Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:18])[CH2:16]Cl)[CH:9]=[CH:10][C:11]=2[O:13]C)[CH:6]=[CH:5][C:3]1=[O:4]>CC(O)CN>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:18])[CH2:16][NH:2][CH:12]([CH3:7])[CH3:11])[CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][C:3]1=[O:4]
Reactant: COc1ccc(C(=O)CCl)c2ccc(=O)n(C)c12
Agent: CC(O)CN
Product: CC(C)NCC(=O)c1ccc(O)c2c1ccc(=O)n2C
Yield: 133.2 %

Procedure:
10 ml of isopropanolamine (III) was added to 1.6 g of 1-methyl-5-chloroacetyl-8-hydroxycarbostyril (IV) prepared as described in Example 2, and the mixture was allowed to react at a temperature of 35° C. for 2 hours while stirring. The reaction mixture was concentrated under reduced pressure, and the residue was distilled azeotropically with ethanol to dryness. The resulting residue was dissolved in 20 ml of ethanol, and the solution was filtered to recover the insoluble material which was then dissolved in hot ethanol. The solution was adjusted to a pH of 2-3 with concentrated hydrochloric acid and cooled with ice. The precipitate formed was filtered and dissolved in 20 ml of water. The solution was adjusted to a pH of 6.5-7.5 with sodium bicarbonate and the precipitate formed was filtered and recrystallized from ethanol to obtain 1.1 g of white amorphous 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril (IIa) having a melting point of 136° to 138° C. (with decomposition).
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNC.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:52]([C:54]2[C:55](=[O:79])[C:56]([O:71]CC3C=CC=CC=3)=[C:57]3[C:68](=[O:69])[N:61]4[C@@H:62]([CH3:67])[CH2:63][CH2:64][N:65]([CH3:66])[C@@H:60]4[CH2:59][N:58]3[CH:70]=2)=[O:53])=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH:51][C:52]([C:54]2[C:55](=[O:79])[C:56]([OH:71])=[C:57]3[C:68](=[O:69])[N:61]4[C@@H:62]([CH3:67])[CH2:63][CH2:64][N:65]([CH3:66])[C@@H:60]4[CH2:59][N:58]3[CH:70]=2)=[O:53])=[CH:46][CH:45]=1
Reactant: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: CNCC[C@H](C)N
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Product: C[C@H]1CCN(C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12
Yield: 44 %

Procedure:
In a similar manner to that described in example Z-35, from 16 (18 mg, 0.0398 mmol) and [(3S)-3-aminobutyl]methylamine bis-hydrochloride (10 mg, 0.109 mmol, (4S,12aS)-N-[(4-fluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-87 to give the title compound as a tan solid (7 mg, 44% 2 steps). 1H NMR (CDCl3) δ 12.53 (s, 1H), 10.47 (s, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 5.04 (1H), 4.60 (m, 2H), 4.28 (s, 3H), 2.88-2.80 (m, 2H), 2.32 (s, 3H), 2.18 (m, 1H), 1.48 (m, 1H), 1.34 (m, 3H); ES+MS: 415 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccncc1N1CCc2cc(C)c([N+](=O)[O-])cc2C1=O
Yield: 80 %

Procedure:
6-Methyl-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-69e: 1 g, 3.953 mmol) in conc. H2SO4 (11.9 mL) was reacted with KNO3 (439 mg, 4.348 mmol) to afford 940 mg of the product (80.3% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[NH:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:6][C:5]=2[C:4](=[O:22])[CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[C:4](=[O:22])[CH2:3]1
Reactant: CC1CC(=O)C2=C(C1)NN=C(c1cccc(C(F)(F)F)c1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC1CC(=O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a pyridine solution (1 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-4,6,7,8-tetrahydro-1H-cinnolin-5-one (136.2 mg, 0.44 mmol) obtained in Example 65 was added p-toluenesulfonic acid hydrate (84 mg, 0.44 mmol) and stirred at room temperature for 3 days. The reaction liquid was concentrated, followed by purification of residue obtained with silica gel column chromatography (methylene chloride/methanol=30/1) to obtain an objective compound (89.0 mg, 66.1%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2cccc(Cl)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cccc(Cl)c5cn4)c3)cn2)CC1
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (70.1 mg, 0.149 mmol), trifluoromethanesulfonic acid 8-chloroisoquinolin-3-yl ester (47.9 mg, 0.154 mmol), and Pd(PPh3)4 (11.5 mg, 0.00995 mmol) in 1,4-dioxane (2.3 mL, 29 mmol in a sealable microwave tube was added a solution of Cs2CO3 (95.5 mg, 0.293 mmol) in H2O (0.65 mL, 36 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, sat. NaHCO3 solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, yielding the title compound as a glassy, yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.70 (t, J=0.8 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.82 (dt, J=5.8, 3.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.66-7.62 (m, 2H), 6.47 (brs, 2H), 4.40-4.19 (m, 3H), 2.92 (brt, J=11.6 Hz, 2H), 2.19 (brdd, J=12.2 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=505.16/507.13 (100/42) [MH+], 449.05/451.07 (3/1) [MH+-isobutene]. HPLC: tR=3.15 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:26]2[CH:27]=[CH:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33]O)[CH:31]=2)=[CH:21][CH:20]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:33][CH2:32][N:30]3[CH:31]=[C:26]([CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH:27]=[CH:28][C:29]3=[O:35])[C:10]=2[N:9]=[C:8]1[CH3:11])[CH3:17]
Reactant: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)cn1CCO
Reactant: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)nc2c(OCCn3cc(C(c4ccc(F)cc4)c4ccc(F)cc4)ccc3=O)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (476 mg), 5-[bis(4-fluorophenyl)methyl]-1-(2-hydroxyethyl)pyridin-2(1H)-one (694 mg), 1,1′-azobis(N,N-dimethylformamide) (385 mg) and toluene (9.5 mL) was added tributylphosphine (452 mg) at ambient temperature. The mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with a mixture of EtoAc (50 mL) and THF (20 mL), and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was crystallized from solvent(EtOAc and n-hexane) to give ethyl[4-(2-{5-[bis(4-fluorophenyl)methyl]-2-oxopyridin-1(2H)-yl}ethoxy)-2-methyl-1H-benzimidazol-1-yl]acetate (1.07 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:44]5[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 16.8 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added 1-methane sulfonyl pyperazine (139.9 mg, 0.852 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (47 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.62-7.25 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.15 (m, 4H), 2.85 (m, 5H), 2.60 (m, 4H), 1.25 (s, 9H); LC-MS (ESI) m/z 656 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)[C:13]#[N:14].[NH2-].[Na+].[CH:31](Br)([CH3:33])[CH3:32].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][CH2:11][C:12]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)([CH:31]([CH3:33])[CH3:32])[C:13]#[N:14]
Reactant: CC(C)Br
Reactant: COc1cccc(CCN(C)CCCC(C#N)c2cc(OC)cc(OC)c2)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(CCN(C)CCCC(C#N)(c2cc(OC)cc(OC)c2)C(C)C)c1
Reaction time: 2 h
Yield: 110.5 %

Procedure:
38.3 g (0.1 mole) of 5-[(3-methoxyphenethyl)-methylamino]-2-(3,5-dimethoxyphenyl)-valeronitrile were dissolved in 200 ml of toluene, and the stirred solution was refluxed with 4.7 g (0.12 mole) of powdered sodium amide for 1 hour. Thereafter, a solution of 15.7 g (0.12 mole) of isopropylbromide in 30 ml of toluene was added dropwise in the course of 60 minutes, and refluxing was continued for a further 2 hours. The cooled reaction mixture was poured into water, the toluene phase was washed several times with water and the toluene was then distilled off. The residue was dissolved in 100 ml of isopropanol, and ethanolic hydrochloric acid was added. The hydrochloride was recrystallized from isopropanol. 46.9 g (92%) of a hydrochloride of melting point 141°-143° C. were isolated.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg (0.21 mmol) spiro[piperidin-4,4′-pyrido[2.3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 65 mg (0.21 mmol) 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.84 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[N:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2cc[nH]c2)(c2cccc(OCc3ccccc3)c2)N=C1N
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(c2cc[nH]c2)(c2cccc(O)c2)N=C1N

Procedure:
A mixture of 2-amino-5-(3-benzyloxyphenyl)-5-(1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one (70 mg, 0.2 mmol) and Pd/C (8 mg) in ethanol (10 ml) is hydrogenated at 45 psi overnight. The catalyst is removed by filtration and the filtrate is concentrated. The crude material is purified by flash chromatography (silica gel, EtOAc/2.0M ethanolic NH3: 90/10 to 80/20) to afford the title compound as a solid, 49 mg (93%) mp 142-145° C., MS (+) ES: 271 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>CC#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[N:4][C:3]=1[C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1ccccc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A mixture of 3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (3.62 g, 12.35 mmol), 4-boronobenzoic acid (2.049 g, 12.35 mmol) and Na2CO3 (2.618 g, 24.70 mmol) was suspended in MeCN (60 mL)/water (60 mL). The mixture was degassed (5×N2 vacuum cycles) and Pd(PPh3)4 (1.427 g, 1.235 mmol) added. The mixture was degassed again and heated to 90° C. After 4 hours, the mixture was allowed to cool, concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH4 (2M HCl) and the resulting precipitate collected, washed with water and dried overnight under vacuum to give the product as a bright yellow solid, (3.05 g, 69% Yield). 1H NMR (400 MHz, DMSO) d 7.17 (1H, t), 7.41 (2H, t), 7.83 (4H, d), 8.03 (2H, d), 8.37 (2H, d), 9.01 (1H, s), 10.45 (1H, s), 13.03 (1H, brs) ppm; MS (ES+) 335
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:37][CH2:36][N:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1)=[O:7]
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (800 mg, 1.97 mmol, 1.0 eq), 2-morpholinoethanol (284 mg, 2.17 mmol, 1.1 eq), HATU (974 mg, 2.56 mmol, 1.3 eq), and TEA (598 mg, 5.91 mmol, 3 eq) in DCM (10 mL) and DMF (10 mL) was stirred at room temperature overnight under N2. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo and the residue purified by column chromatography, (MeOH:DCM 0:1 to 1:50) to give the title compound as a yellow oil (710 mg, 70%).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCC(=O)O)c2cccnc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(CCCCCCO)c2cccnc2)c1C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred tetrahydrofurane solution (40 ml) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid (3.0, 7.8 mmol) prepared in the Reference Example 11 was added lithium aluminum hydride (450 mg, 11.9 mmol) under ice-cooling. The reaction mixture was allowed to rise to room temperature and stirred for 30 min. After that water was carefully added to the reaction mixture and the product was extracted with ethylacetate. The extract was washed with water, dried, and evaporated in vacuo to yield 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanol (2.3 g, 79.6%) as, an oil, after chromatography of the crude product on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1ccccc1F
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3F)cc2F)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-fluorophenethylamine (0.382 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.718 g, 75%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F2 387.2032 (M+H)+, found 387.2032, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% Over 18], tR=11.4 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][O:15][C:16]2[CH:37]=[CH:36][C:19]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:23]([O:33][CH2:34][CH3:35])=[N:22]3)=[CH:18][CH:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[C:3]([CH2:14][O:15][C:16]2[CH:37]=[CH:36][C:19]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:23]([O:33][CH2:34][CH3:35])=[N:22]3)=[CH:18][CH:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
After a mixture of ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (738 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (669 mg, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [PH:1]([O:4][P:5]([O:8][PH:9]([OH:11])=[O:10])([OH:7])=[O:6])([OH:3])=[O:2].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+:20]>>[PH:1]([O:4][P:5]([O:8][PH:9]([O-:11])=[O:10])([O-:7])=[O:6])([O-:3])=[O:2].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+:20].[Na+:20].[Na+:20].[Na+:20].[Na+:20].[Na+:20].[PH:1]([O:4][P:5]([O:8][PH:9]([O-:11])=[O:10])([O-:7])=[O:6])([O-:3])=[O:2]
Reactant: O=[PH](O)OP(=O)(O)O[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[PH]([O-])OP(=O)([O-])O[PH](=O)[O-]

Procedure:
To 1 mole of phenyl methane triphosphonate acid there were added 6 moles of 10% aqueous sodium hydroxide and the mixture was evaporated to dryness to produce hexasodium phenyl methane triphosphonate.