Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]>ClCCl>[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][CH:51]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]
Reactant: C1COCCN1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCOCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Morpholine (228 mg, 1.64 mmol), sodium triacetoxyborohydride (372 mg, 1.76 mmol), and acetic acid (0.134 ml, 2.34 mmol) were added to a dichloromethane (3.5 ml) solution of N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide (476 mg) synthesized in Example 40, and stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The resultant was washed with a solvent mixture of ether-hexane=1:1; and the solid was filtered off to yield the title compound (110 mg) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.N.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Nc1ccc(N2CCNCC2=O)cc1

Procedure:
To a solution of 670 mg 1-(4-Nitro-phenyl)-1H-pyrazin-2-one in 100 mL MeOH, 8 g Raney Nickel (washed three times with MeOH) were introduced under a nitrogen atmosphere. Then 10 mL of a 7 M solution of NH3 in MeOH were added. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the mixture was hydrogenated under normal pressure at RT. After 2 h the reaction mixture was filtered through a pad of celite. The solvents were removed under reduced pressure and the residue was subjected to the next reaction step without further purification.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:27][NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:27][N:28]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:4]=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1.[CH3:22][S:23]([O-:26])(=[O:25])=[O:24]
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Reactant: CNC1CCCCC1
Reactant: CS(=O)(=O)O
Agent: F[B-](F)(F)F
Product: CN(c1ccccc1C=CC1=NCCC1)C1CCCCC1
Product: CS(=O)(=O)[O-]

Procedure:
Crude 2-[2-(N-methylcyclohexylamino)-phenylethenyl]-1-pyrroline is produced by heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 20 ml of N-methyl-cyclohexylamine for 2 hours at 100°, and processing the reaction mixture analogously to Example 1. By addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanol, evaporation of this solution in the rotary evaporator and recrystallisation of the residue from ethyl acetate, there is obtained 2-[2-(N-methyl-cyclohexylamino)-phenylethenyl]-1-pyrroline-(1:1)-methanesulphonate, m.p. 163°-164°.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].Cl[C:16]1[N:21]=[C:20]([N:22]2[CH:27]=[C:26]([CH:28]3[C:34]4[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=4[CH:32]=[CH:31][C:30]4[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:29]3=4)[C:25](=[O:45])[NH:24][C:23]2=[O:46])[CH:19]=[CH:18][N:17]=1>>[CH3:39][C:37]1[CH:36]=[CH:35][C:34]2[CH:28]([C:26]3[C:25](=[O:45])[NH:24][C:23](=[O:46])[N:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([NH:7][C@H:6]([C:5]([O:4][CH3:3])=[O:14])[CH2:8][C:9]5[N:13]=[CH:12][NH:11][CH:10]=5)[N:21]=4)[CH:27]=3)[C:29]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:30]=3[CH:31]=[CH:32][C:33]=2[CH:38]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)Nc1nccc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from L-histidine methyl ester dihydrochloride (1.15 g) and the product of example 8 step (ii) (0.7 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5-10% methanol in dichloromethane. Yield 0.25 g.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[CH:48][C:47]([Cl:52])=[CH:46][N:45]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[N:45][CH:46]=[C:47]([Cl:52])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: ClCc1cc(Cl)cnc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)cnc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,5-dichloro-3-(chloromethyl)pyridine and isolated as light-yellow gum. MS(m/e): 442.3 (MH+).
Reaction SMILES: N.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].N[C@H](C(O)=O)CC(O)=O>>[C:8]([O-:10])(=[O:9])/[CH:3]=[CH:4]/[C:5]([O-:7])=[O:6].[NH4+:2]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N
Product: O=C([O-])/C=C/C(=O)[O-]
Product: [NH4+]

Procedure:
Aspartase (L-aspartate ammonia-lyase, E.C. 4.3.1.1) catalyzes the reversible deamination of L-aspartic acid to yield fumarate and ammonium ions (or salts). This dearnination reaction is represented by the Formula I: ##STR1##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24](=[O:35])[N:25]([C:28]1[S:32][C:31](Br)=[N:30][C:29]=1[Cl:34])[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:23][C:24](=[O:35])[N:25]([C:28]1[S:32][C:31]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:30][C:29]=1[Cl:34])[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(C(=O)OC(C)(C)C)c1sc(Br)nc1Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 100 °C
Yield: 79.6 %

Procedure:
To a suspension of 3-pyridine boronic acid (1.5 g, 12.2 mmol) in toluene (50 mL) was added absolute ethanol (25 mL) followed by a 2.0 M solution of K2CO3 (12.5 mL). To this mixture was added (2-bromo-4-chloro-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (4.2 g, 12.2 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (708 mg, 0.61 mmol). The reaction mixture was heated to 100° C. for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The organic layer was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a red oil (3.3 g, 79%): 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 8.19 (dd, J=5.9, 4.2 Hz, 1H), 7.39 (dd, J=7.6, 5.2 Hz, 1H), 3.68 (q, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.22 (t, J=7.0 Hz, 3H); ESIMS m/z 340 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methylpyrazole (1.98 g, 24.11 mmol) in DMF (8 mL) was added to sodium hydride (60% in oil, 0.97 g, 24.25 mmol) in DMF (6 mL) and the resulting mixture was stirred 2 h at RT. 4-Fluorobenzaldehyde (1.26 g, 7.45 mmol) was added dropwise and the resulting mixture heated to 80° C. for 3 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) followed by recrystallization from hexane yielded the title compound. MS 187 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CCOCC>[OH:15][CH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#CC(O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of potassium cyanide in ether (100 mL) at 0° C. was added dropwise a mixture of 1-naphthalenecarbaldehyde (1.56 g, 10 mmol) and acetic acid (1.41 g, 23.5 mmol) in ether (10 mL). The resulting mixture was warmed to 25° C. for 20 h, where the precipitate was filtered and the filtrate was concentrated affording the title compound as a clear oil (1.67 g, 9.14 mmol, 91%): LCMS (ES) m/z 184 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([C@H:66]([NH2:68])[CH3:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@@H:66]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. (1R)-1-Phenylethanamine (58 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (188 mg) as a light yellow solid. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1.CCN(C(C)C)C(C)C>C(O)(C)C>[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27]1
Reactant: NC1CCCOC1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4NC4CCCOC4)cc3)nc2c1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a microwave vial was charged with N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.25 g, 0.71 mmol), tetrahydro-2H-pyran-3-amine hydrochloride (0.19 g, 1.4 mmol), and DIPEA (0.49 mL, 2.8 mmol) in isopropyl alcohol (2 mL). The reaction was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 200° C. for 30 min (200 watts, Powermax™ feature on), then at the same temperature for another 15 min. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×) and the combined organics was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 420.0 (M+1). IC50 (uM) ++++.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[CH:10]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:19][C:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cncn1-c1ccc(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Temperature: 75 °C
Yield: 27.8 %

Procedure:
To 5.0 g (21 mmol) of ethyl 1-(2,4-dimethylphenyl)-1H-imidazole-5-carboxylate in 40 mL of DMF was added 7.3 g (41 mmol) of N-bromosuccinimide and the resulting solution was heated to 75° C. for 75 min. The reaction was cooled to room temperature, diluted with 400 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 17-20% ethyl acetate/hexanes gradient mixture to give 1.89 g (29%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)NCc1cc(C(=O)OC(C)(C)C)ccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)NCc1cc(C(=O)O)ccc1N
Reaction time: 12 h

Procedure:
To a solution of t-butyl 4-amino-3-[(N-methylacetylamino)methyl]benzoate (2.13 g, 7.65 mmole) in CH2Cl2 (150 mL) at RT was added TFA (30 mL). After 12 hr, the reaction solution was concentrated to an oil and dried under high vacuum overnight. The resulting residue was washed with hexanes and Et2O to afford the title compound (2.56 g, 7.60 mmole) as an off-white solid. This compound was used without further purification: MS (ES) m/e 223 (M+H-TFA)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]3[CH2:19][CH2:18]3)[N:13]=[C:12](Cl)[C:11]=2[NH:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CO>C(N)C=C.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:8][C:12]1[C:11]2[NH:10][C:9](=[O:21])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[CH:15]=[C:14]([CH:17]2[CH2:19][CH2:18]2)[N:13]=1)[CH:2]=[CH2:3]
Reactant: O=c1[nH]c2c(Cl)nc(C3CC3)cc2n1Cc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C=CCN
Solvent: ClCCl
Solvent: CO
Product: C=CCNc1nc(C2CC2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 85 °C
Yield: 151.9 %

Procedure:
1-Benzyl-4-chloro-6-cyclopropyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (100 mg, 0.3 mmol) was dissolved in allylamine (2 mL) in a Reactivial™. Copper (II) sulphate (83 mg, 0.3 mmol) was added and the vial was sealed. The mixture was heated at 85° C. overnight. Further portions of copper (II) sulphate (83 mg, 0.3 mmol) and allylamine (1 mL) were added and the vial was sealed once again. The mixture was heated at 85° C. over the weekend. The mixture was allowed to cool to room temperature. The excess allylamine was removed in vacuo and the residue was dissolved in EtOAc (50 mL) and treated with saturated aqueous NaHCO3 (20 mL). The layers were separated and the organics washed with more saturated aqueous NaHCO3 (10 mL), then brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the crude product (120 mg). Column chromatography through silica gel eluting with 98:2 DCM:MeOH gave the title compound (73 mg) as an off white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C@@H:25]1([NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH2:31].[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[N:40]([CH3:44])[N:39]=[C:38]2[C:45]1[N:46]=[C:47]2[C:53]([C:54](O)=[O:55])=[CH:52][N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:48]2=[N:49][CH:50]=1>CN(C=O)C>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:32][C:54]([C:53]1[C:47]2[C:48](=[N:49][CH:50]=[C:45]([C:38]3[C:37]4[C:41](=[CH:42][CH:43]=[C:35]([O:34][CH3:33])[CH:36]=4)[N:40]([CH3:44])[N:39]=3)[N:46]=2)[N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:62])([CH3:64])[CH3:63])[CH:52]=1)=[O:55]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Reactant: N[C@@H]1CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCCC[C@@H]1N)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and (1R,2S)-cyclohexane-1,2-diamine (20.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give the desired N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 38.2 μmol, 21.7%). MS (M+H)+=550 (>90% purity); 1H NMR (CDCl3) δ: 9.02 (s, 1H), 8.51 (s, 1H), 7.51 (s, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.22 (dd, J=9.3, 2.1 Hz, 1H), 5.61-5.84 (m, 2H), 4.78 (br. s., 1H), 4.18 (s, 3H), 4.02 (t, J=3.2 Hz, 1H), 3.91 (s, 3H), 3.76 (br. s., 1H), 3.62-3.71 (m, 2H), 2.09 (br. s., 2H), 2.03 (s, 2H), 1.80-1.98 (m, 4H), 1.52-1.78 (m, 4H), 0.98 (dd, J=9.3, 7.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][CH:11]([OH:12])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][O:18][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:13][CH:11]([OH:12])[C@@H:10]1[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](OCc2ccccc2)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1O
Temperature: 80 °C

Procedure:
A mixture of 3 (6 g)-and freshly purified chlorotriphenylmethane (5 g) in dry pyridine (50 mL) was heated for 2 hrs at 80° C. and then cooled to 0° C. 3-O-benzyl-6-O-triphenylmethyl-D-glucopyranose (16) could be isolated at this stage, or used further for acetylation. Acetic anhydride (15 mL)-was added, and the reaction mixture was heated at 80° C. until compound 16 had disappeared (TLC, ether:hexane, 1:2). The mixture was concentrated and a solution of the residue in chloroform (100 mL) was washed with aqueous potassium hydrogen sulfate and water, and concentrated. The crude 3-O-benzyl-6-O-triphenylmethyl-1,2,4-tri-O-acetyl-D-glucopyranose (17) was used in the next reaction. Small scale chromatography gave a material with 1H NMR data: 60:40 mixture of alpha:beta anomers 7.19-7.44 (m, 20 H, arom), 6.42 (d, 1 H, alpha-H)-, 5.67 (d, 1 H, beta-H), 3.07-5.23 (8 H), 2.17 (s, 3 H, Ac-alpha), 2.16 (s, 3H, Ac-beta) 2.01 (s, 3 H Ac-α, 1.99 (s, 3 H, Ac-beta), 1.69 (s, 3 H, Ac-β), 1.66 (s, 3 H, Ac-alpha).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[C:6]1([CH2:16][NH2:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[O:28][CH2:27][CH2:26][NH:25]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:23][CH:24]1[C:30]2[CH:31]=[C:32]([O:37][CH3:38])[C:33]([O:35][CH3:36])=[CH:34][C:29]=2[O:28][CH2:27][CH2:26][N:25]1[CH2:2][C:3]([NH:17][CH2:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Reactant: NCc1cccc2ccccc12
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3OCCN2CC(=O)NCc2cccc3ccccc23)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and 5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O.[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Br-:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N+:8]2([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(N2CCCCC2)cc1
Reactant: Cc1ccc(CBr)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C[N+]2(c3ccc(C)cc3)CCCCC2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A reaction container was charged with 1-(4-methylphenyl)piperidine (4.0 g, 22.8 mmol) and 10 ml of acetone and the mixture was stirred at ambient temperature. Then, α-bromo-p-xylene (5 g, 27.4 mmol) was added to the reaction solution. The reaction solution was stirred for 3 hours and 20 ml of ethyl acetate was added to the solution. The reaction mixture was further stirred for 30 minutes and subjected to suction filtration to collect a white powder. The resulting powder was dried to obtain 4-methylbenzyl(4-methylphenyl)piperidiniumbromide (6.8 g, yield: 83%).