Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=[C:15](C(C)(C)C)[C:14](O)=[C:13](C(C)(C)C)[CH:12]=3)=[N:7][C:6]=2[CH:26]=1.BrC1C=CC=C[N:31]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:31]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: Brc1ccccn1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nc2ccccc2o1)c1ccccn1
Temperature: 90 °C
Yield: 104.2 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mM), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mM), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 uM) and copper (I) iodide (1.2 mg, 6 uM) in triethylamine (12 ml) was heated at 90° C., under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridylethynylbenzoxazole. The crude benzoxazole was purified by column chromatography (SiO2 ; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (top 138°-9° C.).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])O.[Na+].C(O)C>O>[OH:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CNc1cc(O)ccc1[N+](=O)[O-]
Yield: 98 %

Procedure:
3-fluoro-4-nitrophenol 50 g (0.138 mole), glycine 48 g (0.637 mole) and sodium hydrogen carbonate 107 g (1.27 mole) were added to a mixture of ethanol 600 ml and water 100 ml and refluxed for 5 days. The solvent was distilled off in vacuo. The reaction mixture was acidified by adding dilute HCl and filtered. The filtrate was washed with dilute HCl and water, then dried in vacuo to obtain N-(5-hydroxy-2-nitrophenyl)-amino acetic acid as a yellow solid. Yield: 66.4 g (yield: 98%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[N:2]1.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[CH3:12][N:2]1[CH:3]=[C:4]2[C:9]([C:8]([C:10]#[N:11])=[CH:7][CH:6]=[CH:5]2)=[N:1]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc2cn[nH]c12
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc2cccc(C#N)c2n1
Temperature: 80 °C

Procedure:
To a solution of 1H-indazole-7-carbonitrile (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.[H-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH:4]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
Diethyl 2,5-difluoro-4-nitrobenzylphosphonate (0.67 g, 2.17 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.43 g, 2.17 mmol) were stirred in tetrahydrofuran (8.3 mL) and cooled in an ice bath. Sodium hydride (0.133 g, 2.82 mmol) was added then the reaction was taken off ice bath and stirred for 4 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane, dried (magnesium sulphate), filtered and evaporated under reduced pressure. The crude material was purified by silica chromatography using a dichloromethane solvent system. The solid obtained was triturated with heptane to give the title compound as a yellow solid (0.24 g). 1H NMR (CDCl3, 400 MHz): δ 7.80 (dd, 1H), 7.12 (dd, 1H), 6.24 (s, 1H), 3.54 (t, 2H), 3.45 (t, 2H), 2.40 (t, 2H), 2.56 (t, 2H), 1.48 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:35]C3C=CC([N+]([O-])=O)=CC=3)[C:22]2=[O:45])[CH2:17][CH2:16]1.Br.[CH2:47](C1C(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)N(C)C2=O)CCNC1)[CH3:48]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH3:35])[C:22]2=[O:45])[CH:19]([CH2:47][CH3:48])[CH2:20]1
Reactant: CCC1CNCCC1n1c(=O)c2cc([N+](=O)[O-])ccc2n(C)c1=O
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc([N+](=O)[O-])cc5)c4=O)CC3)c2cc1OC
Agent: Br
Product: CCC1CN(c2ncnc3cc(OC)c(OC)cc23)CCC1n1c(=O)c2cc([N+](=O)[O-])ccc2n(C)c1=O
Yield: 39 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 61.1 mg (0.15 mmol) of 3-(1-exthoxycarbonyl-3-ethyl-4-piperidinyl)-1,2,3,4 -tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline (Compound 11: diastereomixture) was used in place of Compound a, whereby 70.4 mg of crude 3-(3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline hydrobromide was obtained. The product was treated in the similar manner as in Example 15 to give 30.4 mg (yield: 39%) of Compound 104 as a 6:4 diastereomixture.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19][CH2:18][C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH:20]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:19][CH2:18][C:16]=2[N:17]=1
Reactant: Cc1nc2c(s1)CC(CO)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3nc(C)sc3C2)cc1
Yield: 71 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV) according to the procedure described in Example 1. M.p.=70°-71° C. Yield: 71%.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].S(=O)(=O)(O)[OH:27]>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]([NH2:25])=[O:27])=[C:6]12)=[O:4]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Product: NC(=O)c1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 20 ml of concentrated sulfuric acid was stirred at room temperature for 2 hours, then poured into ice water, stirred, and filtered. The product was washed with water and dried giving 2 g of the desired intermediate,. mp 174°-176°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:8]=[C:7]2[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(N)ccc21
Yield: 89.2 %

Procedure:
5-Amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a solution of 0.4 g of 5-nitro-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 16 ml of ethyl acetate containing 40 mg of 10% palladium-on-charcoal is hydrogenated under a pressure of 200 kPa at a temperature in the region of 25° C. for 18 hours. After filtration of the catalyst through Celite® under argon and washing with ethyl acetate, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. 0.33 g of crude 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a burgundy-colored oil. A second attempt using 1.1 g of 5-nitro-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole makes it possible to obtain, in the same way, 0.99 g of crude 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in the form of a burgundy-colored oil. The two crude products are pooled and purified by chromatography under argon pressure (50 kPa), on a column of 53 g of silica (particle size 40-63 μm), eluting successively with pure cyclohexane then with cyclohexane/ethyl acetate (97/3; 95/5; 90/10; 80/20 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. 0.78 g of 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a burgundy-colored oil (EI mass analysis: m/z 371 (M+) (base peak)).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C:14]1([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1([CH:17]([F:7])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(C(O)CCCCc2ccccc2)CO1
Solvent: ClCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 58.8 %

Procedure:
To a solution of 2.44 g (15 mmol; 2.0 ml) of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to -78° C. under a nitrogen atmosphere is added dropwise a solution of 2.00 g (7.6 mmol) of 2-[1-hydroxy-5-phenylpentyl]-2-oxiranecarboxylic acid methyl ester (isomer A) in 50 ml of methylene chloride over 30 minutes. The mixture is stirred at -78° C. for 90 minutes and then is allowed to come to room temperature. The mixture is stirred at room temperature for 1.5 hours, is quenched with a saturated aqueous solution of sodium bicarbonate and is extracted with ethyl ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and rotoevaporated. The resulting oil is purified chromatographically (silica gel; hexane:ethyl acetate (9:1)) to give 1.19 g of the title compound (Rf 0.54 in hexane:ethyl ether (3:2)): IR (neat) γ 1750 cm-1 ; NMR (CDCl3) δ 1.40-1.96 (6H, m), 2.64 (2H, t, J=8 Hz), 3.07 (1H, dd, J=4, 6 Hz), 3.15 (1H, d, J=6 Hz), 3.15 (1H, d, J=6 Hz), 3.79 (3H, s), 5.14 (1H, ddd, JHF =48 Hz, J=10, 3 Hz), 7.21 (2H, d, J=8 Hz) and 7.31 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(=O)C>[CH2:6]([O:5][P:4]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:16]=2)[NH:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1cnc2ccc(C(F)(F)F)cc2c1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C1CNc2ccc(C(F)(F)F)cc2C1
Yield: 52.2 %

Procedure:
6.66 g of 6-trifluoromethyl-quinoline-3-phosphonic acid diethyl ester is dissolved in 70 ml of glacial acetic acid and hydrogenated on platinum dioxide at room temperature under normal pressure. After column chromatography, 3.52 g of 6-trifluoromethyl-1,2,3,4-tetrahydroquinoline-3-phosphonic acid diethyl ester of melting point 112° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (585 mg, 3.0 mmol) in DCM (5 mL) was added DIPEA (1.5 mL, 9.0 mmol), followed by 3-(S)-methylmorpholine (909 mg, 9.0 mmol) dropwise. The reaction mixture was stirred at 40° C. overnight whereupon it was washed with water (10 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a colourless oil (850 mg) used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=O)=[CH:15][CH:14]=1>C1(C)C=CC(C)=CC=1>[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[N:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]3=[N:20][N:19]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:15][CH:14]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: Clc1nccc2ccccc12
Solvent: Cc1ccc(C)cc1
Product: Brc1ccc(-c2nnc3c4ccccc4ccn23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
To a 50-mL three-neck flask were added 0.8 g (5.0 mmol) of 1-chloroisoquinoline, 1.1 g (5.0 mmol) of 4-bromobenzoylhydrazine, and 10 mL of para-xylene. This mixture was stirred at 100° C. for 4 hours under a nitrogen stream. After a predetermined time elapsed, this mixture was cooled to room temperature, and the precipitated solid was collected by suction filtration. The obtained solid was purified by silica gel column chromatography (chloroform:ethyl acetate=10:1), so that the substance which was the object of the synthesis was obtained as 0.5 g of a white powder in 29% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl

Procedure:
Ethyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxy-phenyl)-1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and ethyl bromo-isobutyrate according to general procedure D.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C:37]([CH:44]=O)=[CH:36]1>N1C=CC=CC=1>[CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[C:15](=[CH:44][C:37]2[C:38]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:35][CH:36]=2)[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: c1ccncc1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ncccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 47.1 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (500 mg, 1.10 mmol) was condensed with 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (160 mg, 1.16 mmol) in pyridine (5 mL). Purification by medium pressure chromatography eluting with a solvent gradient (5% acetone in CH2Cl2 to 50% acetone in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 300 mg of N-isopropyl-2-[5-oxo-1-phenyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-phenyl-acetamide. 1H NMR (CDCl3) δ 8.31 (d, 1H), 8.05 (d) and 7.96 (d, total 1H), 7.71 (m, 1H), 7.59 (m, 2H), 7.33-7.51 (m, 9H), 7.17 (m, 2H), 7.01 (m, 1H), 6.80 (t, 1H), 5.09 (m, 1H), 4.50 (d) and 4.30 (d, total 1H), 4.15 (m, 1H), 3.92 (d, 1H), 1.14 (m, 6H); MS 580.6 (M+1).
Reaction SMILES: N[C@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].N([O-])=[O:11].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O.O>[CH3:7][C:6]([CH3:9])([CH3:8])[C@@H:2]([OH:11])[C:3]([OH:5])=[O:4]
Reactant: O=N[O-]
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[C@@H](O)C(=O)O

Procedure:
To a stirred solution of (2R)-2-amino-3,3-dimethylbutyric acid (5.0 g, 38.12 mmol) in 80 mL of 1N sulfuric acid at −10° C. was dropped in slowly a solution of sodium nitrite (5.26 g, 76.23 mmol) dissolved in 25 mL of water. After addition, the reaction was allowed to slowly equilibrate to ambient temperature over 20 h. Sodium chloride (10 g) was added and the solution was extracted twice with 100 mL portions of diethyl ether. The organic layers were separated, combined, dried over anhydrous sodium sulfate, and filtered. The filtrate solvent was removed under reduced pressure. The residue was purified by preprative HPLC using a chiralpak AD column (5 cm×50 cm) using 5% ethanol in 95% hexanes with 0.2% TFA as the mobile phase at a flow rate of 80 mL/min. The product-containing fractions were concentrated in vacuo. (2R)-3,3-Dimethyl-2-hydroxybutyric acid was obtained as an oil that crystallizes on sitting (2.2 g; 44%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccc(F)c(Cl)c1)N1CCOCC1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)N3CCOCC3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[F:15].[CH:16]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[C:4]([CH3:16])[C:3]=1[F:15]
Reactant: Fc1cc(OC2CCCCO2)ccc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(OC2CCCCO2)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-(4-bromo-3-fluorophenoxy)tetrahydro-2H-pyran (1200 mg, 4.4 mmol) was dissolved in tetrahydrofuran (22 mL, 0.2M) under nitrogen and cooled to −78° C. To this was added (600 mg, 5.6 mmol) lithium diisopropylamide in solution dropwise over 5 minutes. The reaction mixture was stirred for 1 h at −78° C. Methyl iodide (948 mg, 6.5 mmol) was then added dropwise. The reaction was stirred at −78° C. for 30 min and allowed to warm to RT overnight. The mixture was quenched with water and 10 mL of saturated aqueous ammonium chloride solution. The reaction was extracted with diethyl ether (3×). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 1.17 g (93%) of a light yellow mix of solid and oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.78 (m, 3 H) 1.85-1.93 (m, 2 H) 1.95-2.08 (m, 1 H) 2.21 (d, J=2.34 Hz, 3H) 3.61 (m, J=11.27, 3.98, 3.98, 1.46 Hz, 1 H) 3.78-3.88 (m, 1 H) 5.41 (t, J=3.12 Hz, 1 H) 6.81 (dd, J=8.98, 1.37 Hz, 1 H) 7.27 (d, J=16.98 Hz, 1 H)
Reaction SMILES: [C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:41].[C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:24]=[CH:25][C:26]([C:29](=[NH:46])[NH2:30])=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1)C.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:21]1([N:20]2[C:8]3[N:9]=[C:10]([NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:11]=[CH:12][C:7]=3[CH2:6][CH:5]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:4]2=[O:3])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cccnc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1C(c2cccnc2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester (60 mg, 0.36 mmol) (from Example 10b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 8-phenyl-2-phenylamino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a white solid. (Yield 37.3 mg, 69.3%).