Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[C:13]1([C@H:11]2[CH2:10][O:9][C:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[O:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a vigorously stirred mixture of 4,5-dihydro-2-(3-hydroxyphenyl)-4(S)-phenyloxazole (2.04 g, 8.5 mmol) and potassium carbonate (2.36 g, 17 mmol) in DMF (40 ml) was added dropwise over 5 min. a solution of ethyl bromoacetate (1.71 g, 10.2 mmol) in DMF (5 ml) at ambient temperature. The reaction mixture was stirred for 12 h and then poured into water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), and the combined extracts were washed with brine (50 ml), dried (MgSO4) and concentrated under reduced pressure to afford title compound (2.77 g, quant.) as a pale yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>O>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: CC(C)O
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.454 g (48% yield, 96% GC purity, 93% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (31%), 178 (100%), 150 (45%), 100 (26%), 43 (34%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.81 to 159.74 (m), 149.22 to 148.78 (m), 148.04 to 147.86 (m), 146.49 to 146.10 (m), 145.65 to 145.47 (m), 138.53 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.4, 11.2 Hz), 129.02 to 128.74 (m), 70.97 (s), 21.60 (s). 19F NMR (376 MHz, CDCl3) δ −80.31 to −80.49 (m), −136.04 to −136.18 (m), −137.10 to −137.25 (m), −149.81 to −149.95 (m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[S:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=2)[C:28](O)=[O:29])[CH2:21][CH2:20]1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][N:33]=[C:25]([N:22]5[CH2:21][CH2:20][S:19][CH2:24][CH2:23]5)[CH:26]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(O)c1ccnc(N2CCSCC2)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnc(N2CCSCC2)c1
Yield: 50 %

Procedure:
Method Method H2 was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-thiomorpholinoisonicotinic acid to afford the title compound as a light pink solid (93 mg, 50%). 1H-NMR (δ, ppm, DMSO-d6): 2.62 (d, 4H, HThiomorph, J=7.2 Hz), 3.96 (d, 4H, HThiomorph, J=7.2 Hz), 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93 (dd, 1H, Harom, J=7.9 Hz, J=1.8 Hz), 7.01 (d, 1H, Harom, J=5.1 Hz), 7.19 (s, 1H, Harom), 7.43 (t, 1H, Harom, J=8.2 Hz), 7.60-7.64 (m, 2H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 8.25 (d, 1H, Harom, J=5.1 Hz), 10.39 (s, 1H, NHamide), 11.19 (s, 1H, NHurea), 11.39 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 25.18 (CThiomorph), 47.14 (CThiomorph), 105.01, 106.50, 110.05, 110.75, 113.67, 114.63, 116.26, 130.08, 140.24, 141.28, 143.63, 144.42, 147.04, 148.30, 154.08, 154.64, 158.13, 164.81. HRMS (EI): m/z [M+H] calculated for C22H20N6O3S: 449.1390, found: 449.1396.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:16][CH:15]=1
Reactant: C#CC(=O)OC
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(N(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 6.7 ml (80 mmol) of methyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon with 53.1 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.94 g (80 mmol) of 4-dimethylaminobenzaldehyde in 80 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether, the combined organic phases were washed in sequence with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-[4-(dimethylamino)phenyl)-4-hydroxy-2-butynoate as a red oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][O:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].O>COCCOC>[CH3:16][C:14]1[C:13]([C:2]2[CH:3]=[N:4][O:5][C:6]=2[CH3:7])=[CH:12][CH:11]=[C:10]([O:9][CH3:8])[N:15]=1
Reactant: Cc1oncc1I
Reactant: COc1ccc(B(O)O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnoc2C)c(C)n1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A mixture of 4-iodo-5-methylisoxazole (18.2 g, 87 mmol), 6-methoxy-2-methylpyridine-3-boronic acid (14.6 g, 87 mmol), sodium bicarbonate (22.0 g, 262 mmol), water (150 mL) and DME (150 mL) was degassed three times with stirring by the application of a vacuum and then introduction of a nitrogen atmosphere. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (2.14 g, 2.6 mmol) was added in one portion. The reaction mixture was degassed as before. The reaction mixture was then stirred at 80° C. for 4 h, then it was cooled to ambient temperature. Three extractions with EtOAc, drying the combined organic layers over MgSO4, filtration and removal of solvent in vacuo afforded an oil. Flash chromatography (EtOAc:hexane::1:9) and removal of solvent in vacuo from the desired fractions gave the product (7.15 g): 1H-NMR(CDCl3, 300 MHz): δ 8.16 (s, 1H), 7.33 (d, 1H, J=8), 6.63 (d, 1H, J=8), 3.95 (s, 3H), 2.35 (s, 6H); APCI+-MS: 205 (M++H).
Reaction SMILES: [CH3:1][C@H:2]1[C:18]23[CH:21]=[C:22]([CH3:25])[C@H:23]([OH:24])[C@@:17]2([OH:26])[C@H:16]2[C:11]([CH2:12][O:13]C(C)(C)[O:15]2)=[CH:10][CH:9]([C:19]3=[O:20])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1.[C:29](O)(=[O:34])/[C:30](=[CH:32]\[CH3:33])/[CH3:31]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:33]/[CH:32]=[C:30](\[C:29]([O:24][C@@H:23]1[C@@:17]2([OH:26])[C@H:16]([OH:15])[C:11]([CH2:12][OH:13])=[CH:10][C@H:9]3[C@@H:5]4[C:6]([CH3:7])([CH3:8])[C@@H:4]4[CH2:3][C@@H:2]([CH3:1])[C@:18]2([C:19]3=[O:20])[CH:21]=[C:22]1[CH3:25])=[O:34])/[CH3:31]
Reactant: C/C=C(/C)C(=O)O
Reactant: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)O[C@H]1C(C)=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]12O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Yield: 71.5 %

Procedure:
A solution of ingenol-5,20-acetonide (100 mg, 0.26 mmol), angelic acid (39 mg, 0.39 mmol, 1.5 mol. equiv.) and DMAP (48 mg, 0.39 mmol, 1.5 mol. equiv.) in toluene (4 ml), was stirred at room temperature for 2 hours and was then filtered through a bed of celite and evaporated. The resulting material was filtered in silica gel (ca. 5 g) and evaporated. The residue was purified by means of silica gel gravity column chromatography (5 g, petroleum ether:EtOAc 85:15) until obtaining over 80 mg of ingenol-3-angelate with a purity>99%. For physical and spectroscopic data, see Hohmann J et al. Planta Medica 2000, 66, 291-294.
Reaction SMILES: [CH:1]1([PH:7](=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]=[O:15]>>[CH:1]1([P:7]([CH2:14][OH:15])(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: CCCCO[PH](=O)C1CCCCC1
Product: CCCCOP(=O)(CO)C1CCCCC1

Procedure:
The title compound was prepared from cyclohexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH2:16][CH2:15][NH:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:14]1[CH2:15][CH2:16][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH2:13]1)=[O:21]
Reactant: c1ccc(-c2ncnc3c2CCNC3)cc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccccc2)C1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of Intermediate 1 (55 mg, 0.26 mmol) in DCM (3 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (60 mg, 0.26 mmol) followed by EDCI (75 mg, 0.39 mmol), HOBt (28 mg, 0.21 mmol) and TEA (0.72 mL, 0.52 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product as a colorless foam (80 mg, 73%). MS (ESI) mass calcd. C21H15ClF3N3O, 417.09. m/z found 418.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.16-9.03 (m, 1H), 7.82-7.77 (m, 1H), 7.65-7.46 (m, 7H), 5.16-5.02 (m, 1H), 4.61-4.42 (m, 1H), 4.09-3.97 (m, 1H), 3.52-3.38 (m, 1H), 3.11-2.83 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)[CH3:3].C(Cl)Cl.[O:33]=[O+][O-].CSC>O=O>[OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[C:8]([OH:33])[CH2:9][S:10][C@H:5]12)[CH3:3]
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2C(C(C)O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: CC(O)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 0.33 h

Procedure:
Benzhydryl 7-(1-hydroxyethyl)-3-methylene-cepham-4-carboxylate (4.6 g.) is dissolved in 500 ml. of CH2Cl2, cooled to -78° and treated with a stream of ozone in oxygen until a blue color persists in the reaction mixture. After 1 minute at -78° the reaction mixture is treated with 5 ml. of dimethyl sulfide and the reaction mixture is allowed to stand at -78° for 20 min. followed by 1 hour at 25° C. The solvent is removed under reduced pressure to give the crude benzhydryl 7-(1-hydroxyethyl)-3-hydroxy-3-cephem-4carboxylate.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:4][C:3]2[C:11](=[CH:12][CH:13]=[CH:1][CH:2]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CN2Cc3ccccc3C2)cc1

Procedure:
In Scheme 3, the bis-bromomethyl benzoic acid ester (26) is reacted with benzylamine in a polar aprotic solvent such as tetrahydrofuran (THF) in the presence of a non-interfering base such as triethylamine to give the N-benzyl dihydroisoindole intermediate (27). The ester group in intermediate (27) is then reduced to the corresponding alcohol using lithium aluminium hydride in THF to give the hydroxymethyldihydroisoindole intermediate (28). Debenzylation of the hydroxymethyldihydroisoindole intermediate (28) is then carried out by hydrogenation over palladium on charcoal catalyst in an alcohol (e.g. ethanol) solvent at a mildly elevated temperature (e.g. up to about 50°) to give the intermediate (29). Intermediate (29) is then converted to intermediate (20) by reaction with a reagent suitable for introducing a benzyloxycarbonyl (“Z”) group onto the nitrogen atom of the dihydroisoindole ring. For example, the intermediate (29) can be reacted with benzyl chloroformate in a polar non-protic solvent such as THF in the presence of a non-interfering base such as triethylamine to give intermediate (20).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C#N)cc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccc(C#N)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-cyanophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][CH2:2][C:3]([N:5]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: Cc1cccnc1Br
Reactant: CCC(=O)Nc1ccccc1
Product: CCC(=O)N(c1ccccc1)c1ncccc1C
Yield: 99.8 %

Procedure:
Using 2-methylacetanilide (4.48 g) and 2-bromo-3-methylpyridine (10.3 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:3) produced 2-methyl-N-(3-methyl-2-pyridyl)acetanilide (7.2 g, crude product) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC(C)C(=O)O)cc1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(OC(C)c2nnc(N)s2)cc1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(4-methylphenoxy)propanoic acid, 3.6 grams (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane, and heated to 90° C. the addition funnel was charged with phosphorous oxychloride (POCl3), (6.7 grams, 0.4 mole) which was slowly added for 15 minutes while maintaining the temperature within 90°-95° C. When the addition was completed, the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipitate was filtered off, washed with water and dried in a vacuum oven at 80° C. to 7.7 grams of tan crystals (melting point 142°-162° C.) which were recrystallized from the minimum amount of a water ethanol mixture, filtered off and dried in a vacuum oven at 80° C. to 4.8 grams of yellow crystals of 5-[1-(4-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (melting point 178°-180° C.).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9](C)[C:8]2=[NH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O-].[Na+]>>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]=[C:8]2[NH:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(=N)N(c2ccccc2)CC1=O
Reactant: C[O-]
Agent: [Na+]
Product: CNC1=NC(=O)CN1c1ccccc1

Procedure:
2.2 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 0.26 g. of sodium methoxide and 65 ml. of absolute alcohol were heated to reflux for 20 hours. The insoluble solid was filtered and ethanol was evaporated leaving a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26]Cl)[N:9]=2)[CH:7]=1.Cl.[NH2:31][CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:31][CH:32]3[CH2:36][CH2:35][O:34][CH2:33]3)[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(CCCl)cc1NC(=O)c1cnn2cccnc12
Reactant: NC1CCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-c1nn(CCNC2CCOC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 18 h
Yield: 30.7 %

Procedure:
A solution of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-chloroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.040 g, 0.090 mmol, 1 equiv), 3-aminotetrahydrofuran hydrochloride (29 mg, 0.23 mmol, 2.50 equiv), and N,N-diisopropylethylamine (73 μL, 0.42 mmol, 4.5 equiv) in N-methylpyrrolidinone (1 mL) was heated at 100° C. After 18 h, the reaction mixture was partitioned between ethyl acetate (10 mL) and half-saturated aqueous sodium chloride solution (10 mL). The aqueous was extracted with ethyl acetate (2×10 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC provided product (13.3 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.67 (s, 1H), 9.32 (dd, J=7.0, 1.5 Hz, 1H), 8.77 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 7.49 (dd, J=8.9, 2.7 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.30 (m, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.85 (s, 3H), 3.60-3.76 (m, 4H), 3.38 (m, 2H), 2.96 (m, 2H), 1.96 (m, 1H), 1.62 (m, 1H). LCMS (ESI): M+H=482.2.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
190 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was dissolved in methanol (6.9 mL), and 40 mg of 10% palladium carbon (50% water content) was added, followed by stirring for 1.5 hours under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure and dried under vacuum to afford 126 mg of the title compound as a colorless solid (quantitative).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:37])[CH2:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2]1.[CH3:39][CH:40]([CH2:43][CH3:44])[CH:41]=O>>[CH3:39][CH:40]([CH2:43][CH3:44])[CH2:41][N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][NH:8][C:9](=[O:38])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:37])[CH2:17][C:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:2]1
Reactant: CCC(C)C=O
Reactant: O=C(CCCCCNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC[C@H]1CCCNC1
Product: CCC(C)CN1CCC[C@H](CNC(=O)CCCCCNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using N-{6-{((3S)-3-piperidyl)methyl}amino-6-oxohexyl}-3,3,3-triphenylpropanamide and 2-methylbutanal. The compound was obtained as a white foamy substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[CH3:19][O:20][C:21]1[N:28]=[CH:27][CH:26]=[C:25]([O:29][CH:30]([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:22]=1[CH:23]=O>CO.C(O)(=O)C>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][N:6]1[C:5](=[O:18])[C:4]2[CH:3]=[C:2]3[NH:1][C:23]([C:22]4[C:21]([O:20][CH3:19])=[N:28][CH:27]=[CH:26][C:25]=4[O:29][CH:30]([CH3:38])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:11][C:10]3=[CH:9][C:8]=2[C:7]1=[O:12]
Reactant: CN(C)CCN1C(=O)c2cc(N)c(N)cc2C1=O
Reactant: COc1nccc(OC(C)Cc2ccccc2)c1C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(OC(C)Cc2ccccc2)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
5,6-Diamino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione (0.47 g, 1.88 mmol) was dissolved in MeOH (30 mL) and acetic acid (10 mL). 2-Methoxy-4-((1-phenylpropan-2-yl)oxy)nicotinaldehyde (0.51 g, 1.88 mmol) was added under air at rt. The reaction mixture was stirred at rt under air overnight. The volatile was removed. The residue was subjected to column chromatography (silica-gel, CH2Cl2/MeOH=17/3 v/v) to give a white solid product, 0.65 g, 69.2% yield. MS: 500.3 [M+H]+. 1H-NMR (DMSO-d6, 500 MHz): δ 13.23 (s, 1H), 8.20 (d, 1H, J=6.0 Hz), 8.12 (s, 1H), 7.95 (s, 1H), 7.09-7.07 (m, 1H), 7.11-7.95 (m, 5H), 4.84-4.81 (m, 1H), 3.82 (s, 3H), 3.72 (t, 2H, J=6.5 Hz), 2.78 (d, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.5 Hz), 2.19 (s, 6H), 1.17 (d, 3H, J=6.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:13]Br.Br>C(O)(=O)C.O>[Br:13][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc2c(c1)CCC2=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)CC(Br)C2=O

Procedure:
1-Oxoindane-5-carbonitrile is brominated with bromine in glacial acetic acid with addition of a catalytic amount of 48% strength HBr solution in water and affords 2-bromo-1-oxoindane-5-carbonitrile with a melting point of 115-118° C.