Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:25]=[C:26](/[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)\[CH3:27])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(F)ccc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccc(F)cc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.98 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (18 mg, 0.09 mmol) L-proline (22 mg, 0.19 mmol) and potassium phosphate (410 mg, 1.96 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (250 mg, 1.17 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.76 (m, 2H), 7.50 (m, 1H), 7.30 (t, 2H), 7.10 (d, 2H), 7.0 (t, 1H), 4.30 (m, 2H), 3.0 (s, 3H), 2.80 (m, 4H), 1.90 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH:21][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:20]=2)[CH:14]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)c1
Yield: 30 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-chloro-phenylboronic acid provided the title compound (30% yield). 1H NMR (acetone-d6) δ1.35 (t, 3H, J=7.0 Hz, CH3), 4.08 (q, 2H, J=7.0 Hz, CH2), 5.32 (bs, 2H, NH2), 6.21 (d, 1H, J=1H, J=1.2 Hz, Ar), 6.32 (t, 1H, J=1.1 Hz, Ar), 7.09 (d, 2H, J=8.6 Hz, Ar), 7.23 (d, 2H, J=8.9 Hz, Ar), 7.31-7.78 (m, 2H, Ar), 8.04 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:14][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cnc(Cl)cc2c1O
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Temperature: 120 °C

Procedure:
To 1 g of 6-chloro-4-hydroxy-[1,7]naphthyridine-3-carbonitrile in 5 mL each dimethyl formamide and triethyl amine was added 1 g triphenyl phosphine, 7 mL of trimethylsilanylethyne, and 225 mg of palladium (II) acetate. The reaction was heated at 120° C. for 18 hours, stripped of solvent, and purified by flash chromatography on silica gel with a methanol/chloroform gradient. Recrystallization from ethanol containing a small amount of water yielded 690 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile: melting point 307° C. (decomposed); mass spectrum (m/e): M+H 268.0.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH:17]=[CH2:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH2:18][CH:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Reactant: C=CC(O)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1)c1ccc(Cl)cc1
Yield: 28.6 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (218 mg, 1 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (2 mmol) was added a solution of triethylamine (111 mg, 1.1 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:EtOAc, 4:1) to afford the title compound as a white solid (107.3 mg). 1H NMR δ 3.54 (s, 1H), 3.60 (dd, 1H), 3.76 (dd, 1H), 5.12 (t, 1H), 7.45 (d, 2H), 8.14 (d, 2 H); ESIMS: m/z 374 (M−H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([O:29]COC)=[N:20][N:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[C:18]2[C:19]([OH:29])=[N:20][N:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(COC(=O)c2ccccc2)n1
Agent: Cl
Solvent: CO
Product: O=C(OCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of (4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazol-2-yl)methyl benzoate (1.02 g) in methanol (30 mL) was added concentrated hydrochloric acid (0.28 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-methanol to give {4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate (0.79 g, yield 79%) as colorless crystals. melting point: 215-216° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].Cl.Cl.NC1C=CC(N2CCC[C@@H](C(N3CCCC3)=O)C2)=NC=1N.NC1N=C(N2CCC[C@@H](C(N3CCOCC3)=O)C2)C=CC=1[N+]([O-])=O.[CH:72]1([C:75]2[N:80]=[C:79]([C:81](=N)OCC)[CH:78]=[N:77][CH:76]=2)[CH2:74][CH2:73]1>>[CH:72]1([C:75]2[N:80]=[C:79]([C:81]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:20][CH2:21][O:22][CH2:23][CH2:24]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH:78]=[N:77][CH:76]=2)[CH2:74][CH2:73]1
Reactant: CCOC(=N)c1cncc(C2CC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)nc1N
Agent: Cl
Agent: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cncc(C5CC5)n4)[nH]c3n2)C1)N1CCOCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 95, but using (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(morpholino)methanone dihydrochloride (synthesized by hydrogenation analogous to the one used for Intermediate 1, starting from Intermediate 40) and Intermediate 30. 1H NMR (300 MHz, DMSO-d6) δ 1.06 (dd, 2H), 1.20-1.33 (m, 3H), 1.54-1.74 (m, 3H), 1.80-1.93 (m, 1H), 2.19-2.33 (m, 2H), 2.79 (br s, 1H), 2.87-3.09 (m, 3H), 3.55 (m, 5H), 4.30-4.53 (m, 2H), 6.88 (d, 1H), 7.86 (d, 1H), 8.61 (s, 1H), 9.06 (s, 1H), 13.05 (s, 1H)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[CH3:20][O:21][C:22](=[O:52])[CH:23]([O:50][CH3:51])[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:28][C:27]=1[F:49])O>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:52])[CH:23]([O:50][CH3:51])[CH2:24][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:28][C:27]=1[F:49]
Reactant: COC(=O)C(OC)C(O)c1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.1 %

Procedure:
Trifluoroacetic anhydride (0.043 mL, 0.37 mmol) and pyridine (0.074 mL, 0.93 mmol) were added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionic acid methyl ester (0.142 g, 0.31 mmol) in methylene chloride (1 mL) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and 10% palladium on carbon (0.064 g) was added to the solution. The mixture was stirred under hydrogen pressure (5 atm) for 16 hours. The mixture was filtered through celite and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid methyl ester as a white solid (30 mg, 22%). 1H NMR (200 MHz, CDCl3): 7.60–7.50 (m, 4H); 7.46–7.27 (m, 3H); 7.18–7.09 (m, 1H); 7.03–6.96 (m, 2H); 6.70–6.61 (m, 2H); 4.17 (dt, 4H, J=9.1, 6.2); 4.00 (dd, 1H, J=7.3, 5.9); 3.74 (s, 3H); 3.37 (s, 3H); 3.13–2.93 (m, 2H); 2.28 (qn, 2H, J=6.2).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cc2ncnc(Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 4-chloro-6-methoxyquinazolin-7-ol (compound 5, 3.0 g, 14.25 mmol) and ethyl 4-bromobutanoate (4.53 g, 28.49 mmol) in tetrahydrofuran (30 mL) was added potassium carbonate (5.90 g, 42.74 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were concentrated to give the crude product as a yellow solid. The crude product was purified by silica gel column (gradient of hexane:ethyl acetate 10:1 to 2:1) to give Compound 6 (3.7 g) as a yellow solid.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](N(CC2C=CC=CC=2)CC2C=CC=CC=2)=[S:13])=[CH:7][CH:6]=1)=[O:2].[C:29](NNC1C=CC(N)=CC=1)(=O)C.C(N1C=CN=C1)(N1C=CN=C1)=S>>[C:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)(=[O:2])[CH3:29]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: S=C(n1ccnc1)n1ccnc1
Product: CC(=O)NNc1ccc(N=C=S)cc1

Procedure:
4-(2-Acetylhydrazino)phenyl isothiocyanate was prepared as described for NA-11 in Example 4 with 1-acetyl-2-(4-aminophenyl)hydrazine (1.23 g, 0.0075 mole) and 1,1'-thiocarbonyldiimidazole (1.35 g, 0.0075 mole). Yield 1.20 g (77 percent), m.p. 172°-174° C.
Reaction SMILES: COC1C=CC([C:7]([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11](OC)=[CH:10][CH:9]=2)=CC=1.C1C=CC(C2(Cl)C3C(=CC=CC=3)[O:53][C:52]3[C:47]2=[CH:48][CH:49]=[CH:50][CH:51]=3)=CC=1.COC1C(OC)=C(C=CC=1)C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1>CCOC(C)=O>[C:16]1([C:7]2([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:27])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:53][C:52]3[C:51]2=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C(OCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Agent: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Solvent: CCOC(C)=O
Product: O=C(CCCOC1(c2ccccc2)c2ccccc2Oc2ccccc21)Oc1ccc([N+](=O)[O-])cc1
Yield: 80 %

Procedure:
This compound was synthesized using the same method used to synthesize 1a except that pixyl chloride (PxCl) was substituted for dimethoxytrityl chloride, to give 1b in 80% yield, mp 130°-130.5° C. (EtOAc). 1H NMR (CDCl3) δ 1.98 (m, 2H, H3), 2.7 (t, J=7.3 Hz, 2H, H2), 3.0 (t, J=5.8 Hz, 2H, H4), 7.0-7.5 (m, 15H, ArH), 8.2 (d, J=7.1 Hz, 2H PhNO2 m-H). 13C NMR (CDCl3) δ 25.0 (C3), 31.5 (C2), 61.8 (C4), 75.4 (CPh3), 116.3, 123.2, 123.5, 126.4, 126.6, 127.9, 129.1, 129.4, 148.9, 151.3 (Px C), 122.4, 125.1, 145.2, 155.4 (PhNO2C), 171.0 (CO2). Anal. Calcd for C29H23NO6 : C, 72.3; H, 4.8; N, 2.9. Found: C, 72.0; H, 4.4; N, 3.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])([CH3:25])[CH3:24].CS(C)=O>C1COCC1>[Cl:46][C:40]1[N:39]=[C:38]([N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:29]([C:27]([O:26][C:23]([CH3:22])([CH3:24])[CH3:25])=[O:28])[C:47]([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48])[C:43]([F:44])=[C:42]([N:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:41]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CN1CCN(NCc2nccs2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)CC1
Reaction time: 8 h
Yield: 3.8 %

Procedure:
4-Methyl-N-(1,3-thiazol-2-ylmethyl)-1-piperazinamine (2.2169 g, 10.44 mmol) was dissolved in THF (30 mL) and triethylamine (4.37 ml, 31.3 mmol). Then tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (3.89 g, 7.83 mmol) and DMSO (5 mL) were added. The reaction was left to stir overnight. The THF was evaporated away, and the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organics were dried (Na2SO4) and evaporated. Purification by silica gel chromatography and RP-HPLC provided tris(1,1-dimethylethyl) 2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.2014 g, 3%). LCMS: (M+H)+=674.6.
Reaction SMILES: [C:1]1([P:7](Cl)(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClP(Cl)[C:17]1[CH:22]=CC=[CH:19][CH:18]=1.C(O)CCC>C(OCC)C>[C:1]1([P:7]([O:13][CH2:22][CH2:17][CH2:18][CH3:19])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: CCCCOP(=O)(Cl)c1ccccc1
Solvent: CCCCO
Solvent: CCOCC
Product: CCCCOP(OCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material, butyl phenylphosphonochloridate, was prepared from dichlorophenylphosphine as follows: To a cold, stirred solution of 30.0 g of butanol and 41.4 g of trtiethylamine in about 300 ml of ethyl ether was added dropwise a solution of 34.6 g of dichlorophenylphosphine in about 200 ml of ethyl ether while the temperature was maintained below 0°. When addition was completed, the mixture was allowed to warm to room temperature. Stirring was continued overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residual oil was distilled under reduced pressure to give 39.5 g of dibutyl phenylphosphonite, b.p. 120°-131°/ca 1.0 mm. Chlorine gas was bubbled into 38.5 g of dibutyl phenylphosphonite for about three hours. The mixture was warmed to 50° under aspirator vacuum to remove butyl chloride. The residual colorless oil was dissolved in 100 ml of benzene, washed with 1% sodium hydroxide and with water, dried over magnesium sulfate, and the dried solution concentrated under reduced pressure to give 30.6 g of pale yellow butyl phenylphosphonochloridate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:33])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][OH:29])[CH:24]=2)[N:19]([C:30]([NH2:32])=[O:31])[CH:18]=1)=[O:8].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[C:30]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([N:10]2[C@H:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[C:3]=3[F:37])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[O:33])=[CH:18]1)(=[O:31])[NH2:32]
Reactant: NC(=O)n1cc(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCCO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 453: 3-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-(2-hydroxy-ethoxy)-indole-1-carboxylic acid amide (45 mg, 0.08 mmol) and Et3N (56 μL, 0.41 mmol) in CH2Cl2 (1 mL) at 0° C. was added methanesulfonyl chloride (31 μL, 0.41 mmol) and the white suspension was stirred at RT under nitrogen overnight. Et3N (56 μL, 0.41 mmol) and methanesulfonyl chloride (31 μL, 0.41 mmol) were added and the mixture was further stirred for 1.5 h to complete the reaction. The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: EtOAc to EtOAc/acetone 1-1). TLC, Rf (EtOAc)=0.2; MS (UPLC/MS): 607.4/609.3 [M+H]+, 629.2/631.2 [M+Na]+, 562.2/564.1 [M−CONH2]−, 651.3/653.3 [M+HCOO]−; tR (HPLC conditions f): 1.88 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH:17]=1
Reactant: CCOC(=O)c1cc2c(Oc3cccc(C)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)O)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
136 (520 mg, 1.761 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (84.3 mg, 3.52 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:9]=[C:8]([Cl:17])[CH:7]=1.I[CH3:20]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([N:12]([S:13]([CH3:16])(=[O:14])=[O:15])[CH3:20])[N:9]=[C:8]([Cl:17])[CH:7]=1
Reactant: CI
Reactant: COC(=O)c1cc(Cl)nc(NS(C)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(N(C)S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Add sodium hydride (257 mg, 6.43 mmol, 60% dispersion in mineral oil) at 0° C. to a solution of 2-chloro-6-methanesulfonylamino-isonicotinic acid methyl ester (1.31 g, 4.95 mmol) in DMF (10 mL). After stirring at 0° C. for 15 min, add iodomethane (0.4 mL, 6.43 mmol). Stir the reaction at 0° C. for 1 h and at room temperature for 2 h. Quench the reaction with ice and extract the reaction mixture with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (1.0 g, 72%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:26])[C:15]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][O:23]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:26])[C:15]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][O:23]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCCC3
Yield: 93 %

Procedure:
3-(4-Morpholinyl)propylamine (0.71 mL, 4.8 mmol) was added to a stirred solution of chloride 240 (380 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 243 (514 mg, 93%) as a yellow solid: mp (MeOH/EtOAc) 151-152° C.; 1H NMR δ 7.60 (s, 1H, H-10), 7.30 (s, 1H, H-5), 6.00 (br s, 1H, NH), 4.26 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.75 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.55 (dt, J=6.3, 5.9 Hz, 2H, CH2N), 2.97 (br t, J=6.3 Hz, 2H, H-6), 2.45-2.52 (m, 6H, 3×CH2N), 2.02-2.08 (m, 2H, H-7), 1.79-1.86 (m, 2H, CH2); 13C NMR δ 158.1, 152.9, 143.6, 135.1, 130.0, 126.1, 104.4, 67.0 (2), 66.9, 57.3 (2), 53.8, 40.7, 25.9, 25.3, 21.7. Anal. calcd for C17H23N5O3: C, 59.1; H, 6.7; N, 20.3. Found: C, 59.4; H, 6.6; N, 20.3%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(6-methoxypyridin-3-yl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (90 mg, 1.2 eq, 0.2 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (20%).