Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
To a solution of 9.0 g (27.0 mmol) of ethyl 2- (2, 3, 4, 5-tetrafluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 mL of absolute ethanol at 5° C. was added 1.68 g (29.4 mmol) of cyclopropylamine. The mixture was stirred at 5° C. for 1.5 hours and at room temperature for 2.5 hours. The solution was concentrated to an oil which was triturated with hexane to give a tan solid. The crude product was recrystallized from hexane to give 9.07 g of the title compound, mp 72°-74° C.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3[O:41]CCOC=3C=2)C(F)=CN=1.OCCN>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:25][OH:41])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: NCCO
Product: OCCNc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-hydroxyethylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.7 (bs, 1H), 7.32 (d, 1H, J=2.4 Hz), 7.05 (dd, 1H, J=2.4 and 9 Hz), 6.75 (d, 1H, J=8.9 Hz), 4.21 (s, 4H), 3.67 (t, 2H, J=5.7 Hz), 3.38 (t, 2H, J=5.4 Hz); 19F NMR (CD3OD): −48518; LCMD: ret. time: 15.54 min.; purity: 100%; MS (m/e): 307 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:19]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]=3)=[CH:14][N:15]2[CH3:18])=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:19]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]=3)=[CH:14][N:15]2[CH3:18])=[CH:11][C:10]=1[O:38][CH3:39]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [1.24 g, Reference Example 13(p)] in acetonitrile (100 mL) was treated with iodotrimethylsilane (820 μl). The reaction mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. The residue was treated with water (40 mL) and the mixture was extracted three times with dichloromethane (100 mL). The combined organic phases were washed with brine (40 mL), then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound (686 mg) as a white foam. TLC: RF=0.27 (cyclohexane/ethyl acetate: 1/1). MS: EI (70 eV); m/z=447 M+.(45%); 292 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:32]>O1CCOCC1>[NH2:32][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[CH3:12])[N:5]=1
Reactant: N
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1cscn1
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1cscn1
Temperature: 60 °C
Yield: 70 %

Procedure:
To a sealed tube were added (S)-4-amino-6-((1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (20 mg, 0.044 mmol) in dioxane (5 mL) along with 0.5M ammonia in dioxane (0.440 mL, 0.220 mmol). The reaction mixture was heated at 60° C. overnight and then concentrated. The crude product was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30-40% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (12 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 1.42 (d, J=6.83 Hz, 3 H), 3.87 (s, 3 H), 5.76 (d, J=6.83 Hz, 1 H), 6.60-6.67 (m, 1 H), 7.56 (s, 1 H), 7.76 (s, 1 H), 7.91 (d, J=0.98 Hz, 1 H), 9.16 (d, J=1.95 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H17N9S, 392; found 392.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([O:33]CC)=[O:32].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCc4ccc(Cl)c(Cl)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 75.6 %

Procedure:
ethyl 6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate (69.0 mg, 0.129 mmol) was reacted with 1.0 molar sodium hydroxide (516 μL, 0.516 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (542 μL, 0.542 mmol) and partitioned between saturated aqueous sodium chloride The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (49.4 mg, 0.0975 mmol, 75.6% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3ccc(CC)cc3)CC2)ccc1OC
Temperature: 85 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (94.8 mg, 0.36 mmol, 1.2 equiv; intermediate C1) and 4-ethyl-phenylamine (36.4 mg, 0.30 mmol, 1.0 equiv; commercially available) in ethanol (2 mL) and acetic acid (0.38 mL) was heated to 85° C. After 2 h, sodium cyanoborohydride (22.6 mg, 0.36 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 85° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.2 mg (16%) of the title compound. MS (ISP): 369.4 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][NH:75][C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79]>CN(C=O)C>[C:78]([O:77][C:76]([NH:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][NH:66][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1)=[O:31])=[O:82])([CH3:79])([CH3:81])[CH3:80]
Reactant: O=C(NC1CCN(Cc2ccc(C(=O)O)cc2)CC1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)c1ccc(CN2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-[(4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidin-1-yl)methyl]benzoic acid (1.20 g; 2.63 mmol), TBTU (1.01 g; 3.15 mmol) and DIPEA (1.8 ml; 3.15 mmol) in DMF (10 ml) is stirred for 5 min. tert-Butyl N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}carbamate (783 mg; 3.15 mmol) is added and the mixture is stirred overnight. Volatiles are evaporated and the product is purified by RP-HPLC (modifier: TFA) to yield 9H-fluoren-9-ylmethyl N-(1-{[4-({2-[2-(2-{[(tertbutoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]methyl}piperidin-4-yl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[C:5]([CH3:17])[N:4]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][NH:26][C:27]([NH:29][S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])=[O:28])=[CH:22][CH:23]=2)[N:3]=1
Reactant: COC(=O)c1cccc(-c2c(C)nn(-c3ccc(CCNC(=O)NS(=O)(=O)c4ccc(C)cc4)cc3)c2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(=O)O)c4)c3C)cc2)cc1
Yield: 85.3 %

Procedure:
To a stirred solution of methyl 3-[3,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-pyrazol-4-yl]benzoate (step 5, 1.1 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added 2 M NaOH aq. (10 mL), and then the resulting mixture was refluxed for 3 h. After removal of the solvent, the crude product was partitioned between saturated citric acid aq. (40 mL) and dichloromethane (50 mL). The organic layer was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 500 mg (87%) of the title compound as white solids: MS (ESI) m/z 533 [M+H]+, 531 [M−H]−, 1H-NMR (CDCl3) δ 8.05 (2H, s), 7.71-7.29 (6H, m), 3.55 (2H, t, J=6.1 Hz), 2.88 (2H, t, J=6.1 Hz), 2.42 (3H, s), 2.34 (3H, s), 2.27 (3H, s).
Reaction SMILES: I.[CH3:2][S:3][C:4]([N:6]([CH3:15])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[NH:5].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[CH3:2][S:3][C:4]([N:6]([CH3:15])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:5][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(=NC(C)=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate-hydroiodide* (4 g) and triethylamine (2.5 g) were dissolved in dichloromethane (50 ml). To this solution acetyl chloride (1.05 g) was added slowly maintaining temperature below 20° C. The mixture was stirred at room temperature in a dry nitrogen atmosphere for 1.5 h. The organic residues were washed with water (5×20 ml), dried over anhydrous sodium sulphate and the solvent removed in vacuo giving a yellow solid which upon trituration with ether gave the title compound (2.30 g) as an off-white solid of m.pt. 102°-104° C.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][CH2:10][CH2:11][N:12]([CH3:26])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.NC1C=CC(OCCN(CCC2C=CC(N[S:48]([CH3:51])(=[O:50])=[O:49])=CC=2)C)=CC=1.Cl.Cl.S(Cl)(C)(=O)=O>N1C=CC=CC=1>[CH3:51][S:48]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH3:26])=[CH:27][CH:28]=1)(=[O:50])=[O:49]
Reactant: CN(CCOc1ccc(N)cc1)CCc1ccc(NS(C)(=O)=O)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
The title compound was prepared by mesylation of 1-(4-aminophenoxy)-2-[N-methyl-N-(4-methanesulphonamidophenethyl)amino]ethane dihydrochloride hemihydrate (95 mg) with mesyl chloride ir pyridine according to the procedure of Example 19(C), yield 30 mg, m.p. 147°-149°, confirmed spectroscopically to be identical to the product of Example 7(C).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Br:24][CH:25](Br)[CH3:26].O>C(COC)OC>[Br:24][CH2:25][CH2:26][C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CCBr)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Diethyl 2-(4,4,5,5,5-pentafluoropentyl)propane-1,3-dioate (51 0 mg, 1.592 mmol) was dissolved in anhydrous dimethoxyethane (5 ml). Sodium hydride (60%. 88 mg, 2.2 mmol) was added to the solution and then stirred at room temperature for 1 h under nitrogen atmosphere. Dibromoethane (0.82 ml, 9.55 mmol) was added to the mixture and then stirred at 70° C. for 5 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:dichloromethane=3:1) to obtain 489 mg (yield: 72° C.) of the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>O1CCCC1>[CH3:17][CH:15]1[O:16][CH:11]([CH3:10])[CH2:12][N:13]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14]1
Reactant: CC1CNCC(C)O1
Reactant: N#Cc1cccnc1F
Solvent: C1CCOC1
Product: CC1CN(c2ncccc2C#N)CC(C)O1
Yield: 19.6 %

Procedure:
A solution of 2-fluoro-nicotinonitrile (1.06 g, 8.69 mmol) and 2,6-dimethyl-morpholine (1.0 g, 8.69 mmol) in tetrahydrofuran (10 ml) was heated at 110° C. for 10 min in a microwave reactor. The reaction mixture was concentrated and purified by flash column chromatography using hexanes:ethylacetate (2:1) to yield 0.37 g (40%) of product. MS (ESI4) m/z 218 (M+H)+;
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.O>C(O)(=O)C>[Cl:4][C:9]1[C:10](=[O:15])[NH:11][C:12](=[O:14])[NH:13][C:8]=1[CH2:7][Cl:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Sulfuryl chloride (120 ml) was added dropwise to a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml) over 20 minutes at room temperature, and the mixture was stirred for an additional 3 hours at room temperature. The resultant solution was poured into iced water (500 ml), and then precipitated crystals were collected through filtration, to there by obtain 182.3 g of 5-chloro-6-chloromethyluracil (92% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:22]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Br)[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[C:6]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:5][CH:4]=1)[CH3:2].[CH3:37][NH:38][CH3:39].[I-].[Na+]>>[CH2:1]([C:3]1[C:8]2[C:9]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:22]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17]([N:38]([CH3:39])[CH3:37])[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[C:6]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CNC
Reactant: CCc1ccc(S(C)(=O)=O)c2c1C(c1cc(Cl)cc(S(=O)(=O)CC)c1)=NCc1nnc(C(Br)CC)n1-2
Agent: [I-]
Agent: [Na+]
Product: CCc1ccc(S(C)(=O)=O)c2c1C(c1cc(Cl)cc(S(=O)(=O)CC)c1)=NCc1nnc(C(CC)N(C)C)n1-2

Procedure:
In the manner given in Example 1, 7-ethyl-10-methylsulfonyl-1-(α-bromopropyl)-6-(3-ethylsulfonyl-5-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 7-ethyl-1-[α-(dimethylamino)propyl]-10-methylsulfonyl-6-(3-ethylsulfonyl-5-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(O)(=O)C.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)=[C:22]([O:37][CH2:38][CH3:39])[CH:21]=2)=[CH:14][N:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:38]([O:37][C:22]1[CH:21]=[C:20]([CH2:19][C:15]2[C:16]([NH2:18])=[N:17][C:12]([NH2:11])=[N:13][CH:14]=2)[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][CH:30]=1)[CH3:39]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C=O)cc1
Reactant: NCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(CNCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 2,2,2-trifluoroethylamine (0.477 ml; 6 mmol) in 4 ml methanol is adjusted to pH 6 with glacial acetic acid, and 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-2′,6′-diethoxy-biphenyl-4-carbaldehyde (392 mg; 1 mmol) is added. The reaction mixture is then cooled to 0° C. and sodium cyanoborohydride (38 mg; 0.6 mmol) is added. After half and hour at 0° C., the mixture is stirred for 3 h at room temperature. After evaporation of the reaction mixture, the residue is stirred in 20 m water and the mixture is adjusted to pH 8 with 1 N aqueous sodium hydroxide solution. The substance which has precipitated out is filtered off with suction and dried under a high vacuum. The residue is stirred in 20 ml methylene chloride and filtered off with suction again and dried. 105 mg (22%) 5-{2,6-Diethoxy-4′-[(2,2,2-trifluoro-ethylamino)-methyl]-biphenyl-4-ylmethyl}-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:51])([CH3:50])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38]#[N:39])=[CH:33][CH:32]=3)=[C:26]([CH2:44][CH2:45][CH3:46])[N:25]3[N:47]=[CH:48][N:49]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:50])([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:44][CH2:45][CH3:46])[N:25]3[N:47]=[CH:48][N:49]=[C:24]23)[CH2:21][CH2:22]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)s2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.37) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 2-[5-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)thiophen-2-yl]benzonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.043 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.05 g, 38%).
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:30]5[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: OCCN1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCN(CCO)CC4)c(F)cc3cc2c1=O
Yield: 18.3 %

Procedure:
The reaction is carried out under conditions analogous to Reference Example 5 but starting from 4 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 1-(2-hydroxyethyl)-piperazine in 40 cm3 of pyridine The reaction mixture is heated for 22 hours at a temperature close to 115° C. The pure product is isolated after recrystallizing 3 times from 3 times 200 cm3 of ethanol containing 10% of dimethylformamide each time. 0.94 g of 1-cyclopropyl-7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 255° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 2 h

Procedure:
A stirred solution of the product of Example 1 (550 mg) in methanol (10 ml) was treated with a M sodium hydroxide solution (1.65 ml) and stirring continued for a further 2 hours. The mixture was diluted with water (10 ml) and the resulting solution concentrated in vacuo. Water (20ml) was added and then a M hydrochloric acid solution (1.65 ml). On cooling to 4° C., a solid precipitated. This mixture was concentrated in vacuo, the solid collected and washed with ice-water, then dried to give the title compound, 320 mg, as a solid: m.p. 294°-296° C.; NMR (d6DMSO+TFA) δ8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s), 4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)+ ; calculated for C19H21N3O4 : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.