Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27](I)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cncc(OCc3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of benzyl alcohol (25 μL, 0.24 mmol) in dimethyl acetamide (0.5 mL) in the sealed tube was added NaH (10.4 mg, 0.26 mmol). The reaction mixture was stirred at room temperature. After 30 min, a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 0.22 mmol) and diisopropyl ethylamine (96 μL, 0.55 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100° C. After 12 hr, the reaction mixture was cooled to room temperature, quenched with methanol, diluted with CH2Cl2, washed with water and brine, then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound in 60% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.92 (s, 1H), 8.29 (s, 1H), 7.47-7.51 (m, 2H), 7.31-7.40 (m, 5H), 7.02-7.08 (m, 2H), 6.20 (bs, 1H), 5.44 (s, 2H), 4.57 (d, J=8.0 Hz, 2H), 2.72 (s; 3H); MS (ES+) m/z 435.2 (M+1), Rt=1.65 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])[CH:7]=1)=O.CO.[CH3:29][NH2:30].[BH4-].[Na+].O>CO>[CH3:29][NH:30][CH2:1][C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: COC(=O)c1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)OC)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
Methyl 2-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (664 mg) was dissolved in methanol (10 mL), 40% methylamine methanol solution (419 mg) was added at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added sodium borohydride (227 mg) at 0° C., the mixture was stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→0:1) to give the title compound as a pale-yellow oil (yield 472 mg, 68%).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH:1]=[CH:8][C:9](=[O:11])[CH:10]=[CH:20][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 146.0 g (1.0 mole) of benzalacetone and 122.0 g (1.02 mole) 4-tolualdehyde (Compound II-A) was dissolved in 750 ml ethanol, and the solution was diluted with 200 ml water. With stirring, at room temperature, all at once, 100 ml of 10% NaOH solution were added. After 1.5 hours the thick, cream precipitate was filtered off, resuspended in 1 liter 20% ethanol in water, refiltered, sucked dry and recrystallized from ethanol/ethyl acetate to give 180 g of 1-phenyl-5-(4-tolyl)-1,4-pentadiene-3-one (Compound IV-A). The product structure was confirmed by field desorption mass spectrometry (FDMS) and infrared (IR) spectrometry.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([O:12][C:13]([C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=3[CH:23]=[C:22]([C:31](O)=[O:32])[CH:21]=2)=[CH:17][C:16]=1[F:36])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:14])[C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[C:25]3[CH2:26][C:27]([CH3:29])([CH3:30])[O:28][C:24]=3[CH:23]=[C:22]([C:31](=[O:32])[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)[CH:21]=2)=[CH:17][C:16]=1[F:36])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)OC(C)(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 15 except that the reaction was carried out at 75° C. for 2 hr, from 1-methyl-3-aminopyrazole (892 mg, 9.18 mmol) and 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (66b) (2.46 g, 6.11 mmol) to give a white solid (1.77 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H) 7.87 (t, J=8.59 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.07 (s, 1 H) 7.04 (s, 1 H) 6.79 (d, J=2.02 Hz, 1 H) 6.75 (dd, J=8.84, 2.27 Hz, 1 H) 6.68 (dd, J=11.75, 2.40 Hz, 1 H) 3.80 (s, 3 H) 2.87 (s, 2 H) 1.60 (s, 9 H) 1.49 (s, 6H); LCMS for C26H28FN3O5 m/z 505.00 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:30]>>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][N:10]2[CH2:11][CH2:12][C:13]3[C:14]([CH3:16])([CH3:17])[O:15][C:6]4[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[C:2]([OH:1])[C:7]=4[C:8]=3[CH2:9]2)=[CH:37][CH:36]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccc(Cl)cc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-(4-chlorophenyl)acetamide according to the method of Example 1; m.p. 159°-160°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CCCCCC.[F:20][C:21]([F:29])([F:28])[C:22]([C:24]([F:27])([F:26])[F:25])=[O:23]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([C:22]([OH:23])([C:24]([F:27])([F:26])[F:25])[C:21]([F:29])([F:28])[F:20])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cccc(Br)n1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2,6-dibromo pyridine 260 (2.37 g, 10 mmol) in dry THF, cooled to 0° C., n-BuLi 1.4 mmol in hexane (7.9 ml, 11 mmol) was added drop wise, and stirred for 10 min. Then hexafluoroacetone (CF3—CO—CF3) 244 was added to the reaction mixture and continued stirring for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude compound 2-(6-bromopyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 261, which was purified through 100-200 mesh silica gel by eluting the compound at 15% Ethylacetate in hexane to get the thick oil compound 261.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH2:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)[CH2:39][CH2:40][CH3:41]>>[CH2:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 46.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and N-butyl-2-chloro-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)=O)(C)(C)C.[ClH:27].CO>CO>[ClH:27].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([CH:21]2[CH2:25][NH:24][C:23](=[O:26])[CH2:22]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CNC(=O)C1
Agent: Cl
Solvent: CO
Product: O=C1CC([C@@H]2C[C@@H](O)CN2)CN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (62.48 g, 163 mmol, compound of Reference Example 12) was dissolved in methanol (600 ml), and the solution was cooled to 0° C. Then, a 2.5N hydrochloric acid/methanol solution (230 ml, 570 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and dried to obtain white powder (30.01 g, yield: 89.1%) of (2S,4R)-4-hydroxy-2-(2-pyrrolidon-4-yl)pyrrolidine hydrochloride. This white powder (10.53 g, 50 mmol) was dissolved in a solvent mixture of dioxane (50 ml) and water (50 ml), and the pH was adjusted to 8 with triethyl amine. Then, 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (17.55 g, 55 mmol) was added thereto, and the mixture was reacted for 6 hours while maintaining the pH at a level of 8. The reaction solution was concentrated, and tetrahydrofuran (100 ml) was added thereto. Insoluble matters were filtered off, and the filtrate was concentrated. The residue was subjected to column chromatography (Wakogel™ C-300, chloroform-methanol 40:1) to obtain (2S,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (17.48 g, yield: 98.2%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:16][CH3:17])[C:5]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[N:6][CH:7]=1.[H-].[Na+].[I:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([O:16][CH3:17])[C:5]([N:8]([C:9]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15])[S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[I:20])(=[O:29])=[O:28])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)cnc1NC(=O)OCC(C)C
Reactant: O=S(=O)(Cl)c1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
Isobutyl N-(5-chloro-3-methoxypyrazin-2-yl)carbamate (3.34 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.56 g) in dry N, N dimethylformamide (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and then a solution of 2-iodobenzenesulphonyl chloride (obtained as described in J Org Chem, 1977, 42, 3265) (4.68 g) was added. The mixture was stirred for 2 hours and then volatile material was removed by evaporation. The residue was dissolved in water (50 ml) and the solution was acidified with 20% aqueous citric acid and extracted with ethyl acetate (3×20 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 10-35% ethyl acetatesohexane through a silica gel Mega Bond Elut column to give N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-2-iodobenzenesulphonamide (2.64 g); 1H NMR (d6 -DMSO): 0.67 (s, 6H), 1.65-1.8 (m, 1H), 3.9 (d, 2H), 4.0 (s, 3H), 3.9 (s, 3H), 7.4 (dd, 1H), 7.8 dd, 1H), 8.2 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[C:27]([C:28](Cl)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=1>>[CH3:22][C:23]1[C:27]([C:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])=[C:26]([CH3:31])[O:25][N:24]=1
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1noc(C)c1C(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 40 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3,5-dimethylisoxazole-4-carbonyl chloride and conditions outlined in procedure N. M.p.=274-275° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.08 (d, 1H), 7.73 (m, 2H), 7.54 (t, 1H), 3.42 (t, 2H), 2.99 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H), 2.21 (m, 2H), 1.90 (brm 2H), 1.58 (s, 2H); LCMS: 425 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Cl.[OH:19][NH2:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:20][OH:19])=[O:10])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: NO
Reactant: CCOC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(NO)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Ethyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (10 g, 0.0373 mol) and hydroxyl amine hydrochloride (13 g, 0.1868 mol) were refluxed in acetic acid for 12 hours and the organic layer was evaporated under vacuum to get oil. This oil was mixed with water (100 ml) and the obtained precipitate was stirred at room temperature for 1-2 hours. The obtained solid was filtered and washed thoroughly with water. The wet cake was vacuum dried at 50° C. to afford 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (6.8 g) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1c(C#Cc2ccccc2)nc(N)nc1-c1ccccc1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Following the method of Thorand and Krause (J. Org Chem. 1998, 63, 8551), to a stirred solution of 500 mg (2.17 mmol) 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile in 8.5 ml dry degassed THF under argon at room temperature were added 300 mg (0.43 mmol) bis(triphenylphosphine)palladium(II) chloride, 14 mg (0.05 mmol) triphenylphosphine, 0.36 ml (3.28 mmol) phenylacetylene and 0.45 ml (3.23 mmol) triethylamine. Stirring was continued for 30 minutes then 4.0 mg (0.02 mmol) copper(I) iodide was added and the reaction mixture stirred for an additional 16 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (1/2 ethyl acetate/hexane) afforded 350 mg (55%) 2-amino-4-phenyl-6-phenylethynyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 296 (M+, 100), 270 (80).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[O:14]C(=O)[NH:16][C:11]=2[CH:10]=1.O>C(O)(=O)C>[C:2]1([NH:1][C:13](=[O:14])[C:12]2[C:11](=[CH:10][C:9]([F:8])=[CH:20][CH:19]=2)[NH2:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1

Procedure:
A solution of aniline (1.77 g) in acetic acid (50 ml) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (1 g) in acetic acid (100 ml) and the mixture heated at 100° for 20 minutes. It was then poured into water and the precipitate collected, dried and recrystallised from toluene to give N1 -phenyl-4-fluoroanthranilamide, m.p. 120°-122°. (Compound 4).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7]O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[C@@H:14]([N:13]1[CH:7]([NH:13][CH:14]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:22][CH3:23])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH2:22][CH3:23])([CH3:19])([CH3:21])[CH3:20]
Reactant: O=c1occc2ccc(Cl)cc12
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Product: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1[C@@H](CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of 7-chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert butyl ester (22 g) were heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%). 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:18][C:19]([F:29])([F:28])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]([F:29])([F:18])[F:28])[CH2:22][CH2:23]3)=[O:15])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2ccc(C(=O)O)cn2)c1
Reactant: NC1CCN(CC(F)(F)F)CC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(C(=O)NC3CCN(CC(F)(F)F)CC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 6-(3-cyanophenyl)nicotinic acid (50 mg, 0.222 mmol) in dimethylformamide (1 mL) was added 1,11-carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1,11-carbonylbis(1H-imidazole) (18 mg, 0.132 mmol) was added and the reaction stirred for 30 minutes and then further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and the solution stirred for one hour. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to a white solid. This was triturated with t-butyl methyl ether and the white solid was filtered off and dried to give 6-(3-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide 53 mg 1H NMR (400 MHz, DMSO-d6) ppm 1.57-1.67 (m, 2H) 1.80-1.87 (m, 2H) 2.43-2.54 (m, 2H) 2.93-2.99 (m, 2H) 3.20 (q, J=10.1 Hz, 2H) 3.83 (m , 1H) 7.76 (t, J=8.2 Hz, 1H) 7.97 (m, 1H) 8.24 (m, 1H) 8.34 (dd, J=6.2, 2.4 Hz, 1H) 8.52 (m, 2H) 8.61*m, 1H) 9.12 (m, 1H) LCMS 389 (M+1) ELSD 1.27 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:75]5[CH2:76][CH2:77][N:72]([CH3:71])[CH2:73][CH2:74]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 54.4 %

Procedure:
To a stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with 1-methylpiperazine (132 μL, 1.188 mmol) to give 1-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea as a white solid (95 mg, 54% yield); MS (ESI) m/z=588.4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(C(=O)[C@@H](O)C)CC3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.C([Li])CCC.CN(C)C=[O:38]>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH:11]=[O:38])=[C:8]([CH3:23])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Scheme 2 shows the synthesis of intermediate (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II from 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholino VI. Treatment of VI with isopropylmagnesium chloride Grignard reagent followed by n-butyllithium at −10° C. was followed by addition of dimethylformamide and quenching with aqueous acid gave formylated intermediate 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (Example 4). Reductive amination of IV was effected by mixing IV with the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V followed by a reducing agent, such as sodium triacetoxyborohydride (Method A), 2-picoline borane (Method B) or 5-Ethyl-2-methylpyridine borane to give II which was crystallized in toluene/heptane (Example 5) or Me-THF/heptane.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][N:26]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[CH2:14][C@H:13]([NH:15][C:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12]2)[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Product: c1ccc2nc(N[C@H]3C[C@H](n4cnc5c(N6CCOCC6)ncnc54)C3)ncc2c1
Temperature: 100 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.0681 g, 0.194 mmol) was dissolved in morpholine (2.0 ml, 22.97 mmol) and heated in the microwave to 100° C. for 20 minutes. The solution was evaporated to dryness under reduced pressure and further dried under high vac. Purification using silica chromatography (0-10% methanol in dichloromethane gradient) gave the desired N-(trans-3-(6-morpholino-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (0.038 g, 0.094 mmol, 48.8% yield) as an off white solid. M+1: 403.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.80 (ddd, J=13.30, 8.31, 4.79 Hz, 2 H) 3.02-3.20 (m, 2 H) 3.85 (t, J=4.69 Hz, 4 H) 4.33 (br. s., 4 H) 4.78-4.94 (m, 1 H) 5.30 (quin, J=7.60 Hz, 1 H) 5.93 (br. s., 1 H) 7.23-7.34 (m, 1 H) 7.62 (d, J=8.22 Hz, 1 H) 7.66-7.75 (m, 2 H) 7.96 (s, 1 H) 8.37 (s, 1 H) 9.02 (s, 1 H).