Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:23]([O:25][C:26](=[O:45])[C:27](=[CH2:44])[CH2:28][CH:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:24].CCCCCC>C1COCC1>[CH2:23]([O:25][C:26](=[O:45])[CH:27]([CH2:44][S:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:28][CH:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH3:24]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Triphenylmethanethiol (20.58 g, 74.5 mmol) in dry THF (40 mL) was first added drop wise at 0° C. to a suspension of sodium hydride (3.00 g, 74.5 mmol) in dry THF (60 mL). After the addition was complete, the mixture was stirred for 15 min at 0° C. followed by 45 minutes at room temperature. To the resulting suspension, the compound of example 32 (20.58 g, 62.4 mmol) dissolved in dry THF (40 ml) was added drop wise at 0° C. The mixture was then stirred at room temperature until complete consumption of the starting material (2 hours as confirmed by TLC: 97% hexane-3% ethyl acetate). The crude product was isolated as in example 32 and was then purified by flash chromatography (SiO2, 5% hexane-95% ethyl acetate) to afford 28.28 g (75.5% yield) of the desired compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 15H), 4.17 (q, 2H), 3.03 (m, 1H), 2.49 (m, 1H), 2.42 (m, 1H), 2.31 (m, 2H), 2.21 (m, 1H), 1.44 (s, 18H), 1.29 (t, 3H); 13C NMR (CDCl3, 400 MHz) 176.3, 167.9, 144.4, 129.4, 127.7, 126.5, 81.5, 66.6, 60.6, 51.4, 42.6, 33.6, 30.4, 27.7, 14.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[CH3:11][N:8]1[C:7](=[O:9])[CH:6]=[CH:5][N:4]=[C:3]1[S:2][CH3:1]
Reactant: CSc1nccc(=O)[nH]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nccc(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A 0° C. suspension of 2-(methylthio)pyrimidin-4(3H)-one (2.0 g, 14.1 mmol) in DMF (40 mL) was treated with solid LiHMDS (3.06 g, 18.3 mmol), followed by methyl iodide (1.14 mL, 18.3 mmol), warmed to RT and stirred overnight. The mixture was quenched with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.37 g, 62%). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, J=6.5 Hz, 1H), 6.17 (d, J=6.5 Hz, 1H), 3.39 (s, 3H), 2.54 (s, 3H); MS (ESI) m/z: 157.1 (M+H+).
Reaction SMILES: C(Cl)(Cl)Cl.C[N:6]([CH:8]=[C:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=2)[N:11]([C:23](=[O:26])[CH2:24][CH3:25])[CH2:10]1)C.O.[NH2:28]N.C(O)(=O)C>CO>[N+:20]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([C:23](=[O:26])[CH2:24][CH3:25])[CH2:10][C:9]3[CH:8]=[N:6][NH:28][C:18]=3[C:17]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NN
Reactant: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCC(=O)N1Cc2cn[nH]c2-c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Chloroform (50 ml) was added to a mixture of 3-dimethylaminomethylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.03 g), hydrazine hydrate (0.6 g), and acetic acid (0.78 g) in methanol (50 ml) and stirred at room temperature for 8 hours. To the mixture was added acetic acid (2 ml) and evaporated in vacuo. The residual solid was washed with water, dried, and recrystallized from a mixture of chloroform and methanol to give 4,5-dihydro-8-nitro-5-propionyl-1H-pyrazolo[4,3-c]quinoline (2.53 g).
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.N(OCCCCC)=O>C1COCC1>[CH3:13][N:10]1[CH2:11][CH2:12][C:7]([O:6][C:5]2[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9]1
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Agent: CCCCCON=O
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccccc2)(c2ccccc2)CC1
Yield: 26.2 %

Procedure:
A solution of 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine (2.82 g, 10 mM), in THF (75 ml) was added over 2 hours to a refluxing solution of amyl nitrite (2.7 ml, 20 mM) in THF (30 ml). After 5 hours at reflux amyl nitrite (1.5 ml) was added and the mixture maintained at reflux for 24 hours. The solvent was removed under reduced pressure and the residue partitioned between 2 N hydrochloric acid (50 ml) and ether (50 ml). The aqueous phase was basified (pH9) and extracted with ether (2×100 ml). The organic phase was dried and the solvents removed under reduced pressure. Sublimation of the residue at 1.0 mbar pressure (bath temp. 100°) gave the title compound (700 mg), m.p. 103°-4°.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2c(C)cccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1noc2c(C)cc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 72.7 %

Procedure:
3,7-dimethylbenzo[d]isoxazole (Step 46.4) (2 g, 12.77 mmol) was dissolved in H2SO4 (5 mL), cooled down and stirred at 0° C. HNO3 (0.878 mL, 12.77 mmol) was slowly added and the resulting mixture was stirred at 0° C. for 1 hr. The reaction was diluted with water (60 mL) and extracted three times with CH2Cl2. The combined organic layers were washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting yellow solid was triturated with Et2O, filtrated off, washed with Et2O and dried to afford the title product (1.86 g, 9.29 mmol, 73% yield) as yellow solid. tR: 0.98 min (LC-MS 2); ESI-MS: 193 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:20]([O-])=O>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH2:20]
Reactant: COC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N

Procedure:
Hydrogenate, at 50 psi, a mixture of 10% Pd-C (150 mg) and 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid methyl ester (2 g) in 95% EtOH (100 mL). Filter through a celite pad and concentrate the filtrate to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CN.[BH3-][C:19]#[N:20].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][CH3:19])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCC1)c1ccc(Br)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
1-(4-Bromophenyl)-2-(1-pyrrolidinyl)ethanone (4.45 g, 16.6 mmol) and methyl amine (33 mL, 66.4 mmol of 2 M solution in THF) were dissolved in 75 mL THF and maintained for 15 minutes at room temperature. NaBH3CN (3.13 g, 49.8 mmol) was added and the reaction mixture was treated with 1 mL acetic acid and stirred at room temperature for 4 days. The solvent was removed under reduced pressure. The residue was dissolved in 100 mL of EtOAc and washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4.7 g (99%) of the title compound as a yellow oil. MS (ES) m/e 284 [M+H]+.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O-2].[Mg+2]>CCCCCC>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:1](=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCCCCC
Product: CCCCCCCCCCCC(=O)CCCCCCCCCCC
Yield: 77.7 %

Procedure:
Lauric acid (50 g, 0.25 mol) and magnesium oxide (12.6 g, 0.3125 mol) were charged in a 500 ml round bottom flask equipped with an air condenser having a length of 50 cm, and then the mixture was heated at 300° to 320° C. for 8 hours using a heating mantle. After the completion of the reaction, the reaction solution was cooled. Then, 250-300 ml of n-hexane was added and the reaction solution was sufficiently dissolved in n-hexane with heating. The resulting solution was filtered in a hot state and about 200 ml of an aqueous 4N-sulfuric acid solution was added to the filtrate, followed by sufficiently stirring to decompose unreacted magnesium laurate. The hexane layer was separated, washed with water, and then washed with 200 ml of an aqueous 5% NaOH solution to remove dissolved lauric acid. The hexane layer was washed again with water, dried over anhydrous sodium sulfate and filtered, and then hexane was removed by using a rotary evaporator to isolate a reaction product. The resulting product was recrystallized from a mixed solvent of ethanol and benzene in the ratio of 2:1 to obtain 32.9 g of 12-tricosanone as a white flakelike crystal (yield 77.8%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([NH:39][CH2:40][C:41](O)=[O:42])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:39][CH2:40][C:41]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:42]
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)CN)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 54 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 60 mg Boc-Glycine via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 45.3 mg of 356 after reverse phase HPLC purification. MS (Q1) 484.3 (M)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:44]1([S:41]([NH:40][C:36]2[CH:35]=[C:34]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]5[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]5)[C:10]=4[N:11]=3)[CH:39]=[N:38][CH:37]=2)(=[O:43])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.3 g, 0.822 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene-sulfonamide (Intermediate 2) (0.355 g, 0.987 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.067 g, 0.082 mmol) and 1N aq. sodium bicarbonate (1.64 ml, 1.64 mmol) in dioxane (4.11 ml) was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give tert-butyl 4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.15 g, 32%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.95-2.05 (2H, m), 2.14-2.18 (2H, m), 3.36-3.43 (2H, m), 3.89-3.95 (2H, m), 5.63-5.37 (1H, m), 7.46-7.52 (2H, m), 7.56-7.60 (1H, m), 7.85 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=8.8 Hz), 8.34 (1H, s), 8.37 (1H, d, J=2.4 Hz), 8.41 (1H, d, J=2.0 Hz), 8.83 (1H, s), 9.14 (1H, d, J=1.6 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:20]>CS(C)=O.CCOC(C)=O>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:19]([NH:18][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:20])=[CH:22][CH:23]=1
Reactant: C[C@H](N)c1ccc(O)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(O)cc2)n1
Yield: 5.2 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (42 mg, 0.17 mmol), (S)-4-(1-aminoethyl)phenol hydrochloride (107 mg, 0.616 mmol, 3.5 equiv) and iPr2Net (0.121 mL, 0.695 mmol, 4.0 equiv) in DMSO (1 mL) was heated at 110° C. for 3 h and at 130° C. for additional 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 80%) provided (S)-3-(2-((S)-1-(4-hydroxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (3 mg) in 5% yield. 1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=5.8 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H), 7.12 (d, J 8.1 Hz, 2H), 6.72-6.68 (m, 2H), 4.95 (q, J=6.9 Hz, 1H), 4.69-4.65 (m, 1H), 4.35-4.28 (m, 2H), 1.47 (d, J=7.1 Hz, 3H), 0.75 (br s, 3H), 0.62 (br s, 3H); HRMS(B) m/z 343.1776 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:27][C:24]=1[CH:25]=O>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([CH2:33][C:34]([F:35])([F:36])[F:37])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(OC)c(CC(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Product: COc1cc(OC)c(CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 85 in the same manner of Compound 13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:6]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(25.1 mg, 71%); from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 23.0 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H20N2OF2, calculated MH+ : 355.16220; found: 355.16313.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23](=[O:25])[NH:22][N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].Br[CH:27]([CH3:29])[CH3:28].[H-].[Na+]>CN(C=O)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:24][C:23](=[O:25])[N:22]([CH:27]([CH3:29])[CH3:28])[N:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4nn(C(C)C)c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a stirred solution of 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (0.2 g, 0.5 mmol) and 2-bromo propane (0.08 g, 0.6 mmol) in DMF (1 mL) at 0° C. was added 60% sodium hydride (in mineral oil) (0.040 g, 0.1 mmol) and the reaction was stirred for 2 h at RT. The reaction was quenched with water (25 mL) and extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20% EtOAc in hexanes) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one (50 mg, 22%) as a white solid. MS (ESI, pos. ion) m/z: 380.0 (M+1); 1H NMR (400 MHz, CDCl3): δ ppm 8.86 (br s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 8.01 (dd, J=8.4, 1.6 Hz, 1H), 7.78 (d, J=2.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 5.51-5.57 (m, 1H), 4.42-4.49 (m, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.48 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[N:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1>CN(C)C(=O)C.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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:6]3[CH:7]=[N:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:26][C:25]=1[C:39]1[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1cc2ncc(Br)n2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3cc(C(F)(F)F)ncn23)ccc1F
Temperature: 80 °C
Yield: 4.7 %

Procedure:
A stirred mixture of 3-bromo-7-trifluoromethylimidazo[1,2-c]pyrimidine (100 mg, 0.375 mmol), dried potassium phosphate (0.159 g, 0.750 mmol) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (0.2424 g, 0.750 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 3 h. The mixture was partitioned between ethyl acetate (250 ml) and brine (250 ml), and the aqueous layer was extracted further with ethyl acetate (250 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 40% EtOAc/isohexane), then recrystallisation (EtOAc) to give 6.8 mg (5%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.46 (1H, t, J 8.6 Hz), 7.56 (1H, td, J 7.7, 1.3 Hz), 7.60 (1H, m), 7.65-7.74 (3H, m), 7.85 (1H, dd, J 7.8, 1.6 Hz), 7.89 (1H, s), 7.99 (1H, s), 9.37 (1H, s); MS (ES+) m/z 383 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[NH:17]1[CH2:16][CH:15]([S:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])=[CH:13][CH:12]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(Sc2ccc(C(=O)N3CCCC3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc(SC2CNC2)cc1)N1CCCC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of 59C (1.40 g, 3.89 mmol) in dioxane (20 mL) was added a solution of HCl (4M in dioxane, 20 mL). The mixture was stirred at RT over night and then the solvent was removed by evaporation. The residue was partitioned between DCM and water. The Organic solution was extracted with an aqueous solution of HCl (0.1 M). The combined aqueous solutions were pH adjusted to pH>11 by carefully adding a saturated aqueous solution of Na2CO3. The mixture was extracted several times with DCM. The solvent was removed by evaporation. There was obtained 0.56 g (55%) of 59D as an oil. 1H NMR (500 MHz, CDCl3): δ 1.88 (m, 2H), 1.94 (m, 2H), 3.43 (m, 2H), 3.62 (m, 2H), 3.68 (m, 2H), 4.04 (m, 2H), 4.29 (m, 1H), 7.19 (d, 2H), 7.44 (d, 2H), MS (APCI+) m/z 263 [M+H]+.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:20])[C:6]([C:18]#[N:19])=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])[CH3:8]>C(OCC)C.[Cu]I>[CH3:3][O:4][C:5](=[O:20])[CH:6]([C:18]#[N:19])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:1])[CH3:8]
Reactant: COC(=O)C(C#N)=C(C)c1ccc(F)cc1OC
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C(C)(C)c1ccc(F)cc1OC
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a chilled (0° C.) suspension of 4.3 g (22.58 mmol) of copper (1) iodide (purified by Soxhlet extraction with THF) in 100 mL of diethyl ether was added 26 mL (41.60 mmol) of a 1.6 M solution of methyl lithium in ether over a 15 minute period. After the addition, the mixture stirred for 10 min and was then cooled to −25° C. and a solution of 4.0 g (15.19 mmol) of 2cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester in 50 mL of diethyl ether was added over a 20 minute period. The mixture stirred at −25° C. for 30 minutes and was then allowed to warm to room temperature. The reaction was monitored by proton NMR. After 1.5 hours, an aliquot partitioned between EtOAc and 1 N aqueous HCl indicated starting material was gone and desired product was present. The reaction was cautiously poured into brine and then saturated aqueous ammonium chloride was added followed by 1 N aqueous HCl and EtOAc. The mixture was filtered through diatomaceous earth and the aqueous layer was separated and extracted with three 50 mL portions of EtOAc. The combined organic layers were washed with 30 mL of 1 N aqueous HCl, 30 mL of brine, and three 25 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 4.2 g (99%) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester.