Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9]
Reactant: CC(C)OC(=O)Cl
Reactant: COCc1cc(N)cc(Cl)c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
3-Chloro-4-hydroxy-5-methoxymethylaniline (52.8 g) and N,N-diethylaniline (42.0 g) were dissolved in ethyl acetate (300 ml). To the resultant solution was dropwise added isopropyl chloroformate (34.6 g) in 15 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water. The organic layer was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g). Sodium hydride (9.60 g, 60% dispersion in mineral oil) was added to dimethylformamide (240 ml). To the resultant mixture was added isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and chloroacetonitrile (19.0 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-cyanomethoxy-5-methoxymethylphenyl)carbamate (Compound No. 5) (67.5 g) in a yield of 76.8%. M.P., 58.5°-60.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.O.[C:11]([O-:14])(O)=O.[Na+].[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:11](=[O:14])[CH2:18][CH2:17][CH2:16][CH2:20][CH2:20][CH2:16][CH2:17][CH2:18][CH2:20][CH2:16][CH2:17]/[CH:18]=[CH:20]\[CH2:16][CH2:17][CH2:18][CH2:6][CH2:7][CH2:8][CH2:4][CH3:3]
Reactant: O=C([O-])O
Reactant: C1CCOC1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC

Procedure:
In methylene chloride (10 ml) was dissolved erucic acid (2 g). To the solution was added dropwise oxalyl chloride (1.1 ml), and the mixture was refluxed for one hour under heating, followed by concentration to give acid chloride. The acid chloride was stirred, together with L-proline methyl ester (980 mg), in THF (15 ml)-water (1 ml) in the presence of NaHCO3 (800 mg) at room temperature for 15 hours. The solvent was concentrated. To the residue was then added water, and the mixture was subjected to extraction with methylene chloride. The extract was dried and concentrated, followed by purification by means of a silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain a colorless oily product [1.09 g (yield 41%)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCCO4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([O:32][C:33]([N:35]1C2C(CNCC2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH:15]2[CH:14]([CH2:13][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:21][CH2:20]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Product: CC(C)(C)OC(=O)N1CCC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCC21

Procedure:
Prepared according to the method used in the preparation of 8-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane using octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester in place of 1,4-dioxa-8-aza-spiro[4.5]decane. The title compound was obtained as white solid (153 mg, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])=[CH:14][CH:15]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4cccnc4)c3cc2OC)cc1
Yield: 42 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol) with 3-aminopyridine (21 mg, 0.22 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 42% yield (39 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].ClCCCl.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a stirred solution of 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (500 mg, 0.002 mol) in 1,2-dichloroethane (20 mL, 0.2 mol) was added morpholine (0.23 mL, 0.0027 mol) and acetic acid (0.15 mL, 0.0027 mol). Sodium triacetoxyborohydride (670 mg, 0.0032 mol) was then added to the reaction mixture and the contents stirred at room temperature overnight. The reaction mixture was cooled to 0° C., diluted with methylene chloride (20 mL), quenched with aqueous ammonium chloride (5 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a brown residue. The reaction mixture was purified by ISCO chromatography on silica gel (40 g column) using 10-30% ethyl acetate-hexane gradient. The major fractions corresponding to product as confirmed by LCMS were combined and concentrated in vacuo to give a light brown solid, 4-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine (450 mg, 70%). 1HNMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.98 (d, 1H, J=8 Hz), 7.44 (d, 1H, J=8 Hz), 3.62 (m, 4H), 3.37 (m, 1H), 3.04 (m, 4H), 2.77 (m, 4H), 2.05 (m, 2H), 1.4 (m, 2H); MS (m/e) 276 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]1([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=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>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:23][N:22]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(I)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-iodophenyl)acetic acid 53-1 (816 mg, 3.14 mmol), 5-phenylpyridin-2-amine 53-2 (534 mg, 3.14 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (1 mL) was added DIEA (1.57 mL, 9.42 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-Iodophenyl)-N-(5-phenylpyridin-2-yl)acetamide 53-3 as pale yellow solid. MS m/z 415.2 (M+1)
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[CH:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[CH:25]=[C:13]2[C:14]([C@@H:18]3[CH2:4][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.64 g, 41.0 mmol) in dimethyl sulfoxide (30 mi.') was added trimethylsulfoxonium iodide (9.01 g, 41.0 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylpyrazolo[1,5-a]pyridin-4-yl)acrylate (7.86 g, 34.1 mmol) in dimethyl sulfoxide (120 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (5.10 g, yield 61%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:25][C@@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)[N:19]=[N:20][C:21]=3[C:22]([NH2:24])=[O:23])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[C:32]#[C:33][CH3:34].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:18]2[N:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[N:17]=2)[CH2:27]1)(=[O:35])[C:32]#[C:33][CH3:34]
Reactant: NC(=O)c1nnc(N[C@@H]2CCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC#CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CC(=O)N1CC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide (83) (90 mg, 0.22 mmol) in NMP (4 mL) were 2-butynoic acid (55 mg, 0.66 mmol), DIEA (380 μL, 2.2 mmol) and then PyBOP (230 mg, 0.44 mmol). The mixture was stirred at RT for 30 min, quenched with TFA (0.6 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC using 0.1% formic acid in water and neat MeCN to isolate the title compound, (R)-3-(1-but-2-ynoylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (505) as formic acid salt. LC-MS (ESI): m/z (M+1) 479.1. UV: λ=280 nm. Proton NMR (CD3OD): δ 7.87 (2H, m), 7.47 (2H, m), 4.56 (1H, m), 4.07 (1H, m), 3.88-3.77 (2H, m), 3.75-3.44 (9H, m), 2.37 (1H, m), 2.15 (1H, m), 2.05 (3H, s) ppm.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[O:51]1[CH2:55]CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:55][O:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C1CNOC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCCO2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and isoxazolidine hydrochloride and isolated as white solid (13.1 mg, 74%). MS (m/e): 373.4 (MH+).
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4].Cl.[CH3:19][O:20][CH2:21][C:22](=[NH:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][O:20][CH2:21][C:22]1[NH:23][C:3]([C:5]2[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:17])[N:24]=1.[CH3:19][O:20][CH2:21][C:22]1[O:4][C:3]([C:5]2[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:17])[N:23]=1
Reactant: COCC(=N)N
Reactant: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Product: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52 %
Yield: 19 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 600 mg, 2.01 mmol), 2-methoxyethanimidamide hydrochloride (510 mg, 4.09 mmol), potassium carbonate (840 mg, 6.08 mmol) and acetonitrile (30 mL). The resulting mixture was stirred at 80° C. overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL). The organics was washed brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as the eluent to yield methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 2.1) (0.11 g, 19%) and methyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4-dimethylbenzoate (compound 2.2) (0.30 g, 52%), both as a yellow oils.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]([NH:15]CC2C=CC=CC=2)[C:12]([N+:23]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>[Pd].C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]([NH2:15])[C:12]([NH2:23])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COCCOc1cc(NCc2ccccc2)c([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc(N)c(N)cc1C(=O)O

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (685a) using palladium on charcoal in THF and methanol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([CH:17]=[CH:18][N:19]=2)[C:13]([CH3:16])=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:17]1[N:12]2[C:13]([CH3:16])=[CH:14][N:15]=[C:10]([Cl:9])[C:11]2=[N:19][CH:18]=1
Reactant: Cc1cnc(Cl)c2nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cnc(Cl)c2ncc(Br)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N-bromosuccinimide (348 mg, 1.96 mmol) is added to a solution of 8-chloro-5-methyl-imidazo[1,2-a]pyrazine (327 mg, 1.98 mmol) in DCM (6 mL) and the reaction stirred at room temperature for 2 h. Once the reaction is finished the reaction mixture is diluted with DCM and washed twice with 4 mL of Na2CO3 sat., dried (MgSO4), filtered and concentrated in vacuo to give a crude mixture that is purified by column chromatography using a gradient of (Pet.Ether40-60/AcOEt: 9/1 to 7/3) to give 3-Bromo-8-chloro-5-methyl-imidazo[1,2-a]pyrazine as a brown solid (335 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[H][H].C1(C)C=CC(S(O[CH2:33][CH2:34][CH2:35][CH:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)(=O)=O)=CC=1>CN(C=O)C.CCOCC.C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][CH2:34][CH2:35][CH:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2COC(C)(C)O2)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)OCC(CCCn2cnc3c(OCc4ccccc4)nc(N)nc32)O1
Temperature: 60 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
A solution of 2.41 g (10 mmole) of 2-amino-6-benzyloxypurine [M. J. Robins and R. K. Robins, J. Org. Chem., 24, 2160 (1969)] in 24 ml of dry DMF was treated with 0.44 g (11 mmole) of sodium hydride (60% dispersion in oil). The mixture was stirred under nitrogen as hydrogen was evolved. After gas evolution had ceased and a clear solution had formed, a solution of 3.46 g (11 mmole) of (±)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl p-toluene-sulfonate (prepared as above) in 2 ml of DMF was added. The mixture was stirred at 60° C. for 3 days. The cooled mixture was then neutralized with glacial acetic acid and concentrated in vacuo. The residue was taken up in ethyl acetate, filtered, re-concentrated and chromatographed on silica gel (elution with ethyl acetate). Evaporation of fractions containing clean product gave a residue which, on trituration with ether, yielded 975 mg (25%) of white crystals, mp 111°-112° C. The analytical batch, similarly prepared, had m.p. 115.5°-118°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH:6]=[N:5]2
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1cnc2cc(Br)ccc2n1
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1ccccc1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 6-Bromo-2-chloro-quinoxaline (0.45 g, 1 eq, 1.85 mmol) in DMSO (6 mL), was added (R)-1-phenylethanamine (0.67 g, 3 eq, 5.55 mmol) at room temperature. The mixture was stirred overnight. After completion of the reaction (confirmed by TLC), cold water (40 mL) was added to the reaction mixture and this was stirred for 1 hour at room temperature. The precipitate was filtered off, washed with water (10 mL) and then dried under vacuum to afford the title compound (0.48 g, 79%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16]O)=[O:15]>COCCOC.CCCCCCC>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15].[N+:1]1([O-:15])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Solvent: CCCCCCC
Product: O=C(O)c1cccc(Cl)c1
Product: [O-][n+]1ccc2ccc[nH]c1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 162.3 %

Procedure:
To a solution of 7-azaindole (Int-5, 23.6 g, 200 mmol) in DME/heptane (1:2, 300 mL) was added 3-chloroperoxybenzoic acid (85 wt %, 44.7 g, 220 mmol) portion-wise. The slurry was stirred at room temperature for 3 h. The precipitate was collected by filtration and washed with heptane (100 mL). After dried, 51.9 g of 7-azaindole N-oxide 3-chlorobenzoate was obtained (51.9 g, 89%). mp 140-143° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:42]=1[CH2:43][CH2:44][NH:45]2.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:45]2[C:46]3[C:42](=[C:41]([Cl:40])[CH:49]=[CH:48][CH:47]=3)[CH2:43][CH2:44]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Clc1cccc2c1CCN2
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3c(Cl)cccc32)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 1 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (78.8 μmol) was added to 4-chloroindoline (14.52 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (197 μL, 5 eq) and the reaction was stirred at room temperature for 24 hr (2-3 drops of concentrated hydrochloric acid was added if the deprotection was incomplete and the resulting mixture was stirred for another 24 hr). The ether and hydrochloric acid were evaporated under a stream of nitrogen and the resulting material was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 43.5% yield. LCMS m/z (%)=412 (M+H 35Cl, 100), 414 (M+H 37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10-3.24 (m, 4H), 3.71 (s, 3H), 4.13-4.21 (m, 4H), 6.34 (d, J=2.02 Hz, 1H), 6.96 (d, J=8.08 Hz, 1H), 7.13-7.21 (m, 2H), 7.48-7.50 (m, 2H), 7.64 (dd, J=8.84, 2.78 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H), 7.92 (s, 2H), 8.63 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:18])[C:17]([I:19])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(-c2cc(Cl)nc3cc(C)nn23)c1
Solvent: ClCCl
Product: Cc1cccc(-c2cc(Cl)nc3c(I)c(C)nn23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
5-Chloro-7-(3-methylphenyl)-2-methylpyrazolo[1,5-a]pyrimidine (381 mg) is dissolved in CH2Cl2 (70 mL) and N-iodosuccinimide (NIS, 467 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (580 mg). 1H NMR (CDCl3, 300 MHz) δ 7.76 (m, 2H), 7.45 (m, 3H), 6.84 (s, 1H), 2.50 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[CH:3]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(#N)C.CN(C1C=CN=CC=1)C>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[C:4](=[O:16])[CH:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a solution of 4-amino-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.263 g, 1.2 mmol) in acetonitrile (7 mL) was added a DMAP (ca.), triethylamine (0.25 mL, 1.8 mmol) and 4-fluorobenzoyl chloride (0.213 mL, 1.8 mmol). The reaction mixture stirred at 0° C. for 25 minutes and then filtered. The solid was washed with 10% citric acid and water to afford the desired compound (0.326 g, 79%) after drying. 1H-NMR (d6DMSO, 400 MHz) δ 7.98 (m, 2H), 7.71 (d, 1H, J=7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98 (d, 1H, J=2.4 Hz), 6.61 (dd, 1H, J=2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m/z 341.1.