Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Yield: 63.1 %

Procedure:
A solution of lithium aluminum hydride (0.25 g, 6.59 mmol) in tetrahydrofuran (5.0 mL) and a solution of 3-benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.247 g, 0.642 mmol) in tetrahydrofuran (5.0 mL) were reacted in a manner similar to Example 1 to give 0.15 g (63%) of the title compound as pale yellow crystals: mp 157-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.86, 7.37-7.24, 7.18-7.10, 6.91, 3.72, 3.00-2.90, 2.75-2.61, 2.57-2.48, 2.42-2.33; 13C NMR (100 MHz, CDCl3) δ 161.9, 159.4, 137.6, 135.3, 132.5, 130.0, 129.3, 128.7, 128.0, 127.5, 127.0, 124.1, 122.4, 121.0, 115.7, 115.4, 114.1, 110.7, 62.0, 56.1, 53.9, 28.8, 24.9; IR (drift) 3405, 2887, 2811, 1485, 1453, 1418, 1346, 1335, 1221, 1121, 924, 817, 782, 757, 740 cm−1; MS (EI) mrz 370 (M+); Anal. Calcd for C25H23FN2: C, 81.05; H, 6.26; N, 7.56. Found: C, 80.82; H, 6.35; N, 7.47.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](C)[CH:17]=2)=[N:4][C:3]=1[C:23](OC)=[O:24].[NH3:27].[CH3:28]O>>[OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:28])[CH:17]=2)=[N:4][C:3]=1[C:23]([NH2:27])=[O:24]
Reactant: CO
Reactant: N
Reactant: COC(=O)c1nc(Cc2ccccc2-c2cccc(C)c2)[nH]c(=O)c1O
Product: Cc1cccc(-c2ccccc2Cc2nc(C(N)=O)c(O)c(=O)[nH]2)c1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture containing methyl 5-hydroxy-2-((3′-methylbiphenyl-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (55 mg, 157 μmol) and ammonia (7M in MeOH) (4 ml, 28.0 mmol) in MeOH (2 ml) was heated at 100° C. overnight. The cooled reaction mixture was concentrated in vacuo and then triturated from methanol to give the title product as an off-white solid (0.025 g; 47%). LCMS: m/z=336 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]([CH3:37])([CH3:36])[S:5]1(=[O:39])=[O:38])[CH:2]=[CH2:3].[CH3:40][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[CH2:1]([C:4]1([CH3:40])[S:5](=[O:38])(=[O:39])[C:6]([CH3:37])([CH3:36])[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C@@:9]1([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20])[CH3:10])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: C=CCC1(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a mixture of tert-butyl N-[(2S,3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (0.22 g, 0.38 mmol) in THF (2 mL) at −78° C. was added potassium bis(trimethylsilyl)amide, 1M in THF (1.13 ml, 1.13 mmol) and the solution was stirred for 15 minutes. Iodomethane (0.070 ml, 1.13 mmol) was added and the mixture was stirred at −78° C. for 0.5 h. The reaction was quenched by water, extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a BioTage column (25 g), eluting with a gradient of 5% to 40% EtOAc in hexane, to provide tert-butyl N-[(5R)-6-allyl-5-(2-fluoro-5-nitro-phenyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]-N-tert-butoxycarbonyl-carbamate (0.19 g, 85% yield) as a white solid. m/z (ESI) 606.1 (M+Na)+.
Reaction SMILES: OCCCCCC[CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]1CCN[CH2:61][CH2:60]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>>[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]1[CH2:8][CH2:9][N:10]([C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:61][CH2:60]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCN1CCNCC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 25 in place of 8-aminooctanol. ES/MS calcd. for C41H56N5O6SSi+ 774.4. Found m/z=774.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 304 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 92 mg of 2-propyn-1-ol, to which 66 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 256 mg of 2-methyl-4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (77)).
Reaction SMILES: [O-2:1].[Mg+2].O.[OH:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:15])[CH2:10][NH:11][CH2:12][CH2:13][OH:14].[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCOCC1>[OH:4][CH2:5][CH2:6][N:7]([C:31](=[O:1])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:8][CH:9]([OH:15])[CH2:10][N:11]([C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][OH:14]
Reactant: OCCNCC(O)CNCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: [O-2]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CC(O)CN(CCO)C(=O)CCCCCCCCCCCCCCC
Yield: 76.1 %

Procedure:
Subsequently, into a 500 ml rounded-flask, were introduced 4.0 g of magnesium oxide and 80 g of distilled water. The mixture was stirred, and was added 8.9 g of N,N'-bis(2-hydroxyethyl)-2-hydroxy-1,3-propanediamine prepared above, and then was added 250 ml of 1,4-dioxane. 26.8 g of palmitoyl chloride was gradually added dropwise to the resulting mixture for 1 hour under violent stirring at a room temperature. After stirring for 2 hours, the mixture was filtered, and then the filtrate was mixed with 200 ml of chloroform, and washed twice with 200 ml of distilled water. The organic phase was seperated; on cooling a precipitated, which was collected and recrystallized from acetone, to give 24.3 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1.[H][H]>CO.O.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1
Reactant: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Yield: 98.4 %

Procedure:
A solution of benzyl 2(S)-[N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (726 mg) in methanol (150 ml) and water (10 ml) was hydrogenated over 10% palladium on carbon (80 mg) at atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give 2(S)-[N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (573 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 91 %

Procedure:
By using (−)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 253-254° C. [α]D=−77.4° (c=0.500, methanol).
Reaction SMILES: C1[O:6][CH:2]1[C:3](=[CH2:5])[CH3:4].[CH3:7]N(C=O)C.[SH:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.Cl>C(Cl)Cl.[Cu]I.CCOC(C)=O.CCCCCC>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[S:12][CH2:7]/[CH:5]=[C:3](\[CH3:4])/[CH2:2][OH:6]
Reactant: CN(C)C=O
Reactant: Sc1nc2ccccc2s1
Reactant: C=C(C)C1CO1
Agent: [Cu]I
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C/C(=C\CSc1nc2ccccc2s1)CO
Yield: 9 %

Procedure:
Isoprene monoxide (2.64 g, 31.40 mmol) of Chemical Formula 2 was mixed with DMF (30 mL) and stirred, and the resulting stirred solution was added with 2-mercaptobenzothiazole (5.25 g, 31.40 mmol) and CuI (299 mg, 1.57 mmol). The reaction mixture was stirred at room temperature for 21 hr, and added with a 1 M HCl solution to terminate the reaction, and the resulting reaction product was diluted with CH2Cl2. The unreacted yellow starting material was removed using a porous glass funnel filter, and the filtrate was washed with a 1 M NaOH solution and H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, thus obtaining a crude product. The crude product was analyzed with 1H-NMR, yielding a 1,2-addition product (0.68 g, 2.71 mmol, 9% yield, Rf=0.31/1:4 EtOAc/hexane), a 1,4-addition product (Z-configuration, 0.85 g, 3.38 mmol, 11% yield, Rf=0.24/1:4 EtOAc/hexane), and a 1,4-addition product (E-configuration, Chemical Formula 3, 3.40 g, 13.53 mmol, 43% yield, Rf=0.15/1:4 EtOAc/hexane) at a ratio of 1:1.25:5 from the sulfide.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine in 250 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After adding 7.74 ml of DMF and stirring at −75° C. for 1 hour, the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.6 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].[C:14]([N:21]1[CH:25]=[CH:24]N=[CH:22]1)(N1C=CN=C1)=[O:15].[CH2:26]([N:33]1[CH2:40]C2C[CH:35]([CH2:36]NC2)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([N:33]1[CH2:34][CH:35]2[CH2:36][CH:24]([CH2:25][N:21]([C:14]([O:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])[CH2:22]2)[CH2:40]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCOC(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1OC
Yield: 29 %

Procedure:
3,4-Dimethoxyphenethyl alcohol (3.64 g; 20 mmol) was added to a stirred suspension of 1,1′-carbonyldiimidazole (3.24 g; 20 mmol) in THF (20 mL), and the mixture was refluxed for 12 h. A solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (4.33 g; 20 mmol; see Example E above) in THF (20 mL) was added and the reaction mixture was refluxed overnight. The solvent was removed and the residue dissolved in H2SO4 (2M; 25 mL) and extracted with diethyl ether. NaOH (3.5 mL; 5M) was added and the aqueous phase extracted with DCM. The organic layer was separated, dried and subjected to column chromatography (DCM:MeOH; gradient 0 to 30% MeOH) to give the sub-title compound in a 29% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27][C:28]([CH3:30])=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:30][C:28](=[O:29])[CH2:27][C:26]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Yield: 61.5 %

Procedure:
Following the general procedure of Example 8, 196 mg (0.58 mmole) of 5,5-bis(4-fluorophenyl)-4-(1H-tetrazol-1-yl)-2,4-pentadienal was condensed with two equivalents (1.2 mmoles) of the dianion of ethyl acetoacetate. The product thereby produced was purified by silica gel chromatography using ethyl acetate-hexanes as eluent to yield 173.8 mg (61.5%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[F:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:23]1[C:22]([C:12]2[CH:13]=[C:14]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[CH:32][N:31]=[C:30]([F:29])[CH:35]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C
Yield: 74.5 %

Procedure:
A vial was charged with (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Argon, and then dioxane (5383 μL) and water (1794 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg, 95% purity) as an off-white solid. Step 2: A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (104.72 mg, 0.264 mmol), 2-fluoropyridin-4-ylboronic acid (74.4 mg, 0.528 mmol), potassium phosphate (168 mg, 0.792 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.34 mg, 0.013 mmol). The vial was flushed with Argon, then dioxane (990 μL) and water (330 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (90 mg) as a light-yellow solid. MS m/z=458.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CS(C)=O.[CH3:18][C@H:19]1[C@@H:23]([OH:24])[CH2:22][CH2:21][NH:20]1.C(=O)([O-])[O-].[Li+].[Li+]>>[OH:24][C@H:23]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[C@H:19]1[CH3:18]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
Using 4-fluoro-3-(trifluoromethyl)benzonitrile (398 mg), 0.9 mol/L (2S,3S)-2-methylpyrrolidin-3-ol dimethyl sulfoxide solution (2.35 mL) and lithium carbonate (156 mg), the title compound was obtained as yellow crystals (yield: 135 mg) by an operation similar to that in Example 3.
Reaction SMILES: [I-:1].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(C)=O>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][I:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCCCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCc1ccccc1
Temperature: 70 °C
Yield: 0.1 %

Procedure:
Sodium iodide (8.9 g, 59.2 mol) and 4-phenyl-1-chlorobutane (5.0 g, 29.6 mol) were added to acetone (29.6 mL) at rt. The mixture was heated to 70° C. for 12 h. The resulting solution was gravity filtered to remove salts. The solvent was removed under reduced pressure and excess salts were dissolved in water (100 mL). Hexane (100 mL) was added to the aqueous mixture. The phases were separated and the organic phase was washed with saturated sodium bisulfite solution (3×50 mL), treated with decolorizing carbon, and gravity filtered. The organic layer was then dried (MgSO4), filtered, and concentrated in vacuo to afford 4-phenyl-1-iodobutane (6.94 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8](/[CH:9]=[N:10]/[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:4].CO.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)c1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the intermediate from step B (8.4 g, 30.18 mmol) in THF (150 mL) was added methanol (15 mL), Na(CN)BH3 (5.7 g, 90.54 mmol) and AcOH (30 mL). The resulting solution was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo. To the residue was added 1 M Na2CO3 solution (800 mL) and extracted with ether (3×). The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo to give the desired product as a white solid. 1H NMR (CDCl3, 500 MHz): 8.04 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 4.08 (s, 2H), 3.94 (s, 3H), 1.49 (s,9H). LC-MS=2.43; (M+H−56)=224.9.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:21][C:22]([F:33])([F:32])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[F:21][C:22]([F:32])([F:33])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:29][CH:30]=1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Agent: C[Al+]C
Agent: [Cl-]
Product: O=C1CC2(CCN1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared as a light brown solid (0.685 g) in analogy to example 1 step D) from 4-(2-methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (1 g), dimethylaluminium chloride (1 M in hexane, 17.4 ml) and 4-(2,2,2-trifluoro-ethoxy)-phenylamine (1.25 g). MS (ESI): 343.12 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.CO>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)c(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2nc(C(=O)O)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinate (1.0 equiv.) in THF/MeOH (2:1, 0.09 M) was added LiOH (1.5 equiv.). The reaction mixture was stirred overnight at room temperature, then 1N HCl and ethyl acetate were added, the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinic acid as a mixture of isomers (3:1) in 82% yield. LC/MS=354.2 (M+H), Rt=1.38 and 1.41 min.