Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][N:20]=1>C1COCC1.CCOC(C)=O>[F:32][C:29]([F:30])([F:31])[C:27]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[C:19]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:28]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CC(O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1cc(C(F)(F)F)c(C(=O)O)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 180 mg (1.56 mmol) of 1,1,1-trifluoro-2-propanol in 10 mL of THF at −78° C. was added 1.56 mL (1.56 mmol) of sodium bis(trimethylsilyl)amide (1.0M in THF). After 30 min at −78° C., 250 mg (1.04 mmol) of methyl 6-chloro-4-(trifluoromethyl)nicotinate was added. The reaction mixture was gradually warmed up to rt and stirred over night. The mixture was diluted with 10 mL of EtOAc and washed with brine. The organic layer was dried over MgSO4 and concentrated. Purification using HPLC B gave 160 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J=6.6, 3H), 5.91 (m, 1H), 7.26 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][CH2:12][C:11]=12)=[O:5])[CH3:2]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH2:12][O:13][CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C2COCC(=O)N2CCC1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCN2C(=O)COCC12
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A solution of 65 (225 mg, 1.0 mmol) in 5 ml of acetic acid is hydrogenated over 225 mg of platinum dioxide at RT and normal pressure for 18 hours. Another 225 mg of platinum dioxide is added and hydrogenation continued for 24 hours. The black suspension is diluted with 10 ml of DCM and filtered through a pad of celite. The filtrate is evaporated to give 268 mg of a yellow oil which is purified by chromatography (Biotage 12Si, 1=7.5 cm, ethyl acetate/ethanol 9:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([SH:25])[N:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([S:25][CH2:27][C:28]2[N:29]=[C:30]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[S:31][CH:32]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Reactant: Fc1ccc(Nc2nc(CCl)cs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(F)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.20 mmol) of the compound from Example 17A (70% pure) and 130 mg (0.24 mmol) of 4-(chloromethyl)-N-(4-fluorophenyl)-1,3-thiazole-2-amine (from 4-fluorophenylthiourea and 1,3-dichloroacetone) are dissolved in 2.5 ml of dry DMF, and 100 mg (0.98 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. After filtration the filtrate is concentrated under reduced pressure and the residue that remains is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC#N>[CH3:23][O:22][C:20]([C:3]1[C:2]2[NH:1][C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[O:25][CH3:24])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(N)c1C(=O)OC
Reactant: COc1ccccc1C=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)c1ccc2nc(-c3ccccc3OC)[nH]c2c1C(=O)OC
Yield: 71 %

Procedure:
A solution of diethyl [3,4-diamino-2-(methoxycarbonyl)phenyl]malonate (4.39 g, 13.5 mmol), 2-methoxybenzaldehyde (1.97 g, 14.5 mmol) and p-chloranil (6.10 g, 14.5 mmol) in MeCN (135 mL) was stirred at room temperature for 22 h. The resulting suspension was filtered and the solid recovered was washed with MeCN (filtrate 1 kept). The solid was dissolved in EtOAc (800 mL) and the resulting solution was successively washed with aqueous 1N NaOH solution (3×150 mL), water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was triturated with hexane:EtOAc (1:1; 135 mL) to give the title compound (4.22 g) as a white solid (filtrate 2 kept). The filtrates 1 and 2 were combined and concentrated under reduced pressure. The residue was treated as the initial solid but the residue after washings was concentrated and purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 1:1) before being triturated with hexane:EtOAc (3:2; 35 mL) to give an additional 0.72 g amount (total of 4.96 g, 83% yield) of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([OH:22])=O)=[CH:12][CH:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C)C=O>[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([N:56]2[CH2:57][CH2:58][S:54][CH2:55]2)=[O:22])=[CH:14][CH:15]=1
Reactant: C1CSCN1
Reactant: O=C(O)CC(O)CCc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(O)CCc1ccc(-c2ccccc2)cc1)N1CCSC1
Reaction time: 0.08 h
Yield: 47.2 %

Procedure:
Diisopropylethylamine (32 μL, 0.19 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1, 25 mg, 93 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.19 mmol) in dimethylformamide (1 mL) at room temperature under nitrogen. After stirring for 5 minutes, thiazolidine (11 μL, 0.14 mmol) was added then stirring was continued for a further 2 hours. The volatiles were removed by evaporation under reduced pressure and the residue partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated and the organic phase evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:1 ethyl acetate: 40–60 petroleum ether) to give the title compound (15 mg, 47%) as a white solid. LC/MS: 3.22 min; z/e 342, calcd (M+1) 342.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:14]1C=C(Cl)C=C(Cl)[C:15]=1O.C([Zn]CC)C.C(I)I.BrC1C=CC(C(=C)CC)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: COC1(c2ccc(Br)cc2)CC1
Agent: C=C(CC)c1ccc(Br)cc1
Agent: CC[Zn]CC
Solvent: ICI
Product: CCC1(c2ccc(Br)cc2)CC1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to 1-bromo-4-(1-methoxycyclopropyl)-benzene (described in example S89) using 2,4,6-trichlorophenol (580 mg, 2.94 mmol), diethyl zinc (2.94 ml, 1M solution in hexane, 2.94 mmol), CH2I2 (237 μl, 2.94 mmol) and 1-bromo-4-(1-methylenepropyl)-benzene (310 mg, 1.47 mmol). The isolated residue was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-ethylcyclopropyl)-benzene (280 mg, 85%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.39 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 1.55 (q, J=7.5 Hz, 2H), 0.82 (t, J=7.5 Hz, 3H), 0.75-0.71(m, 2H), 0.68-0.64 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[Cl-].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
7.65 gm (0.05 mol) of 1,4-diamino-2-nitrobenzene were added to 80 ml of absolute tetrahydrofuran and 5.1 gm (0.05 mol) of triethylamine at room temperature to form a solution. While this mixture was being stirred, 7.5 gm (0.05 mol) of malonic acid monoethylester chloride were added dropwise thereto. After termination of the addition, the mixture was stirred at room temperature for another 6 hours. Then the solvent was evaporated in vacuo for the most part. The residue was suctioned off and recrystallized once from ethanol/activated charcoal and a second time from water. The product had a melting point of 133°-136°C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:48]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.34 ml, 7.69 mmol), 3-aminopyridine (0.43 g, 4.61 mmol) and HATU (2.19 g, 5.77 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.25 g, 3.84 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours. The solid was then filtered and washed with ethyl acetate to yield the title compound as a white solid. 650 mg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([O:20][C@H:21]([CH3:25])[C@H:22]([OH:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[Cl-].[Na+]>C(OCC)C.C(#N)C>[CH2:13]([O:20][C@H:21]([CH3:25])[C@@H:22]([CH3:23])[O:24][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.00 g (23.0 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 5.40 g (30.0 mmol) of (2R,3R)-3-benzyloxybutan-2-ol in 60 ml of diethyl ether and 65 ml of acetonitrile were admixed at 0° C. with 1.21 g (27.7 mmol) of sodium hydride (55% strength), divided into 3 portions, and then stirred for 90 minutes at 15° C. The mixture was admixed with dilute sodium chloride solution and extracted (3×) with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 95:5). This gave 1.60 g (4.4 mmol; yield: 19%) of the product.
Reaction SMILES: [C:1]([NH:11][CH:12]1[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[CH3:17][N:11]([CH:12]1[CH2:14][CH2:13]1)[C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(NC1CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CC1

Procedure:
The synthesis of N-carbobenzyloxy cyclopropylamine is carried out according to the method outlined in J. Heterocycl. Chem (1983), 1035, using N-carbobenzyloxy cyclopropylamine (14a)(10.5 g, 0.055M) in DMF (80 ml), sodium hydride(1.4 g) and methyl iodide (4 ml). The product is purified by vacuum distillation. Bp 86-92° C., 0.02 Torr.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(N(CC)CC)C>C(O)CCC>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:1]([C:3]2[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=2)(=[O:10])=[O:2])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: NCCCN1CCCC1=O
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1ccc(S(=O)(=O)NCCCN2CCCC2=O)cc1

Procedure:
Sulphanilyl fluoride (6.5 g, 37.1 mmol), 3-(pyrrolidin-2-on-1-yl)propylamine (5.79 g, 40.8 mmol) and triethylamine (5.69 ml, 40.8 mmol) in n-butanol (15 ml) was heated at reflux for 10 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/MeOH (100:0) increasing in polarity to (90:10) to give the title compound m/z: 297.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH:9]=[CH2:10].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+].Cl>C1(C)C=CC=CC=1>[CH2:8]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12]1)[CH:9]=[CH2:10]
Reactant: C=CCC1(C(=O)OCC)CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=CCC1(C(=O)OCC)CCN(CC(=O)OCC)CC1
Temperature: 80 °C

Procedure:
The crude TFA salt of ethyl 4-allyl-isonipecotate and ethyl bromoacetate (23.5 g, 141 mmol) were dissolved in toluene. To this solution was added anhydrous K2CO3 (70.7 g, 512 mmol), and the resulting suspension was warmed to 80° C. for 15 minutes. The reaction mixture was cooled down, and adjusted at pH=8.0 with dil.HCl. The resulting solution was worked-up by an ordinal procedure (extraction with ethyl acetate, washing with brine, drying over Na2SO4, concentration by evaporation) to provide 37.4 g of crude ethyl 4-allyl-N-ethoxycarbonylmethyl-isonipecotate, 56.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:35]1[CH:36]=[CH:37][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:34]1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (969 mg; compound B50) is reacted with 3-(chloromethyl)-1-ethyl-1H-pyrazole (454 mg) in the presence of potassium carbonate (630 mg; compound D17) in DMF (15 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 15/1 (v/v)] as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][Si](C)(C)C)=[C:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)C>[CH3:5][C:4]([N:24]=[N:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])[C:3]([O:2][CH3:1])=[O:7]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)(C)N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1.0 mmol of (1-methoxy-2,2- dimethylethenyl)-oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5 N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.90 mmol of methyl 2-methyl-2-phenylazopropionate.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CCCCCC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:2])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 98 %

Procedure:
A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with water (1×100 ml.) and a saturated sodium bicarbonate solution (1×75 ml.), dried over magnesium sulfate and evaporated to yield N-(t-butoxycarbonyl)-L-isoleucine methyl ester as an oil [30.7 g.; 93% yield; 1H-NMR (CDCl3): delta 0.92 (d, J=7,6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butoxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Following 15 minutes of addition stirring at -78° C. after completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried over sodium sulfate and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g., 98% yield, Rf=0.32 in 35% ether in hexane; 1H-NMR (CDCl3): delta 1.00 (d, J=7,6H), 1.46 (s, 9H), 9.65 (s, 1H)].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 60.3 %

Procedure:
The mixture of 2-hydroxy-4-fluorobenzaldehyde (10 g, 71.4 mmole), ethyl 4,4,4-trifluorocrotonate (15 mL, 100 mmole), and anhydrous potassium carbonate (14.8 g, 107.1 mmole) in 40 ml dry dimethylformamide was heated to 90° C. for five hours. LC-MS indicated that the reaction was done. After cooling to room temperature, to the reaction was added 500 mL of ethyl acetate. The organic phase was washed with brine (×3), and was then dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:18 EtOAc:hexane. It gave 12.5 g (60%) of a light yellow oil. LCMS(ES+) 291.0(M+1, 100), EIHRMS m/z 290.0586 (M−H, C13H9F4O3 calc'd 290.0566). 1H NMR (CDCl3/300 MHz) 7.73(s, 1H), 7.30-7.22(m, 1H), 6.79-6.73(m, 2H), 5.76(q, 1H, J=6.9 Hz), 4.38(m, 2H), 1.37(t, 3H, J=7.2 Hz). 13C (CDCl3/300MH) 167.2, 164.0, 163.9, 155.0(d, J=13.0 Hz), 136.3 (d, J=1.28 Hz), 131.0(d, J=10.4 Hz), 123.5 (q, J=287.5 Hz), 115.0 (dd, J=2.4, 7.3 Hz), 110 (d, J=22.5 Hz), 104.4(d, J=26.0 Hz), 71.0(q, J=33.2 Hz), 61.7 (d, J=10.4 Hz), 14.4. 19F(CDCl3/300 MHz) −79.0(d, J=6.5 Hz), −104.8 m).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[OH:14]N1C2C=CC=CC=2N=N1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:14]
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:3].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:23][C:24]1[N:25]=[CH:26][N:27]=[C:28]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:3])[C:29]=1[C:30]#[N:31]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3ccccc3)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)n12
Temperature: 110 °C
Reaction time: 5.5 h

Procedure:
To the crude (S)-methyl 2-(1-aminoethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylate (500 mg, 1.69 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (268 mg, 1.69 mmol) in n-butanol (5 mL) was added DIEA (0.5 mL, 2.54 mmol) at 25° C. The reaction mixture was stirred at 110° C. for 5-6 h. The mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide (S)-methyl 2-[1-((6-Amino-5-cyanopyrimidin-4-yl)amino)ethyl]-3-phenylimidazo-[1,2-a]pyridine-5-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 1.471 (d, J=6.8 Hz, 3H), 3.111 (s, 3H), 5.352-5.420 (m, 1H), 6.935-6.954 (m, 1H), 7.259-7.518 (m, 9H), 7.882-7.941 (m, 2H); LC-MS (ESI) m/z 414.1 [M+H]+.