Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[ClH:20].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH3:28])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 171.7 %

Procedure:
7-{2-(2-Formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.4 g.) was suspended in methanol (15 ml.). After adding conc-hydrochloric acid (0.16 g.) to the suspension, the mixture was stirred at room temperature for 2.5 hours. Methanol was distilled off from the resultant mixture under reduced pressure, and the residue was dissolved in water (15 ml.). The solution was washed with ethyl acetate (30 ml.) and dichloromethane (30 ml.) in turn. To the acqueous layer was introduced nitrogen gas to remove the remaining organic solvent completely, and the solution was lyophilized to give 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn isomer 0.35 g.), m.p. 170° to 180° C. (dec.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:44]2[CH:45]=[C:40]([CH:39]=[O:47])[CH:41]=[N:42][C:43]=2[CH3:46])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Product: Cc1ncc(C=O)cc1-c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-6,N-dimethyl-nicotinamide.
Reaction SMILES: [C:1]1([CH:7]([NH:16][C:17](=[O:31])[CH:18]([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)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[C:1]1([CH:7]([NH:16][C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CS(=O)(=O)Nc1ccc(CC(NC(=O)C(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
Treat the product of Example 3 with methanesulfonylchloride to obtain N-[1-phenyl-2-(4-methanesulfonylaminophenyl)ethyl]-α-phenyl-benzeneacetamide, m.p. 200°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[NH:20][C:21](=[O:24])[CH2:22]Cl)=O)[CH:7]=1.[N:27]1C=CC=CC=1>C1C=CC=CC=1>[NH2:27][C:22]1[C:21](=[O:24])[NH:20][C:11]2[C:10]([C:8]=1[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:25][CH3:26])=[CH:15][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:13][CH:12]=2
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)CCl
Reactant: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1-c1c(N)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Yield: 98 %

Procedure:
A mechanically stirred solution of N-[2-[(5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]chloroacetamide (12.2 g, 0.03 mol) in anhydrous pyridine (150 mL) was heated to reflux for 20-25 min. The resultant suspension of the pyridinium salt was allowed to cool and then diluted with benzene (100 mL). The pyridinium salt was filtered, washed with benzene and then dried in vacuo to afford the desired titled compound (13.75 g, 98%): mp 325-330° C. (dec.); IR (KBr, cm-1) 1678,1322,1270,1118; 1H NMR (300 MHz, DMSO-d6)δ 3.59 (3H, s), 7.09 (1H, d, J=9.0 Hz), 7.38 (1H, s), 7.44 (1H, d, J=2.6 Hz), 7.52 (1H, dd, J=8.9 and 2.6 Hz), 7.83 (1H, d, J=8.7 Hz), 8.11 (1H, dd, J=8.7 and 1.8 Hz), 8.19-8.27 (2H, m), 8.70-8.75 (1H, m), 9.05-9.07 (2H, m), 13.54 (1H, brd s); MS m/e 431 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:11][CH:12]([CH:15]=O)[CH:13]=O>C(O)(=O)C>[Br:11][C:12]1[CH:13]=[N:10][C:8]2[N:7]([N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=2)[CH:15]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)c1n[nH]c(N)n1
Solvent: CC(=O)O
Product: CC(C)(C)c1nc2ncc(Br)cn2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
3-tert-Butyl-1H-1,2,4-triazol-5-amine (CAS 202403-45-0) (35%, 13 g, 32.5 mmol) was dissolved in acetic acid (50 ml) and 2-bromomalonaldehyde (7.35 g, 48.7 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 3 hours at 60° C. The reaction mixture was evaporated and neutralized with saturated NaHCO3 solution 2N and extracted two times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography on 70 g silica gel (heptane:EtOAc 100:0→50:50). The desired 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (6.83 g, 83% yield) was obtained as a white solid, MS: m/e=255.0/257.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180° C. under nitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhat and 200 ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature, 40.1 g of solid was filtered off and recrystallized twice from methanolisopropyl ether giving 4.3 g, presumably the hydrochloride salt; m.p. 187°-90° C. This solid was dissolved in a mixture of water-methanol, basified with 3N sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product; m.p. 91°-3° C. Drying prior to analysis was overnight at room temperature/0.02 mm Hg.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:34])[CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C>C(Cl)Cl>[C:31]([C@H:26]([N:15]([CH2:14][C:13]([OH:34])=[O:12])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:33])[NH2:32]
Reactant: CC(C)C[C@H](C(N)=O)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of {N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid tert-butyl ester (0.50 g, 1.2 mmol) in CH2Cl2 (15 mL). The reaction was stirred at rt for 4 h. The reaction was then concentrated to a white solid (0.40 g, 92%), which was used without further purification. MS(ESI), (M+H)+363.1; 1H NMR (DMSO-d6, 500 MHz) δ7.90 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8), 7.60 (s, 1H), 7.06 (s, 1H), 4.32 (d, 1H, J=18), 4.12 (t, 1H, J=8.0), 4.02 (d, 1H, J =18), 1.55-1.65 (m, 1H), 1.35-1.45 (m, 2H), 0.78 (d, 3H, J=6.1), 0.73 (d, 3H, J =6.1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=1)(=O)=O.[Si:23]([O:40][CH2:41][C:42]#[CH:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NCC)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:23]([O:40][CH2:41][C:42]#[C:43][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=1)([C:36]([CH3:37])([CH3:38])[CH3:39])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S(=O)(Oc1ccc2ncc3c(c2c1)CCCC3)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC#Cc1ccc2ncc3c(c2c1)CCCC3)(c1ccccc1)c1ccccc1
Reaction time: 11 h
Yield: 96.9 %

Procedure:
To a mixture of Compound 277 (1.28 g, 3.86 mmol), 3-[(tert-butyldiphenylsilyl)oxy]propyne (Compound 278, 1.48 g, 5.02 mmol), and diethylamine (800 mL, 7.73 mmol) in dry degassed N,N-dimethylformamide (7.7 mL) was added copper (I) iodide (74 mg, 0.39 mmol) followed by bis(triphenylphosphine)palladium(II) chloride (135 mg, 0.19 mmol). After being stirred in the dark for 11 hours under argon, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (20 mL×2) and brine (20 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and the residue was purified by flash column chromatography (silica, 10 percent ethyl ether in dichloromethane) to give 1.78 g (97 percent) of Compound 279: Rf =0.39 (10 percent ethyl acetate in dichloromethane); IR (film) νmax 3048, 2932, 2857, 2227, 1589, 1568, 1502, 1428, 1370, 1112 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1 H, H6), 7.95 (d, J=8.6 Hz, 1 H, H4), 7.92 (d, J=1.5 Hz, 1 H, H1), 7.84-7.78 (m, 4 H, aromatic), 7.53 (dd, J=8.6, 1.5 Hz, 1 H, H3), 7.48-7.39 (m, 6 H, aromatic), 4.62 (s, 2 H, C≡CCH2O), 3.04 (t, J=5.8 Hz, 2 H, H10), 2.87 (t, J=5.8 Hz, 2 H, H7), 2.01-1.93 (m, 2 H, CH2), 1.93-1.85 (m, 2 H, CH2), 1.12 (s, 9 H, t-Bu); 13C NMR (125 MHz, CDCl3) δ 152.8, 145.6, 141.0, 135.6, 133.1, 130.6, 130.2, 129.7, 129.6, 127.6, 127.5, 127.2, 120.7, 88.4, 85.3, 53.2, 27.0, 26.7, 24.8, 22.2, 22.1, 19.2; MS (FAB+) m/e (rel intensity) 476 (M+H, 100), 418 (9), 388 (12), 220 (11), 197 (9); HRMS for C32H34NOSi (M+H), calcd 476.2410, found 476.2410.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
1.19 g (5 mmol) of 2-bromo-5-chloro-nitrobenzene were dissolved in 50 ml THF. At a temperature of −45° C. 15 ml of a 1M vinyl magnesium bromide solution in THF were added under nitrogen in such a way that the temperature did not exceed −40° C. After complete addition the dark solution was stirred for 30 min at −40° C. The reaction mixture was quenched with 10 ml aqueous saturated ammonium chloride solution and extracted twice with diethyl ether. The combined organic layers were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (100 g silica gel; heptane/EtOAc 19:1) to yield 562 mg (49%) of 7-bromo-4-chloro-1H-indole as an orange oil. MS (EI) 229.0 (80), 231.0 (100), 233.0 (30) (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C(O)C.[NH2:14][OH:15]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: Cc1ccc(C#N)cc1F
Reactant: NO
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a suitable vessel equipped with mechanical stirrer under N2 atmosphere was charged 202.0 g of 3-fluoro-4-methylbenzonitrile followed by 1.0 L of ethanol. Hydroxylamine (144 mL of 50% solution in water) was added via addition funnel over 20 minutes. The mixture was stirred at ambient temperature until HPLC analysis showed that reaction was complete (no starting material remained). Water (3.0 L) was added dropwise to the pale yellow solution over 1 hour to give a thick slurry. The slurry was cooled in an ice water bath to 2° C. for 1.5 hours, filtered and dried under vacuum at 35° C. for 22 hours to give the title compound (230.3 g, 91.6%) as a white solid. 1H-NMR (CDCl3, 500 MHz) 67.30 (m, 2H), 7.19 (m, 1H), 4.87 (s, 2H), 2.28 (s, 3H); 13C-NMR (CDCl3, 500 MHz) δ162.15, 160.19, 151.58, 131.82, 131.76, 131.66, 131.62, 127.01, 126.87, 121.06, 112.69, 112.51, 14.48; 19F-NMR (CDCl3, 500 MHz) δ−116.35, −116.37, −116.39. LC-MS M+H169.19.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][N:20]=1)[CH3:17]>C(#N)C.[Cu]I>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)[CH:22]=[CH:21][N:20]=1)[CH3:17]
Reactant: CCOc1cc(I)ccn1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: [Cu]I
Solvent: CC#N
Product: CCOc1cc(C#Cc2ccc(CC(C)NC(C)=O)cc2)ccn1
Temperature: 25 °C

Procedure:
To 100 mg (0.50 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.2) and 124 mg (0.50 mmol) 2-ethoxy-4-iodo-pyridine (I6.1) in 5.00 mL ACN are added 20.3 mg (0.03 mmol) 1,1′-bis[diphenylphosphino]ferrocenepalladium dichloride dichloromethane complex (1:1), 4.83 mg (0.03 mmol) CuI and 0.16 mL (1.16 mmol) TEA. The mixture is stirred at r.t. over night, then poured onto water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by column chromatographie (silica gel; PE/EtOAc 1/1→EtOAc 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH:17][C:25]([C:24]2[CH:28]=[C:29]([CH3:31])[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=2)=[O:26])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: COC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C)n1

Procedure:
The title compound is prepared from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (Amine-5, single enantiomer) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:10]([CH3:20])(OCC)([O:14]CC)[O:11]CC>CC(O)=O>[C:10]([OH:14])(=[O:11])[CH3:20].[Br:1][C:2]1[C:3]2[NH:9][C:10]([CH3:20])=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cncc(Br)c1N
Solvent: CC(=O)O
Product: Cc1nc2cncc(Br)c2[nH]1
Yield: 52 %

Procedure:
A mixture of 5-bromopyridine-3,4-diamine (20 g, 107 mmol) and (EtO)3CMe (100 mL) in HOAc (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-1H-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS (ESI) m/z: 212 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.CC1(C)[O:44][C@@H:43]([CH2:45][N:46]2[CH:50]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:48]=[N:47]2)[CH2:42][O:41]1>>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][N:46]1[CH:50]=[C:49]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][CH:21]=4)[N:10]=3)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=2)[CH:48]=[N:47]1
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C[C@H](O)CO)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 101A). After Suzuki reaction and SPE pre-purification, the dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was ourified by MDP. MS (ES+): m/z 678.38 (100) [MH+]; HPLC: tR=0.87 min (UPLC, purity).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:29][CH3:30]>CN1C(=O)CCC1>[CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([O:21][CH2:29][CH3:30])=[O:20])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.5 %

Procedure:
A suspension of 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (Example 1 (b), 13.1 g, 43.9 mmol), sodium carbonate (5.2 g, 48.3 mmol) and iodoethane (10.6 g, 67.7 mmol) in NMP (60 ml) was stirred at ambient temperature for 19 h under a nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was collected, washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with tert-butyl methyl ether/methanol (10:0.4) to give the title compound as a light brown solid (12.5 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>ClCCCl>[CH3:38][C:33]1[C:32]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH:14]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])[CH2:10][CH2:9]3)=[C:4]([F:28])[CH:3]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1N=C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (1.0 mmol) in DCE (10 mL) was stirred at rt for 16 h. The solid that had formed was collected by filtration and dried under vacuum to give the title compound (100 mg, 64%). MS (ESI): mass calcd. for C28H35FN6O3, 522.28. m/z found, 523.4 [M+H]+. 1H NMR (CDCl3): 8.60-8.40 (br s, 1H), 7.60-7.25 (m, 6H), 6.78-6.71 (m, 1H), 6.68-6.57 (m, 1H), 4.21 (s, 1H), 3.60-3.40 (m, 2H), 3.39-3.15 (m, 2H), 2.95-2.45 (m, 8H), 2.24 (s, 3H), 2.13 (s, 3H), 1.11 (t, J=7.1, 3H), 1.05 (t, J=7.1, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Product: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 106 using tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (1.50 g, 4.10 mmol) and ethyl bromoacetate (460 μl, 4.10 mmol) as starting materials.
Reaction SMILES: [C:1]([C:9]1[C:13]([S:14]C(=O)C2C=CC=CC=2)=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:36]([C:40]1([CH2:43][CH3:44])[CH2:42][NH:41]1)[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CO>[C:1]([C:9]1[C:13]([S:14][CH2:42][C:40]([NH2:41])([CH2:43][CH3:44])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC1(CC)CN1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(SC(=O)c2ccccc2)c(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(N)(CC)CSc1c[nH]cc1C(=O)c1ccccc1
Yield: 86.3 %

Procedure:
A mixture of the product from step (c) (24.9 g), 250 ml methanol and 106 ml 1N sodium hydroxide was warmed to reflux for 10 minutes then 1N hydrochloric acid (53 ml) was added followed by 2-butyl-2-ethylaziridine (7.7 g, Synthetic Example 1(f)). After one hour the reaction was diluted with ethyl acetate and washed with 1N sodium hydroxide and then water. The organic layer was dried, filtered and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate-ethanol (3:1) to give a tan viscous oil (15.32 g). 1H NMR is consistent with proposed structure.