Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Br[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[S:11]1[CH:12]=[CH:13][N:14]=[C:10]1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Brc1nccs1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCCN1c1nccs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 80 mg (0.70 mmol) of L-Proline in 3 mL of anhydrous N,N-dimethylformamide at ambient temperature was added 0.062 ml (0.70 mmol) of 2-bromothiazole, 288 mg (2.09 mmol) of potassium carbonate, and 13 mg (0.068 mmol) of copper(I)iodide. The reaction mixture was heated to 100° C. overnight then filtered through a plug of Celite®. The crude residue was purified by reverse-phase HPLC (TMC Pro-Pac C18; 0-60% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give the title compound as a light brown solid. (0.065 g, 50%). LC-MS: m/z (ES) 199.2 (MH)+.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:25][CH:24]=1)[C:16](=[O:17])[N:27]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34])[CH2:21]2
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(Cl)cc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-formylbenzoate (0.12 g), trans-2-aminocyclohexanol hydrochloride (0.05 g), triethylamine (0.05 mL) and anhydrous magnesium sulfate (0.08 g) in THF (2.50 mL) was stirred at room temperature for 1 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.50 mL) and THF (2.50 mL), sodium triacetoxyborohydride (0.15 g) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 mg).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH:13]2[C:17]3[NH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:16]=3[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([CH2:11][CH2:12][CH:13]2[C:17]3[NH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:16]=3[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2

Procedure:
The title compound was synthesized from methyl 6-(2-(naphthalen-1-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.051 g, 0.16 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-60% EtOAc/heptane. 17 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.85 (dq, J=13.45, 7.90 Hz, 1H) 2.08-2.27 (m, 2H) 2.46-2.62 (m, 1H) 2.62-2.80 (m, 2H) 3.04-3.22 (m, 3H) 6.61 (s, 1H) 7.29-7.41 (m, 2H) 7.41-7.54 (m, 2H) 7.64-7.73 (m, 1H) 7.80-7.87 (m, 1H) 8.03 (d, J=8.35 Hz, 1H); LCMS-MS (ESI−) 304.0 (M−H); HPLC (UV=95.2%), (ELSD=100%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CBr)cc1
Yield: 79 %

Procedure:
To the solution of 4-hydroxymethylphenol acetate (2.50 g, 15.0 mmol) and carbon tetrabromide (5.97 g, 18.0 mmol) in 40 ml of methylene chloride was added triphenylphosphine (4.73 g, 180 mmol) under nitrogen. The resultant mixture was stirred for 3 hours. The product was purified by flash chromatography using heptane/ethyl acetate (90/10-80/20) as eluent in a yield of 79%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:22])[C:17](OCC)=[O:18])#[N:14]>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17](=[O:18])[C:16](=[O:22])[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]#[N:14])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of 6.6 g. (0.044 mol.) of p-chlorophenylacetonitrile and 20 ml. of dry glyme was added 6.2 g. (0.13 mol.) of sodium hydride (50% in oil). Ethyl 3-cyano-3-phenylpyruvate (9.55 g., 0.044 mol.) was added in portions at -10° and the reaction mixture was stirred at 25° for 12 hours. The mixture was diluted with 150 ml. of water, extracted with ether, acidified with 15 ml. of acetic acid and the solid was collected by filtration to yield 2-(p-chlorophenyl)-5-phenyl- 3,4-dioxoadiponitrile, m.p. 210° dec.
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.S([O-])([O-])=O.[Na+].[Na+].[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:22][C:21]([OH:25])([CH3:24])[CH3:23])[C:6]([CH3:14])([CH3:13])[CH2:5]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C

Procedure:
A solution of 50% aqueous hydrogen peroxide is added to a mixture of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed with aqeuous sodium sulfite. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford a sample of 4-hydroxy-1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (4.55 g, 35.5 mmol) in THF (90 mL) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 24 mL, 46 mmol) was added. After 30 min., Benzaldehyde (4.90 g, 46 mmol) was added. After 15 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 9.46 g (88%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[O:9])=[C:6]([F:17])[CH:5]=1.[Cl-].[NH4+].C(OCC)C>C(O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]([OH:9])[CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[C:6]([F:17])[CH:5]=1
Reactant: N#CC1CC1C(=O)c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: N#CC1CC1C(O)c1ccc(Cl)cc1F
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
1.01 g (26.6 mmol) of sodium borohydride were added to 5.40 g (24.1 mmol) of the compound from Example 130A in 99 ml of ethanol and 25 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 45 minutes. The reaction mixture was added to saturated aqueous ammonium chloride solution and diethyl ether, the phases were separated, the aqueous phase was extracted twice with diethyl ether, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 5.25 g (96% of theory) of a mixture of the diastereomers of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[H-].[Na+].[CH2:31](Br)[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:31][CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(OCC=Cc3ccccc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
The product from Example 33A (0.1 g, 26 mmoles) in DMF (0.65 mL) was treated with sodium hydride (0.011 g, 0.26 mmoles). After 10 minutes, the reaction mixture was treated with cinnamyl bromide (0.10 g, 0.52 mmoles) and shaken overnight. The mixture was diluted with diethyl ether (50 mL), washed with saturated ammonium chloride (50 mL) and water (2×50 mL), brine (50 mL), dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([NH:21][NH2:22])=[N:17][C:16]=2[CH3:23])=[CH:11][CH:10]=1>CO.C(O)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[C:5]([CH3:6])=[CH:4][C:1]([CH3:2])=[N:22]3)=[N:17][C:16]=2[CH3:23])=[CH:13][CH:14]=1
Reactant: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)n(-c2nnc(-c3ccc(Cl)cc3)c(C)n2)n1
Yield: 85.1 %

Procedure:
A solution of acetylacetone (2.415 g) in methanol (10 ml) was added to a mixture of 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.946 g) and acetic acid (3 drops) in methanol (20 ml), and the solution was refluxed for 2 hours with stirring and allowed to stand at room temperature. The resultant crystals were collected by filtration, washed with cold methanol, and dried to give 6-(4-chlorophenyl)-3-(3,5-dimethylpyrazol-1-yl)-5-methyl-1,2,4-triazine (5.354 g), m.p. 151° to 152.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]2[C@@H:17]([NH:18][C:19](=O)[C:20]3[CH:25]=[CH:24][C:23]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15][N:14]([CH3:38])[CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>P(Cl)(Cl)(Cl)=O.C(#N)C>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:28])=[O:29])=[CH:22][CH:21]=3)=[N:18][C@@H:17]3[C@H:12]([C:6]=2[CH:5]=1)[CH2:13][N:14]([CH3:38])[CH2:15][CH2:16]3)[CH3:2]
Reactant: CCOc1cc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(NS(=O)(=O)c3ccc(C)cc3)cc1)=N[C@H]1CCN(C)C[C@@H]21

Procedure:
2.52 g (−)-cis-3-(3-Ethoxy-4-methoxyphenyl)-1-methyl-4-[4-(p-toluenesulfonamido)-benzamido]-piperidine are heated to boiling under reflux for 5 h in 4.3 ml phosphorus oxychloride and 60 ml of acetonitrile. After destilling off the excess acetonitrile and phosphorus oxychloride, the residue is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. After evaporation of the dichloromethane, the residue is purified over silica gel by chromatography. The main product fraction is separated and concentrated. The title compound is obtained after recrystallisation in ethyl acetate/diethyl ether (1:10) as faint yellow fine crystalls. M.p. 207-219° C. (unsharp, destruction and red colouring).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][CH3:21])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COc1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 86.6 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.442 mmol) and o-methoxyaniline (76 mg, 0.62 mmol) to give 170 mg of the title compound (86%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 9.27 (s, 1H), 7.88 (d, 1H, J=8.1 Hz), 7.24 (s, 1H), 7.17 (s, 1H), 7.08 (t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=8.1 Hz), 6.90 (t, 1H, J=8.1 Hz), 5.16~5.27 (m, 1H), 3.81 (s, 3H), 3.12 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J =17.1 Hz), 2.77 (dd, 1H, J=13.5, 10.8 Hz), 2.62 (dd, 1H, J=13.5, 5.4 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.77~1.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[C:29]1(=O)[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:29]1([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=4[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (52.3 mg, 0.125 mmol, 1.0 equiv; Example 147) in methanol (0.5 mL) was added cyclobutanone (188 mg, 0.2 mL, 2.68 mmol, 21.4 equiv; [CAS RN 1191-95-3]), acetic acid (28 mg, 27 μL, 0.5 mmol, 4.0 equiv; [CAS RN 64-19-7]) and the reaction mixture stirred at rt. After 90 min, sodium cyanoborohydride (15.7 mg, 0.25 mmol, 2.0 equiv; [CAS RN 25895-60-7]) was added and stirring at rt continued for 18 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.3 mg (6%) of the title compound. MS (ISP): 474.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1O
Product: C=CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C(=O)OCC

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate, using allyl bromide.
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:6][C@@H:4]([CH2:3][C@H:2]([O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:1])[CH3:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)C[C@@H](C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C[C@@H](C)OS(C)(=O)=O)OS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of (2R,4R)-2,4-pentanediol (15.0 g), triethylamine (45.2 mL) and dichloromethane (350 mL) is cooled at a temperature close to 0° C. Methanesulfonyl chloride (24.5 mL) is added dropwise. The mixture is stirred for 3 h at a temperature close to 0° C., hydrolysed with a 1.5 N aqueous hydrochloric solution (100 mL) and extracted with dichloromethane. The organic extracts are pooled, washed with a saturated aqueous solution of sodium hydrogenocarbonate, then a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 36.06 g of (2R,4R)-2,4-pentanediol dimethanesulfonate as a brown oil used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27].C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:7](=[O:18])[C:6]4([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]4[C:4]=3[N:3]=2)=[CH:31][CH:30]=1)=[O:27]
Reactant: CC12COCCN1c1nc(Cl)ncc1N(C1CCOCC1)C2=O
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C2CCOCC2)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
In a microwave reaction vial, 2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.046 g, 0.136 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.041 g, 0.149 mmol), PdCl2(dppf) (0.020 g, 0.027 mmol) and sodium bicarbonate (saturated solution) (0.3 ml, 0.136 mmol) were suspended in dioxane (1.36 ml). The suspension was heated by microwave irradiation at 100° C. for 1 hour, then heated by microwave irradiation at 120° C. for an additional 30 minutes. The reaction was purified by preparative HPLC (eluting with 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). Product containing fractions were combined, concentrated in vacuo and lyophilized, affording the title compound (41.4 mg, 67.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 1.55-1.74 (m, 2H) 2.62-2.70 (m, 3H) 3.25 (td, J=13.14, 4.04 Hz, 1 H) 3.34-3.45 (m, 1H) 3.47-3.72 (m, 3H) 3.87-4.00 (m, 3H) 4.06 (dd, J=11.62, 3.79 Hz, 2 H) 4.19 (dd, J=13.77, 2.15 Hz, 3H) 6.01-6.24 (m, 1H) 7.48-7.57 (m, 2H) 8.13-8.22 (m, 2 H) 8.48 (s, 1H) 8.81 (s, 1H). MS [M+H] found 453.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4](=[O:10])[CH2:3]1.[Br:12]Br>C(O)(=O)C>[Br:12][CH:5]1[C:4](=[O:10])[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:8][NH:7][C:6]1=[O:9]
Reactant: CC1(C)CNC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)C(Br)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
To a solution of 6,6-dimethylazepan-2,4-dione (10.0 g, 64.5 mmol) in glacial acetic acid (160 mL) was added bromine (3.3 mL, 64.5 mmol) dropwise. The reaction mixture was stirred at r.t. for 1 h. The resulting precipitate was collected by filtration to give the title compound (16.83 g, quantitative) as a white solid. δH (DMSO-d6) 0.86 (3H, s), 0.99 (3H, s), 2.31 (1H, d, J 11.7 Hz), 2.73 (1H, d, J 11.7 Hz), 2.75 (1H, dd, J 15.2, 6.6 Hz), 3.31 (1H, dd, J 15.2, 6.6 Hz), 5.77 (1H, s), 8.40 (1H, t, J 6.2 Hz). LCMS (ES+) 234/236 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)#[N:2].[C:21]([Mg]Br)#[CH:22].Cl>O1CCCC1>[C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9]([C:21]#[CH:22])([OH:12])[CH2:10][CH2:11]1)#[N:2]
Reactant: C#C[Mg]Br
Reactant: N#CC(C#N)(CCC1CCC(=O)CC1)CCC(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1(O)CCC(CCC(C#N)(C#N)CCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 1.14 g of 4-(3,3-dicyano-6,6,6-trifluorohexyl)cyclohexanone in 10 mL of tetrahydrofuran was added 10 mL of a 0.5 M solution of ethynyl magnesium bromide in tetrahydrofuran at 0° C. under a nitrogen atmosphere, followed by stirring at 0° C. for 5 hours. To the reaction mixture was added 30 mL of a 1 N aqueous hydrochloric acid solution, followed by extraction twice with 30 mL of ethyl acetate. The combined organic layer was washed sequentially with 30 mL of a saturated aqueous sodium hydrogen carbonate solution and 30 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.78 g of 1-(3,3-dicyano-6,6,6-trifluorohexyl)-4-ethynyl-4-hydroxycyclohexane (hereinafter referred to as the present compound (6)) represented by the following formula:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromopyridine (116 μL, 1.20 mmol) was added slowly dropwise to a stirred suspension of n-butyllithium (480 μL of a 2.5 M hexanes solution, 1.20 mmol) in THF (1.00 mL) at −78° C. After 15 min, tert-butyl 4-formylpiperidine-1-carboxylate (213 mg, 1.00 mmol) was added, and the resulting mixture was allowed to stir at −78° C. After 1 h, the reaction was quenched with 1.0 M HCl, poured into satd. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-100% EtOAc/DCM as eluent) afforded the title compound i-15a. 1H NMR (500 MHz, CDCl3): δ 8.55 (m, 2H), 7.70 (d, 1H, J=8.0 Hz), 7.32 (dd, 1H, J=4.9, 7.4 Hz), 4.49 (m, 1H), 4.15 (m, 4H), 2.65 (m, 2H), 1.83 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H), 1.31 (m, 1H).