Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:34][CH2:35][CH:36]([OH:39])[CH2:37][N:38]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([O:18]CC)=[O:17])[CH:5]=[C:6]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:21][C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[C:26]2[CH:31]=[C:30]([NH:32][C:33]3[NH:38][CH2:37][CH:36]([OH:39])[CH2:35][N:34]=3)[CH:29]=[C:28]([OH:40])[CH:27]=2)[CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: N#CC1(c2cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c3cc(O)cc(NC4=NCC(O)CN4)c3)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (1.006 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (212 mg, 5.052 mmol) and the reaction mixture was stirred at room temperature overnight (16 h). The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The DCM layer was removed and discarded after analyzed by LC-MS, shows the DIPU, byproducts and baseline impurities only. The aqueous layer was acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA. The pure fractions were mixed together and evaporated in vacuo to give the desired product, after lyophilization, as a colorless lyophilized powder (305 mg). LC-MS analysis of the solid shows the desired product: (3S)-3-(3-chloro-5-(1-cyanocyclobutyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 569 (35ClM+H) and m/z 571 (37ClM+H); Calcd for C27H29ClN6O6: 569.01
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([OH:36])=O)[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:63][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=6)=[CH:51][CH:50]=5)[C:46]([OH:64])=[O:45])=[O:36])[N:21]([C@H:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(OC)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (16 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 858.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[N:27]=[C:26]([C:44]2[CH:45]=[N:46][CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[CH:25]=1.N1CCC(N2CCC[C@H]2[CH2:65][O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)CC1>>[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][CH2:41][C@H:42]3[CH2:65][O:66][C:67](=[O:74])[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[N:27]=[C:26]([C:44]2[CH:45]=[N:46][CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=2)[CH:25]=1
Reactant: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4B,4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid (example 42) was converted into its acid chloride and reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-[1-(4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carbonyl)-piperidin-4-yl]-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless amorphous solid. MS: 463.2 (MH+).
Reaction SMILES: C1(OC)C=CC=CC=1.C([O:13][C:14](=[O:36])[C@@H:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[Br:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:25]=[CH:24][C:23]([S:20]([NH:19][C@@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([OH:36])=[O:13])(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of anisole (4.9 g, 0.045 mol) in trifluoroacetic acid (200 mL) was added in small portions the tert-butyl ester (21.1 g) prepared in Step (c). The solution was stirred at room temperature for 16 hours, then poured over ice. The aqueous suspension was diluted with chloroform, the layers separated, and the organic portion was washed with saturated sodium chloride, dried (MgSO4) and concentrated to dryness. The resulting solid was suspended in hexanes/diethyl ether (9:1) and collected by filtration to give the title compound (17.7 g, 96%) as a white solid, mp 192°-193° C.
Reaction SMILES: Cl[CH:2]([SiH:4]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5])[CH3:3].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>>[CH2:8]([CH2:7][CH2:6][SiH:4]([CH3:5])[CH:2]([N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25])[CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(Cl)[SiH](C)CCCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: CC(N1C(=O)c2ccccc2C1=O)[SiH](C)CCCc1ccccc1

Procedure:
The title compound was prepared from (α-chloroethyl)benzylethylmethylsilane and potassium phthalimide by a procedure similar to the one described in Example 1, Step A.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][CH2:16][C:17]#[N:18])([CH3:3])[CH3:2].[H-].[Na+].CI>>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][C:16](=[CH:4][CH2:5][O:15][CH3:16])[C:17]#[N:18])([CH3:3])[CH3:2]
Reactant: Cc1cn(C)c2cc(C(C)C)c(OCC#N)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCC=C(C#N)Oc1cc2c(C)cn(C)c2cc1C(C)C

Procedure:
2-(6-Isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-4-methoxy-but-2-enenitrile was prepared from (6-isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-acetonitrile by treatment with sodium hydride and methyl iodide using the procedure of step 6 of Example 2 above.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:34][CH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: NCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 44.8 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(aminomethyl)azetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 42 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:16]1([C:22]2[N:31]=[C:30](Cl)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[OH-].[Na+]>O>[OH2:6].[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH:4]([OH:15])[CH2:3][NH:2][C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:31]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccccc1OCC(O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1OCC(O)CNc1nc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture containing 5.8 g (0.025 mole) of 1-amino-3-ortho-methoxyphenoxy 2-propanol hydrochloride, 6 g (0.025 mole) of 2-phenyl-4-chloroquinazoline, 150 ml of methanol, 1.0 g of sodium hydroxide (in one ml of water) was refluxed for 6 hrs. Another one gram of sodium hydroxide (in one ml of water) was added and refluxing was continued for 2 hrs. The resulting reaction mixture was cooled to room temperature and filtered. The gummy substance which as obtained when the filtrate was mixed with 300 ml of water was separated, washed with water, then dissolved in acetone. The acetone solution was treated with one ml of 12 N hydrochloric acid and the white crystalline precipitate was separated, dissolved in water, adjusted to pH=7.5. A white crystalline solid was obtained. This crystalline solid was recrystallized with methanol and water to give 1.5 g of the title compound, m.p. 138°-140° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][C:34](F)([F:36])[F:35])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C=CC=C2C=1N=C(NCC(F)F)C(C)=N2)=O.C(OC(N[C@H](C)C(=O)CC(OCC)=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][CH:34]([F:35])[F:36])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
This compound (950 mg, 82% yield) as yellow crystalline solid was prepared according to the procedure described for Intermediate 293b, using 2-bromo-1-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)ethanone (617) (790 mg, 2.295 mmol), (R)-ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (714 mg, 2.75 mmol) and K2CO3 (793 mg, 5.74 mmol) in DMF (7.0 mL) as the starting material, followed by the treatment of the resulting 4-ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-((2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (1.03 g, m/z (ESI, +ve ion) 523.1 (M+H)+) with NH4OAc (1.42 g, 18.36 mmol) in EtOH (6 mL) and AcOH (2 mL). 19F NMR (376 MHz, CDCl3) δ ppm −122.78 (1F, s), −123.02 (1F, s). m/z (ESI, +ve ion) 504.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:24].S(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CN(C)C(=O)C>[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)cc(C)c1O
Temperature: 155 °C
Yield: 18.8 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1.[C:42](OC(=O)C)(=[O:44])[CH3:43].N1C=CC=CC=1>C(OCC)(=O)C>[C:42]([O:1][C:2]([CH3:40])([CH3:41])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)OC(C)=O)CC2)c2nc(C)nn12
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), acetic anhydride (5 mL) and pyridine (5 mL) was stirred at 120° C. for 6 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.1 g, 47%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:37])=[CH:12][C:11]=1[O:17][CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)ccc1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COc1cc(CBr)ccc1OC(=O)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 2 using 22.59 g (0.093 mol) of 2-methoxy-4-methylphenyl benzoate, a catalytic amount of benzoyl peroxide and 19.92 g (0.11 mol) of N-bromosuccinimide. The crude product (29.36 g) was purified by HPLC to give 8.95 g, m.p. 86°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([F:10])[C:3]=1[CH3:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC#N>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([CH3:11])=[C:4]([F:10])[C:5]=1[O:9][CH3:12]
Reactant: Cc1c(Br)cc(Br)c(O)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1c(Br)cc(Br)c(C)c1F
Temperature: 30 °C
Reaction time: 21 h

Procedure:
1,5-dibromo-3-fluoro-2-methoxy-4-methylbenzene was prepared from a homogeneous CH3CN (1 L) solution of 4,6-dibromo-2-fluoro-3-methylphenol (˜225.1 g, 792.8 mmol) by adding, at room temperature, K2CO3 (131.5 g, 1.18 mol), followed by MeI (74 mL, 951 mmol). The cloudy solution was stirred at 30° C. and, as monitored by LC, the reaction went to completion at 21 h. The reaction mixture was cooled to room temperature, solid was filtered off by filtration, washing with CH2Cl2 (˜100 mL×2). Filtrate was collected, solvent was removed in in vacuo. Crude product was suspended in CH2Cl2 (200 mL) and the solution was passed through a silica gel pad (˜50 g of silica gel) (note, to remove some darker color baseline impurities and solid initially dissolved in CH3CN), washing with CH2Cl2 (˜100 mL×3). Filtrate was collected, solvent was removed in vacuo. 1,5-dibromo-3-fluoro-2-methoxy-4-methylbenzene was obtained as an off-white solid: 249.46 g (>99% yield); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=2.1, 1H), 3.92 (s, 3H), 2.29 (d, J=2.8, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])N=N[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24](N1CCCC1)=[CH2:25]>C(Cl)(Cl)Cl>[C:13]1([C:12]2[CH:24]=[CH:25][C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
General Procedure D. Ethyl 5,6-diphenyl-1,2,4-triazine-3-carboxylate (Compound 11, 200 mg, 0.66 mmol) and crude 1-vinylpyrrolidine (Compound 38, 2 g) in CHCl3 (20 ml) was heated at 75° C. overnight under nitrogen. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) to yield the title compound as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>O>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: COc1ccc(C2COc3cc(O)ccc3C2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 7-hydroxy-4′-methoxyisoflavanone (2.0 g, 7.5 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C. for 1 hour. After cooling the mixture to room temperature, it was poured into water (100 ml), stirred for 2 hours and then extracted with dichloromethane (3×50 ml). The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The white residue was crystallised from methanol to yield 7-acetoxy-4′-methoxyisoflavone as colourless prisms (2.1 g, 91%). 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.84 (s, 3H, OCH3), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.16 (dd, 1H, J 1.9 Hz 8.6 Hz, H6), 7.30 (d, 1H, J 1.9 Hz H8), 7.50 (d, 2H, J 8.7 Hz, ArH), 8.00 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, H5).
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]2[N:10]=[N:11][N:12]=[C:8]2[N:7]=[C:6]([CH3:13])[CH:5]=1.Cl>O>[SH:1][C:4]1[N:9]2[N:10]=[N:11][N:12]=[C:8]2[N:7]=[C:6]([CH3:13])[CH:5]=1
Reactant: [SH-]
Reactant: Cc1cc(Cl)n2nnnc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nnnc2n1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of 108 g (1.35 mole) of sodium hydrosulfide dissolved in 4 liters of water, 70 g (0.41 mole) of 7-chloro-5-methyltetrazolo[1,5-a]pyrimidine was added and the mixture was heated to 60° C. and stirred for 2.5 hours. The pH of the mixture was adjusted to about 1 with 2N hydrochloric acid under ice-cooling and stirring. The precipitates were collected by filtration and washed with water, isopropanol and then ether, followed by drying, to obtain 64 g of the title compound (Yield: 93%).
Reaction SMILES: O[CH:2]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3CCCC[O:23]3)[C:13](=[O:28])[N:12]([CH3:29])[C:11]=2[N:10]=[CH:9][C:8]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>C(O)=O.[Zn]>[CH:22]([O:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:8]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:29])[C:13]1=[O:28])=[O:23]
Reactant: CC(C)CC(O)c1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)CCc1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 57.4 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 0.106 mmol) in HCOOH (5 mL) was added Zn dust (34.7 mg, 0.53 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated and dried to give 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (30 mg, 57.3% yield) as a solid. LCMS: MH+ 494 and TR=2.193 min.