Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:13][C:11]1[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=[C:7]([Cl:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(OCC)c1cc(CO)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.3 %

Procedure:
Methanesulfonyl chloride (0.369 mL, 4.73 mmol) was added to an ice-cold solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methanol (846 mg, 3.94 mmol) in DCM (8 mL) containing N,N-diisopropylethylamine (1.0 mL, 5.91 mmol). The mixture was stirred at 0° C. for 10 min. DCM (30 mL) was added and the mixture was washed with water (5 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give the title compound (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (1249 mg, quant.).
Reaction SMILES: C(O[C:4](=[O:14])[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.[NH:15]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([CH3:32])[C:26]([CH3:34])([CH3:33])[CH2:25]2)=[O:22])=[CH:19][CH:18]=1)[NH2:16]>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[NH:16][N:15]([C:17]2[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH:24]3[CH2:25][C:26]([CH3:33])([CH3:34])[N:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH2:29]3)=[O:22])=[CH:19][CH:18]=2)[C:4](=[O:14])[C:5]=1[CH3:13]
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Solvent: CC(=O)O
Product: Cc1c(-c2ccco2)[nH]n(-c2ccc(C(=O)NC3CC(C)(C)N(C)C(C)(C)C3)cc2)c1=O

Procedure:
3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. MH+=437.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].B.FC(F)(F)C(O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10]
Reactant: CC(C)(C#N)c1ccccc1Br
Agent: B
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)c1ccccc1Br
Temperature: 25 °C
Yield: 60 %

Procedure:
The derivative 2-(2'-bromophenyl)-2-methylpropionitrile from Example 1/A (2.24 g; 10 mmole) was dissolved in THF (25 ml) in an inert atmosphere. A solution of borane BH3 in THF (1 M; 25 ml; 25 mmole) was slowly added to the reaction medium. The new solution obtained was refluxed for 3 h. After cooling to room temperature, an aqueous solution of trifluoroacetic acid (50 ml; 1/1) was added dropwise to the reaction mixture. The mixture was refluxed for 1 h, then the solvents were evaporated off under reduced pressure. The residue was taken up in 60 ml of hydrochloric acid HCl (10%) and washed with 3×100 ml of ethyl acetate. The aqueous phase was alkalinised (12<pH<14) then extracted with 3×50 ml of dichloromethane. The organic phases were combined, washed with 2×100 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired compound was obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:4]([C:5](OC)=[O:6])[C:3]=1[OH:13].[NH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:4]([C:5]([NH2:14])=[O:6])[C:3]=1[OH:13]
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1O
Reactant: N
Product: NC(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 liter Parr autoclave was charged with 221 g. (1 mole) -dichlorophenyl)- of methyl 3,5-dichlorosalicylate and 140 g. (8 moles) of anhydrous ammonia. The mixture was stirred at 25° C for 24 hours. After venting excess ammonia, the product was ground to a fine powder and triturated with boiling chloroform. The mixture was filtered while hot and the residue weighed 153 g. Analysis by infrared, gas chromatography, and nuclear magnetic resonance confirmed that the product was 3,5-dichlorosalicylamide.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:30])[CH2:10][N:11]([CH3:29])[C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:13])=O)C.Cl.C(OCC)(=O)C>>[NH2:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:30])[CH2:10][N:11]([CH3:29])[C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:13]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CC(=O)[C@@H](N)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 97.7 %

Procedure:
A solution of 1-[[[(S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (7.12 g., 13.6 mmole) is stirred in a saturated solution of hydrochloric acid/ethyl acetate for one hour. The resulting precipitate is collected and washed with ethyl acetate to give 5.63 g of 1-[[[(S)-3-amino-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester; m.p. 174°-175°; [α]D25 =+16.20°. TLC (silica gel; chloroform:methanol:acetic acid, 4:1:1) Rf =0.60.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)(=O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH2:26][CH3:27])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(CCO)CC3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(CCO)CC3)nc21
Reaction time: 2 h
Yield: 53.3 %

Procedure:
5.14 g. of the ester are added to an aqueous-alcoholic solution of sodium hydroxide (N NaOH: 15 cm3, ethanol: 10 cm3); the mixture is stirred for 2 hours at ordinary temperature and is then brought to pH 6 by adding acetic acid. After concentration to dryness in vacuo, the residue is taken up in a saturated solution of sodium acetate (50 cm3) and is extracted with chloroform (3× 50 cm3). After drying (MgSO4), the solvent is evaporated and the residue is recrystallised from 80 cm3 of ethanol. 2.4 g. (53.3%) of 2-(4'-β-hydroxyethyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid are obtained; melting point 222° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:23][C:24]1[C:29]([F:30])=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:28]3[CH:27]=[CH:26][C:25]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:24]([F:23])[C:29]=3[F:30])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (101 mg, 0.27 mmol, 1.00 equiv), ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate (prepared according to PCT Application WO2010/048207A2) (81 mg, 0.35 mmol, 1.30 equiv), N,N-dimethyl formamide (3.0 mL), potassium carbonate (113 mg, 0.82 mmol, 3.01 equiv). The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-Plate with Petroleum ether/EtOAc=6:1. This resulted in 0.10 g (73%) of ethyl 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl)propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C22H17ClF5NO3S, 506.1 (M+H). found 506.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)C1(CO)CC1
Product: COC(=O)C1(COc2ccc(Br)cc2)CC1
Yield: 70.9 %

Procedure:
By using 4-bromophenol (1.33 g) and methyl 1-(hydroxymethyl)cyclopropane carboxylate (663 mg), the procedure was carried out in the same manner as in Reference example 2-1) to obtain methyl 1-[(4-bromophenoxy)methyl]cyclopropane carboxylate (1.03 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[N:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1nc(C(=O)O)ccc1=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.16 g, 1.04 mmol) and BOP-Cl (0.29 g, 1.13 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (0.223 g, 70% yield) as a solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[O:22][C:21](=[O:23])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH3:24].Br[CH2:26][CH:27]=[CH:28]C.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:28]([C@H:20]1[CH2:19][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:24])[CH:14]=2)[O:22][C:21]1=[O:23])[CH:27]=[CH2:26]
Reactant: CC=CCBr
Reactant: Cc1cc([C@H]2CCC(=O)O2)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2ccc(F)c(C)c2)OC1=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in anhydrous THF (20 mL) was added (R)-5-(4-fluoro-3-methyl-phenyl)-dihydro-furan-2-one (194 mg) in 1 mL THF at −70° C. over a period of 15 minutes. After completing the addition, the mixture was stirred for an additional 20 min at −70° C. and then for 10 min at room temperature. The mixture was cooled down again to −70° C. and a pre-cooled solution of 200 mg 1-bromo-but-2-ene and 400 μL HMPA in 1 mL THF slowly added. The mixture was further stirred at −70° C. for 2 h and the temperature was slowly raised to room temperature over a period of 2 h. The reaction was quenched by pouring into saturated NH4Cl (20 mL) and followed extraction with ethyl acetate (3×30 mL). The combined organic layers were washed with 20 mL brine twice and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by flash column chromatographed eluting with 0% to 50% ethyl acetate/hexane gradient solvent to give the anti/syn products (94:6 ratios).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:40])[C:7]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25]C(=O)C)[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36]C(=O)C)C>O.C(O)C>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:8]1[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:7]=1[C:6]([OH:40])=[O:5]
Reactant: CCOC(=O)c1cc(OCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(OCCCCCCO)c(C(=O)O)cc1OCCCCCCO

Procedure:
A solution of 25.0 g (379 mmol) 85% KOH in 300 ml water is added to 40.0 g (74.3 mmol) diethyl-2,5-bis-(6-acetoxyhexoxy)terephthalate in 250 ml ethanol and the whole is heated under reflux for 1.5 hours. After distilling off approx. 150 ml ethanol, the reaction mixture is acidified by adding 40.0 g conc. HCl and stored at 2° C. for 20 hours for complete crystallization of the crude product. The colourless crude product is then filtered off, washed neutral with water and recrystallized from ethanol.
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (700 mg, 2.0 mmol) and a 1.0 M solution of hydrogen chloride in diethyl ether (5 ml, 5.0 mmol) in methanol (100 ml) was stirred at room temperature overnight. After concentrating under reduced pressure, the residual solid was treated with ethyl acetate (20 ml) and stirred at room temperature for 2 hours. Filtration provided (R)-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-13430) (400 mg, 65% yield) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16]Cl)=[CH:10][CH:9]=1>C(O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C=CCCl)cc1
Solvent: CCO
Product: Fc1ccc(C=CCN2CCNCC2)cc1
Yield: 66.3 %

Procedure:
To a boiling solution of 32.4 g (376 mmoles) of anhydrous piperazine in 45 ml of anhydrous ethanol a solution of 6.3 g (37 mmoles) of 3-(4-fluorophenyl)-2-propenyl chloride in 60 ml of anhydrous ethanol is dropped under stirring and reflux cooling, within 1 hour. The solvent is removed in vacuo, the residue is dissolved in chloroform and washed with water to be free from piperazine. The organic phase is dried, evaporated and the crude product is--if necessary--distilled off in vacuo. Thus 5.4 g (66%) of the desired compound are obtained. B.p.: 148° C./80 Pa.
Reaction SMILES: O[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnnc(O)c1
Product: COc1cnnc(Cl)c1
Temperature: 75 °C
Reaction time: 0.03 h
Yield: 78.2 %

Procedure:
3-Hydroxy-5-methoxypyridazine (629.6 g, 4.99 moles) and phosphorous oxychloride (2.5 L, 27 moles) were added to a 5 L round bottomed flask equipped with a heating mantle and a mechanical stirrer. The resulting stirred slurry was rapidly heated (<30 min) to 75° C. At this temperature the heating mantle was removed. The reaction mixture continued to exotherm to a final temperature of 82.3° C. After the solids had dissolved in the darkening reaction mixture, stirring was continued an additional 2 minutes. The homogeneous reaction mixture was then rapidly cooled to room temperature with an ice/water bath. The reaction mixture was concentrated via rotary evaporator using pump vacuum and a water bath temperature of 45° C. The residue was taken up in 2 L of CH2Cl2 and slowly poured into a stirring mixture of 2 L CH2Cl2 and 6 L of H2O chilled to 10° C. The layers were separated and enough 50% NaOH was added to the aqueous phase to give a pH of 2-4. The aqueous phase was extracted with additional CH2Cl2 (2×2 L). The combined organic layers were washed with 4 L of H2O and dried (MgSO4). The solution was vacuum filtered through 1 kg of silica gel. The silica gel was washed with 4 L of ethyl acetate/hexanes (1:1). The filtrate was concentrated in vacuo to afford 564 g (78% yield) of 3-chloro-5-methoxypyridazine as a pale yellow solid. The product was stored in a freezer to prevent gradual decomposition. The product was recrystallized from ethyl acetate/cyclohexane to give a white solid, mp=98°-100° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[CH:15][NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[CH:26][C:25]([N:14]2[CH:15]=[C:16]([C:17]#[N:18])[C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[N:13]2)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-n2cc(C#N)c(Nc3ccc(S(C)(=O)=O)cc3)n2)cc1

Procedure:
1-(4-acetylphenyl)-3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 15 Step 4 using 3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile (0.24 g, 0.915 mmol) and (4-acetylphenyl)boronic acid (0.300 g, 1.830 mmol) as the starting materials.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.N.C(O)(=[O:25])C>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N+:10]2[O-:25]
Reactant: CC(=O)O
Reactant: COc1ccc2ncccc2c1Oc1ccc(F)cc1F
Agent: N
Product: COc1ccc2c(ccc[n+]2[O-])c1Oc1ccc(F)cc1F
Yield: 68 %

Procedure:
The solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline in glacial acetic acid containing 4 ml hydrogen peroxide was stirred at 80–85° C. for 18 hours. After cooling the reaction mixture was neutralized with aqueous ammonia, and the resultant precipitate was filtered and washed with water. The aqueous layer was extracted with dichloromethane, and the organic layer was dried (MgSO4). Evaporation gave 1.3 g ( 68%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline N-oxide as a beige crystalline material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J18) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow solid (570 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([O:5][CH2:6][C:7]1[C:8]2[C:15](C)=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)=[O:4].[C:19]1(C)C=CC=CC=1>>[F:18][C:2]([F:1])([F:17])[C:3]([O:5][CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:9]=2[S:10][CH:11]=1)=[O:4]
Reactant: Cc1cccc2scc(COC(=O)C(F)(F)F)c12
Reactant: Cc1ccccc1
Product: Cc1ccc2c(COC(=O)C(F)(F)F)csc2c1

Procedure:
A mechanical stirrer, a 200-mL dropping funnel and an internal thermometer were attached to a 3000-mL three neck flask. A solution obtained by dissolving the mixture (300.00 g) of the (4-methylbenzo[b]thiophen-3-yl)methyl 2,2,2-trifluoroacetate and the (6-methylbenzo[b]thiophen-3-yl)methyl 2,2,2-trifluoroacetate obtained by the reaction in Example 3 in 1500 mL of toluene was introduced into the flask, which was dipped in a water bath. Into the flask, was introduced 30.00 g of sodium borohydride. Methanol (150 mL) was introduced into the dropping funnel. The dropping was carried out for 60 minutes, and the mixture was intactly stirred at room temperature for 60 minutes. Water (1000 mL) was added to the flask and the resulting mixture was filtered through Celite. An organic layer was separated from an aqueous layer, and the aqueous layer was extracted with 500 mL of toluene. The organic layer was washed with 1000 mL of a saturated brine twice. The organic layers were dried with anhydrous magnesium sulfate, filtered and concentrated to obtain a yellow oil, a mixture (295.12 g) of the (4-methylbenzo[b]thiophen-3-yl)methan-1-ol and the (6-methylbenzo[b]thiophen-3-yl)methan-1-ol.
Reaction SMILES: O[CH:2]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][OH:4]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:4][CH2:3][CH2:2][C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)CO)OCC2c1ccc(C(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(CCO)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 20.8 %

Procedure:
A solution of N-(7-(1,2-dihydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.455 mmol) obtained in Example 84 and palladium hydroxide on carbon (20 mg) in ethanol (20 mL) was stirred at 60° C. for 3 hours under a hydrogen atmosphere. The catalyst was removed and the reaction solution was concentrated under reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=7:3) to obtain 40 mg (yield: 21%) of the title compound. Amorphous powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23]([O:24]CC)=[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]=[N:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](I)[CH3:33]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:20]([CH2:32][CH3:33])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)c1cnc2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-benzyl-1-piperazinyl)-5-ethoxypyrido[2,3-d] pyrimidine-6-carboxylate with ethyl iodide, there is obtained the product, m.p. 151° - 153°C.