Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28](OCC)=[O:29])=[CH:9]2)=[CH:4][CH:3]=1.[NH3:33]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:25]=[N:24][C:23]([CH3:26])=[N:22][CH:21]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28]([NH2:33])=[O:29])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CCc3cnc(C)nc3)cc2c1=O
Solvent: CO
Product: Cc1ncc(CCc2ccc3c(c2)c(=O)c(C(N)=O)cn3-c2ccc(F)cc2)cn1
Temperature: 150 °C
Yield: 65 %

Procedure:
Compound T (11 mg, 0.026 mmol, 1.0 eq) was dissolved in 7N ammonia in methanol (1 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 60 minutes. The reaction was concentrated and purified by reverse phase chromatography to afford 6.7 mg (65%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=4.4 Hz, 1H), 8.55 (s, 2H), 8.53 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.76-7.71 (m, 2H), 7.62-7.58 (m, 2H), 7.51 (t, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 1H), 3.06 (t, J=8.3 Hz, 2H), 2.90 (t, J=8.3 Hz, 2H), 2.53 (s, 3H); ES-MS [M+1]+: 403.2.
Reaction SMILES: Cl.[C:2](=[NH:12])([O:9][CH2:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClC(Cl)C>[Cl:20][CH2:21][C:22](/[N:12]=[C:2](\[O:9][CH2:10][CH3:11])/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCO/C(=N\C(=O)CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a suspension of ethyl benzimidate hydrochloride (500 mg, 2.69 mmol) in dichloroethane (25 mL) was added under argon atmosphere triethylamine (872 mg, 1.2 mL, 8.62 mmol). The stirred reaction mixture was cooled to 0° C. and chloroacetyl chloride (608 mg, 431 μL, 5.39 mmol) was added. After 30 min the cooling bath was removed and stirring was continued at RT for 4 h. After filtration the organic phase was extracted with KHSO4 (10% aqueous solution), dried and evaporated to yield the product as light brown semi-solid (740 mg with 80% purity, 2.62 mmol, 97%) which was used without further purification for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23]Cl)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][I:28])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCI)C(C)C

Procedure:
Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was converted to iodide by the method described in Example A-I-1, step e to give the title compound (3.64 g) practically pure. Rf (2% MeOH/CHCl3) 0.85.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[NH:20][C:19](=O)[CH2:18][O:17][CH2:16]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[NH:20][C:19](=[S:34])[CH2:18][O:17][CH2:16]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=S)N1
Yield: 79 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of (RS)-5-[3-(6-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-one with Lawesson's reagent yielded the title compound (79% of theory). MS (ISP): m/z=359.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]#[C:11]Br>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([NH2:10])=[N:9][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(N)c(N)c1
Solvent: CCO
Product: Nc1ccc2[nH]c(N)nc2c1
Temperature: 60 °C

Procedure:
Alternate synthesis of a substituted 2-aminobenzimidazole. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an amine (2 mmol) in THF (20 mL) is heated at about 60° C. overnight. After cooling the mixture to room temperature, the reaction mixture is concentrated. The crude material is purified on a silica gel column to yield a 5-amino-2-nitro-phenylamine. The 5-amino-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1:1, 10 mL) in a round-bottom flask. To this solution Pd—C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows completion of the reaction, the solution is filtered on celite and then washed with methanol and concentrated to obtain a 4-amino-benzene-1,2-diamine. The 4-amino-benzene-1,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution is heated at 60° C. for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then, the mixture is co-evaporated with toluene about two times to obtain a 5-amino-1H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:21][C:16]1[CH:15]=[C:14]([C@@H:13]2[C@@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
Under an atmosphere of nitrogen to a solution of rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in dichloromethane (30 mL) was added at ambient temperature trifluoroacetic acid (4.3 mL, 56 mmol) and stirred for 20 h at this temperature. The reaction mixture was added slowly onto an aqueous solution of sodium carbonate (1M, 60 mL). The organic layer was separated and washed with brine (50 mL). The aqueous layers were extracted with dichloromethane (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (1.79 g, 73%) as a light brown oil. MS m/e: 338.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:13])[C:9](=[O:12])OC)=[CH:6][C:5]([F:14])=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1.CC(C)([O-])C.[Na+]>[Pd+2]>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C@H:25]1[CH2:26][C@H:27]([N:29]2[C:2]3=[N:3][CH:4]=[C:5]([F:14])[CH:6]=[C:7]3[N:8]([CH3:13])[C:9]2=[O:12])[CH2:28]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: COC(=O)N(C)c1cc(F)cnc1Cl
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncc(F)cc21
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Methyl (2-chloro-5-fluoropyridin-3-yl)(methyl)carbamate (intermediate 37, 0.310 g, 1.418 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.311 g, 1.418 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-tri-1-1,1′-biphenyl)]2-(2-aminoethyl)phenyl)palladium(ii) (0.085 g, 0.106 mmol), and sodium t-butoxide (0.341 g, 3.55 mmol) were scaled in a microwave vial under argon. Dry, sparged dioxane (1.5 mL) was added and the suspension heated at 50° C. After 20 minutes the vial was opened and the crude partitioned between 10% saturated ammonium chloride (100 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (dichloromethane to ethyl acetate gradient) then triturated with diethyl ether. Filtration gave the desired 3-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.295 g, 0.799 mmol, 56.3% yield) as a free flowing cream colored solid. M+1: 370.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.59 (m, 2 H) 2.63 (s, 3 H) 3.46-3.56 (m, 2 H) 4.50-4.59 (m, 1 H) 5.31 (quin, J=8.20 Hz, 1 H) 7.03 (dd, J=8.02, 2.54 Hz, 1 H) 7.09 (td, J=7.58, 1.08 Hz, 1 H) 7.30 (td, J=7.73, 1.17 Hz, 1 H) 7.52 (dd, J=8.02, 0.39 Hz, 1 H) 7.60 (dd, J=7.82, 0.78 Hz, 1 H) 7.95 (t, J=2.15 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[N:5]([CH3:17])[C:4]=2[CH:3]=1.[CH3:18][S-:19].[Na+]>CN(C)C=O>[CH3:16][C:14]1[CH:15]=[C:6]2[N:5]([CH3:17])[C:4]3[CH:3]=[C:2]([S:19][CH3:18])[N:11]=[CH:10][C:9]=3[C:8](=[O:12])[N:7]2[N:13]=1
Reactant: C[S-]
Reactant: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(cn1)c(=O)n1nc(C)cc1n2C
Reaction time: 10 h
Yield: 73 %

Procedure:
0.1 mole of 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 5 is suspended in 100 ml. of dimethylformamide. 0.15 mole of sodium methyl mercaptide is added and the mixture is heated at reflux temperature with stirring for 10 hours. After this time, the precipitated sodium chloride is filtered off and 100 ml. of water are added. 2,4-dimethyl-6-(methylthio)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one crystallizes and is filtered off, yield: 73%; m.p. >300° (butyl alcohol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:9])[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][Mg+].[Br-]>C1COCC1>[OH:9][C:8]([CH:6]1[CH2:5][CH2:4][CH:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]([CH3:1])[CH2:7]1)([C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH3:20]
Reactant: CCOC(=O)C1CCC(C(=O)c2nccs2)CC1C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C(C)(O)c2nccs2)CC1C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 2-methyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (2.8 g, 10 mmol) in THF (28 mL) at −40° C. was added MeMgBr (3.0 M in THF, 4.0 mL, 12 mmol) at such a rate the internal temperature did not exceed −30° C. The reaction mixture was stirred for 15 minutes at −40° C., and was then quenched with saturated aqueous ammonium chloride (50 mL) and warmed to room temperature. EtOAc (20 mL) was added, the layers separated, and the aqueous layer was extracted a second time with EtOAc (50 mL). The organic layers were combined, dried over MgSO4, filtered, absorbed on silica, and purified by silica gel chromatography to afford ethyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2-methylcyclohexanecarboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](F)[C:9]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[C:9]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1c(Br)cccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (2.58 g, 18.73 mmol) was added to a solution of 1-bromo-3-fluoro-2-nitro-benzene (2.06 g, 9.36 mmol) and benzylamine (1.13 mL, 9.364 mmol) and the resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was poured onto 500 mL of ice water and extracted four times with 100 mL ethyl acetate. The combined organic fractions were dried over sodium sulfate, and concentrated in vacuo to give an oil that was purified by recrystallization from 75 mL refluxing ethanol with 3 mL water. 1.83 g of benzyl-(3-bromo-2-nitro-phenyl)-amine was collected by filtration as fine red needles. MS: 308, 309 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24]SC2C=CC=CC=2)=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: O=S([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Sodium 4-fluorobenzenesulphinate (0.517 g) was added to a suspension of ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87, 0.4 g) and sodium bicarbonate (0.24 g) in dimethylacetamide (8 ml) and water (2 ml) and the mixture was stirred at room temperature for 3 hours. The resultant mixture was diluted with water and loaded onto a C-18 SPE column. The column was flushed with water then eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient of 0-60% to give ethyl 3-bromo-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoate (0.37 g) as a colourless gum.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)#[N:2].[F:24][C:25]([F:32])([F:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:27]([CH2:26][C:25]([F:32])([F:31])[F:24])(=[O:29])=[O:28])=[CH:10][CH:11]=1)#[N:2]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: N#Cc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Product: N#Cc1ccccc1Oc1ccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)cc1

Procedure:
Using the method of Example 342 using N-(4-(2-cyanophenoxy)phenyl)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 78:22 DCM/ethyl acetate gave the title compound. Anal Calcd for C21H16F3N3O3S.0.2H2O: C, 55.92; H, 3.67; N, 9.32. Found: C, 55.77; H, 3.51; N, 9.18. MS found 447.8 [M+H]+
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.[OH-].[K+]>CN(C)C=O>[F:1][C:2]([F:6])([O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[CH:3]([F:5])[F:4]
Reactant: Cc1ccc(O)cc1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(OC(F)(F)C(F)F)cc1
Temperature: 68 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
For one hour, tetrafluoroethylene and nitrogen are bubbled into a magnetically stirred mixture of 10.8 g (0.100 mol) of p-cresol, 1.67 g (1.67 g (1.43 g real, 0.0255 mol) of potassium hydroxide pellets, and 70 ml of dried dimethylformamide (DMF) maintained at 68° C. After dilution with 250 ml of water, the reaction mixture is extracted with 100 ml of ether. The ether solution is washed with 200 ml of 5% sodium hydroxide and twice with 400 ml of water. The ether solution is dried, filtered, and then rotary evaporated to give 18.14 g (87%) of p-(1,1,2,2-tetrafluoroethoxy)toluene.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1)[NH2:38]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:38][C:37]5[CH:39]=[CH:40][C:41]([N:42]6[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]6)=[C:35]([F:34])[CH:36]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(F)c2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 70 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.73 (m, 6H) 1.86-2.06 (m, 2H) 2.22 (s, 3H) 2.35-2.49 (m, 4H) 2.97 (br. s., 4H) 3.94 (s, 3H) 4.09 (t, J=13.89 Hz, 2H) 4.82 (t, J=7.83 Hz, 1H) 7.01 (t, J=9.35 Hz, 1H) 7.26 (d, J=6.82 Hz, 1H) 7.32-7.45 (m, 1H) 7.63 (dd, J=15.03, 1.89 Hz, 1H) 8.10 (s, 1H) 8.19-8.46 (m, 2H) 10.16 (s, 1H). [M+H] calc'd for C32H36F4N8O3, 657. found 657.
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)[CH3:7].C(C1[C:38]2[C:29](=[S+][C:31]3[C:36]([N:37]=2)=C(C)C=CC=3)C=CC=1)C.C(C1C2C(=[S+]C3[C:53]([N:54]=2)=C(C)C=CC=3)C=CC=1)C.C(C1C2C(=[S+]C3C(N=2)=C(C)C=CC=3)C=CC=1)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CO>[I-:2].[CH3:74][N:75]1[CH2:80][CH2:79][N:78]([C:10]2[C:9]([N:37]3[CH2:36][CH2:31][N:54]([CH3:53])[CH2:29][CH2:38]3)=[C:8]([CH2:6][CH3:7])[C:21]3[C:12]([CH:11]=2)=[S+:13][C:14]2[C:19](=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=2)[N:20]=3)[CH2:77][CH2:76]1
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Reactant: CN1CCNCC1
Agent: [I-]
Solvent: O
Solvent: CO
Product: CCc1c(N2CCN(C)CC2)c(N2CCN(C)CC2)cc2[s+]c3cccc(C)c3nc12

Procedure:
A solution of 1-ethyl-9-methylphenothiazin-5-ium tetraiodide hydrate (50 mg, 0.07 mmol) in methanol (10 mL) and 1-methylpiperazine (30 mg, 0.3 mmol) was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH3:16][NH2:17]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:17][CH3:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC)c([N+](=O)[O-])c1

Procedure:
6-Methylamino-5-nitro-nicotinic acid ethyl ester (911 mg) was prepared by following General Procedure A starting from 6-chloro-5-nitro-nicotinic acid ethyl ester (1.0 g) and methylamine (2 M in THF, 3.25 mL) in DMF.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8]1([P:14](Cl)[Cl:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[Cl:15][P:14]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)N(C(C)C)P(Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A solution of diisopropylamine (8.90 grams, 88.3 mmol) in dry hexane (100 ml) was added dropwise to a stirred solution of phenyldichlorophosphine (7.91 grams, 44.2 mmol) in hexane (100 ml) cooled to 0° C., during 45 minutes. The resulting mixture was allowed to warm to room temperature and was then stirred for additional 18 hours and thereafter filtered. The precipitate was washed with hexane, and the product was further purified by distillation under reduced pressure, to give 8.62 grams (80% yield) of Compound 59 (see, Scheme 34 below) as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:29][CH2:28][CH2:27]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Fc1ccc2c(c1)CCCN2
Product: O=C(O)c1ccnc(-c2cn(CCN3CCCc4cc(F)ccc43)cn2)c1
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 6-fluoro-1,2,3,4-tetrahydroquinoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.75 (2H, t, J=5.5 Hz), 2.64 (2H, t, J=6.2 Hz), 3.06 (2H, t, J=5.4 Hz), 3.60 (2H, t, J=6.2 Hz), 4.19 (2H, t, J=6.3 Hz), 6.60 (1H, m), 6.74 (1H, s), 6.76 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=4.6 Hz), 7.72 (1H, s), 7.85 (1H, s), 8.25 (1H, s), 8.55 (1H, d). [M+H] Calc'd for C20H19FN4O2, 367. Found, 367.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromopyridin-2(1H)-one (0.250 g, 1.44 mmol) was dissolved in DMF (3 mL) then added iodomethane (0.0943 ml, 1.51 mmol) and potassium carbonate (0.218 g, 1.58 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (3×). The organic layers were combined and dried over sodium sulfate then concentrated under vacuum to afford 5-bromo-1-methylpyridin-2(1H)-one as an orange waxy solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])C.Cl>O>[CH:4]([CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:3]
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cl
Solvent: O
Product: CCOP(=O)(CC=O)OCC
Temperature: 50 °C

Procedure:
A 2-litre, four-necked flask equipped with a mechanical stirrer, an addition funnel and a nitrogen inlet was charged with diethyl 2,2-diethoxyethylphosphonate (150 g) and water (300 mL), and a slight stream of nitrogen was continuously passed through the system. The resulting mixture was heated to 50° C. and hydrochloric acid (5.6 mL) was added. The mixture was then left under stirring for 4 hours after which water was added and the mixture concentrated under reduced pressure. Sodium chloride was added to the resulting mixture which was then extracted with 4 portions of ethyl acetate. The combined organic phases were distilled under reduced pressure.