Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C(OC([C@@H]1C[C@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1)=O)C.[Cl:46][C:47]1[N:51]=[C:50](Cl)[S:49][N:48]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:50]1[S:49][N:48]=[C:47]([Cl:46])[N:51]=1)=[O:4]
Reactant: Clc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: CCOC(=O)[C@@H]1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nc(Cl)ns1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (prepared as described for the corresponding (2S,4S)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester in example 192e) was reacted with 3,5-dichloro-[1,2,4]thiadiazole (CAS Reg. No. 2254-88-8) in a shaking reactor at 55° C. for 12 h to give the title compound as orange solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:5]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:4]=[C:3]1SC.C(Cl)Cl.C[OH:31].Cl>O1CCOCC1.[OH-].[Na+]>[OH:31][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:5]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(O)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 3-methyl-2-methylsulfanyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (10.1 g, 28.1 mmol) was heated to 100° C. in 100 mL 1,4-dioxane and 60 mL 2.5M sodium hydroxide. After 7 h, TLC (95:5 DCM/MeOH) shows the solution to have no remaining starting material. The reaction was cooled to room temperature and acidified to pH 5 with 5M HCl. The resulting precipitate was collected by filtration, and then suspended in 100 mL hot methanol. The solid was cooled to room temperature then collected by filtration and washed with 100 mL diethylether. The product was air dried overnight to give a pale yellow solid. M+1=330.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H][H].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=1>CCCCCC.CN(C)C=O>[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([F:21])[CH:18]=1)[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(O)cc1
Reactant: Fc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
Sodium hydride (7.56 g, 0.189 mol; 60% in oil) was washed with n-hexane to eliminate the oil, and N,N-dimethylformamide (100 ml) was added thereto to make a suspension. To the thus prepared suspension, 4-methoxyphenol (25.84 g, 0.208 mol) was gradually added with stirring, and stirring was continued until the generation of hydrogen gas ceased. 1,3,5-Trifluorobenzene (30.00 g, 0.227 mol) and cuprous chloride (0.50 g) were added thereto. The resultant mixture was heated under reflux for 8 hours with stirring. After allowed to cool, the reaction mixture was poured into ice-water and extracted with toluene. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residual oil was distilled under reduced pressure to give 4-(3,5-difluorophenoxy)anisole (25.42 g). B.P., 98.5° C./0.2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.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>[Cl:12][C:6]1[CH:5]=[C:4]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(C(F)(F)F)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 53 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.62 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.38 g, 2.16 mmol), Cs2CO3 (1.8 mL, 2M, 3.6 mmol) and Pd(PPh3)2Cl2 (38 mg) in THF (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.295 g; yield 53%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.433 (s, 2H), 6.073 (s, 1 H), 5.846 (s, 1 H) ppm.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:15](N(C)C)N(C)C.Cl.CNC>C1(C)C=CC=CC=1>[N:1]12[P:15]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNCCN1
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Agent: Cl
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(CCN1)P23
Yield: 100 %

Procedure:
A solution of 1.75 g of 1,4,7,10-tetraazacyclododecane and 1.63 g of hexamethylphosphorous triamide in 50 ml of toluene is refluxed for 12 hours. Titration of the off-gases with 1 N HCl indicates that 97% of the theoretical amount of dimethylamine is evolved in this time. The toluene is removed under reduced pressure to give 2.0 g of 1,4,7,10-tetraaza-13-phosphatricyclo[5.5.1.04,13 ]tridecane as a white solid which melts at 109°-111° C. with sintering from 90° C. (possibly because of the presence of a trace of toluene). Sublimation of this product at 75° C. and 0.55 mm gives large colorless crystals, which melt at 111°-113° C. The mass spectrum shows an M+ ion at 200; measured mass, 200.1194; calc'd, 200.1190.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](Cl)=[O:16].[CH3:18][C:19]([NH:28][CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:20].O>ClCCl>[CH3:20][C:19]([N:28]([CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])[C:15](=[O:16])[CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:18]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(=O)C(C)NC(C)(C)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)C(C)N(C(=O)Cc1ccccc1F)C(C)(C)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
In 30 ml of dichloromethane containing 4.0 g of pyridine, 5.0 g of 2-(2-fluorophenyl)acetyl chloride was added dropwise to 3.2 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine at 20° to 30° C. After stirring for 1 hour, the solution was poured into water, and then extracted with dichloromethane. Next, the solution was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated by an evaporator, and then subjected to column chromatography to obtain 2.4 g of N-[1-methyl-1-(3chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-(2-fluorophenyl)acetamide.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:22]([OH:15])[CH2:21][CH2:20][CH3:19].[CH3:16][N:4]1[C:3](=[O:17])[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:32])([F:33])[F:18])[CH2:31][CH2:30]2)=[N:7][N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]1=[O:15]
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Product: CCCCO
Product: Cn1c(=O)c(N2CCN(c3ccccc3C(F)(F)F)CC2)nn(CCCC(F)(F)F)c1=O
Yield: 82 %

Procedure:
The compound 9 (solid) is prepared from the triazine 4a and from 1-(2-trifluoromethyl-phenyl)-piperazine according to the synthesis method 1 in n-butanol (yield: 82%).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OCC)=[O:11]>>[OH:11][CH:10]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C1CCCCCCC1
Reactant: CCOC=O
Product: O=C1CCCCCCC1=CO

Procedure:
As in previous examples, 126 g of cyclooctanone, XXVIc, was reacted with ethyl formate to give 95 g (0.62 mol) of 2-hydroxymethylene-cyclooctanone, XXVIIc, bp 87°-92° C. (0.4 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][N:3]=2)[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2cc(-c3ccccc3)[nH]n2)n1
Temperature: 40 °C

Procedure:
The mixture of 3-amino-5-phenylpyrazole (103 mg, 0.65 mmol), 2,4,5-trichloropyrimidine (74.5 μL, 0.65 mmol), and sodium carbonate (68.9 mg, 0.65) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford 2,5-Dichloro-N-(5-phenyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 306.0 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([CH2:30][OH:31])[CH2:3][C:4]1[C:12]2[C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:5]=1.O[C@H](CO)CC1C2C(C#N)=CC=CC=2N(C2C=CC(OC3C=CC(F)=CC=3)=CC=2)C=1>CCO.O>[OH:1][C@H:2]([CH2:30][OH:31])[CH2:3][C:4]1[C:8]2[C:7](=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[N:6]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:5]=1
Reactant: NC(=O)c1cccc2c1c(C[C@H](O)CO)cn2-c1ccc(Oc2ccc(F)cc2)cc1
Agent: N#Cc1cccc2c1c(C[C@H](O)CO)cn2-c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc2c(C[C@H](O)CO)cn(-c3ccc(Oc4ccc(F)cc4)cc3)c2c1
Temperature: 84 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
General procedure for the preparation of compounds 122 and 123: To a mixture of compound 120 (100 mg, or 105) in EtOH/water (6 mL/2 mL) at room temperature was added the catalyst 121 (10 mg). The resulting mixture was shaken at 84° C. for 16 hours. The solvent was evaporated and the residue was purified by column (TCM/MeOH 10/0.5) to get the desired product as a white solid (˜80%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].Br[C:23]([Br:26])([CH3:25])C>C(C(C)=O)C>[Br:26][CH2:23][CH2:25][CH2:16][O:13][C:10]1[CH:11]=[CH:12][C:6]2[C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][C:7]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)Br
Reactant: Oc1ccc2c(c1)oc1cc(Cl)ccc12
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc2c(c1)oc1cc(OCCCBr)ccc12
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of 98.4 g (0.45 mole) of 7-chlorodibenzofuran-3-ol, 200 ml of methyl ethyl ketone, 93 g (0.67 mole) of potassium carbonate and 283 g (1.4 moles) of dibromopropane was refluxed for 24 hours, while stirring. The inorganic precipitate was filtered off under suction, the filtrate was evaporated down under reduced pressure, the residue was dissolved in 500 ml of methylene chloride, and the solution was washed with 100 ml of water, 100 ml of 2N sodium hydroxide solution and 100 ml of water in succession, dried over sodium sulfate and evaporated down under reduced pressure. The solid residue was left to stand with 30 ml of pentane at 0° C. for 30 minutes, after which it was filtered off under suction and washed with 30 ml of cold n-pentane. 77 g (50% of theory) of pure 1-bromo-3-(7-chlorodibenzofuran-3-yloxy)-propane of melting point 83°-85° C. were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.NC1[N:25]2[CH2:26][CH2:27]N=[C:24]2[C:23]2[CH:22]=CC(O)=C(OC)C=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[C:49]2[N:48]=[C:47]([NH2:50])[N:46]3[CH2:51][CH2:52][N:53]=[C:45]3[C:44]=2[CH:43]=[CH:42][C:41]=1[O:54][CH2:55][C@H:56]1[CH2:58][O:57]1.N1CCCCC1>CN(C=O)C>[OH:57][C@H:56]([CH2:58][N:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)[CH2:55][O:54][C:41]1[CH:42]=[CH:43][C:44]2[C:45]3[N:46]([CH2:51][CH2:52][N:53]=3)[C:47]([NH2:50])=[N:48][C:49]=2[C:40]=1[O:39][CH3:38]
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: COc1c(O)ccc2c1N=C(N)N1CCN=C21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNCC1
Product: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
To a slurry of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 3.00 g, 6.52 mmol) in DMF (72 mL) was added caesium carbonate (10.62 g, 32.6 mmol, 10.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 45 mL, 0.29 M in DMF, 13.0 mmol, 2.0 equiv.). This mixture was stirred at 60° C. for 12 hr and concentrated under reduced pressure to a volume of approximately 50 mL and divided into 3 portions. Each portion was treated with 2.15 mL piperidine (6.45 mL total, 65.2 mmol, 10 equiv.) and was heated in a microwave reactor for 45 min. at 140° C. The combined resulting mixtures were concentrated under reduced pressure. The resulting solids (1.93 g) were purified by MPLC to give N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (1.93 g, 79%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.30-1.43 (m, 1H), 1.56-1.70 (m, 2H), 1.70-1.84 (m, 2H), 2.88-3.04 (m, 2H), 3.11-3.32 (m, 2H), 3.42-3.52 (m, 2H), 3.82 (s, 3H), 4.09-4.17 (m, 4H), 4.28-4.38 (m, 3H), 7.24 (d, J=9.4 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC.O1CCOCC1>[Cl-].[Na+].O.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>[F:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccco4)sc23)c(F)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (0.300 g, 0.7768 mmol) from Example 6, Step A, PdCl2(PPh3)2 (0.02726 g, 0.03884 mmol), tributyl(furan-2-yl)stannane (0.2931 ml, 0.9322 mmol), and dioxane (8 mL). Heat to 90° C. for 6 hours under nitrogen and cool to room temperature. The reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (100 mL). The reaction mixture was purified by triturating with hot MeOH. The product (170 mg, 57%) was isolated as a brown solid. LRMS (APCI+) m/e 327 (M+1) detected.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 51.5 %

Procedure:
DIPEA (0.343 mL, 1.97 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-s nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 300 mg, 0.79 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 109 mg, 0.87 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were then concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (198 mg, 52%) as a slightly impure orange/red solid which was used without further purification; 1H NMR (CDCl3): 1.89 (1H, dd), 2.06-2.18 (1H, m), 2.21 (3H, s), 2.31 (1H, dd), 2.47 (2H, ddd), 2.65 (1H, t), 2.99-3.10 (1H, m), 3.26 (1H, t), 3.51-3.60 (1H, m), 3.98 (3H, s), 4.39-4.46 (1H, m), 6.46 (1H, s), 6.93 (1H, td), 7.04 (1H, d), 7.38 (1H, s), 7.43 (1H, ddd), 8.36 (1H, d), 8.46 (1H, s), 8.52 (1H, m), 8.58 (1H, m), 8.98 (1H, s); m/z: ES+ MH+ 487.15.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:21][CH3:22]>>[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:21]([C:13](=[O:15])[CH2:12][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH3:11])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to N-methyl-L-phenylalanine methyl ester using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-N-methylphenylalanine methyl ester. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water. Proton and carbon NMR analysis indicated a mixture of amide bond rotomers in about a 65:35 ratio.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[N-:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[Na+]>CS(C)=O>[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: c1c[n-]cn1
Reactant: Cn1c(-c2ccc(F)cc2)cc(=Nc2ccccc2)n(C)c1=O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(-c2ccc(-c3ncc[nH]3)cc2)cc(=Nc2ccccc2)n(C)c1=O

Procedure:
The invention encompasses compounds of Formula I which are prepared by arylating a starting material such as 3,4-dihydro-6-(4-fluorophenyl)-1,3,dimethyl-4-phenylimino-2(1H)-pyrimidinone with excess sodium imidazolide in DMSO in the presence of heat, whereby the fluoro group on the 6-phenyl ring is substituted by the imidazolyl group to produce 3,4-dihydro-6-(4-imidazolylphenyl)-1,3-dimethyl-4-phenylimino-2(1H)-pyrimidinone.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.N([O-])=O.[Na+].C1C=CN=CC=1.[FH:35].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:35][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Reactant: F
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(F)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Temperature: 0 °C
Yield: 57.7 %

Procedure:
3-Ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (5.0 g, 15.23 mmol) (Example 1, Step C) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Sodium nitrite (5.25 g, 76.15 mmol) was added followed by HF-Pyridine (4.0 mL, 160 mmol). The reaction was stirred at ambient temperature until complete by LCMS. Ethyl acetate and sodium bicarbonate solution was added, the precipitated solid was filtered, and the filtrate was extracted with ethyl acetate, dried over sodium sulfate, and purified by silica-gel chromatography (0-30% hexanes/ethyl acetate) to afford the title compound as a colorless oil (2.91 g, 58%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.24 (m, 2 H) 7.12-7.18 (m, 2 H) 4.11 (q, J=7.22 Hz, 2 H) 3.55-3.60 (m, 3 H) 2.55-2.59 (m, 3 H) 2.39 (s, 3 H) 1.03 (t, J=7.12 Hz, 3 H); LCMS (m/z) ES+=332 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C@H:22]([C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C@H:22]([C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:24][C:25](=[O:26])[NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@H](CCC(=O)NCCOCCOCCNC(=O)OC(C)(C)C)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To (S)-4-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-5-methoxy-5-oxopentanoic acid (240 mg, 0.53 mmol, crude), triethylamine (0.3 mL, 2.2 mmol), and tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (150 mg, 0.60 mmol) in N,N-dimethylformamide (3 mL), 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (261 mg, 0.88 mmol) was added in one portion. The reaction was stirred at ambient temperature for 16 hours. After this time, the product was crashed out with diethyl ether and collected by suction filtration. The solids were washed with methylene chloride (30 mL) to afford crude (S)-methyl 18-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonadecan-19-oate (225 mg, 62%) as an orange-brown solid, which was used in the next step without further purification: MM-APCI MS m/z=684 [M−H]−.