Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH:21]=[C:22]([CH:24]=O)[N:23]=3)[CH:20]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[CH3:26][NH:27][CH3:28].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH3:26][N:27]([CH2:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:13][CH3:14])[N:5]=3)=[CH:20][N:19]2[CH:21]=1)[CH3:28]
Reactant: CNC
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(C=O)cn2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(CN(C)C)cn2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of methyl 5-ethyl-6-(2-formylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinate (90 mg, 0.27 mmol) in dichloroethane (1.5 mL) was added solution of dimethylamine (2M THF, 0.20 mL, 0.40 mmol) followed by AcOH (25 μL, 0.42 mmol). After stirring at room temperature for 5 min NaBH(OAc)3 (90 mg, 0.42 mmol) was added. Reaction was stirred at room temperature ˜1.5 h and monitored by LC/MS until starting aldehyde was completely consumed. Reaction was diluted with DCM (5 mL) and then quenched with NaHCO3 (aqueous saturated, 5 mL). Product was extracted with DCM (3×5 mL). Organic phase was washed with NaCl (aqueous saturated, 10 mL) and dried over Na2SO4. Removal of the solvent afforded methyl 6-(2-((dimethylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate (100.6 mg) which was used directly in the next step. LC-MS 369.3 [M+H]+, RT 0.83 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[N:3]=[N:2]1.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH2:17][CH2:18]2)=[O:10])[N:3]=[N:2]1
Reactant: O=C(O)CCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(1H-1,2,3-Triazol-4-yl)propanoic acid (step 2) (42 mg, 0.294 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (Example 17, step 2) (100 mg, 0.294 mmol) were dissolved in DMF (1 ml) and treated with DIPEA (257 μl, 1.472 mmol) followed by 50% T3P® solution in DMF (344 μl, 0.589 mmol). The reaction mixture was stirred at RT for 2 days and then concentrated under reduced pressure. The crude product was dissolved in DCM and washed with 10% citric acid. The organic portion was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. Purification by chromatography on silica eluting with 0-10% MeOH in EtOAc afforded the title compound;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:20]3[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]3)=[C:13]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]3)[C:5]([C:27]([F:30])([F:29])[F:28])=[CH:4][N:3]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35]([CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:34][CH:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([C:27]([F:30])([F:29])[F:28])=[CH:4][N:3]=[C:2]([NH:31][C:32]4[N:37]=[CH:36][C:35]([CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:34][CH:33]=4)[N:7]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:19])[C:16]3=[O:18])[CH2:21][CH2:22]1
Reactant: CCOP(=O)(Cc1ccc(N)nc1)OCC
Reactant: CN1Cc2c(c(Nc3nc(Cl)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)nc1)OCC
Temperature: 25 °C

Procedure:
To a suspension of 7-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 308C, 200 mg, 0.45 mmol. 36:64 mixture of regioisomers with the minor as the desired one), diethyl [(6-aminopyridin-3-yl)methyl]phosphonate (Compound 309A, 111 mg, 0.45 mmol), Pd(OAc)2 (5.09 mg, 0.023 mmol), Xantphos (26.2 mg, 0.045 mmol), and Cs2CO3 (296 mg, 0.91 mmol) in dry dioxane (2.8 mL) was bubbled nitrogen for 2 min. This mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography (1-5% MeOH in DCM) to give 32.6 mg of the title compound (yield: 11%), the more polar of the two regioisomers on the TLC. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.2 Hz, 6 H), 1.44 (m, 2 H), 1.63 (m, 2 H), 1.91 (m, 2 H), 2.16 (m, 2 H), 2.50 (m, 1 H), 3.12 (d, J=21.2 Hz, 2 H), 3.22 (s, 3 H), 3.77 (m, 1 H), 4.02-4.10 (m, 4 H), 4.39 (s, 2 H), 7.32 (d, J=8.4 Hz, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.98 (s, 1 H), 8.22 (s, 1 H), 8.36 (d, J=8.4 Hz, 1 H), 8.45 (s, 1 H), 8.62 (d, J=8.4 Hz, 1 H), 10.59 (s, 1 H). MS (ES+): m/z 649.18 [MH+]. HPLC: tR=3.38 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:15])[NH2:14]>>[O:7]1[CH:8]=[CH:9][N:10]=[C:6]1[S:5][CH2:4][CH2:3][CH2:2][NH:1][C:13]([NH2:15])=[NH:14]
Reactant: CSC(=N)N
Reactant: NCCCSc1ncco1
Product: N=C(N)NCCCSc1ncco1

Procedure:
Reacting 2-(3-aminopropylthio)oxazole with S-methylisothiourea by the procedure of Example 1 gives the title compound.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.Cl>CCCCCC.CCOCC>[CH:3]1[C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][C:2]=1[B:21]([OH:26])[OH:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1ccc2c(ccc3ccccc32)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc2c(ccc3ccccc32)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Under an argon atmosphere, 98 g of 2-iodophenanthrene and 3 L of dehydrated ether were loaded, and then the reaction solution was cooled to −60° C. After that, 210 mL of a 1.6-M solution of n-butyllithium in hexane were added to the reaction solution. The reaction solution was stirred for 1 hour while its temperature was increased to 0° C. The reaction solution was cooled to −60° C. again, and then a solution of 151 g of triisopropyl borate in 100 mL of dehydrated ether was dropped to the reaction solution. The reaction solution was continuously stirred for 5 hours while its temperature was increased to room temperature. Subsequently, 1 L of a 10% aqueous solution of hydrochloric acid was added to the reaction solution, and then the mixture was stirred for 1 hour. The water layer was removed, and the organic layer was washed with water and a saturated salt solution, and was then dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the organic layer was concentrated. The resultant solid was washed with hexane and toluene. Thus, 42 g of phenanthrene-2-boronic acid as a target were obtained (in 58% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([N:37]([CH2:38][CH2:39][OH:40])[CH3:36])=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)CCO
Yield: 56 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (205 mg, 0.43 mmol) was reacted with 2-methylaminoethanol (326 mg, 4.3 mmol) to give the title compound as a white solid (124 mg, 56%) except that the reaction mixture was heated at 45° C. for 24 hours and the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum (2 rotamers) 1.59-1.62 (m, 3H), 3.18 and 2.93 (s, 3H), 3.53-3.65 (m, 4H), 5.00 and 4.74 (t, 1H), 5.71 (s, 2H), 5.90 and 5.81 (q, 1H), 7.05-7.07 (m, 3H), 7.30-7.37 (m, 3H), 7.71-7.77 (m, 2H), 7.82-7.88 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 and 8.58 (s, 1H), 11.10 (br s, 1H); Mass spectrum MH+ 515.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].[C:10](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[Br:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COc1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of 5-bromo-6-chloropyridin-3-ol (2.95 g, 14.15 mmol) and potassium carbonate (1.28 mL, 21.23 mmol) in acetonitrile (45 mL) under a nitrogen atmosphere was added iodomethane (0.93 mL, 14.86 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give 3-bromo-2-chloro-5-methoxypyridine. MS (ESI, pos. ion) m/z: 221.9 and 223.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:19])[F:18])[CH:7]=1.C(N(CC)CC)C.C[O:30][C:31](=O)[C:32]1[C:37]([NH:38][C:39]([CH:41]2[CH2:43][CH2:42]2)=[O:40])=[CH:36][CH:35]=[C:34]([Cl:44])[C:33]=1[CH2:45]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:18])[F:19])[CH:7]=1)[N:20]1[CH2:45][C:33]2[C:32](=[C:37]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[CH:36]=[CH:35][C:34]=2[Cl:44])[C:31]1=[O:30]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OC(F)F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2c(Cl)ccc(NC(=O)C3CC3)c2C1=O
Temperature: 90 °C
Yield: 17.2 %

Procedure:
To a solution of 3-amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester (50 mg, 0.16 mmol) and triethyl amine (0.09 ml, 3.1 mmol) in DMF (2 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (67 mg, 0.19 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester as a off-white solid (15 mg, 17%). mp, 175–177° C.; 1HNMR (CDCl3): δ 0.88–0.94 (m, 2H, cyclopropyl ring CH2), 1.07–1.13 (m, 2H, cyclopropyl ring CH2), 1.65–1.68 (m, 1H, cyclopropyl ring CH), 3.14 (dd, J=6, 15 Hz, 1H, CHHCO), 3.28 (dd, J=10, 15 Hz, 1H, CHHCO), 3.70(s, 3H, OCH3), 4.13 (d, J=17 Hz, 1H, CHHN), 4.36 (d, J=17 Hz, 1H, CHHN), 5.79–5.85 (m, 1H, CHN), 6.23 (t, JH-F=75 Hz, 1H, OCF2H), 6.26 (t, JH-F=75 Hz, 1H, OCF2H), 7.28–7.41 (m, 4H, Ar), 8.45 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO); 13C NMR (CDCl3): 8.45, 15.25, 16.16, 36.46, 46.34, 51.62, 52.31, 65.38, 111.38, 111.42, 115.57, 115.61, 118.64, 119.76, 119.80, 121.76, 121.81, 122.77, 125.45, 133.14, 136.89, 137.03, 138.86, 142.29, 142.21, 168.79, 170.20, 172.73; Anal. Calcd. for C24H21ClF4N2O6: C, 52.90; H, 3.88; N, 5.14. Found: C, 52.78; H, 3.80; N, 5.01.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][NH2:25])[CH2:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]4)[CH:22]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CN1CCN(c2cccc(CN)c2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2cccc(CNc3ccc4c(=O)[nH]nc(Cl)c4c3)c2)CC1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-(4-methyl-piperazin-1-yl)-benzylamine (111 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-[3-(4-methyl-piperazin-1-yl)-benzylamino]-2H-phthalazin-1-one: 50 mg (22.5%): m/z (M+H)=384. 1H-NMR (DMSO-d6) δ: 12.33 (s, 1H), 7.91 (d, 1H), 7.59 (m, 1H), 7.16 (m, 2H), 6.98 (s, 1H), 6.80 (m, 3H), 4.34 (d, 2H), 3.11 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H).
Reaction SMILES: COC([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=O.N1C=CC=CC=1.[I-].[Li+]>C(OCC)(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[NH:7][C:6](=[O:24])[CH2:5]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C2CC(=O)Nc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1.0 g (3.08 mmol) of 2,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one [prepared by the method of Floyd, et al., J. Med. Chem., 35, 756-772 (1992)]in 10 mL of pyridine was treated with 1.65g (12.3 mmol, 4eq) of lithium iodide and the resulting mixture refluxed in an oil bath under a nitrogen atmosphere for 20 hours. The dark brown mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1N HCl (3×50 mL) and water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent followed by column chromatography on silica gel gave 520mg (63%) of the product. 1H NMR (200 MHz, CDCl3): 257 (dd; 4,8 Hz; 2H), 2.81 (dd; 7, 13 Hz; 1H), 3.13 (dd; 8, 14 Hz; 1H), 3.63 (dt; 14, 7 Hz; 1H), 3.74 (s, 3H), 6.82 (d, 8 Hz, 2H), 7.02 (d, 8 Hz, 1H), 7.14-7.34 (m, 5H), 8.03 (br s, 1H). FAB-MS: calculated for C17H17NO2 267; found 267 (100%).
Reaction SMILES: C([NH:14][C:15]1([P:20]([OH:22])[OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][C:15]1([P:20]([OH:22])[OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OP(O)C1(NC(c2ccccc2)c2ccccc2)CCCC1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC1(P(O)O)CCCC1

Procedure:
The procedure described in Example 1C was repeated using 1-benzhydrylaminocyclopentanephosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give 1-amino-cyclopentanephosphonous acid of melting point 223°-225°.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32](=[O:33])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:18])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-dimethylaminophenyl)methyl](4-methylphenyl)amine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.69 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-methylphenyl)urea (0.41 g) was obtained. melting point: 124–125° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([CH2:15][N:16]([CH2:33][C:34](=[O:48])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43](=[O:46])[NH:44][OH:45])=[C:39]([OH:47])[CH:38]=2)[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)=[O:22])=[O:14])=[CH:7][C:6]=1[OH:49])=[O:4].FC(F)(F)C(O)=O>ClC(Cl)C>[OH:45][NH:44][C:43]([C:40]1[CH:41]=[CH:42][C:37]([CH2:36][NH:35][C:34]([CH2:33][N:16]([CH2:15][C:13](=[O:14])[NH:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[NH:2][OH:1])=[C:6]([OH:49])[CH:7]=2)[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][NH2:24])=[O:22])=[O:48])=[CH:38][C:39]=1[OH:47])=[O:46]
Reactant: CC(C)(C)OC(=O)NNC(=O)CCCC(=O)N(CC(=O)NCc1ccc(C(=O)NO)c(O)c1)CC(=O)NCc1ccc(C(=O)NO)c(O)c1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)CCCC(=O)N(CC(=O)NCc1ccc(C(=O)NO)c(O)c1)CC(=O)NCc1ccc(C(=O)NO)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
The crude N,N-bis-({N-[(4-(N-hydroxycarbamoyl)-3-hydroxyphenyl)methyl]-carbamoyl}methyl)-N′-[(tert-butoxy)carbonylamino]pentane-1,5-diamide from above was suspended in 20 mL of dichloroethane and 10 mL of trifluoroacetic acid was added. The deprotection reaction was stirred for 4 hours at room temperature. Dichloroethane and trifluoroacetic acid were removed in vacuo, and the resulting residue was dissolved in 10 mL of methanol, which was added dropwise to 150 mL of stirred ethyl acetate. A precipitate formed which was collected by filtration, washed with ethyl acetate and then dried in vacuo under a high vacuum. Obtained 1.41 grams (68% yield) of product as a white powder.
Reaction SMILES: CC([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[C:16]#[C:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2/[C:20](=[CH:28]/[C:29]2[NH:30][CH:31]=[CH:32][C:33]=2[O:34][CH3:35])/[C:21](=[O:27])[NH:22]3)=[CH:11][CH:10]=1)(C)C.O[Li].O>C1COCC1.O>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][NH:30][C:29]=1/[CH:28]=[C:20]1\[C:21](=[O:27])[NH:22][C:23]2[C:19]\1=[C:18]([C:17]#[C:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:14][CH:13]=1)[OH:36])[CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCC(=O)OC(C)(C)C)cc3)c21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(OCC(=O)O)cc3)c21

Procedure:
Using Method F above, rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]phenoxy]acetic acid 1,1-dimethylethyl ester (from Example 58 above) (30 mg, 0.061 mmol) was hydrolyzed with LiOH.H2O (58 mg, 1.22 mmol) in THF (0.5 mL) and H2O (0.5 mL) for 12 h, yielding rac-(Z)-[4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]phenoxy]acetic acid. (Yield 24 mg, 89%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: Nc1ccnn1-c1ccc(F)cc1
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1ccc(F)cc1

Procedure:
5-Amino-1-(4-fluorophenyl)pyrazole HCl (21 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 20.76 g. product mp 162°-164°
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[C:3]1=[O:13].[H-].[Na+].C([CH:20]1[CH2:24]OS(=O)(=O)[N:21]1[C:27]([O-:29])=[O:28])(C)(C)C>C1COCC1>[C:6]([O:29][C:27](=[O:28])[NH:21][CH2:20][CH2:24][N:9]1[CH:10]=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:13])[N:4]([CH3:12])[C:5]2=[O:11])=[CH:8]1)([CH3:7])([CH3:10])[CH3:5]
Reactant: CC(C)(C)C1COS(=O)(=O)N1C(=O)[O-]
Reactant: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cn(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione) (step 1) (4.43 g, 24.72 mmol) and sodium hydride (commercial) (60% dispersion in mineral oil) (1.286 g, 32.1 mmol) were degassed with nitrogen for 15 min. The reagents were then suspended in anhydrous THF (44.5 mL) and stirred for 15 mins at room temperature, then cooled to 0° C. (external). After 10 mins, a solution of tert-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (step 2) (6.07 g, 27.2 mmol) in anhydrous THF (44.5 mL) was charged in two portions (2×24 mL). After addition was complete, the ice-bath was removed and the reaction stirred at room temperature for 50 mins. The reaction was then quenched by addition of saturated NH4Cl solution (30 mL). The reaction mixture was diluted with water (30 mL), EtOAc (60 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), saturated with NaCl (s) and extracted with MeCN (4×50 mL). The aqueous layer was evaporated to (˜20 mL) and extracted further with MeCN (3×50 mL). The combined organic layers were dried (Na2SO4) and filtered under reduced pressure and the solvent was evaporated. The resulting solid was adsorbed onto silica and purified via ISCO SiO2 125 g column eluting with 60-95% EtOAc/hexane. The fractions containing product were combined and evaporated to afford a white crystalline solid. The solid was dried under vacuum at 50° C. for 3 h. The title compound was afforded as a white crystalline solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][N:25]=[C:26](F)[CH:27]=3)[N:22]=[CH:21][C:20]=2[C:30]#[N:31])[CH:14]=[CH:15][C:16]=1[F:17]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][N:25]=[C:26]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:27]=3)[N:22]=[CH:21][C:20]=2[C:30]#[N:31])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: NCCN1CCOCC1
Solvent: c1ccncc1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 26.7 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (0.44 mL, 2.73 mmol) and 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.50 g, 1.58 mmol) in pyridine 5.3 mL was heated to 80° C. for 7 days. The solvent was evaporated and the crude product was purified by flash column chromatography (7% MeOH in CHCl3) to give a yellow solid (0.18 g, 44%). 1H NMR (400 MHz, CDCl3) δ 2.5 (m, 4 H) 2.6 (d, J=11.9 Hz, 2 H) 3.2 (m, 2 H) 3.7 (m, 4 H) 5.5 (t, J=5.1 Hz, 1 H) 6.2 (s, 1 H) 6.9 (s, 1 H) 7.1 (m, 1 H) 7.2 (t, J=8.6 Hz, 1 H) 7.3 (m, 1 H) 8.5 (s, 1 H) 9.1 (d, J=0.5 Hz, 1 H).