Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:34])[CH3:33]
Reactant: Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Hydroxy alkene 5a (0.577 g, 1.5 mmol) was dissolved in 20 mL of CH2Cl2 with 1.25 mL (1.22 g, 15.5 mmol) of pyridine. Acetyl chloride (0.6 mL, 0.662 g, 8.4 mmol) was dissolved in 5 mL of CH2Cl2 and added dropwise to the solution with 5a. A precipitate formed immediately. After stirring for 2 hours, the solvent was removed to give a yellow-orange solid. This material was treated with 50 mL of CH2Cl2 to leave a white solid which was separated by filtration. The CH2Cl2 solution was then concentrated and chromatographed over silica with 5% ethyl acetate/hexane to give 0.502 g (77.2%) of 5c as a white solid: mp 162°-163° C.; 1H NMR (CDCl3 delta 1.80-2.05 (m, 12H), 2.265 (s, 3H), 3.45-3.55 (m, 2H), 6.833 (dd, 1H, J=8.38, 2.32 Hz), 6.961 (d, 1H, J=2.33 Hz), 7.072 (ddd, 1H, J=8.11, 5.45, 2.08 Hz), 7.12-7.28 (m, 4H); 13C NMR (CDCl3) delta 20.96, 27.78, 32.50, 36.88, 39.36, 110.08, 115.72, 116.41, 122.75, 124.38, 126.44, 126.90, 127.42, 127.68, 146.81, 149.24, 154.86, 155.48, 169.18. ##STR41##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[CH:20][C:21]=1[OH:22])=[O:15].[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)([O-:26])=[O:25]>CC(C)=O.O>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:23][CH2:30][C:29]2[CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:34]=[CH:33][CH:32]=2)=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:13]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1O
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of potassium carbonate (anhydrous, 31.7 g) and cesium carbonate (catalytic amount) is pulverized with mortar and pestle, then added to a solution of 2,4-dihydroxyacetophenone (35 g) in acetone (250 ml). The mixture is refluxed for 30 minutes. A solution of m-nitrobenzyl bromide (50 g) in acetone (100 ml) is added in one portion and the reaction refluxed for 3 days. After cooling to room temperature, water is added until a precipitate forms. The product is collected on a Buchner funnel, washed with water and ether. Recrystallization from acetone provides 36.9 g (56% yield) of needles, m.p. 117°-118° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.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(OCC)(=O)C>[C:28]([O:27][C:25]([C:24]1[CH:32]=[CH:33][C:21]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=2)[C:5]([OH:7])=[O:6])=[CH:22][CH:23]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)cc(-c2ccc(C(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
2-Chloro-6-methoxyisonicotinic acid (15.0 g, 80.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (29.2 g, 96.0 mmol), 1,4-dioxane (500 mL) and sodium carbonate (25.4 g, 240 mmol) dissolved in water (160 mL) were combined in a 1 L, 3 necked flask equipped with an internal thermometer, condenser and nitrogen inlet. The solution was degassed by bubbling with nitrogen for 15 min while stirring. Tetrakis(triphenylphosphine)palladium (3.70 g, 3.20 mmol) was then added and the mixture heated to reflux for 17 h. The mixture was then cooled to room temperature and concentrated under vacuum to give a thick brown suspension, which was portioned between ethyl acetate (400 mL) and water (150 mL). The aqueous layer was separated and extracted with further ethyl acetate (2×100 mL). The organic portions were combined and washed with 1 N HCl and water, and the black solids removed by filtration through a pad of celite. The aqueous layer was discarded and the organic solution dried over anhydrous magnesium sulfate and filtered. The solution was then treated with decolorlizing charcoal and heated to 70° C. for 20 min. The solution was then filtered through celite while hot and the solvent removed under vacuum to afford a yellow powder. This material was purified by addition of methyl tert-butyl ether (55 mL) followed by the slow addition of 1.85 L heptane with stirring. The mixture was stirred for 2 days and then filtered to give 2-(4-(tert-butoxycarbonyl)phenyl)-6-methoxyisonicotinic acid (22.01 g, 84%) as a pale yellow powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (s, 9H) 4.08 (s, 3H) 7.34 (d, J=0.98 Hz, 1H) 7.97 (d, J=1.17 Hz, 1H) 8.09 (s, 2H) 8.13 (s, 2H); m/z: 330.2+ [M+H].
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1.[CH:30]1([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:38][C:35]2[S:36][CH:37]=[C:33]([CH:30]4[CH2:32][CH2:31]4)[N:34]=2)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1nc(C2CC2)cs1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc(C2CC2)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 10 (200 mg, 0.476 mmol) with 4-cyclopropyl-1,3-thiazol-2-amine (73 mg, 0.523 mmol) in the presence of EDCI hydrochloride (182 mg, 0.952 mmol) and DMAP (53 mg, 0.476 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 120 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.80-0.86 (m, 2H), 0.88-0.96 (m, 2H), 1.23-1.29 (m, 1H), 1.85-1.94 (m, 4H), 2.00-2.10 (m, 2H), 2.72-2.80 (m, 1H), 3.98 (d, J=6.6 Hz, 2H), 6.36 (s, 1H), 6.58 (t, J=75.3 Hz, 1H), 6.95 (d, J=4.5 Hz, 1H), 7.00-7.10 (m, 2H), 7.48-7.53 (m, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.24-8.30 (m, 1H); APCI-MS (m/z) 543.31 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][Br:8])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1>CC(C)=O>[Br-:8].[NH2:12][C:13]1[NH:14][C:15]2[C:29]([CH2:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[CH:28][CH:27]=[CH:26][C:16]=2[N+:17]=1[CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: Nc1nc2ccccc2n1CCN1CCOCC1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CC(C)=O
Product: Nc1[nH]c2c(CC(=O)c3ccc(Cl)cc3)cccc2[n+]1CCN1CCOCC1
Product: [Br-]
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2.33 g (10 mmol) of 4-chlorophenacyl bromide in 25 ml of acetone is added to a hot solution of 2-amino-1-(2-morpholinoethyl)benzimidazole (2.46 g, 10 mmol) in 75 ml of acetone. The mixture is stirred, heated at the boil for 5 minutes and maintained at room temperature. Three hours later a precipitate of the title compound appears, which is filtered and washed with acetone and with ether.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[CH:25]=[CH:24][NH:23][C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-:28].[K+].[Cl-].C[C:32]([CH3:34])=[O:33]>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:25]([C:34](=[O:28])[C:32]([N:23]5[CH2:24][CH2:25][CH2:17][CH2:18]5)=[O:33])=[CH:24][N:23]([CH2:20][O:21][CH3:22])[C:18]4=[N:19][C:20]=3[O:21][CH3:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1nc2[nH]ccc2cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: [OH-]
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [K+]
Product: COCn1cc(C(=O)C(=O)N2CCCC2)c2cc(C(=O)N3CCC(Cc4ccc(F)cc4)CC3)c(OC)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of [4-(4-Fluoro-benzyl)-piperidin-1-yl]-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanone (150 mg, 0.41 mmol) and ground KOH (114 mg, 2 mmol) in anhydrous acetone (15 mL) was added MOM chloride (82 mg, 1 mmol) at 0° C. The reaction mixture was warmed to RT slowly and stirred overnight. The solvent was removed, and the residue was treated with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with EtOAc:hexane (1:1) to give the desired product 130 mg (77% yield) as a white solid. M+H+(411).
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([Li])CCC.CI>C1COCC1>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:3]1[C:2]([CH3:20])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=1
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2cc(F)ccc2F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 10 g of 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 250 mL anhydrous THF was cooled to -78° C. and stirred with an overhead stirrer. The cold solution was treated with 12 mL of 2.5M n-butyllithium in hexanes never allowing the temperature to exceed -70° C. After stirring for 5 minutes, 1.9 mL of methyl iodide was added quickly. The cooling bath was removed and the solution allowed to warm to room temperature. The solution was diluted with diethyl ether and the combined organic extracts were washed twice with brine, dried over anhydrous magnesium sulfate and concd in vacuo. Chromatographic purification (silica, 5% ethyl acetate in hexanes) gave 5.8 g (72.4%) of 3-(2,5-difluorophenyl)-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole as an oil; 1HNMR (CDCl3) δ2.0 (quintet, 3H, J=2.1 Hz), 3.9 (d, 3H, J=1.2 Hz), 6.9-7.1 (m, 3H). Anal. Calcd for C13H9F5N2: C, 52.18; H, 3.28; N, 10.14. Found: C, 52.20; H, 3.30; N, 10.11.
Reaction SMILES: Cl.N[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.N([O-])=[O:26].[Na+]>Cl.O1CCOCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:3](=[O:26])[NH:4][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[CH3:13]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc(N)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a mixture of 90 ml of 2% hydrochloric acid and 60 ml of dioxane was dissolved 3.50 g (10 mmol) of 2-amino-3,4-diethoxycarbonyl-6-phenylpyridine hydrochloride. A solution of 0.83 g (1.2 eq.) of sodium nitrite dissolved in 3 ml of water was added dropwise thereto. The mixture was stirred at room temperature for 4 hours and left standing overnight. The solvent was distilled off. The resulting crystals were collected by filtration with water. The crystals were recrystallized from ethanol, to give pale yellow prisms.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[OH:50][CH2:51][C@H]1[C@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:51]([OH:50])[C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@@H]1NCC[C@H]1O
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC[C@@H](O)[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3R)-2-(hydroxymethyl)pyrrolidin-3-ol and isolated as light-yellow gum (9.6 mg, 49%). MS(m/e): 417.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[N:19]=[C:18]3[N:9]([C:10](SC#N)=[N:11][C:12]4[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=43)[N:8]=2)=[CH:4][CH:3]=1.[NH3:24]>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:19]=[C:18]3[N:9]([C:10](=[NH:24])[NH:11][C:12]4[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=43)[N:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: N#CSc1nc2ccc(Cl)cc2c2nc(-c3ccc(Br)o3)nn12
Solvent: C1CCOC1
Product: N=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccc(Br)o3)nn12

Procedure:
To a solution of 4.9 g of 2-(5-bromo-2-furyl)-9-chloro-5-thiocyanato[1,2,4]triazolo[1,5-c]quinazoline in 80 cc of tetrahydrofuran is added gaseous ammonia under ice cooling over 1.3 hr. The precipitate which forms is collected washed with tetrahydrofuran, recrystallized from N,N-dimethyl acetamide and dried under high vacuum at 100° to afford pure 2-(5-bromo-2-furyl)-9-chloro-5-imino-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline, mp 282°-283°.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:25])=[C:10]([F:24])[C:11]([N:16]3[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]3)=[C:12]([CH:15]=2)[CH:13]=[O:14])=[N:6][CH:7]=1.[C:26](=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.CB(O)O>CCOC(C)=O.O>[CH3:23][CH:18]1[O:19][CH:20]([CH3:22])[CH2:21][N:16]([C:11]2[C:10]([F:24])=[C:9]([F:25])[C:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:26])=[CH:7][N:6]=3)=[CH:15][C:12]=2[CH:13]=[O:14])[CH2:17]1
Reactant: CC1CN(c2c(C=O)cc(-c3cnc(Br)cn3)c(F)c2F)CC(C)O1
Reactant: O=C([O-])[O-]
Agent: CB(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(-c2cc(C=O)c(N3CC(C)OC(C)C3)c(F)c2F)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a suspension of 5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (0.375 g, 0.91 mmol) and sodium carbonate (0.29 g, 2.7 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added methyl boronic acid (0.11 g, 1.8 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.026 g, 0.036 mmol) was added at room temperature and the reaction was heated for 5 hours at 85° C. Analysis indicated that starting material had not fully been consumed so an additional 1 equivalent of methyl boronic acid was added to the reaction and stirred overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-35%) to obtain 132 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.61 (s, 3H), 3.00 (m, 2H), 3.38 (m, 2 H), 4.19 (m, 2H), 8.26 (dd, J=8.2, 2.1 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.89 (dd, J=2.3, 1.6 Hz, 1H), 10.33 (s, 1H); MS(APCl+) m/z 348 (MH+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:37][C@H:38]([CH2:43][OH:44])[CH2:39][CH2:40][S:41][CH3:42]>C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:37][C@H:38]([CH2:43][OH:44])[CH2:39][CH2:40][S:41][CH3:42].[CH3:19][C:27]([OH:29])=[O:28]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CSCC[C@H](N)CO
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 159.9 %

Procedure:
A solution of 2.47 g of Boc-Tyr-DAla-Phe-Methioninol in 20 ml of 10% anisole in TFA was stirred for 30 min and then evaporated to a syrup. The syrup was dissolved in 20 ml of methanol, water, acetic acid (50:49:1) and applied to an Amberlite XAD-2 column (44-74 μm, 2.7×60 cm). Elution of the sample at 5 ml/min with a linear gradient formed from 2 liters each of water:methanol:acetic acid (94:5:1) to methanol:water:acetic acid (94:5:1) gave a product peak which was evaporated to a syrup. The syrup was dissolved in 20 ml of isopropanol and diluted with 150 ml of ether to give 1.85 g (82%) of H-Tyr-DAla-Phe-Methioninol HOAc, m.p. 110°-120° C., [α]D25 =24.05° (C, 0.98, methanol).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[N:9]1([CH2:14][CH:15]([N:17]2[C:30]3[CH:29]=[C:28]([C:31](=S)N)[CH:27]=[CH:26][C:25]=3[S:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:30]=2[CH:29]=1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 140 °C

Procedure:
1,2-Diaminocyclohexane (7.98 g) is added to an ethanolic solution (32 cc) of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (2.96 g). The mixture is heated in an autoclave to 140° C. for 18 hours, then diluted with ethyl acetate (150 cc) and washed with distilled water (3×50 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 24 cm; diameter: 2.5 cm) of neutral alumina, eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 75:25 (500 cc), 50:50 (750 cc) and 25:75 (750 cc) and collecting 50-cc fractions. Fractions 10 to 29 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 2-(3a, 4, 5, 6, 7, 7a-hexahydro-1H-benzimidazol-2-yl)-10-[1-(1-pyrrolidinyl)-2-propyl]phenothiazine, L series (0.38 g) in the form of a brown product of meringue-like consistency.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[B-](F)(F)(F)[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1.[K+].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([C:25]3[CH:24]=[CH:23][NH:27][N:26]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Reactant: F[B-](F)(F)c1ccn[nH]1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)nc2c1cc(-c1cc[nH]n1)c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-6-bromo-8-((trans)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.283 mmol), potassium 1H-pyrazole-5-trifluoroborate (98.5 mg, 0.566 mmol), and triethylamine (197 uL, 1.42 mmol) in ethanol (3.0 mL) was bubbled with argon. PdCl2(dppf)1:1 w/CH2Cl2 was added, the vial was sealed and the mixture was bubbled with argon again, then heated in the microwave for 30 minutes at 100° C., then 60 minutes at 150° C. The reaction mixture was concentrated and purified by flash chromatography eluting with 1:1 ethyl acetate:chloroform/7 N ammonia in methanol (0.5-7%). The fractions containing the desired product were combined and concentrated and the solids were recrystallized from methanol/chloroform to afford 2-amino-8-((trans)-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, 33%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([OH:3])=O.[C:14]([NH:21][CH2:22][CH2:23][NH2:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>CN(C=O)C>[C:14]([NH:21][CH2:22][CH2:23][NH:24][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
A solution of methyl 3-carboxybenzoate (16-3) (Aldrich) (0.9 g, 5 mmol), 16-2 (0.8 g, 5 mmol), and HOBT (0.74 g, 5.5 mmol) in DMF (20 ml) was treated with Et3N (1.0 g, 10 mmol) followed by EDC (1.15 g, 6.0 mmol). After stirring for 16 h the solvent was removed, the residue was taken up in H2O (100 mL), and extracted with 3×75 ml portions of EtOAc. The organic extract was washed consecutively with 10% KHSO4, brine, satd. NaHCO3, brine, and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography (silica, 95% hexanes/EtOAc) to give crude 16-4. This was further purified by chromatography (silica, 70%/acetone/hexanes) to give pure 16-4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O-:11])=O)[CH2:4][CH:3]1[CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].[Na+].[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][NH2:33])=[N:30][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][NH:33][C:9](=[O:11])[CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:12][O:13][Si:14]([CH:21]([CH3:22])[CH3:23])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])[CH2:4]2)=[N:30][CH:31]=1
Reactant: CC(C)[Si](OCC1CN(CC(=O)[O-])CCN1C)(C(C)C)C(C)C
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OCC1CN(CC(=O)NNc2ccc(F)cn2)CCN1C)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 56b (390 mg, 1.06 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (135 mg, 1.06 mmol) and HOBt.H2O (14.4 mg, 106 mop in DCM (15 mL) was added EDC (245 mg, 1.27 mmol) and stirred for 18 h. The mixture was washed with water, sat. aq. NaHCO3 and brine, and concentrated in vacuo to leave the title compound as a brown residue (412 mg, 86%). LCMS (Method 3): Rt 3.00 min, m/z 454 [MH+].