Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9](=[O:18])[NH:10][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:12][C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:19][C:20]1[C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=2)[NH:22][N:21]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([C:29]([N:15]3[CH2:16][CH2:17][C:11]4([NH:10][C:9](=[O:18])[C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][C:7]=5[CH2:12]4)[CH2:13][CH2:14]3)=[O:30])[CH:27]=2)[NH:22][N:21]=1
Reactant: Cc1n[nH]c2c(C)cc(C(=O)O)cc12
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2c(C)cc(C(=O)N3CCC4(CC3)Cc3cnn(C(C)C)c3C(=O)N4)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7 (1′H)-one hydrochloride salt (Intermediate 2, 430 mg, 1.3 mmol) and 3,7-dimethyl-1H-indazole-5-carboxylic acid (306 mg, 1.6 mmol) in dimethylformamide (2 mL) was added triethylamine (0.75 mL, 5.4 mmol), 4-dimethylaminopyridine (33 mg, 0.37 mmol), and 1-propanephosphonic acid cyclic anhydride (0.52 mL, 1.74 mmol, 50% solution in ethyl acetate), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to a solid. The solid was purified via flash column chromatography (0-15% methanol/dichloromethane) to afford a glassy solid. The glassy solid was stirred in ethyl acetate for 16 hours and the resulting solid collected by vacuum filtration to afford the desired product as a white solid (138 mg). +ESI (M+H) 421.0; 1H NMR (400 MHz, CD3OD, δ): 7.65 (s, 1H) 7.42 (s, 1H) 7.21 (s, 1H) 5.50 (m, 1H) 3.95 (br. s., 1H) 3.50-3.62 (br. s., 3H) 2.97 (s, 2H) 2.56 (m, 6H) 1.83 (br. s., 4H) 1.44 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a refluxing solution of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (10.0 g, 58.1 mmol) in EtOH (50 mL) was added drop wise a solution of divinyl sulfone (5.9 mL, 6.86 g, 58.1 mmol) in EtOH (50 mL). The resulting mixture was stirred at reflux for 15.5 h, cooled to room temperature and concentrated in vacuo. The resulting beige solid was triturated with Et2O, affording the title compound as a white solid (10.8 g, 64%). 1H NMR (CDCl3, 300 MHz): δ 3.97 (dd, J=8.8, 7.1 Hz, 2 H); 3.76 (dd, J=8.8, 7.1 Hz, 2 H); 3.36-3.26 (m, 1 H); 3.13-3.05 (m, 4 H); 2.90-2.83 (m, 4 H); 1.44 (s, 9 H).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]/1=O)C.[ClH:21].[NH2:22]N>C(O)C.C(O)(=O)C>[ClH:21].[CH3:11][C:8]1([CH3:12])[C:9]2[NH:22][N:2]=[CH:4][C:5]=2[CH:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:7]1
Reactant: NN
Reactant: CN(C)/C=C1\C(=O)C(C)(C)CC1c1ccc(C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccc(C#N)cc2)c2cn[nH]c21
Temperature: 80 °C
Yield: 42 %

Procedure:
To (+/−)-4-[(2Z)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-cyclopentyl]benzonitrile (3.2 g, 20 mmol) in ethanol (100 mL) and acetic acid (4 drops) is added hydrazine hydrochloride (4.17 g, 60 mmol) and the reaction is heated to 80° C. for three hours. The reaction is then cooled to room temperature and concentrated in vacuo. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers are separated and the organic is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel flash chromatography eluting with 1:2 ethyl acetate:pet ether. The resulting material is treated with HCl in ethyl acetate to provide the title compound (2.3 g, 70%). ES/MS (m/z) 238.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1.[NH3:22]>C(O)C>[NH2:22][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1
Reactant: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(Cl)n1
Reactant: N
Solvent: CCO
Product: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(N)n1

Procedure:
A mixture of 4-chloro-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and ethanol was saturated with ammonia gas and reacted under heating in a shield tube to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH2:15]([N:22]1[CH2:30][C@H:29]2[C@H:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][CH2:27][C:28]2=[O:31])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].O>O1CCCC1.C(OCC)(=O)C>[CH2:15]([N:22]1[CH2:30][C@H:29]2[C@H:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:27][C@H:28]2[OH:31])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
4.0 cm3 of a 1M solution of lithium tri-sec-butyl borohydride in tetrahydrofuran is added over 5 minutes to a solution, cooled to 0° C., of 1.3 g of (3aR, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone in 6.0 cm3 of tetrahydrofuran. After stirring for 3 hours at 0° C., the reaction mixture is again supplemented with 0.5 cm3 of the 1M solution of borohydride. After 1 hour at 0° C. and the addition of 50 cm3 of water and 50 cm3 of ethyl acetate, the organic phase is decanted, washed with 20 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm3 of diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR, 4R, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of white crystals; melting point 154° C.
Reaction SMILES: [C:1]1(NC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:13]([N:16](C(C)C)CC)(C)C.[C:22]([O:26][C:27](=[O:47])[NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:37]2[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][N:40]=[C:39](Cl)[N:38]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:47])[NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:37]2[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][N:40]=[C:39]([NH:16][CH2:13][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][N:2]=3)[N:38]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CNc1nccc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3nccc4ccccc34)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a solution of isoquinolin-1-yl-methylamine (1.32 g, 8.35 mmol) and diisopropylethylamine (2.7 mL, 15.5 mmol) in DMF (20 mL) was added {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.5 g, 3.89 mmol). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed and the resulting residue was diluted with a mixture of ethyl acetate (350 mL) and CH2Cl2 (100 mL). The solution was then washed with 1M Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting solid was treated with ethyl acetate (poor solubility of the product in ethyl acetate) and the un-dissolved solid was filtered through a Buchner funnel. The white solid was dried in vacuo to yield 1.64 g of [4-({2-[(isoquinolin-1-ylmethyl)-amino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH3:11][O:12][N:13]=[CH:14][CH3:15].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:11][O:12][N:13]1[CH:14]([CH3:15])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: C=C(C)C1CCCCC1=O
Reactant: CC=NOC
Agent: CON1C(=O)CCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCC=C(C)CC1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An argon flushed three-necked flask which was cooled by an ice-water bath was charged with 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), acetaldehyde O-methyl oxime (0.56 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml). The mixture was stirred for 48 hours at room temperature. The completion of reaction was checked by GC analysis of reaction aliquots quenched with a solution of saturated NaHCO3 in water. The reaction mixture was quenched with sat. aqueous NaHCO3 solution (50 mL). The organic phase was separated and the aqueous layer was extracted with MTBE three times. The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified by distillation under reduced pressure to yield the title product as a colorless liquid (1.13 g, 84%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl>[CH:13]([NH:16][C:17]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: NOCC(O)CN1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)NOCC(O)CN1CCCCC1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 25 ml abs. chloroform and under stirring, 0,98 ml (0,01 mol) isopropyl isocyanate was added. The reaction was monitored by chromatography. At the end of the reaction the solution was evaporated and the oily residue purified by column chromatography. The oil thus obtained was crystallized with methanol-ether.
Reaction SMILES: [N:1]1([CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:23](Cl)(=[O:25])[CH3:24]>C(O)(=O)C>[N:1]1([CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:25])[CH3:24])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
(a-4) A mixture of 1.45 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, 0.78 parts of acetyl chloride and 25 parts of acetic acid was stirred over weekend at room temperature. The methanol layer was removed in vacuo and the residue was taken up in water and dichloromethane. After treatment with ammonium hydroxide, the dichloromethane layer was dried, filtered and evaporated, yielding 1.6 parts (95%) of N-[4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrophenyl]-acetamide as a residue (int. 127).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:28]#[N:29])[CH2:25][CH2:24][C:23]3[N:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:28]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH3:26])[N:20]=[C:19]([O:27][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:36])[C:18]=2[CH2:17]1)#[N:29]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2(C#N)CCc3nc(C)[nH]c(=O)c3C2)c2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1nc(C)nc2c1CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in example 21 (150 mg, 1.76 mmles) in dry DMF (5 ml) was added ethylbromoacetate (322.3 mg, 1.93 mmol) and cesium carbonate (688 mg, 2.11 mmol). The reaction mass was stirred at room temperature for 1 hr, diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to get both pure compounds.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:14])([F:13])[CH:4]([OH:12])[CH2:5][CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH3:15]O>>[ClH:1].[F:2][C:3]([F:13])([F:14])[CH:4]([OH:12])[CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:15])=[O:10])[NH2:8]
Reactant: CO
Reactant: N[C@@H](CCC(O)C(F)(F)F)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CCC(O)C(F)(F)F

Procedure:
1.4 ml of saturated hydrochloric acid in methanol were added to 150 mg (0.7 mmol) of rac-6,6,6-trifluoro-5-hydroxynorleucine (stereoisomer mixture), and the mixture was stirred under reflux overnight. The reaction solution was concentrated, another 1.5 ml of saturated hydrochloric acid in methanol were added and the mixture was stirred under reflux overnight. The reaction solution was concentrated and the residue was dried under high vacuum. This gave 185 mg (99% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Yield: 82 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and 3-methylbenzeneboronic acid resulting in an 82% yield.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[C:13]3[N:14]([C:26](/[CH:29]=[C:30]4\[NH:31][C:32](=[O:36])[NH:33][C:34]\4=[O:35])=[CH:27][N:28]=3)[CH:15]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([NH:4][C:12]2[C:13]3[N:14]([C:26](/[CH:29]=[C:30]4/[C:34](=[O:35])[NH:33][C:32](=[O:36])[NH:31]/4)=[CH:27][N:28]=3)[CH:15]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1nc(C#Cc2ccccc2)cn2c(/C=C3\NC(=O)NC3=O)cnc12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2cnc3c(NC4CC4)nc(C#Cc4ccccc4)cn23)N1
Reaction time: 1 h
Yield: 52 %

Procedure:
(Z)-Tert-butyl cyclopropyl(3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-(phenylethynyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (12 mg, 0.03 mmol) was dissolved in dichloromethane (0.3 mL) and trifluoroacetic acid (0.3 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with Et2O and filtered to yield (Z)-5-((8-(cyclopropylamino)-6-(phenylethynyl)imidazo[1,2-a]pyrazin-3-yl)methylene)imidazolidine-2,4-dione (6 mg, 63%) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:17]([Cl:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(Nc2nc(Cl)c3cc[nH]c3n2)cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a solution of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 8 mmol) in DMF (35 mL) was added N-chlorosuccinimide (1.28 g, 9.6 mmol). The reaction mixture was stirred at 50° C. overnight. Water (50 mL) was added and the solution was extracted with EtOAc (three×25 mL) and the combined organic layers were dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (0.5 g, 22% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (brs, 1H), 9.62 (brs, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 3.35 (s, 3H). m/z for C10H8Cl2N6: 283.0 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16](C)C=O>O.Cl>[C:15]([C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: COC(=O)c1c(SC)ccc(I)c1C
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: COC(=O)c1c(SC)ccc(C#N)c1C
Temperature: 150 °C

Procedure:
A mixture of methyl 3-iodo-2-methyl-6-methylsulphenylbenzoate (16.6 g) and cuprous cyanide (4.4 g) in dimethyl formamide (50 ml) was stirred and heated at 150° C. for 1 hour. The mixture was cooled to 90° C. and a solution of ferric chloride (18 g) in water (28 ml) and concentrated hydrochloric acid (5 ml) was added. The mixture was stirred and heated at 90° C. for 1 hour. The cooled mixture was filtered and the solid was washed with ether. The layers in the filtrate were separated and the aqueous layer was extracted with ether (100 ml). The combined organic layers were washed with water (2×100 ml), aqueous sodium sulphate solution (10%, 2×100 ml), water (2×100 ml), aqueous sodium hydroxide solution (2×100 ml), water (3×100 ml), dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) as a brown oil NMR (CDCl3) 2.5(s,6H), 3.9(s,3H), 7.05(d,1H), 7.45(d,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=1[CH3:23])=[O:9]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2F)c(C)c1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzoic acid (3.50 g, 15.9 mmol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (2.86 g, 15.9 mmol, see preparation 12) and N,N-diisopropylethylamine (8.35 ml, 47.9 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 20.5 ml, 31.9 mmol) is added via syringe and stirred at ambient temperature. After 36 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (4.20 g, 69%). Mass spectrum (m/z): 380.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[BrH:9].[Br:10]Br>O>[Br:9][C:3]1[C:4](=[O:8])[NH:5][CH:6]=[C:7]([Br:10])[C:2]=1[OH:1]
Reactant: O=c1cc(O)cc[nH]1
Reactant: Br
Reactant: BrBr
Solvent: O
Product: O=c1[nH]cc(Br)c(O)c1Br
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To 4-hydroxypyridin-2(1H)-one (5.55 g, 50 mmol) was added 48% aqueous hydrobromic acid (50 mL, 921 mmol) to produce a pale tan solution. Bromine (5.67 mL, 110 mmol) was added to produce an amber solution. After 3 days a yellow precipitate had formed. To the reaction was added 300 mL of water causing a thick white sly to form which was stirred for 1 hour. The reaction was filtered and washed with 4×50 mL of water. to yield product (13.506 g, 1.81 mmol, quantitative yield) as a white powder. MS (ESI) 190 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[S:27])[CH3:24]>O>[N:7]1[C:8]2[C:3](=[C:2]([O:1][C:26](=[S:27])[N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])[CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2nccnc12
Reactant: CCN(CC)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=S)Oc1cccc2nccnc12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 5-hydroxyquinoxaline (2.13 g, 14.6 mmol), finely ground K2CO3 (4.0 g, 29 mmol), and DMF (50 mL) was stirred at 23° C. for 1 h. Solid diethylthiocarbamoyl chloride (2.43 g, 16.1 mmol) was then added. The resulting mixture was stirred for 2 h, then was diluted with water (150 mL) and extracted with Et2O (2×100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), then dried and concentrated to a viscous orange oil, which was used without purification (3.63 g, 95%). MS (ESI+): mass calcd. for C13H15N3OS, 261.1; m/z found, 262 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.85-8.65 (m, 2H), 7.96 (dd, J=8.5, 1.1, 1H), 7.71 (t, J=7.9, 1H), 7.46 (dd, J=7.6, 1.2, 1H), 3.87 (q, J=7.1, 2H), 3.78 (q, J=7.1, 2H), 1.38 (t, J=7.1, 3H), 1.28 (t, J=7.1, 3H). 13C NMR (125 MHz, CDCl3): 186.6, 149.4, 144.9, 144.5, 143.4, 137.0, 128.9, 127.0, 123.1, 48.2, 44.5, 13.1, 11.5.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(N(C)C)=C(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C>ClCCl>[CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:16])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cnc(N2CCCC2)c(OCC2CCCC2)n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
To a solution of 0.0874 g (0.0003 mol) 6-cyclopentylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid in 1.0 mL dichloromethane was added 0.047 g (0.00035 mol)(1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture was stirred at room temperature for 45 min. To the resulting solution was added 0.0683 g (0.0008 mol) piperidine and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between 10% citric acid and dichloromethane. The phases were separated and the organic phase was washed with water and brine, dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with dichloromethane:ethyl acetate=1:1 to yield 0.064 g (0.00018 mol) of the title compound as beige crystals melting at 61-62° C.