Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([CH2:13][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])[N:19]=1
Reactant: COc1cc(OC)nc(CBr)n1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
1.52 g of methyl salicylate, 2.33 g of 2-bromomethyl-4,6-dimethoxypyrimidine and 1.6 g of potassium carbonate were stirred in 20 ml of dimethylformamide at 60° C. for 2 hours. The reaction mixture was poured in ice water and extracted with ethyl acetate. The extract was dried over sodium sulfate and, after distilling off the solvent, purified using silica gel chromatography to obtain 2.5 g of methyl 2-(4,6-dimethoxy-2-pyrimidyl)methyloxybenzoate (yield 82%).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COC(=O)c1cccnc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccnc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol) was added over 10 min. to a solution of dimethyl methylphosphonate (1.50 mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanol bath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol) in THF (6 mL) was added over 2 min. The solution was stirred in the cooling bath for 45 min. before being allowed to warm to 0° C. over 1 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and then partitioned between saturated aq. brine (50 mL) and methylene chloride (200 mL). The aq. layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried (sodium sulfate) decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate followed by 97:3 v/v methylene chloride/CH3OH, gave material containing some residual impurity. Further purification by flash column chromatography on silica gel, eluting with 50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate/CH3OH gave 1.15 g of the title compound. For the title compound: 1H NMR (500 MHz, CDCl3) δ9.26-9.20 (bs, 1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd, J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH3:17][C:18]1([CH3:36])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:17][C:18]1([CH3:36])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)[CH:25]=2)[CH2:20][CH2:19]1
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Reactant: CC1(C)CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CCc2ccc(-c3csc(N4CCC(NCCO)CC4)n3)cc21
Temperature: 120 °C

Procedure:
130 mg (0.30 mmol) of 2-[1-(4-bromothiazol-2-yl]piperidin-4-ylamino]ethanol from step b, 92 mg (0.29 mmol) of 2-(3,3-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 92 mg (0.03 mmol) of tetrakis(triphenlyphosphine)palladium(0) and 125 mg (1.18 mmol) of sodium carbonate were weighed out, placed under nitrogen. 2.5 ml of dioxane and 0.5 ml of water were added with stirring. The mixture was degassed, homogenised in an ultrasound bath and heated at 120° C. in the microwave for 30 min, diluted with about 20 ml of EA and 20 ml of water and filtered off. The phases were separated, and the water phase was extracted a further once with EA. The organic phases were combined, dried over sodium sulfate, filtered and evaporated. The oily residue was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16])[CH2:8][CH2:9][CH3:10].C(OCC)(=O)C.O>COCCOC>[CH2:7]([NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][NH2:16])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNc1cc(C#N)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred mixture of lithium aluminum hydride (5.0 g) and 1,2-dimethoxyethane (100 ml) a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzonitrile (15 g) in dry 1,2-dimethoxyethane (150 ml) is during about 1 hour at 100° C. dropwise added, and the mixture is stirred and refluxed for a further 16 hours. After cooling, ethyl acetate (10 ml) followed by water (20 ml) are very cautiously added dropwise, whereafter the mixture is stirred for a further 30 minutes. It is then heated on a steam-bath and filtered hot; the filter-cake is carefully washed with hot 2-methoxyethanol (3 portions of 50 ml). The combined filtrates are evaporated in vacuo to yield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. After recrystallization from 2-methoxyethanol it is obtained with a melting point of 197°-198° C. The material (IR, analysis) is identical with the material prepared as in Example 289.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(OC(NNC)=O)(C)(C)C>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(OCc2ccccc2)cc1
Agent: CNNC(=O)OC(C)(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of (R)-benzyl 3-(4-(benzyloxy)phenyl)-2-hydroxypropanoate (Compound XLIII-1) 1.81 g (5.00 mmol) and 2,6-lutidine 874 μl (7.50 mmol) in dichloromethane 15 ml, trifluoromethanesulfonic anhydride 1.26 ml (7.50 mmol) was added and the mixture was stirred at 0° C. for 0.5 hr. N-tert-butoxycarbonyl-N′-methylhydrazine (Compound XXXIV-1) 1.46 g (10.0 mol) was added to the solution mixture and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 100 ml and washed with water 100 ml. The organic phase was washed with brine 100 ml and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by chloroform) to obtain the title compound 0.97 g (17.3%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.50 g, 2.59 mmol), isoxazol-3-amine (0.268 ml, 3.63 mmol) and THF (25.9 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (6.48 ml, 6.48 mmol) was added dropwise. After 10 min, the whole was warmed to rt and stirred for 30 min. 6.48 mL of additional LHMDS was added and the reaction was stirred for 1 h. The mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(4-bromo-5-fluoro-2-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (873 mg, 70.4% yield) as brown solid. m/z (ESI) [M+H]+=477.9. NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.15 Hz, 1 H) 1.86 (s, 2 H) 1.99 (s, 1 H) 5.55 (br. s., 1 H) 5.88 (d, J=1.76 Hz, 1 H) 6.44 (d, J=1.87 Hz, 1 H) 6.78 (d, J=9.02 Hz, 1H) 6.83 (d, J=9.64 Hz, 1 H) 7.55 (d, J=9.12 Hz, 1 H) 7.84 (dd, J=8.91, 2.28 Hz, 1 H) 7.92 (dd, J=7.57, 0.52 Hz, 1 H) 8.27 (d, J=9.54 Hz, 1 H) 8.32 (d, J=1.76 Hz, 1 H) 8.40 (d, J=2.28 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 11.67 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[CH:6][N:5]=[C:4]([NH:17][CH2:18]C)[N:3]=1.Cl.CNC(N)=N>>[CH3:18][NH:17][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[CH:6][N:5]=1
Reactant: CCNc1ncc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Agent: CNC(=N)N
Agent: Cl
Product: CNc1ncc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 58 from 1-methyl-guanidine hydrochloride (Aldrich), mp. 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:2]([NH:1][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)=[O:33])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O

Procedure:
A solution of 3-(2-amino-4-chlorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.4 g), 2-naphthoyl chloride (0.29 g) and triethyl amine (0.19 g) in anhydrous tetrahydro furan (30 ml) was heated at reflux temperature overnight under nitrogen atmosphere.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH2:29][CH3:30])=[C:27]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:46]=[CH:45][C:44]4[CH2:43][CH2:42][CH2:41][NH:40][C:39]=4[N:38]=3)[CH2:33][CH2:32]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:29]([C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:46]=[CH:45][C:44]3[CH2:43][CH2:42][CH2:41][NH:40][C:39]=3[N:38]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1c(NCC(C(=O)OC(C)(C)C)C(=O)c2ccc(OC)cc2)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 112.5 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane (50-50), ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: O=C1CCN(CCCN(Cc2ccccc2)Cc2ccccc2)C(=O)N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCCN1CCC(=O)NC1=O
Yield: 90 %

Procedure:
A mixture of intermediate (53) (0.010 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator. The residue was dried over the weekend under a gentle stream of nitrogen. Toluene was added and azeotroped on the rotary evaporator. The residue was stirred in DCM (50 ml). NaOCH3 (0.504 g) was added and the reaction mixture was stirred for one hour under nitrogen. More methanol (25 ml) was added and the mixture was stirred for 30 minutes. The precipitate was filtered off and the filtrate was evaporated in vacuo, yielding 1.54 g of 1-(3-aminopropyl)dihydro-2,4(1H,3H)-pyrimidinedione (intermediate 54).
Reaction SMILES: C(O[C:4](=[O:22])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:22])[C:18]2[C:13](=[N:14][C:15]([CH2:19][CH2:20][CH3:21])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCCc1cccc(NC=C(C(=O)OCC)C(=O)OCC)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1ccc2c(=O)c(C(=O)OCC)c[nH]c2n1
Yield: 81.1 %

Procedure:
The product of Example 2d (6.87 g, 22.4 mmol) was heated in diphenyl ether following the procedure in Example 1b giving the title compound as a tan solid (4.73 g, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:35][O:34][C:5]2([CH2:33][CH2:32][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH3:37][N:38]([CH3:48])[C:39]([C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][N:42]=1)=[O:40]>>[CH3:37][N:38]([CH3:48])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([C:20]2[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C:8]4([CH2:7][CH2:6][C:5]5([O:34][CH2:35][C:2]([CH3:36])([CH3:1])[CH2:3][O:4]5)[CH2:33][CH2:32]4)[O:13][C:12]3=[O:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:43][N:42]=1)=[O:40]
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 76 %

Procedure:
The title compound is prepared from 12,12-dimethyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one and 5-bromo-pyridine-2-carboxylic acid dimethylamide following a procedure analogous to that described in Example 7. Yield: 76% of theory; LC (method 3): tR=3.48 min; Mass spectrum (ESI+): m/z=522 [M+H]+.
Reaction SMILES: C1([C@H](NC(=O)[O:15][C@H:16]([C:30]#[N:31])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)C)C2C(=CC=CC=2)C=CC=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1C=CC=CC=1>[C:30]([C@@H:16]([OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)#[N:31]
Reactant: C[C@@H](NC(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1)c1cccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1

Procedure:
To a solution of 2.91 g (6.99 mmol) of (S)-α-cyano-3-phenoxybenzyl (R)-N-1-(1-naphthyl)ethylcarbamate in 30 ml of dry benzene under a nitrogen atmosphere is added 1.07 ml (0.78 g, 7.7 mmol) of triethylamine followed immediately by 0.75 ml (1.0 g, 7.4 mmol) of trichlorosilane. The reaction is heated at 50° for 3 hours and is then worked up and purified following the procedure of Example 4. The more polar band on the tlc plate is removed and extracted with trichloromethane to yield (S)-α-cyano-3-phenoxybenzyl alcohol, specific rotation [α]D25 =-14.6° (c=11 mg/ml in acetone).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:6]=2[CH:19]=1.B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([O:31][CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:6]=3[CH:19]=2)=[CH:27][CH:26]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
In toluene/ethanol/water (=10/1/1, 20.4 ml) was dissolved methyl 7-bromo-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.48 g) and potassium carbonate (0.47 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (0.10 g), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1→8/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g). Methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.44 g) was dissolved in THF (8.8 ml)/methanol (8.8 ml). To the solution was added 1N sodium hydroxide (4.4 ml), and the mixture was stirred at 50° C. for 4 hours. After cooled to room temperature, pH was adjusted to approximate. 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (12/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (320 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([O:22]C)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.O.[OH-].[Li+]>C1COCC1>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a solution of methyl 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (270 mg, 0.808 mmol) in THF (10 mL)/MeOH (10 mL)/water (10 mL) was added lithium hydroxide (38.7 mg, 1.615 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis of the reaction mixture identified the molecular ion corresponding to product. The reaction mixture was concentrated in vacuo to remove the organic solvents. The aqueous layer was acidified with 1N aqueous HCl (10 mL), which resulted in a white precipitate formation. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to provide 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid (230 mg, 0.718 mmol, 89% yield) as an off-white solid that was used without further purification. LCMS (+ESI) m/z=321.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:38]#[N:39])[C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:40]#[N:41].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:40]#[N:41])=[C:23]([C:38]#[N:39])[C:24]4[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)cc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)cc1
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
0.50 g (0.93 mmol) of N-(4-methoxyphenyl)-3-(2-cyano-2-(3,5-bis(trifluoromethyl) phenyl)ethenyl)carbazole and 5 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.05 g (1.00 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 0.44 g (1.00 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 20 ml of chloroform was added. To the resultant solution was added 20 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a vermilion solid. The vermilion solid was recrystallized in the presence of ethanol to obtain 0.10 g of an orange crystal. The yield of the synthesized orange crystal was 19%, and its melting point was 170-172° C. The IR chart is shown in FIG. 21.