Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]3[C:20]4[CH:26]=[C:25](Br)[CH:24]=[N:23][C:21]=4[NH:22][C:18]=3[CH:17]=[N:16][C:15]=2[C:28]#[N:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[F-].[K+]>C(#N)C.O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]3[C:20]4[CH:26]=[C:25]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:24]=[N:23][C:21]=4[NH:22][C:18]=3[CH:17]=[N:16][C:15]=2[C:28]#[N:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3[nH]c4ncc(Br)cc4c23)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(OC5CCN(C(=O)OC(C)(C)C)C5)c4c3c2)cn1
Temperature: 130 °C
Yield: 30.5 %

Procedure:
A degassed mixture of 3-(3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (54 mg, 0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.026 mmol) in 1N aqueous potassium fluoride (0.60 mL, 0.60 mmol) and acetonitrile (0.60 mL) was heated at 130° C. under microwave irradiation for 30 minutes. The reaction mixture was allowed to cool to ambient temperature diluted with water (5 mL) and saturated aqueous sodium carbonate (5 mL) then extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resultant was purified by flash chromatography (silica, 2 g column, Si-SPE cartridge, 0-100% ethyl acetate in DCM then methanol) and trituration with acetonitrile to afford the title compound as a white solid (28 mg, 30%). 1H NMR (CDCl3, 400 MHz): 8.78-8.71 (m, 2H), 8.46 (s, 1H), 7.90 (s, 1H), 7.85-7.80 (m, 1H), 5.81 (s, 0.5H), 5.73 (s, 0.5H), 4.01 (s, 3H), 3.86-3.57 (m, 3H), 2.58-2.40 (m, 1H), 2.37-2.17 (m, 2H), 1.39 (s, 4H), 1.33 (s, 5H). LCMS (Method B): RT=3.09 min, M+H+=460.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:4]3[CH:5]=[CH:6][N+:1]([O-:28])=[CH:2][CH:3]=3)=[N:11][C:10]=2[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3)nc2c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)cc1
Yield: 78.2 %

Procedure:
To a mixture of 0.47 g of 2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.64 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred while ice-cooling for 30 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with chloroform, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution. Organic layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 0.39 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 14”).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH:27]([CH3:33])[C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH:27]([CH3:33])[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: CCCCOc1cccc(C(F)(F)CNC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(F)(F)CN(C(=O)OC(C)(C)C)C(C)C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
75 mg (0.23 mmol) of N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamine are dissolved in dry DMF (5 mL). The solution is cooled to 0° C. and NaH (6.7 mg; 1.2 eq) is added. The solution is stirred at RT for 10 min, then cooled again to 0° C. and 2-chloro-N,N-dimethylpropanamide (31 mg; 0.23 mmol) are added. After 4 hours a further 1.2 eq of NaH (6.7 mg) are added. The reaction mixture is stirred overnight at RT, then quenched with water, evaporated, the residue taken up with water and EtAc. The organic layer is separated and the water layer extracted three times with EtAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and evaporated. The resulting crude residue is flash-chromatographed (eluant: petroleum ether/EtAc, 9/1 to 8/2). 2-[N-tert-butoxycarbonyl-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylpropanamide (84 mg; 81%) is obtained as pale yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1.[CH:25](O)([CH3:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[CH:25]([O:1][CH:2]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:10]2[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH2:5]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(CN2CC=C(C3=NNC(=O)CS3)CC2)OC(C)C)cc1
Temperature: 25 °C

Procedure:
2-[1-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-1,2,5,6-tetrahydropyrid-4-yl]-4H,6H-1,3,4-thiadiazin-5-one (300 mg, 0.86 mmol) was suspended in mixed solution of isopropanol(15 ml) and benzene (25 ml), added with p-toluenesulfonic acid monohydrate (4.5 g, 0.02 mol) and refluxed for 5 hours while being dehydrated by a Dean-Stark's dehydrator. After allowing to cool to room temperature, the reaction mixture was added dropwise to 1Naqueous sodium hydroxide (30 ml). The benzen layer was separated and the water layer was further extracted three times with benzen. The benzen layer was combined with the above-mentioned benzen layer and dried over anhydrous magnesium sulfate. Benzene was removed under reduced pressure and the residue was crystallized from a little amount of ether. The solid obtained was further crystallized from ether to obtain the titled compound(145 mg) as white power.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:44])[O:41][CH2:42][CH3:43]>CO.ClCCl>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:40]([O:41][CH2:42][CH3:43])=[O:44])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: CCOC(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in MeOH (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by ethyl carbonochloridate (0.022 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding ethyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (28.0 mg, 24%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(CO)cc1

Procedure:
To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mL) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes:EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mL) and ethyl acetate (4×50 mL) and the organic layer was washed with brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85%); 1H NMR (DMSO-d6): δ 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][C:47]([CH3:104])([CH3:103])[C@H:48]([NH:92][C:93](=[O:102])[O:94][CH2:95][C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)[C:49](=[O:91])[N:50]1[CH2:54][C@@H:53]([C:55]2[CH:64]=[C:63]3[C:58]([CH2:59][C@@H:60]([C:65](=[O:77])[NH:66][C@H:67]4[C:76]5[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=5)[CH2:70][CH2:69][CH2:68]4)[NH:61][CH2:62]3)=[CH:57][CH:56]=2)[CH2:52][C@H:51]1[C:78](=[O:90])[NH:79][C@H:80]1[C:89]2[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=2)[CH2:83][CH2:82][CH2:81]1.CN1CCOCC1>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH2:95]([O:94][C:93]([NH:92][C@@H:48]([C:47]([CH3:104])([CH3:103])[CH3:46])[C:49]([N:50]1[C@H:51]([C:78](=[O:90])[NH:79][C@H:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:83][CH2:82][CH2:81]2)[CH2:52][C@H:53]([C:55]2[CH:64]=[C:63]3[C:58]([CH2:59][C@@H:60]([C:65](=[O:77])[NH:66][C@H:67]4[C:76]5[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=5)[CH2:70][CH2:69][CH2:68]4)[N:61]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:15])[CH3:14])[CH2:62]3)=[CH:57][CH:56]=2)[CH2:54]1)=[O:91])=[O:102])[C:96]1[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H](c2ccc3c(c2)CN[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)CSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)OCc4ccccc4)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-((2-methoxy-2-oxoethyl)thio)-3-methylbutanoic acid (0.19 g, 0.58 mmol) in DMF (4 mL) was added HATU (0.24 g, 0.62 mmol) at ice bath temperature. The reaction mixture was stirred at 0° C. for 10 min, followed by addition of a solution of benzyl ((S)-3,3-dimethyl-1-oxo-1-((2S,4R)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-4-((S)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidin-1-yl)butan-2-yl)carbamate (Compound A, 0.35 g, 0.44 mmol) in DMF (2 mL) and NMM (0.08 mL, 0.71 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was poured into a separatory funnel containing EtOAc and brine. The organic layer was separated and washed with sat. aq. NaHCO3 solution and brine successively. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient elution from 0 to 60% EtOAc/DCM) to afford the title compound (0.40 g, 82%) as a white foam. MS (ESI+) m/z 1099.6 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[O-]CC.[Na+].[CH3:14][C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.[Cl-].[NH4+]>CO.O>[N:1]([C:4](=[CH:20][C:18]1[S:19][C:15]([CH3:14])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]
Reactant: Cc1ccc(C=O)s1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(C)s1)N=[N+]=[N-]
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of ethyl azidoacetate (10.6 g) in methanol (65 mL) was added sodium ethoxide (20% solution in ethanol, 27.2 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. 5-Methylthiophene-2-carbaldehyde (2.5 g) was added to this solution and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated ammonium chloride aqueous solution and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0−90/10) to give the title compound (3.39 g)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[CH:5]=[N:4][CH:3]=1.Cl.[OH-].[Na+]>C(O)C>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([Br:1])=[CH:3][N:4]=[CH:5]2
Reactant: O=[N+]([O-])c1cccc2cncc(Br)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2cncc(Br)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.9 %

Procedure:
The synthesized 4-bromo-5-nitroisoquinoline (1.0 g) and stannous chloride dihydrate (4.5 g, Wako Pure Chemical Industries) were suspended in ethanol (30 ml), added with concentrated hydrochloric acid (2.3 ml) and stirred at 80° C. for 30 minutes and at room temperature for further 12 hours. The reaction mixture was adjusted to pH 12 with addition of 2 N aqueous sodium hydroxide. The target compound was extracted three times with ethyl acetate (100 ml for each time), and the combined organic layer was washed with water (200 ml) and saturated brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (493 mg) as yellow powdery crystals.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:24])[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[N:14]=2)=[CH:8][CH:7]=1>C1COCC1.P([O-])([O-])([O-])=O>[CH3:24][N:12]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:23])[N:14]=1)[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1nc(N(C)c2ccc(OCC(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {4-[methyl-(2-methyl-quinazolin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (200 mg, 0.59 mmol) in THF (5 mL) was added potassium trimethylsilanoate (770 mg, 6 mmol). The mixture was stirred at ambient temperature for 1 h. The mixture was diluted with phosphate buffer (pH=5.5) and extracted with EtOAc (3×). The pH of the aqueous phase was raised to 6 with NaOH and was extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated. The title compound was used without further purification. 1H NMR (DMSO-d6) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.03 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.50 (s, 3H), 2.60 (s, 3H); LC-MS (ESI+; 324 ([M+H]+)).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C1C=CC=CC=1>[CH3:23][N:24]([CH3:28])[C:25]([N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)CCNc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)CCN(C(=O)N(C)C)c1nc2ccccc2[nH]1

Procedure:
Following the procedure of Example 1C, using 9.4 g. (0.046 moles) of N,N-dimethyl-N'-(2-benzimidazolyl)-1,2-ethane diamine, 6.0 g. (0.06 moles) of triethylamine, 5.7 g. (0.053 moles) of N,N-dimethylcarbamoyl chloride and 150 ml. of benzene, there is obtained N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-benzimidazolyl) urea, which, after chromatographic separation on 375 g. of silica gel, and elution with a mixture of 500 ml. of chloroform, 100 ml. of isopropanol, 100 ml. of toluene and 10 ml. of triethylamine, affords 9.4 g. of oil. This is treated with hydrogen bromide and recrystallized from ethanol to give 8.2 g. of dihydrobromide salt, m.p. 193°-195° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:5][O:4][N:3]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][CH:5]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1nocc1C(=O)c1cccs1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nocc1C(=NO)c1cccs1
Yield: 99.9 %

Procedure:
A solution of (3-methyl-1,2-oxazol-4-yl)(2-thienyl)methanone (6.00 g, 31.0 mmol) and hydroxylamine hydrochloride (5.40 g, 77.6 mmol) in pyridine (80 mL) was stirred 5 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford N-hydroxy-1-(3-methyl-1,2-oxazol-4-yl)-1-(2-thienyl)methanimine [6.45 g, yield 99%; HPLC/MS: m/z=219 (M+H); log P(HCOOH)=1.75].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:13])[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)O)C2)c1
Temperature: 60 °C
Yield: 96.7 %

Procedure:
A solution of 638 mg of methyl 3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate (racemate B) in 4 ml of tetrahydrofuran (THF) and 4 ml of methanol is mixed with 4 ml of 2 molar sodium hydroxide solution and heated at 60° C. for one hour. The pH is then adjusted to a value of 3-4 with 2 molar hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. Filtration and evaporation result in a crude product which is purified by recrystallization from diethyl ether. 589 mg of product are isolated.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)=[CH:6][C:5]=1[OH:22].[CH3:23][S:24][CH2:25]Cl.O>CN(C)C=O>[Cl:17][C:16]1[C:11]([C:7]2[CH:6]=[C:5]([O:22][CH2:23][S:24][CH3:25])[C:4]([Cl:3])=[CH:9][C:8]=2[F:10])=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: CSCCl
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.1 g (4.4 mmol) of sodium hydride was added to a solution of 1.3 g (4 mmol) of 2-chloro-5-(3-chloro-5-trifluoromethylpyrid-2-yl)-4-fluorophenol in 50 ml of dimethylformamide. After the mixture has been stirred for 1 hour, it was treated with 0.5 g (5.2 mmol) of methylthiomethyl chloride. Then, the mixture was stirred for another hour. For working-up, the reaction mixture was treated with 50 ml of water. The product was then extracted with 100 ml of methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 0.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23].CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:19]([C:18]([F:17])([F:32])[F:33])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (1 mmol) to obtain a residue. Chromatography of the residue on silica gel eluting sequentially with 1% methanol in dichloromethane and then 6% methanol in dichloromethane gave the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:9]2[N:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccccc2)c2cccnc12
Solvent: c1ccncc1
Product: Clc1nnc(-c2ccccc2)c2cccnc12
Temperature: 110 °C
Yield: 80.1 %

Procedure:
To 5-phenylpyrido[2,3-d]pyridazin-8(7H)-one (1.39 g, 6.2 mmol) and pyridine (0.50 ml, 6.2 mmol) was added phosphorus oxychloride (12 ml, 125 mmol). The slurry was heated to 110° C. for 1 hour. After cooling to room temperature, the reaction was poured into 200 mL of ice-water. The mixture was extracted with 4×50 mL of chloroform. The chloroform layer was washed with 1×50 mL H2O, 1×50 mL 1N NaOH, and 1×50 mL of H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography afforded 8-chloro-5-phenylpyrido[3,2-d]pyridazine 71 (1.2 g). 1H-NMR (400 MHz, CDCl3): δ 9.42 (d, J=2.7 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 7.89 (m, 1H), 7.73 (br s, 2H), 7.61 (br s, 3H). MS 241.0 (calc'd) 242.0 (M+H, found).