Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:43][O:44][CH3:45])[C:17]([NH:19][C@@H:20]2[C:41](=[O:42])[N:22]3[C:23]([C:38]([O-:40])=[O:39])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:37])[C:30]([NH:34]C=O)=[C:31]([CH3:33])[CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=O.Cl.C(OCC)C>CO>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:43][O:44][CH3:45])[C:17]([NH:19][C@@H:20]2[C:41](=[O:42])[N:22]3[C:23]([C:38]([O-:40])=[O:39])=[C:24]([CH2:27][N+:28]4[N:29]([CH3:37])[C:30]([NH2:34])=[C:31]([CH3:33])[CH:32]=4)[CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(C)c(NC=O)n3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(C)c(N)n3C)CS[C@H]12)c1csc(N)n1
Reaction time: 4 h
Yield: 28.3 %

Procedure:
To a solution of trifluoroacetic acid salt of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2,4-dimethyl-3-formamido-1-pyrazolio)methyl-3- cephem-4-carboxylate (syn isomer) (3 g) in methanol (15 ml) was added concentrated hydrochloric acid (1.57 ml) at ambient temperature. After being stirred at the same temperature for 4 hours, the reaction mixture was added dropwise to diethyl ether, and the resulting precipitate was collected by filtration. The precipitate was dissolved in water, and the solution was adjusted to pH 2 with aqueous 5% sodium bicarbonate solution and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired compound was eluted with aqueous 5% isopropyl alcohol solution. The objective fractions were collected and the isopropyl alcohol was evaporated. The resulting aqueous solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-amino-2,4-dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (763.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([CH:17]2[CH2:19][CH2:18]2)[OH:15])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1cnccc1-c1ccc(Cl)cc1F)C1CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.6 g, 6.79 mmol) (prepared as in Example 5, Part B) in THF (32 mL) cooled to −78° C., was added cyclopropylmagnesium bromide (27.2 mL, 13.58 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to stir at −78° C. for 3 h. The dry ice bath was removed and reaction mixture was brought to room temperature. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (30 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (1×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (30% ethyl acetate in pet ether) to afford (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)(cyclopropyl)methanol (900 mg, 3.24 mmol, 48% yield). LCMS (ESI) m/e 278.0 [(M+H)+, calcd for C15H14ClFNO 278.1]; LC/MS retention time (Method C): tR=1.62 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][S:20]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:12])#[N:8].[CH2:35]([SH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[C:7]([CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][S:20]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][S:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[O:12])#[N:8]
Reactant: CS(=O)(=O)OCc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(CSCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (0.114 g, 0.35 mmol) was added to a solution of trans-methanesulfonic acid 4-[2-(cyanomethylcarbamoyl)-cyclohexylmethanesulfonyl]-benzyl ester (0.150 g, 0.35 mmol) and benzyl mercaptan (0.041 mL, 0.35 mmol) in acetone (4 mL). The reaction mixture was stirred overnight at 50° C. The solids were removed by filtration and washed with warm acetone. The combined filtrates were concentrated by rotary evaporation. Purification of the residue by silica gel chromatography using a gradient of 0%-20% ethyl acetate in dichloromethane yielded the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 250 mg, 2.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and a 60% dispersion of sodium hydride in mineral oil (93 mg, 2.32 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (598 mg, 2.50 mmol) was added. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (200 mL), washed with water (2×75 mL), saturated aqueous brine solution (75 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (508 mg, 84%) as a yellow oil: H1-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.86 (9H, s), 4.03 (2H, t, J=5.6 Hz), 4.40 (2H, t, J=5.2 Hz), 7.11 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=2.4 Hz).
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.O[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH2:21][C:22]([NH2:24])=O)[N:14]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH2:21][C:22]#[N:24])[N:14]=1
Reactant: Cc1cc(O)nc(SCC(N)=O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(Cl)nc(SCC#N)n1

Procedure:
To a solution of 19.4 g. (0.13 mole) of N,N-diethylaniline in 250 ml of phosphorus oxychloride was added 25.8 g (0.13 mole) of 2-(4-hydroxy-6-methyl-2-pyrimidinylthio)acetamide, the mixture was heated under reflux for 1 hour. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured onto 1 liter of cracked ice. The precipitate which resulted was collected, dried, and recrystallized from heptane to give 13.0 g. of pure white product, m.p. 62°-65°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[F:3])=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: Cc1onc(-c2ccccc2F)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded the title compound (4.0 g, 49%) which was obtained as a white solid. MS: m/e=343.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][N:76]([C:32]([C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:9]4[N:10]=[C:11]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[N:8]=4)=[CH:24][CH:23]=3)=[O:37])=[CH:29][CH:30]=2)=[O:33])[CH2:75][CH2:74]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 50.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[ClH:26].CO>>[ClH:26].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc2cccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(OC3CCNCC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 128 (604 mg) and 10% hydrogen chloride/methanol solution (20 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (5 ml) and diethyl ether (15 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (513 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:14][C:11]1[S:10][C:9]([C@@H:7]2[CH2:8][C@H:6]2[CH:4]([NH:3][O:2][CH3:1])[CH3:5])=[CH:13][CH:12]=1
Reactant: CON=C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a stirred solution of trans 1-[2-(5-Chloro-thiophen-2-yl)cyclopropyl]-ethanone O-methyl-oxime (1.2 g; 5.2 mmol) prepared as described in example P25, in acetic acid (15 ml) at ambient temperature was added portionwise sodium cyanoborohydride (1.0 g; 15.7 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured on sodium hydroxide solution (0.5M; 150 ml) and extracted with dichloromethane (3×50 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 50:50) to afford 0.91 g (79% of theory) of trans N-{1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine as a mixture of diastereomeres in form of a clear viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][CH:37]([NH:36][C:24]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1)=[O:26])[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1
Reactant: NC(=O)CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (129 mg, 0.34 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (82 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.112 mL, 0.68 mmol) in DMF (4 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 3-amino-3-(4-chlorophenyl)propanamide (Intermediate 107) (45 mg, 0.23 mmol) was then added to the reaction and stirred for 3 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (99 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][NH:5]1.C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[C:22]([S:26]([N:5]2[CH2:6][C@@H:7]([OH:9])[CH2:8][C@H:4]2[C:3]([O:2][CH3:1])=[O:10])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of cis-4-hydroxy-L-proline methyl ester (10.0 g, 68.8 mmol), triethylamine (13.9 g, 138 mmol), and CH2Cl2 (200 mL) was added 3-cyanobenzene-1-sulfonyl chloride (13.9 g, 68.8 mmol). After 1 h, the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes) to afford the title compound as a colorless crystalline solid: 1H NMR (500 MHz, CDCl3) δ 8.19-8.18 (m, 1H), 8.13-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.69-7.65 (t, 1H), 4.52-4.50 (m, 1H), 4.44-4.43 (m, 1H), 3.67 (s, 3H), 3.52 (dd, 1H), 3.47-3.41 (m, 1H), 3.1 (d, 1H), 2.33-2.27 (m, 1H), 2.20-2.17 (m, 1H); LRMS (ESI) m/z 311 (311 calcd for C13H14N2O5S, M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:26]1[CH:27]=[C:28]([NH:38][C:39](=O)[O:40]CC(Cl)(Cl)Cl)[N:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:30]=1)([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C(OCC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:39]([NH:38][C:28]3[N:29]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[N:30]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=3)=[O:40])=[C:16]([CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Heat a solution of 4-(5-amino-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Preparation 3, 41.20 g, 140.9 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 57.03 g, 140.9 mmol), and DIEA (36.8 mL, 211.4 mmol) in DMSO (500 mL) at 60-65° C. for 2.5 hours. Add additional DMSO (100 mL) during the last 30 min to the thick slurry. Cool the slurry to room temperature and allow to stand overnight. Add diethyl ether (600 mL) and stir the slurry for 1 hour at room temperature. Filter and wash with diethyl ether (5×300 mL) then air-dry to afford a white solid (68.70 g, 89% yield uncorrected for DMSO—contains ca. 85 mol % of DMSO. LCMS(ES+): m/z=548 [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12](O)[CH3:13])[CH:11]=1.C(Cl)[Cl:31]>CN(C)C=O>[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12]([Cl:31])[CH3:13])[CH:11]=1
Reactant: ClCCl
Reactant: COc1c(C(C)O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 5 h
Yield: 80 %

Procedure:
Thionyl chloride (800 μL, 10 mmol) was added dropwise to a solution of 5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]N,N-dimethylpyridine-2-carboxamide (2 g, 6 mmol), methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 5 hrs and was complete by LC/MS. The reaction mixture was partitioned between EtOAc and water. The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give crude 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide as an oil (1.8 g, 80%). LCMS calculated for C18H18Cl2N3O2(M+H)+: m/z=378.1; found: 378.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][N:7]1[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)C1c2[nH]c3ccccc3c2CCN1C(=O)c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
The title compound was prepared by the addition of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester (102 mg, 418 μmol), DCE (5 mL), 4-fluorobenzoyl chloride (60 μL, 477 μmol), diisopropyl ethylamine (167 μL, 954 μmol), DMAP (6 mg, 10 mol %) to a 25 mL flask. The solution was allowed to stir at 55° C. under N2 for 17 hours. The solution was concentrated under reduced pressure, and the crude material was chromatographed (SiO2, 100% hexane to 25% EtOAc) to provide 143 mg (63% yield) of title compound; 1H NMR (CDCl3) δ 8.40 (1H, br s), 7.53-7.57 (3H, m), 7.41 (1H, d), 7.10-7.23 (4H, m), 6.19 (1H, s), 4.31 (2H, m), 4.10 (1H, dd), 3.63 (1H, m), 2.87-2.96 (1H, m), 2.78 (1H, dd), 1.36 (3H, t); 13C NMR (CDCl3) 6171, 169, 138, 130, 129, 126, 126, 123, 120, 116, 116, 112, 110, 62, 53, 45, 22, 14; MS (ESI): 367 (MH+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([F:18])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:18])[CH:9]=1)([OH:3])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1F
Agent: Cl
Product: O=C(NC(Cc1ccc(C(=O)O)c(F)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3-fluoro-4-(carbomethoxy)phenylalanine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 120.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[CH:4][S:5][C:6]=1[CH3:7].Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Br)(C)C>C1COCC1.CC1CCCO1>[CH3:16][O:15][N:14]([CH3:13])[C:8]([C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1)=[O:10]
Reactant: COC(=O)c1csc(C)c1C
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1csc(C)c1C
Temperature: 0 °C
Yield: 80.9 %

Procedure:
To a cooled (−30° C. to −20° C.) slurry of methyl 4,5-dimethylthiophene-3-carboxylate (5.44 g, 32.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.80 g, 49.2 mmol) in THF (45 mL) at was added slowly (over 15 min) a solution of isopropylmagnesium bromide (3.85 mL, 11.16 mmol, 2.9 M) in 2-methyl-tetrahydrofuran. After complete addition of the base, the reaction mixture was warmed to 0° C. and partitioned between 1 N HCl (55 mL) and MTBE (50 mL). The aqueous phase was extracted with MTBE (2×) and the combined organic layer was washed with water (until the pH of the aqueous was ˜5). The organic layer was dried over Na2SO4 and concentrated to give a light yellow oil. The crude product was purified on Biotage system (gradient elution 7% EtOAc:93% Hexanes to 60% EtOAc:40% Hexanes) to give the titled compound as a yellow oil (5.17 g, 25.9 mmol, 81% yield). LC/MS m/z 200 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[NH2:31]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:25]3[O:27][N:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[N:29]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NC(=NO)c1ccccn1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccn3)no2)C1

Procedure:
250 mg (about 0.520 mmol) of the compound from Example 49A and 79 mg (0.580 mmol) of N′-hydroxypyridine-2-carboximidamide (Example 69A) were reacted according to the General Method 1. Yield: 49 mg (19% of theory).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:23][C:24]([Cl:34])([O:26][C:27](=O)[O:28]C(Cl)(Cl)Cl)[Cl:25]>C(Cl)Cl>[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][N:13]([C:27]([O:26][C:24]([Cl:34])([Cl:25])[Cl:23])=[O:28])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
DIPEA (105 g, 0.81 mol) was added to a 0° C. solution of tert-butyl piperazine-1-carboxylate (25.0 g, 0.134 mol) in DCM (250 mL), followed by the addition of triphosgene (92 g, 0.27 mol) in portions over a 40 minute time period. The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs, filtered and concentrated to afford 1-tert-butyl 4-trichloromethyl piperazine-1,4-dicarboxylate (50 g) as an oil.