3)[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: COCOc1ccc2c(c1)OCC(C=O)=C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCCN(CC2=Cc3ccc(OCOC)cc3OC2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7-(methoxymethoxy)-2H-chromene-3-carbaldehyde (5.00 g) and ethyl (3R)-piperidine-3-carboxylate (4.20 mL) in dichloroethane (150 mL) was added sodium triacetoxyborohydride (12.0 g), followed by stirring at 80° C. for 4 hours. The reaction liquid was cooled to room temperature and then saturated aqueous NaHCO3 was added thereto, followed by extraction with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the vehicle was evaporated. The residue was purified by silica gel column chromatography (hexane:EtOAc=4:1) to obtain ethyl (3R)-1-{[7-(methoxymethoxy)-2H-chromen-3-yl]methyl}piperidine-3-carboxylate (7.30 g) as a yellow oily substance.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=[O:26])[O:19][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:23]
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)OCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
0.1 g (0.403 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were solubilised in 3 ml of dimethylformamide with magnetic stirring. The mixture was cooled to 0° C., 0.048 g (1.208 mmol) of sodium hydride (60% by mass) were added portion wise. The mixture was stirred for 10 min at 0° C. and then 0.204 ml (1.611 mmol) of diethylcarbamoyl chloride were added. The cold bath was withdrawn, the mixture was stirred at r.t. for 2 h before being treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 3×10 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, 6/4, v/v). 0.101 g (yield=72%) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methyl diethylcarbamate were obtained as a pale yellow solid. LC-MS: m/z=348 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.61 (d, J=6.8 Hz, 1H), 7.74-7.59 (m, 3H), 7.53-7.38 (m, 4H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 5.30 (s, 2H), 3.22 (q, J=7.1 Hz, 4H), 1.01 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][C:20](OCC)=[O:21])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][CH2:20][OH:21])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CCOC(=O)CN[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O[C@@H]2CCC[C@H](NCCO)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
The ethyl N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}glycinate obtained in Example 836 was added to a tetrahydrofuran suspension of lithium aluminum hydride, and the resulting mixture was stirred at room temperature for 3 hours. Water, a 2N-aqueous sodium hydroxide solution and then water were added to the reaction mixture and stirred for 1 hour, followed by filtration using Celite. The filtrate was concentrated and then purified by a preparative thin-layer chromatography (methanol (containing aqueous ammonia)/chloroform=1/10) to obtain 2-({cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}amino)ethanol (17.6 mg, 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Si:22]([O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:8]1[N:6]3[CH:7]=[C:2]([CH:29]4[CH2:31][CH2:30]4)[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)[CH:20]=[CH:19]2)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
2-(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline (0.500 g, 1.10 mmol), cyclopropylboronic acid (0.123 g, 1.43 mmol), Pd(OAc)2 (0.012 g, 0.0549 mmol), P(Cy)3 (0.031 g, 0.110 mmol), and K3PO4 (0.699 g, 3.29 mmol) were combined with 5.5 mL toluene and 0.55 mL H2O (both degassed with nitrogen 30 minutes prior to use). The mixture was sonicated and put on a 100° C. reaction block and stirred for 3 hours. The reaction mixture was cooled to ambient temperature, diluted with toluene, vacuum filtered through compressed Celite, rinsed with toluene, and the filtrate was concentrated. The crude material was purified on silica (5% to 60% ethyl acetate in dichloromethane) to give the title compound (0.159 g, 0.382 mmol, 34.8% yield) as a brown foam.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[N:23]=[CH:22]3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[N:23]=[CH:22]3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (20 mL) and CHCl3 (6 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylic acid (50 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH3:37])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added iodoethane (88 μL). The reaction mixture is allowed to stir at room temperature for 24 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 325 mg (73%) of the title compound as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH2:12]P(OCC)(OCC)=O)=[O:11].[CH3:21][N:22]([CH:24]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)[CH3:23]>CN(C=O)C>[CH2:8]([O:9][C:10](=[O:11])[CH:12]=[CH:31][CH:28]1[CH2:27][CH2:26][CH:25]([CH:24]([N:22]([CH3:21])[CH3:23])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:30][CH2:29]1)[CH3:7]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC1CCC(C(c2cccc(F)c2)N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium tert-butylate (12.34 g, 0.11 mol) was added, under argon, to a solution of phosphonoacetic acid triethyl ester (24.66 g, 0.11 mol) in abs. DMF (200 ml), and the mixture was stirred for 10 minutes. The aldehyde 34 (19.3 g, 0.073 mol) dissolved in DMF (200 ml) was then added dropwise. The mixture was stirred for 3 h at RT and then poured onto ice. The reaction mixture was extracted with diethyl ether (3×200 ml) and the organic phase was washed with water and saturated NaCl solution, dried and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:2).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:30][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
3-(Hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.735 g) was stirred with ice-water cooling in dichloromethane (32 ml) under nitrogen and carbon tetrabromide (0.962 g) and triphenylphosphine (0.646 g) were added successively. After 5 min the cooling bath was removed and the mixture was stirred at 21° for 4 h. The mixture was poured onto an SPE silica cartridge (10 g). The cartridge was eluted with dichloromethane to give the title compound (0.21 g) LCMS RT=4.31 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=C(C#N)[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:27]([C:26]([OH:29])=[O:28])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2

Procedure:
320 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin-5,5-dioxide is refluxed for 24 hours in a mixture of 10 cc. acetic acid and 10 cc. 50% aqueous sulfuric acid. The mixture is cooled down and the crystalline product filtered, washed with water and dried at 70° C., 0.5 mm./Hg., to yield 289 mg. (82%) of pure acid, m.p. 276°-278° C.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[CH3:8][O:9][CH2:10][CH2:11][NH:12][N:13]=[CH:14][NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.Cl.[C:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([CH2:39][C:40](=[O:42])[NH2:41])=[C:34](O)[CH:33]=[CH:32]2)(=[NH:28])[NH2:27].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[CH3:8][O:9][CH2:10][CH2:11][NH:12][N:13]=[CH:14][NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:22][C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:26](=[NH:27])[NH2:28])[CH:30]=3)[C:35]=2[CH2:39][C:40](=[O:42])[NH2:41])=[O:21])=[CH:18][CH:17]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: COCCNN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: COCCNN=CNc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
50 Milliliters of 10% hydrous pyridine was added to 1.5 g of 4-[(2-methoxyethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.22 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.7 g of DCC and 67 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of ethanol and 15 ml of isopropanol, and the precipitate was collected by filtration. To the collected precipitate were added 15 ml of DMF and 1.34 ml of concentrated hydrochloric acid to dissolve the precipitate. Furthermore, 1 g of active carbon was added, followed by stirring for 2 hours at room temperature. The insoluble matter was filtered off and the filtrate was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 15 ml of methanol and 1.34 ml of concentrated hydrochloric acid, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.25 g of the desired product.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]1[C:14](=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH2:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][NH:1][C:14]1=[O:15]
Reactant: O=C1CCc2ccccc2C1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccccc2CCN1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
While maintaining the temperature of the reaction mixture below 65° C., NaN3 (13.35 g; 205.2 mmol) is added in small portions to a solution, heated beforehand to 55° C., of β-tetralone (25 g; 171 mmol) in a mixture of 150 ml of glacial acetic acid and concentrated sulphuric acid (33.39 g; 342 mmol; 18.25 ml). Stirring is then carried out for 8 hours at 70° C. After returning to ambient temperature, the reaction mixture is poured onto ice and diluted with ethyl acetate. After extracting the organic phase, drying over magnesium sulphate and concentrating, the residue obtained is purified by chromatography on silica gel (eluant ethyl acetate) to yield the expected compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:21]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 107.6 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[2-(dimethylamino)ethoxy]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (50 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (56 mg, 0.20 mmol) followed by formation of the dihydrochloride salt to afford the desired product (63 mg, 83%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD) δ 9.35 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.78 (dd, J=8.8, 2.7 Hz, 1H), 7.44 (br s, 2H), 7.02 (d, J=8.8 Hz, 1H), 4.72-4.66 (m, 2H), 3.64-3.58 (m, 2H), 3.00 (s, 6H), 2.84 (s, 3H); ESI MS m/z 512 [M+H]+; HPLC 99% (AUC), tR=9.73 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([Cl:24])=O)=[CH:18][CH:17]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:24].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:19]1[CH:25]=[CH:26][C:16]([F:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)/C=C/c1ccc(F)cc1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-4-fluorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 351.81; mp:>230° C.; 1H-NMR (CDCl3) δ: 9.10 (1H, d, J=16.5 Hz), 8.89-8.84 (1H, m), 8.24-8.12 (2H, m), 7.72-7.43 (6H, m), 7.07 (2H, dd, J=8.4, 8.4 Hz), 6.91 (1H, d, J=16.5 Hz), 6.82 (1H, dd, J=8.8, 8.8 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>C(O)C.O=[Pt]=O.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(OCCCl)cc1
Temperature: 0 °C

Procedure:
36 g (0.178 Mol) of 1-(2-Chloro-ethoxy)-4-nitro-benzene is dissolved in 360 mL of ethanol and subjected to catalytic hydration at rt using PtO2 (1.5 g) as catalyst. The resulting suspension is diluted with CH2Cl2, filtered, and concentrated to approx. 150 mL. After cooling to 0° C. the crystals are filtered off, washed and dried at 60° C. under vacuum to obtain 4-(2-chloro-ethoxy)-phenylamine. Title compound: m.p.: 87-91° C.; ES-MS: 172 [M+H]+; single peak at tR=2.73 min (System 1).
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19].C([O-])(=O)C.[Na+].O>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:6]=1[C:16]([C:17]1[CH:23]=[N:2][O:19][C:18]=1[CH:20]1[CH2:22][CH2:21]1)=[O:27]
Reactant: CCOC=C(C(=O)c1ccc(NS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.53 g) was added to a stirred solution of 1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.8 g) in ethanol. Sodium acetate (0.63 g) was then added portionwise over a period of ten minutes. The mixture was then stirred at room temperature for 0.5 hours. Further quantities of hydroxylamine hydrochloride (0.2 g) and sodium acetate (0.24 g) were added and stirring was continued for 0.5 hours. Water was added, the mixture was extracted with dichloromethane and the combined organic extracts were washed with water, dried and the solvent evaporated. The crude product was purified by column chromatography to yield 4-[2-chloro-4-(methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (compound 1) as a white solid, 1.66 g, m.p. 122.8-124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[NH2:5].[N:21]([O-])=O.[Na+]>C(O)(=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:21])[CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: O=N[O-]
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN)cc1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
In 40 ml of acetic acid was dissolved 3.0 g of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)aniline. To the solution was then added 3 ml of 35% hydrochloric acid. To the mixture was added dropwise, while cooling at temperatures ranging from 10 to 12° C., a solution of 0.8 g of 98.5% sodium nitrite in 3 ml of water. The reaction mixture was stirred for 40 minutes under the same conditions, to which was then added 7.0 g of stannous chloride dissolved in 10 ml of 35% hydrochloric acid. The reaction mixture was poured into ice-water, which was then made into alkaline, followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 96%, m.p. 183-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCCC2)Cc2ccccc2C1
Yield: 21.6 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (491 mg, 1.09 mmol) and 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (937 μL, 4.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 240 mg, 0.11 mmol) and 2M aqueous solution of K2SO4 (2.18 mL, 4.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (140) as white solid (95 mg, 22%).