Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[N-:30]=[N+:31]=[N-:32].[Na+]>CO.O>[N:30]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N+:31]=[N-:32]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 3.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 50 ml of methanol is added a solution of 0.65 g of sodium azide in 5 ml of water under ice-cooling, followed by stirring for two hours at 40°-50° C. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate, and the organic layer is separated, which is washed with water and concentrated. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 1.01 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[O:8][CH2:9][C:10]=2[CH:16]=1)=[O:25]
Reactant: COc1ccccc1CNC1=Nc2ccc(N)cc2CO1
Reactant: O=C(Cl)CCl
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Yield: 52.6 %

Procedure:
Prepared from N2-(2-methoxy-benzyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 4) (1.26 g, 4.45 mmol) and chloroacetyl chloride (0.39 ml, 4.89 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (842 mg, 42%, HPLC 0.889 min 81%), MS (ISP) m/e=360.3 [(M+H)+] and 362.1 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19]OS(C)(=O)=O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:26])[C:23]([N:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:16]([CH3:18])[CH3:17])[C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)n1

Procedure:
A mixture of 2-(2-diisopropylaminoethylamino)-4,6-dimethyl pyrimidine (17.0 g. 0.068 mole) and sodium hydride (50% in mineral oil) (4.19 g., 0.86 mole) in 175 ml. of dry toluene is stirred under nitrogen at 85°-95° C. for one half hour and then heated under reflux for one half hour. Dimethylcarbamoyl chloride (8.6 g., 0.08 mole) is added and heating under reflux is continued for twenty-four hours. The reaction is cooled and ethanol (10 ml) and sodium hydroxide (75 ml., 3.3N) are added. The aqueous layer is extracted with methylene chloride and the extracts are dried over sodium sulfate and concentrated to an oil. The oil is distilled at 0.5 mm of Hg and the product boiling at 155°-158° C. is collected.
Reaction SMILES: [CH:1]1([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39]>CC#N>[C:19]1(=[O:20])[N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:35][CH2:36][CH2:37][C:38]#[N:39])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: N#CCCCBr
Reactant: O=C1c2ccccc2C(=O)N1CCCNC1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To a mixture of N-[3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (569 mg, 1.7 mmol), potassium carbonate (709 mg, 5.1 mmol) and potassium iodide (280 mg, 1.7 mmol) in CH3CN (20 ml) was added 4-bromobutyronitrile (754 mg, 5.1 mmol). The mixture was refluxed under stirring for 18 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 20% ethyl acetate/chloroform) to afford 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butyronitrile (336 mg, 50%): MS(ES+) m/e 402 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=5.4, 2.9 Hz, 2H), 7.70 (m, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.11 (m, 1H), 7.02 (m, 2H), 3.95 (m, 1H), 3.78 (m, 1H), 3.59 (m, 1H), 2.73 (m, 2H), 2.64 (m, 1H), 2.51 (m, 4H), 2.35 (m, 1H), 1.98 (m, 2H), 1.83 (m, 4H), 1.63 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:41]=[C:42]=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:41][C:42]([N:45]([CH3:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:25])[Cl:27])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccccn1
Reactant: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)N=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)N(C)c1ccccn1
Yield: 65.1 %

Procedure:
A solution of (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-isocyanatopentanoyl]oxyhexadecanoate (0.33 g) and 2-(methylamino)pyridine (113 mg) in dichloromethane (5 ml) was stirred at room temperature overnight. The mixture was poured into ethyl acetate (20 ml), and washed with aqueous 1 N-hydrochloric acid (20 ml×2), saturated sodium bicarbonate (20 ml), and brine (20 ml). Then, the solution was dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on a silica gel to give (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-{3-methyl-3-(2-pyridyl)ureido}pentanoyl]oxyhexadecanoate (0.25 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc([N+](=O)[O-])ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chloro-5-nitrobenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and DCM/EA=1:1) and by crystallization from EA and diethyl ether to yield 2-{1-[(2-chloro-5-nitrophenyl)carbonyl]piperidin-4-yl}-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>C1COCC1.O>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:32])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in THF (Volume: 1.5 mL) at 0° C. The reaction was stirred for 10 minutes before iodomethane (0.200 mL, 3.20 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 50%-100% ethyl acetate in hexanes. (Yield: 41.5 mg, white solid) To obtain white solid as a product. 1H-NMR (400 MHz, DMSO-d6) 7.63-7.57, 7.53-7.47, 7.43-7.16, 7.13-7.05, 6.63, 4.67, 4.58-4.00, 3.78-3.71, 3.21-2.91, 2.79, 1.87-1.52
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])([O-:13])=[O:12]>>[CH3:7][N:5]([CH3:6])/[CH:4]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
A 50-ml. glass liner containing 15.6 g. of 95% dimethylformamide diethyl acetal and 13.7 g. of o-nitrotoluene was pressurized with nitrogen in an autoclave to 35 atm. and then heated to 155° for 24 hours.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]1[CH2:23][O:22][C:12]2([CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[O:11]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:15]2[C:16]([CH3:19])([CH3:18])[CH2:17][C:12]3([O:11][CH2:10][CH2:23][O:22]3)[CH2:13][C:14]2([CH3:21])[CH3:20])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2

Procedure:
A solution of 55.3 g (0.3 mol) of cyanuric chloride in 300 ml of xylene is added dropwise with stirring and cooling to 0°-5° to a solution of 119.6 g (0.6 mol) of 4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidine in 100 ml of xylene. The mixture is subsequently heated to reflux and kept at boiling point for 26 hours. After addition of 150 ml of xylene, the mixture is allowed to cool and the precipitate is filtered off. The filtrate is evaporated in vacuo. The residue is recrystallized from 300 ml of acetonitrile. The product obtained is a brownish powder which melts at 169°-172°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCCCCC>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCCCCOCCSCCc1ccccn1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCSCCc2ccccn2)cc1Cl
Yield: 55.4 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (0.56 g,), 2-[2-[[2-[(6-bromohexyl)oxy]ethyl]thio]ethyl]pyridine (0.58 g,) and DEA (0.26 g,) in DMF (10 ml) was stirred under nitrogen for 2 h. The solvent was evaporated in vacuo and the residual oil partitioned between 8% sodium bicarbonate solution (100 ml) and dichloromethane (100 ml). The aqueous phase was re-extracted with dichloromethane (100 ml) and the combined organic phases dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (98:2:1) gave an oil. Trituration with hexane afforded the title compound (451 mg,) as a solid m.p. 59.5°-62°. T.l.c. (System E 40:10:1) Rf 0.32.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[NH4+:41].[NH4+].[ClH:43]>>[ClH:43].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (2.49 mMol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 100 ml of saturated ethanolic hydrochloric acid for 6 hours at room temperature. Then the mixture was evaporated to dryness in vacuo, the residue was dissolved in 100 ml of ethanol, mixed with 2.5 g (26 mMol) of ammonium carbonate and stirred overnight at room temperature. After distillation of the solvent the crude product thus obtained was purified by column chromatography (100 g silica gel; eluant: dichloromethane/ethanol=4:1). By concentrating the eluates the desired compound was obtained as a white, amorphous solid. Yield: 1.10 g (83% of theory), Rf value: 0.18 (silica gel; dichloromethane/ethanol=4:1) C28H30N6O3 ×HCl (498.6) ##EQU8##
Reaction SMILES: [OH:1][C@@H:2]1[C:19]2[C:18]3[N:17]([CH3:20])[C:16]4[N:15]=[C:14]5[CH:21]=[CH:22][CH:23]=[CH:24][C:13]5=[CH:12][C:11]=4[C:10](=[O:25])[C:9]=3[C:8]([O:26][CH3:27])=[CH:7][C:6]=2[O:5][C:4]([CH3:29])([CH3:28])[C@@H:3]1[OH:30].C[C:32](=[O:35])CC>C([O-])([O-])=O.[Na+].[Na+]>[CH3:27][O:26][C:8]1[C:9]2[C:10](=[O:25])[C:11]3[CH:12]=[C:13]4[CH:24]=[CH:23][CH:22]=[CH:21][C:14]4=[N:15][C:16]=3[N:17]([CH3:20])[C:18]=2[C:19]2[C@H:2]3[O:1][C:32](=[O:35])[O:30][C@H:3]3[C:4]([CH3:28])([CH3:29])[O:5][C:6]=2[CH:7]=1
Reactant: CCC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@H]1OC(=O)O[C@H]1C(C)(C)O2

Procedure:
635.62 mg of N,N′-carbonyldiimidazole are added to a solution of 200 mg of the compound of Example 3 in 90 ml of 2-butanone. The reaction mixture is refluxed for 4 days under argon and then, after cooling, diluted with an aqueous 5% Na2CO3 solution (15 ml) and extracted with ethyl acetate. The organic solutions are combined, dried over anhydrous sodium sulphate, filtered and then evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane and then a gradient of methanol in dichloromethane of from 0.1 to 1.5%) allow 78 mg of the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[C:3]2[O:10][C:18]([C:19]([OH:21])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCl
Reactant: O=Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc(Br)c2o1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
10 g (49.75 mmol) of 3-bromo-2-hydroxybenzaldehyde and 1.84 g (4.97 mmol) of tetra-N-butylammonium iodide are, together with 27.5 g (199.0 mmol) of anhydrous potassium carbonate, initially charged. 24.3 g (223.86 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml of THF and 16.75 g (298.5 mmol) of potassium hydroxide in 100 ml of water are added, the mixture is then stirred at 40° C. for 4 h. The solvent is removed under reduced pressure. The residue is diluted with water and acidified with conc. hydrochloric acid. The product is purified on silica gel 60 (mobile phase: toluene/ethyl acetate/acetic acid 40:10:1). The solvent is removed under reduced pressure. Any last solvent residues are finally removed under high vacuum. Fine purification is carried out by preparative HPLC. 303 mg (2.5% of theory) of the title compound are isolated.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[F:24][C:13]([F:23])([F:12])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH3:8])[CH2:21][O:22]2)=[CH:18][N:19]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(C(F)(F)F)nc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C1(COC([NH:11][C@@H:12]([C:14]([N:16]([CH3:22])[CH2:17][C:18](OC)=[O:19])=[O:15])[CH3:13])=O)C=CC=CC=1.CO>C(Cl)Cl.[Pd]>[CH3:22][N:16]1[CH2:17][C:18](=[O:19])[NH:11][C@H:12]([CH3:13])[C:14]1=[O:15]
Reactant: COC(=O)CN(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1NC(=O)CN(C)C1=O
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a slurry of three combined batches of methyl N-{[(phenylmethyl)oxy]carbonyl}-D-alanyl-N-methylglycinate (combined total 489.09 g, 1586 mmol) in DCM (210 mL) was added MeOH (1000 mL) and 10% Pd/C (50 g). The mixture was hydrogenated at 50 psi overnight, and then an additional portion of 10% Pd/C (5 g) was added. The mixture was hydrogenated at 50 psi for an additional 6 h, and was then filtered and washed with MeOH and DCM. The resulting clear liquid was evaporated to give a clear oil, which subsequently solidified upon standing to afford (3R)-1,3-dimethyl-2,5-piperazinedione (214.0 g, 95% yield) as a pale yellow tinted solid. LCMS: (M+H)+: 143.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CN(C)CCN
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Product: Cc1cc(C)c(C#N)c(NCCN(C)C)n1
Temperature: 105 °C

Procedure:
A mixture of 2-chloro-3-cyano-4,6-dimethylpyridine (10.0 g, 60 mmol) and N,N-dimethyl-1,2-diaminoethane (10.6 g, 120 mmol) is heated at 105° C. for 20 hours. Added benzene, evaporated to dryness, dissolved residue in water, made basic with sodium carbonate and extract product into methylene chloride, dried and evaporated to give 13.4 g of oily title A product.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C1(C)C=CC=CC=1>CN(C)C=O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:19]=[C:20]([NH:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Reactant: CC(C)(C)OC(=O)NCC#CCCN
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC#CCCNc1nc(-c2ccccc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 75 mg (173 μmol) N-cyclopropyl-4-[8-(methylsulfonyl)-6-phenylimidazo[1,2-a]pyrazin-3-yl]benzamide which was prepared according to intermediate example 9-1 in 0.3 mL N,N-dimethylformamide were added 60 μL tert-butyl (5-aminopent-2-yn-1-yl)carbamate and the mixture was stirred at 50° C. overnight. Toluene was added and the mixture was evaporated. The residue was purified by chromatography to give 23.6 mg (25%) of the title compound
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1([CH3:20])[CH2:9][C:8]2[C:10]([CH3:19])=[C:11]([NH:16][CH:17]=[O:18])[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH:17]([NH:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]2[O:6][C:5]([CH3:20])([CH2:4][S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:9][C:8]=2[C:10]=1[CH3:19])=[O:18]
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CSc1ccccc1)O2
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% purity, 1.0 g, 21.1 mmol) was added to a solution of 2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.0 g, 19.2 mmol) and thiophenol in dimethylformamide (50 ml) and the mixture was stirred at 80° C. for 1 hour under an argon atmosphere. After the reaction mixture was cooled, the product was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 1:1) and then the purified product was recrystallized from ethanol-isopropyl ether to obtain the desired compound (5.54 g, yield: 83.3% yield), m.p. 130°14 131° C.