Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:31]#[N:32])=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[N+]=[N-].O1CCCC1>O>[CH3:30][C:27]1[N:26]=[C:25]2[C:31]([NH2:32])=[N:20][CH2:23][C:24]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(CN=[N+]=[N-])c(C#N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(n1)C(N)=NC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.6 %

Procedure:
Triphenylphosphine (11 g, 42 mmol) was added to a mixed solution of 3-(azidomethyl)-6-methyl-2-pyridinecarbonitrile (5.79 g, 33.4 mmol) in a tetrahydrofuran (120 ml) —H2O (6 ml) mixed solvent while cooling on ice and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The solvent was distilled off from the ethyl acetate-methanol-29% aqueous ammonia (40:10:1) elution fraction, and washing was performed with ether-n-hexane to yield the title compound (1.65 g, 34%) as a brown solid. The solvent was also distilled off from the washed mother liquor to yield the title compound (0.49 g). The NMR data for both compounds matched exactly.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O)#[N:32].C(OC(N=NC(OCC)=O)=O)C.C1(C)C=CC=CC=1>O1CCCC1>[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]1)#[N:32]
Reactant: O=CN1CCN(CCO)CC1
Reactant: N#Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1OCCN1CCNCC1
Yield: 23.1 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (4.95 g) was dissolved in tetrahydrofuran (100 ml), then triphenyl phosphine (10.14 g) and 2-cyanophenol (3.57 g) were added thereto, and 40% azodicarboxylic acid diethyl ester/toluene solution (13.5 ml) was added dropwise thereto, and the title compound (1.60 g) was obtained in the same manner as in Example 47-1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=2)=[O:28])=[CH:7][CH:6]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Product: O=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
2-(4-Aminophenylthio)quinoline (3.9 mmoles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisocyanate (3.9 mmoles, 0.85 g) were reacted according to procedure A to yield the title compound, 0.8 g, 43%. Mass Spec (FD) 463. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.56; H, 3.43; N. 9.02. M Pt 194°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[C:29]([Cl:31])[CH:30]=[C:22]([O:21][C:20]([F:33])([F:19])[F:32])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cc(Cl)cc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(Cl)cc(OC(F)(F)F)c1
Yield: 38.9 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 3-trifluoromethoxy-5-chlorobenzoyl chloride to afford the title compound (38 mg, 38.9%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93-6.96 (m, 1H, Harom), 7.44 (t, 1H, Harom-5, J=8.0 Hz), 7.58 (s, 1H, Harom-2), 7.63-7.65 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.82 (m, 1H, Harom′), 7.86 (m, 1H, Harom′), 8.08 (t, 1H, Harom′, J=1.6 Hz), 10.53 (s, 1H, NHamide), 11.20 (s, 1H, NHPy7), 11.40 (s, 1H, NHPy9). LC-MS, tR=5.13 minutes, m/z: 467.05 (M+H)+, calculated for C20H13N4O4F3Cl. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F3Cl: 465.0585; found: 465.0583.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12](=[O:14])[CH3:13].[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20]>C(O)C>[ClH:17].[CH3:18][N:19]([CH3:15])[CH2:20][CH2:13][C:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH3:11])[CH:6]=1)=[O:14]
Reactant: CC(=O)c1cn(C)c2ccc(F)cc12
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1cn(C)c2ccc(F)cc12
Yield: 41 %

Procedure:
A solution of 1-(5-fluoro-1-methyl-1H-indol-3-yl)-1-ethanone (0.9 g) in ethanol (60 ml) containing paraformaldehyde (0.45 g) and dimethylamine hydrochloride (1.2 g) was heated at reflux for 18 h, cooled, and the solvent was evaporated in vacuo. The residue was partitioned between sodium carbonate (2N; 100 ml) and ethyl acetate (2×100 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil, which was purified by FCC eluting with System A to give the free base of the title compound as an oil (0.55 g). A sample (0.1 g) was dissolved in absolute ethanol (5 ml) acidified with ethanolic hydrogen chloride, and the salt was precipitated by the addition of dry ether (ca. 150 ml). The salt was filtered off, and dried in vacuo to give the title compound (0.1 g), m.p. 184°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.CCCCC>[Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([N:6]=[C:23]=[O:25])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N
Solvent: CCN(CC)CC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Yield: 279 %

Procedure:
To a stirred solution of 4-chloro-2,6-diisopropylaniline (32 grams) and triethylamine-(7.8 mL) in tetrahydrofuran (505 mL) was added triphosgene (14.9 grams). The mixture was refluxed for two hours with stirring. The tetrahydrofuran was then revolved in vacuo and the resulting oil was taken up in pentane and filtered through silica gel to afford 33.3 grams of the product. 1H NMR δ 7.18 (s, 2), 3.22 (qq, 2, J=7.1Hz), 1.25 (d, 6, J=7.1Hz), 1.25 (d, 6, J=7.1 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)=[N:24][CH:25]=1>>[OH:32][CH:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:24]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCC(O)CC2)nc1
Product: O=C(Nc1ccc(N2CCC(O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=2)[CH:2]=1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
3-Ethynyl-5-methyl-1H-indazole (1.0 g; 6.4 mmol; 1.0 eq.) and 4-azidobenzaldehyde (prepared as described in Chem. Med. Chem. (2009), 4(7), 1182-1188; 1.30 g; 7.04 mmol; 1.1 eq.) were dissolved in 1,4-dioxane (15 mL). D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) followed by a solution of copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) in water (1.5 mL) were added and the reaction mixture was stirred at 90° C. for 3.5 hours. To complete the reaction more D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) and copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) were added again and the reaction mixture was heated at 10° C. for 8 h. 1,4-dioxane was removed under reduced pressure an the residue was sonicated in a mixture of EtOAc and water (1:1). The resulting solid was filtered and dried to afford the title compound as a beige solid (1.94 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 13.29 (brs, 1H), 10.11 (s, 1H), 9.46 (s, 1H), 8.34 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H), 8.14 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4 Hz, 1.4 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:23])=[N:14][C:15]=3[N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl>[NH2:23][C:13]1[N:12]=[C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]2=[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=3)=[O:32])[CH2:21][CH2:22]2)[N:14]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)nsc2n1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4snc(-c5ccc(F)cc5)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a suspension of Example 15 (0.2 mmol) in dichloromethane (5 mL) was added p-tolyl isocyanate (0.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:50), yielding the pure title compound (66 mg, 71%) as a yellowish solid. MS (m/z) 464.1 [M+H]+ (100%). δH (300 MHz, DMSO-d6, 25° C.) 8.36 (s, 1H, NH), 7.72 (dd, J 8.4, 5.6 Hz, 2H), 7.38 (t, J 8.7 Hz, 2H), 7.26 (d, J 8.4 Hz, 2H), 7.06 (s, 2H, NH2), 7.01 (d, J 8.4 Hz, 2H), 3.36 (br s, 4H), 3.17 (br s, 4H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.OS([O-])=O.[Na+].CCOC(C)=O>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Br:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(F)c(N)c1Br
Temperature: 83 °C
Yield: 60.5 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.0 g, 4.9 mmol) was combined with 1,3-dibromo-5,5-dimethylhydantoin (1.7 g, 5.9 mmol) in 1,2-dichloroethane (15 mL) and heated at reflux (83° C.) for 4 h. The cooled mixture was stirred with 10% NaHSO3 solution and EtOAc (30 mL). The organic phase was separated, washed with water (2×20 mL), brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane) to give an orange solid (840 mg, 61%): mp 138-139° C.; EIMS m/z 282, 284; 1H NMR (400 MHz, CDCl3) δ 5.09 (s, 2H, NH2), 3.97 (s, 3H, Me); 19F NMR (376 MHz, CDCl3) δ −135.55 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.OC1(C2C=CC(OC)=CC=2)C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 g, 2.4 mmol), followed by boron trifluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][N:23]=[CH:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][NH:23][CH2:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2cnccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2c1CCNC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-one (Example 84) (0.14 g, 0.34 mmol) in AcOH (1.3 mL) was added NaCNBH3 (0.09 g, 1.4 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C., and diluted with water(10 mL) and 40% aqueous NaOH (10 mL), and the aqueous layer was washed with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2 CH2Cl2/MeOH/NH3) provided 3-chloro-4-(2,4-difluoro-benzyloxy)-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-1H-pyridin-2-one as a white solid (0.13 g, 92%): mp 180-184° C.; 1H NMR (300 MHz, MeOD) δ 7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90-6.80 (m, 1H), 6.60 (d, J=8 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, J=6 Hz, 2H), 2.82 (t, J=6 Hz, 2H). ES HRMS m/z 417.1173 (M+H C22H20ClF2N2O2 requires 417.1176).
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][OH:27])#[N:19]
Reactant: C=O
Reactant: N#CC(CCc1ccccc1)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CO)(CCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice cold stirred solution of α-phenethyl-2,4-dichlorobenzyl cyanide (26.5g., 0.09 mole) in 200 ml. of pyridine containing a suspension of paraformaldehyde (11 g., 0.35 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours. The reaction mixture is poured into 1 liter of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 25.4g. of a thick oil, which is identified by nmr.
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]([F:9])([F:8])[C:5]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:4]=2[O:3]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([F:16])([F:1])[O:7][C:6]([F:9])([F:8])[C:5]=2[CH:10]=1
Reactant: OCc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: O=S(Cl)Cl
Product: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1

Procedure:
A mixture of (2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-methanol (6.5 g) in thionyl chloride (75 mL) was heated at reflux overnight. The resulting mixture was concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over Na2SO4, filtrated, and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g), which was used directly in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1H), 7.61 (dd, J=2.1, 8.7 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]1[CH2:28][CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[C@@H:23]([CH2:28][CH3:29])[CH2:24]2)=[CH:5][CH:4]=1
Reactant: CC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(Br)c2occc12
Product: CC[C@H]1CN(c2ccc(C(F)(F)F)c3ccoc23)CCN1C(=O)OC(C)(C)C
Yield: 83.5 %

Procedure:
Beginning with 1.45 gm (5.47 mMol) 4-trifluoromethyl-7-bromobenzofuran and 1.4 gm (6.53 mMol) 1-(tert-butoxycarbonyl)-2(S)-ethylpiperazine, 1.82 gm (84%) of the desired compound were prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([C:3](=[CH:14][C:15]1[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[C:17]([OH:23])[CH:16]=1)[C:4]([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])#[N:2].C(C(=CC1C=CC(O)=C(O)C=1)[C:27]([O:29][C:30]1[CH:35]=CC=CC=1)=[O:28])#N.Cl[C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[C:1]([C:3](=[CH:14][C:15]1[CH:16]=[C:17]([O:23][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:18]([O:22][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:19]([O:21][C:27]([O:29][CH2:30][CH3:35])=[O:28])[CH:20]=1)[C:4]([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#CC(=Cc1cc(O)c(O)c(O)c1)C(=O)OCCc1cccs1
Reactant: N#CC(=Cc1ccc(O)c(O)c1)C(=O)Oc1ccccc1
Product: CCOC(=O)Oc1cc(C=C(C#N)C(=O)OCCc2cccs2)cc(OC(=O)OCC)c1OC(=O)OCC

Procedure:
By using 2-(2-thienyl)-ethyl 2-cyano-3-(3,4,5-trihydroxyphenyl)-2-propenoate in lieu of phenyl 2-cyano-3-(3,4-dihydroxyphenyl)-2-propenoate and changing the amount of ethyl chloroformate to 3.3 equivalents in the process of Example 1, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:38])[CH:9]([CH3:37])[C:10]([NH:12][CH:13]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:14]([N:16]1[CH:23]2[CH:19]([N:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH:22]2[C:24]([OH:26])=O)[CH2:18][CH2:17]1)=[O:15])=[O:11])=[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.CCN(C(C)C)C(C)C.[C@H:72]1([NH2:82])[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]([C:10](=[O:11])[NH:12][CH:13]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:14]([N:16]1[CH2:17][CH2:18][CH:19]2[N:20]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:21][CH:22]([C:24](=[O:26])[NH:82][CH:72]3[C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH2:75][CH2:74][CH2:73]3)[CH:23]12)=[O:15])[CH3:37])[CH3:38])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 21 (106 mg, 0.19 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (73 mg, 0.19 mmol) and DIPEA (0.1 mL, 0.57 mmol). After 10 min, (1R)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (0.05 mL, 0.35 mmol) in NMP (3 mL) was added. The reaction was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 22 which was used without further purification. Mass spectrum, m/z [688.5] (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=O.Cl.[NH2:27][CH2:28][CH2:29][S:30]([NH2:33])(=[O:32])=[O:31].C[O-].[Na+]>CCO>[S:30]([CH2:29][CH2:28][NH:27][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:2])(=[O:32])(=[O:31])[NH2:33]
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCCS(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCS(N)(=O)=O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), 2-amino-ethanesulfonic acid amide HCl salt (30 mg, 0.24 mmol), and NaOMe (13 mg, 0.23 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 1, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 5.8 mg of the title compound. MS: (−) m/z 426.24 (M−1).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][O:15][P:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])[OH:17])=O)C1C=CC=CC=1.C1OC1C>Cl.CO>[NH2:11][CH2:12][CH2:13][CH2:14][O:15][P:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[OH:18]
Reactant: CCCCP(=O)(O)OCCCNC(=O)OCc1ccccc1
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CCCCP(=O)(O)OCCCN
Temperature: 25 °C

Procedure:
A solution of 6.7 g of 3-(benzyloxycarbonylamino)propyl(n-butyl)phosphonic acid in 125 ml of 36% hydrochloric acid is heated at reflux for 1.5 hour. The mixture is evaporated to an oil and the oil is co-evaporated with water (2×50 ml) to give a white solid. This solid is then dissolved in 50 ml of dry methanol, 1-3 ml of propylene oxide is added and the solution is stirred at room temperature. The precipitated product is collected by filtration and dried to give 3-aminopropyl(n-butyl)phosphonic acid, m.p. 231°-234° (dec.), 31P-NMR: δ=+44.6 ppm (D2O).
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])(C)(=O)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])[CH2:30][CH2:31]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)OCCCCC1C(=O)Nc2ccccc21
Product: O=C1Nc2ccccc2C1CCCCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared according to process B by applying processing method 1 starting from 3-(4-mesyloxybutyl)-1,3-dihydro-2H-indol-2-one and 1-(pyridin-2-yl)-piperazine.