Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@H:21](Br)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]>O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@@H:21]([S:3][C:1](=[O:4])[CH3:2])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]
Reactant: CC([O-])=S
Reactant: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@H](Br)C2CCOCC2)CCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C2CCOCC2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of potassium thioacetate (1.66 g, 14.6 mmol) and N-[1-[(R)-2-bromo-2-(4-tetrahydropyranyl)acetylamino]-cyclopentanecarbonyl]-L-homophenylalanine ethyl ester (1.84 g, 3.52 mmol) in 50 mL of tetrahydrofuran is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate, washed with water, with saturated sodium bicarbonate solution, with brine and then dried over magnesium sulfate. The mixture is filtered and concentrated to dryness in vacuo. The residual oil is chromatographed on silica gel with hexane:ethyl acetate (50:50) to yield the title compound, m.p. 107–111° C.; [αD]−56.27° (c=0.994, methanol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1>>[NH:35]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:37]=[N:36]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4cn[nH]c4)nc3s2)cc1
Yield: 37 %

Procedure:
The titled compound (yield=37%) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.48 (s, 3H) 7.57 (d, J=8.34 Hz, 2H) 7.83 (d, J=8.59 Hz, 1H) 8.02-8.17 (m, 3H) 8.28 (s, 2H) 12.88 (s, 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([C@@H:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([C@@H:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
((S)-Methyl 2-(3-(4-aminophenyl)-N-methylisoxazole-5-carboxamido)-3-methylbutanoate (170 mg. 0.513 mmol) was dissolved in THF (10 ml) and to it 2-fluorophenylisocyanate (105 mg. 0.770 mmol) was added. Reaction mixture was stirred at RT for 24 hours. THF was removed under reduced pressure to get pale brown residue, which was purified by column chromatography using EtOAc and CHCl3 as the solvent system to yield 160 mg (67%) of the title compound. MS: ES (−): m/z 467 (M−1); ES (+): m/z 469(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.356 (s, 1H), 8.648 (d, 1H), 8.176 (t, 1H), 7.906 (d, 2H), 7.631-7.448 (s, 1H+d, 2H), 7.287 (m, 1H), 7.185 (t, 1H), 7.065 (m, 1H), 4.738-4.164 (d, 1H), 3.734-3.702 (s, 3H), 3.151-2.963 (s, 3H), 2.339 (m, 1H), 1.030-0.877 (d, 3H(×2)).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[CH2:8][C:7]2[S:11][C:12]([CH3:14])=[CH:13][C:6]=2[S:5]1(=[O:16])=[O:15].[H][H].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[CH:8]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[C:7]2[S:11][C:12]([CH3:14])=[CH:13][C:6]=2[S:5]1(=[O:16])=[O:15]
Reactant: O=C=Nc1ccccc1
Reactant: [H][H]
Reactant: Cc1cc2c(s1)CC(=O)N(C)S2(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(s1)C(C(=O)Nc1ccccc1)C(=O)N(C)S2(=O)=O
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a suspension of 0.78 g (32.5 mmol) sodium hydride in 50 mL tetrahydrofurane was added at −5° C. under N2 a solution of 5 g (21.6 mmol) 3,4-dihydro-2,6-dimethyl-3-oxo-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide in 50 mL tetrahydrofurane. After termination of the hydrogen formation 6.5 g (55 mmol) phenylisocyanate dissolved in 50 mL tetrahydrofurane were added at −5° C. After stirring at room temperature the resulting mixture was quenched with ice/water and by addition of dilute HCl and then extracted with CH2Cl2 (2 times). The combined CH2Cl2 extracts were washed, dried and concentrated to give 6 g crude product. This material was recrystallized from ethanol to give 5.2 g 3,4-dihydro-2,6-dimethyl-3-oxo-2H-thieno[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[O:16][C:15]2=[O:29])[CH:12]=1.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][C:3]([CH2:2][Cl:1])=[O:4])=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)[O:16][C:15]2=[O:29])[CH:12]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Neat chloroacetyl chloride (0.45 g, 5.6 mmol) was added dropwise to a stirred cold (0° C.) solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1.8 g, 4.9 mmol) and anhydrous pyridine (0.45 g, 5.5 mmol) in anhydrous dichloromethane (30 mL). The resulting mixture was allowed to warm to room temperature and stirred for 4 hr. The dichloromethane was rotary evaporated and the residue was partitioned between diethylether-ethyl acetate and dilute HCl. The organic layer was washed with saturated sodium bicarbonate, water and brine and then dried (MgSO4). Evaporation of the solvents followed by recrystallization of the residue from acetone/hexanes afforded the title compound as off-white crystals (2.2 g, 98%). MS m/e 447 (MH+).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].C1CCC=CCCC=1.[SiH4].[CH2:14]([Cl:17])[CH:15]=[CH2:16]>>[CH2:14]([Cl:17])[CH:15]=[CH2:16].[Cl:3][Si:2]([CH2:16][CH2:15][CH2:14][Cl:17])([CH3:4])[CH3:1]
Reactant: C[SiH](C)Cl
Agent: [SiH4]
Solvent: C=CCCl
Solvent: C1=CCCC=CCC1
Product: C[Si](C)(Cl)CCCCl
Temperature: 80 °C

Procedure:
Dimethylchlorosilane as one feed stream and a mixture of 2.7×10−3 mol % of di-μ-chlorobis[(cycloocta-1c,5c-diene)iridium(I)] and 7×10−1 mol % of 1,5-cyclooctadiene in allyl chloride as a second feed stream were fed in a molar ratio of silane:allyl chloride mixture of 1:1.05 at a rate of 2.8 l/h (based on the total volume of the components introduced) via separate metering pumps into a loop reactor maintained at 80° C. under a pressure of 0.4 MPa and having a volume of 1.4 l. After working up the crude mixture by distillation using a thin film evaporator to separate off the catalyst and the excess of allyl chloride, chloro(3-chloropropyl)dimethylsilane was obtained in a yield of 95% and a purity of >99% based on the silane.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:18]([N:2]([CH3:1])[CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 63.9 %

Procedure:
N-methyl-1-[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (1.05 g, 4.1 mmol), benzylbromide (0.49 ml, 4.1 mmol), potassium carbonate (0.68 g, 4.9 mmol) and ACN (20 ml) were heated at 50° C. for 12 h. EtOAc was added, the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:2) afforded the title compound (0.91 g). 1H-NMR (400 MHz, MeOH): δ 7.38 (1H, dd, J 8.4 Hz, J2 1.6), δ 7.28-7.14 (7H, m), δ 5.17 (1H, t, J 4.0 Hz), δ 4.90 (2H, dd, J 52.0 Hz, J2 19.6 Hz), δ 3.59 (2H, dd, J 18.4 Hz, J2 13.2 Hz), δ 2.99 (3H, s), δ 2.78-2.67 (2H, m), δ 2.29 (3H, s). Chiral separation was performed according to Preparation 16. The flow rate was 30 ml/min. Repeated injections (˜40 mg) every 7-8 min. Totally 25 injections afforded the two different enantiomers. The first eluted peak consisted of (−)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.). The second eluted peak consisted of (+)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:24]([C:22]3[O:23][C:19]([C:16]4[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: Nc1cc(Br)cnc1N
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3nc4cc(Br)cnc4[nH]3)o2)cc1

Procedure:
By a procedure similar to Example 274 but starting from 5-bromopyridine-2,3-diamine and 5-(4-nitrophenyl)-2-furaldehyde, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(N(CC)CC)C.COC(C)(C)C.[CH2:25]([O:27][C:28](Cl)=[O:29])[CH3:26]>O>[C:28](=[O:29])([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])[O:27][CH2:25][CH3:26]
Reactant: CCOC(=O)Cl
Reactant: OCC(F)(F)C(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)OCC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2,2,3,4,4,4-hexafluorobutyl carbonate was prepared by combining 2,2,3,4,4,4-hexafluorobutan-1-ol (184 g, 1.012 moles, available from Lancaster Synthesis Ltd., Ward Hill, Mass.), triethylamine (102 g, 1.008 moles) and methyl-t-butyl ether (350 mL) in a 1-L round bottom flask that was maintained at a temperature between 5° C. and 15° C. with a CO2/water bath. To the stirred mix, ethylchloroformate (100 g, 0.92 moles) was added from a jacketed addition funnel that was maintained between 5° C. and 15° C. The ethylchloroformate was added over a period of 4 h. Once addition was complete, the reaction mixture was stirred for an additional 16 h and was allowed to warm to room temperature. Then 100 mL of distilled water was added to the reaction mixture. The organic phase was collected. The water phase was extracted twice with 100 mL portions of methyl t-butyl ether and all of the organic phases were combined. The organic phase was washed with a 100 mL portion of distilled water and a 100 mL portion of 1N HCl. The ether was removed by rotary evaporation. The remaining sample was purified by fractional distillation, using a concentric tube column. The product was analyzed by GC/MS.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:18]1([S:24]([NH:2][CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)CC(N)c1cccc(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OC)c1

Procedure:
Corresponding to Example 1c, 10 g of (8b) were treated with phenylsulphonyl chloride and triethylamine. A yellowish solid was obtained (yield: 13.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=C(C=C)[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.C[N+]1([O-])CC[O:25]CC1.S(=O)(O)[O-].[Na+].[CH2:34]1C[O:37][CH2:36][CH2:35]1>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:5]=[C:34]([CH:35]([OH:25])[CH2:36][OH:37])[N:7]=1
Reactant: C=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: OCC(O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1

Procedure:
To a solution of (6-chloro-2-vinyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (240 mg, 0.73 mmol) in THF (2 mL), acetone (2 mL) and water (2 mL) is added 4-methylmorpholine N-oxide (342 mg, 2.92 mmol) followed by osmium tetroxide (153 μL, 0.015 mmol). After stirring the mixture at room temperature for 17 hours a solution of sodium bisulfite (728 mg, 7 mmol) in water (15 mL) is added and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-{4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-ethane-1,2-diol (320 mg) as a solid.
Reaction SMILES: [N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([Cl:14])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(N=[N+]=[N-])C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(N=[N+]=[N-])C(=O)Cl
Yield: 89 %

Procedure:
A solution of (2R and 2S) 2-azidopentanoic acid (2.213 g, 15.46 mmol) in dry dichloromethane (20 ml) was treated with oxalyl chloride (1.57 ml, 18.55 mmol) and a drop of N,N-dimethyl formamide. After the evolution of gas had ceased (2 h), the solvent was evaporated under reduced pressure and the residual liquid was distilled off (bulb to bulb) under vacuum to give 2.224 g (89%) of a clear oil: bp 50°-55° C./5 torr (air bath temperature); ir (film) νmax : 2105 (N3), 1785 cm-1 (C=O); 1Hmr (CDCl3) δ: 4.1 (1H, dd, J=7, J=6, H-2), 2.2-1.2 (4H, m, H-3 and H-4), and 0.98 ppm (3H, distorted t, J=6, H-5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([Cl:11])[Cl:10])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:3]=1.[Cl:16]C1N=C(Cl)C=C(C(Cl)(Cl)Cl)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]([Cl:16])([Cl:10])[Cl:11])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:13])[Cl:14])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reactant: Clc1nc(OC(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Product: Clc1nc(OC(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Yield: 83 %

Procedure:
The gas chromatogram of the filtrate (113.8 g) showed that it was composed of 83% title compound, 4% 2-chloro-4-dichloromethoxy-6-trichloromethylpyrimidine and 9% 2,4-dichloro-6-trichloromethylpyrimidine. The total yield of the title compound was 87.6% of theory.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1cccc(Cl)c1
Product: CNCC1Cc2cccc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.59 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 177-178° C.
Reaction SMILES: [CH2:1]([O:5][P:6]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[CH2:9]([O:8][P:6]([O-:13])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:10][CH2:11][CH3:12].[CH3:18][N+:19]1([CH2:14][CH2:15][CH2:16][CH3:17])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Reactant: Cn1ccnc1
Product: CCCCOP(=O)([O-])OCCCC
Product: CCCC[N+]1(C)C=CN=C1
Yield: 98.3 %

Procedure:
Tributylphosphate (137.2 g, 0.505 mole) was added dropwise, slowly, to a 300 ml flask containing 41.5 g (99%, 0.5 mole) N-methylimidazole at 170° C. under nitrogen and stirring. The liquid was stirred at the same temperature for an additional 5 hours. The liquid was cooled and moved to a rotary evaporator and dried at 150° C./5 mm Hg for 4 hours. The product (171.3 g, yield 98%) was pure, as judged from NMR, and was liquid at room temperature. 1H-NMR (CDCl3, 300.13 MHz, δ): 10.37 (s, 1H, —N—CH═N—), 7.50 (s, 1H, —N—CH═CH—N—), 7.29)s, 1H, —N—CH═CH—N—), 4.09 (t, 2H, —N—CH2—CH2CH2CH3), 3.87 (s, 3H, —N—CH3), 3.67 (m, 4H, —O—CH2—CH2CH2CH3), 1.67 (qu, 2H, —NCH2—CH2—CH2CH3), 1.40 (m, 4H, 2×—OCH2—CH2—CH2CH3), 1.16 (m, 4H, —OCH2CH2—CH2—CH3), 1.16 (m, 2H, —NCH2CH2—CH2CH3), 0.70 (m, 6H, 2×—OCH2CH2CH2—CH3), 0.70 (m, 3H, —NCH2CH2CH2—CH3). 31P-NMR (CDCl3, 81.015 MHz, δ): 0.95 [s, (RO)2—P(═O)—O−].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[F:23])[C:17](O)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:24][C:25]1([CH3:33])[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][NH2:32].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:32][CH2:31][CH2:30][N:26]4[CH2:27][CH2:28][CH2:29][C:25]4([CH3:33])[CH3:24])[CH:20]=[CH:21][C:22]=3[F:23])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)CCCN1CCN
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774 ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28 ml) to give a yellow solution. ®T3P (propylphosphonic anhydride) (1.620 ml, 2.036 mmol) was added and the mixture was stirred at room temperature for 90 mins. The reaction mixture was diluted with EtOAc and washed with 0.5M LiCl in H2O and sat NaHCO3. The organic portion was dried MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc/iso-hexane to afford the title compound as a white solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([OH:9])[CH:8]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[C:5]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(OC)cc(OCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
5.0 g (35.7 mmol) of 5-methoxybenzene-1,3-diol and then, after 10 minutes, 8.7 ml (78.5 mmol) of ethyl 2-bromoacetate are added to the suspension of 3.1 g (71.4 mmol) of sodium hydride (60% dispersion in oil) in 180 ml of 1-methyl-2-pyrrolidinone under argon. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is diluted with ethyl acetate and washed with a saturated aqueous solution of potassium hydrogen sulphate and a saturated solution of sodium chloride and dried over sodium sulphate then concentrated to dryness. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate=95/5). 5.9 g (53%) of a colourless gum are obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[C:22]#[N:23]>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:22](=[NH:23])[C:21]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cccc(Cl)c1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1C(=N)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.8 %

Procedure:
Under N2 atmosphere at room temperature to a solution of lithium bis(trimethylsilyl)amide (9.7 mL, 1.0 M solution in THF, 9.7 mmol) was added a solution of 4-bromoaniline (1.67 g, 9.7 mmol) in 10 mL anhydrous THF. After the mixture was stirred at ambient temperature for 40 min, a solution of 2-chloro-6-methylbezonitrile (1.55 mg, 10.2 mmol) in 10 mL anhydrous THF was added. The reaction mixture was stirred at room temperature overnight, and then poured into 300 mL ice water. The orange precipitate was collected by filtration, washed with hexane and air dried to give a light orange solid (2.19 g, 66% yield), which was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]2[OH:27])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si:30]([C:33]#N)([CH3:32])[CH3:31].C1N2C[CH2:42][N:37](CC2)C1>O>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15]([C:42]#[N:37])([O:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:13]2[O:27][Si:30]([CH3:31])([CH3:32])[CH3:33])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1C(O[Si](C)(C)C)C2(C=CC1(C#N)O[Si](C)(C)C)CC(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 883.6 %

Procedure:
To a mixture of rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) (200 mg, 0.496 mmol) and trimethylsilyl cyanide (607 μl, 4.460 mmol) at room temperature (cooled with water bath) was slowly added DABCO (6 mg, 0.050 mmol). The mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:1) to give rac-(4R,5S,6S,7S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-7-cyano-5,7-bis(trimethylsilyloxy)-1-azaspiro[3.5]nona-8-ene-2-one (7) as a orange solid (254 mg, 89%).