Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Na].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[O:16]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: Nc1cc(Cl)ncn1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Nc1cc(Oc2ccccc2)ncn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 13.9 %

Procedure:
6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol) was added to a solution of sodium (0.197 g, 8.57 mmol) in phenol (11.29 g, 120 mmol) at 55° C. The mixture was heated at 140° C. for 2 h, then held at room temperature for 20 h. The reaction mixture was poured into 32% aqueous NaOH on ice/water keeping the mixture temperature below 20° C. The mixture was extracted with chloroform and the organic extract dried over calcium chloride and concentrated. The residue was purified by silica gel chromatography (2-20% ethyl acetate in hexanes) to afford 6-phenoxypyrimidin-4-amine (0.6 g, 3.21 mmol, 75% yield) as a white solid. LCMS R.T.=1.37; [M+H]+=197.95.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](O)[N:8]([CH:12]([CH3:14])[CH3:13])[N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:17])=O.CN(C)[CH:22]=[O:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:22]=[O:23])=[C:9]([Cl:17])[N:8]([CH:12]([CH3:14])[CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(O)n(C(C)C)n1
Product: CCOC(=O)c1nn(C(C)C)c(Cl)c1C=O
Temperature: 100 °C

Procedure:
8 g of 5-hydroxy-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester was added portionwise to a preformed mixture of 3.44 ml of dimethylformamide and 94 ml of phosphorus oxychloride at 0° C. under nitrogen. The mixture was then heated at 100° C. for 20 h. The mixture was evaporated under reduced pressure, the residue poured into ice-cold saturated sodium hydrogen carbonate and then extracted three times with dichloromethane. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 9.1 g of 5-chloro-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a light brown solid which was used without further purification. Mass spectrum (ESI) m/z 245 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:10][CH:11]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[NH3:10].[N:13]1([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:11][N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ClCCCOc1ccc(CN2CCCCC2)nc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N
Product: c1cc(CN2CCCCC2)ncc1OCCCN1CCCCC1
Yield: 3 %
Yield: 18.3 %

Procedure:
A solution of 5-(3-chloro-propoxy)-2-piperidin-1ylmethyl-pyridine (0.25 g, 0.86 mmol), piperidine (0.09 mL, 0.94 mmol), KI (0.003 g, 0.017 mmol), and Na2CO3 (0.045 g, 0.43 mmol) in 1-butanol (5 mL) was heated to 95° C. After 18 h the reaction mixture was concentrated, diluted with DCM (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated and chromatography of the residue (SiO2: 3-8% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.025 g, 10%). MS (ESI): exact mass calcd. for C19H31N3O, 317.3; m/z found, 318.5. 1H NMR (400 MHz, CDCl3): 8.23 (d, J=2.8, 1H), 7.29 (d, J=8.1, 1H), 7.16 (dd, J=8.6, 3.0, 1H), 4.03 (t, J=6.3, 2H), 3.55 (s, 2H), 2.48-2.40 (m, 10H), 2.01-1.96 (m, 2H), 1.61-1.46 (m, 8H), 1.43 (br s, 4H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[C:13]1([C:11]2[O:12][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
Triethylamine (1.08 mL; 7.69 mmol) was added to a mixture of 2-amino-1-phenylethanone hydrochloride (0.550 g; 3.08 mmol) and ethyl 2-chloro-2-oxoacetate (0.369 mL; 3.23 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was then stirred at room temperature for 22 hand diluted with dichloromethane (40 mL). The organic layer was washed successively with a saturated aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure. The crude residue was dissolved in phosphorus (V) oxychloride (10 ml) and the solution was refluxed for 4 hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was then carefully washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 15 to 100% dichloromethane in heptane) to afford 0.146 g (22% overall yield) of ethyl 5-phenyloxazole-2-carboxylate as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-4-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[C:26]([Cl:32])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:26]1[CH:25]=[C:24]([CH:19]([C:20]([F:21])([F:23])[F:22])/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)[CH:29]=[C:28]([Cl:30])[C:27]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCN3)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm−1.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2]C.[CH3:5]N(C=O)C.[Br:10][C:11]1[N:12]=[C:13](Br)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12>>[Br:10][C:11]1[N:12]=[C:13]([S:4][CH:1]([CH3:2])[CH3:5])[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12
Reactant: CN(C)C=O
Reactant: Nc1nccn2c(Br)nc(Br)c12
Reactant: CCCS
Product: CC(C)Sc1nc(Br)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A bohdan block vessel was charged with propanethiol (0.010 g, 0.00014 mol) in DMF (1 mL, 0.01 mol) and the reaction mixture was degassed 3×. Sodium hydride was then added and the reaction mixture was stirred at rt for 10 min. 1,3-Dibromo-imidazo[1,5-a]pyrazin-8-ylamine (20 mg, 0.00007 mol) was added and the reaction mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated in vacuo to give the title compound as a brown solid. 1H NMR (400 MHz, CD3OD-d4): δ=1.09 (d, J=6.82 Hz, 9H), 1.28 (d, 9H), 3.45-3.57 (m, 1H), 7.10 (d, J=5.05 Hz, 1H), 7.69 (d, J=5.05 Hz, 1H). MS(ES+): m/z 288.95 (100)[MH+]. HPLC: tR=2.13 min (Open Lynx polar—5 min).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2cccnc2c1-c1ccccc1F
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-5-chloro-8-(2-fluorophenyl)quinoline (0.037 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0813 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.135 mL, 0.135 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with the same desired mass and was used directly in the next step (28 mg, 82%). LCMS calculated for C17H15ClFN2(M+H)+: m/z=301.1; found: 301.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.N#N.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[O:35][CH3:36].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClC(Cl)C.C(O)(C)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: N#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred chilled solution (0° C.) of 2,4-dichloro-5-(trifluromethyl)pyrimidine (0.800 g, 3.68 mmol) under a stream of dry N2 gas in 1:1 dichloroethane/tert-butanol (50 mL) was added a solution of zinc chloride (1 M in diethyl ether; 4.42 mL, 4.42 mmol). After 1 hour of stirring at 0° C., a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (I2) in 1:1 dichloroethane/tert-butanol (15 mL) (1.13 g, 3.68 mmol, 1 eq.) was added drop wise over 30 minutes followed by the drop wise addition of a solution of triethylamine (0.565 mL, 0.410 mmol, 1.1 eq.) in 1:1 dichloroethane/tert-butanol (5 mL) over 30 minutes. The resulting mixture was then stirred vigorously at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue then dried under high vacuum. Ethyl acetate and water were added and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and evaporated to give the crude product as a dark yellow foam. The crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate/petroleum ether) to yield the title compound (I3) (1.25 g, 69%) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.11 (t, 4H, J=5.2 Hz), 3.59 (t, 4H, J=5.0 Hz), 3.88 (s, 3H), 6.54 (s, 1H), 6.57 (d, 1H, J=9.4 Hz), 7.83 (s, 1H), 8.17 (d, 1H, J=8.5 Hz) and 8.53 (s, 1H). LCMS Method B: rt 9.24 min; m/z 488.3 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([S:7][CH:8]2[CH2:13][C:12](=[O:14])O[C:9]2=[O:10])=[N:5][N:6]=1.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C)C(C)=CC=CC=1>[CH2:15]([N:33]1[C:12](=[O:14])[CH2:13][CH:8]([S:7][C:4]2[S:3][C:2]([SH:1])=[N:6][N:5]=2)[C:9]1=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C1CC(Sc2nnc(S)s2)C(=O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCN1C(=O)CC(Sc2nnc(S)s2)C1=O

Procedure:
A mixture of 2-(2-mercapto-1,3,4-thiadiazol-5-ylthio)-succinic anhydride and oleylamine (1:1 molar ratio) in xylene was refluxed for three hours. After removing the solvent under reduced pressure, the reaction product was a light brown, viscous oil. Both its IR spectrum and elemental analysis appeared to be consistent with the proposed structure. A sample of N-(2-ethylhexyl)-2-(2-mercapto-1,3,4-thiadiazol-5-ylthio)-succinimide was similarly prepared.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:71])[NH:46][C:47]3[CH:48]=[CH:49][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:70])[CH3:69])[C:64]([O:66]C)=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[N:51][CH:52]=3)=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>>[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:71])[NH:46][C:47]3[CH:48]=[CH:49][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:69])[CH3:70])[C:64]([OH:66])=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[N:51][CH:52]=3)=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cn3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 402 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 401.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([CH:35]=[O:36])C.O.CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([CH:35]=[O:36])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (−30° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.000 g; 1.820 mmol) in anhydrous THF (10 ml) was treated dropwise with 1-Methylmagnesium bromide in THF (4.0 ml; 4.0 mmol), and the resulting suspension was then allowed to warm-up to rt in 10 min. After cooling to −35° C., a mixture of anhydrous DMF (2.0 ml; 25.831 mmol) and anhydrous THF (2 ml) was added dropwise, and the resulting mixture was then allowed to warm-up to rt (in 30 min.), and was further stirred at rt for 16 h. Water (2 ml) and EA were then successively added, and this mixture was washed with aq. sat. NH4Cl. The organic extract was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure (yellow oil; 950 mg). Purification by FC (EA/heptane=1/9 to 1/1) gave the pure product 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a colorless oil (640 mg; 78%). LC-MS: tR=1.01 min.; [M+H]+=452.12 g/mol.
Reaction SMILES: C(OC([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=O)(C)(C)C.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[ClH:38].ON1C2C=CC=CC=2N=N1.[O:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][NH2:55]>CCCCCC.C(Cl)Cl>[Cl-:38].[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH:9]([NH3+:8])[C:10](=[O:12])[NH:55][CH2:54][CH:50]2[CH2:51][CH2:52][CH2:53][O:49]2)=[CH:18][CH:17]=1
Reactant: Cl
Reactant: NCC1CCCO1
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1ccc(C([NH3+])C(=O)NCC2CCCO2)cc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
A one-necked round-bottom flask was charged with amino(4-methylphenyl)acetic acid (10 g, 60.5 mmol), 1,4-dioxane (300 mL) and 1M NaOH (170 mL). To the resulting solution di-tert-butyl dicarbonate (19.8 g, 90.8 mmol) was added and the solution stirred at room temperature overnight. The dioxane was removed under reduced pressure and the aqueous solution was adjusted to pH 4 with 3M HCl and the product extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed under reduced pressure to afford [(tert-butoxycarbonyl)amino](4-methylphenyl)acetic acid as a white solid (15.2 g, y=95%). 1H NMR (DMSO-d6) δ (ppm): 7.44 (d, 1H, J=7.4 Hz), 7.27 (d, 2H, J=7.2 Hz), 7.14 (d, 2H, J=7.3 Hz), 5.03 (d, 1H, J=5.4 Hz), 2.28 (s, 3H), 1.38 (s, 9H). MS (ES1+) m/z: 266.42 (M+1). A one-necked round-bottom flask was charged with [(tert-butoxycarbonyl)amino](4-methylphenyl)acetic acid (16 g, 60.5 mmol), DCM (500 mL) and triethylamine (16.7 mL, 121 mmol). The resulting solution was cooled to 0° C. and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 13.9 g, 72.6 mmol) and 1-hydroxybenzotriazole (HOBT, 9.8 g, 72.6 mmol) were added. The mixture was stirred for 40 min at 0° C. Then 1-(tetrahydrofuran-2-yl)methanamine (10.6 mL, 103 mmol) was added and the solution stirred at room temperature overnight. After 18 h the reaction was complete (HPLC-MS analysis). The solution was washed with water (2×150 mL), 1M HCl (2×150 mL), and brine (2×150 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to afford a white solid which was taken up in 100 mL of n-hexane and triturated at room temperature for 2 h. The precipitate was filtered and dried under vacuum at 50° C. for 4 h. The solid was dissolved in 100 mL of 1,4-dioxane and 25 mL of 4M HCl solution in dioxane were added. The resulting solution was stirred at room temperature overnight. After solvent removal under vacuum, the residue was taken up in diethyl ether (40 mL) and triturated at room temperature for 2 h. The precipitate was filtered and dried under vacuum at 50° C. to afford Intermediate C as a white solid (11.6 g, y=67% over two steps). 1H NMR (DMSO-d6) δ (ppm): 8.75 (br s, 3H), 7.45 (d, 2H, J=7.5 Hz), 7.22 (d, 2H, J=7.4 Hz), 4.91 (br s, 1H), 3.90-3.51 (m, 4H), 3.22-3.04 (m, 2H), 2.28 (s, 3H), 1.85-1.26 (m, 4H). MS (ES1+) m/z: 249.04 (M+1).
Reaction SMILES: CN(N[C:5]([S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.[OH-].[Na+].BrC[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CO>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:5][S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CN(C)NC(=O)Sc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccnc1
Yield: 4.5 %

Procedure:
To a solution of 3.64 g (20 mmol) of 3-dimethylaminocarbamoylthiopyridine in 100 ml of methanol was added 1.6 g (40 mmol) of sodium hydroxide. The mixture was heated and refluxed for 3 hours under nitrogen atmosphere. After cooling, 5.64 g (20 mmol) of N-(4-bromobutyl)phthalimide was added. The mixture was heated and refluxed for 2.5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:1) to obtain 280 mg of the desired compound (4.5%, colorless oil).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:8][N:9]=[C:10]2[CH2:15]1)=[O:27]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: c1cc(-c2nnc3n2CCNC3)ccn1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-(4-Pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.745 mmol, e.g. prepared as described below) was treated with N,N-dimethylformamide (DMF) (3 mL) and cooled to 0° C. Triethylamine (0.109 mL, 0.783 mmol) and N,N-dimethyl-4-pyridinamine (DMAP) (0.009 g, 0.075 mmol) were added at 0° C. under argon and the mixture was stirred for 5 minutes; then 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.199 g, 0.820 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added. The reaction mixture was kept at 0° C. for ½ hour. The reaction was quenched with water, extracted with ethyl acetate (two extractions), and the combined organic phases were washed with a saturated sodium bicarbonate solution, followed by water (four washes). The organic phase was dried, and evaporated to give a yellow oil. The residue was purified by silica gel chromatography using 0-20% of methanol in Dichloromethane as the eluent and then triturated with diethyl ether to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine as a white solid. The solid was dried at 50° C. on the high vacuum for 1 day.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:45](=[O:46])[N:32]3[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37]OC(=O)C)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:52]([O-:55])(=[S:54])[CH3:53].[K+].O>C(O)(=O)C.CC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:29][CH:30]2[C:45](=[O:46])[N:32]3[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37][S:54][C:52](=[O:55])[CH3:53])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: CC([O-])=S
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 90 °C

Procedure:
A mixture of 1.63 of the product of Step B, 0.21 g of sodium bicarbonate, 0.66 g of potassium thioacetate, 10 ml of water and 5 ml of acetone was heated at 90° C for 21/2 hours and was then acidified with 1 ml of acetic acid. The mixture was vacuum filtered and the solid product was washed and chromatographed over silica gel. Elution with a 1-1 methylene chloride-ether mixture and then with a 5-1-4 acetone-water-ether mixture yielded 830 mg of 7-[2-(2-tritylamino-4-thiazolyl)-acetamido]-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid.