Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1N2C(C(C)COC2(C)C)C1(C)CO[O:15][C:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])=[O:17].O=C1N2C(C(C)COC2(C)C)C1(C)CO.[CH3:44][C:45]1([CH2:66][OH:67])[CH:48]([CH:49]([CH3:58])[CH2:50][O:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][O:53]2)[N:47]([CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[C:46]1=[O:65]>>[CH3:44][C:45]1([CH2:66][O:67][O:17][C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[O:15])[CH:48]([CH:49]([CH3:58])[CH2:50][O:51][CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][O:53]2)[N:47]([CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)[C:46]1=[O:65]
Reactant: CC1COC(C)(C)N2C(=O)C(C)(COOC(=O)Cc3ccccc3[N+](=O)[O-])C12
Reactant: CC(COC1CCCCO1)C1N(C2CCCCO2)C(=O)C1(C)CO
Agent: CC1COC(C)(C)N2C(=O)C(C)(CO)C12
Product: CC(COC1CCCCO1)C1N(C2CCCCO2)C(=O)C1(C)COOC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2,5,7-tetramethyl-7-(1-o-nitrobenzylcarbonyldioxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2,5,7-tetramethyl-7-(1-hydroxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane and using 3-methyl-1-(2-tetrahydropyranyl)-3-(hydroxymethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone there is obtained 3-methyl-1-(2-tetrahydropyranyl)-3-(o-nitrobenzylcarbonyldioxymethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][NH:11][CH2:10][C@@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[NH:29][N:28]=[C:27]([CH:30]3[CH2:32][CH2:31]3)[CH:26]=2)[CH:21]=[C:20]([CH3:33])[N:19]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:1]1([C@H:7]2[CH2:12][N:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[NH:29][N:28]=[C:27]([CH:30]5[CH2:32][CH2:31]5)[CH:26]=4)[CH:21]=[C:20]([CH3:33])[N:19]=3)[CH2:10][C@@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Reactant: COC(=O)[C@@H]1CNC[C@H](C2CCCCC2)C1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Product: COC(=O)[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3cc(C4CC4)n[nH]3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl cis-5-cyclohexylpiperidine-3-carboxylate instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine prepared in Referential Example 2 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:5])#[N:2].B.O1CCCC1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:1][CH2:3][CH:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: CC(CC#N)N1CCC(c2ccc(F)cc2)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CCN)N1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (+/−)-1-(1-cyano-2-propyl)-4-(4-fluorophenyl)piperidine (457 mg, 1.85 mmol) in tetrahydrofuran (5 mL) was added dropwise to 1 M borane/tetrahydrofuran (5 mL) under an inert argon atmosphere. The reaction mixture was refluxed for two hours and then cooled to ambient temperature. 6 N HCl (4 mL) was added to the reaction, stirred for 0.5 hour and then the tetrahydrofuran boiled off. The resultant aqueous solution was cooled in an ice bath and made basic by addition solid sodium hydroxide pellets. The product was extracted into methylene chloride, the extract dried (anhydrous sodium sulfate), filtered, and the solvent removed to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].FC(F)(F)S(O[CH2:21][CH:22]([F:24])[F:23])(=O)=O.[H-].[Na+]>CN(C)C=O>[F:23][CH:22]([F:24])[CH2:21][N:4]1[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC(F)F)CC1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 75.8 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) in N,N-dimethylformamide (4 ml) at −35° C. under argon was added sodium hydride (80 mg, 1.998 mmol). The reaction mixture was warmed to 0° C. over 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg). LC/MS [M+H]+=265. (ii) 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.757 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene (×2) to give 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (0.757 mmol) which was used in the next step. LC/MS [M+H]+=209.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:2]([CH3:4])=[O:3]>C(O)C.[Ru](=O)=O>[NH:1]([CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:12]1)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)CCc1ccc(CCNC(C)=O)cc1
Agent: O=[Ru]=O
Solvent: CCO
Product: COC(=O)CCC1CCC(CCNC(C)=O)CC1
Yield: 82 %

Procedure:
by the hydrogenation of methyl 3-[4-(2-acetaminoethyl)phenyl]-propionate in the presence of ruthenium dioxide in ethanol. Yield 82% of theory, semi-crystalline product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:31]>C1C=CC=CC=1>[ClH:31].[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: OCCCN1CCNCC1
Reactant: O=C(O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(OCCCN1CCNCC1)c1ccncc1
Yield: 66 %

Procedure:
In 150 ml of absolute benzene there were dissolved 2.88 g of 1-piperazinepropanol, 3.2 g of isonicotinic acid and 30.4 g of p-toluene sulfonic acid. The resulting solution was heated for 15 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate and then extracted with ether. After the ethereal layer was dehydrated with a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. This liquid was converted to the hydrochloride thereof in accordance with a conventional manner. It was recrystallized from ethanol to give 1-piperazinepropanol isonicotinate hydrochloride. The melting point of the product was 201°-202°C. The Yield was 66%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:14][CH2:15][C:16]([O:18]C)=O)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH3:20].C>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:14][CH2:15][C:16]([NH2:20])=[O:18])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: N
Reactant: COC(=O)CNC(C(=O)OC(C)(C)C)c1cccs1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(NCC(N)=O)c1cccs1
Reaction time: 15 h

Procedure:
A mixture of 7.4 g of the compound from Example 3 and 50 ml of concentrated methanolic ammonia is left to stand at room temperature for 15 h. The solvent is stripped off, the residue is treated with active charcoal in hot ethyl acetate, and the mixture is filtered. The residue remaining after evaporation of the solvent is stirred with diethyl ether, filtered off with suction and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][CH2:12][C:11]=12)=[O:5])[CH3:2]>C(O)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH2:12][O:13][CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C2COCC(=O)N2CCC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCCN2C(=O)COCC12
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A solution of 65 (225 mg, 1.0 mmol) in 5 ml of acetic acid is hydrogenated over 225 mg of platinum dioxide at RT and normal pressure for 18 hours. Another 225 mg of platinum dioxide is added and hydrogenation continued for 24 hours. The black suspension is diluted with 10 ml of DCM and filtered through a pad of celite. The filtrate is evaporated to give 268 mg of a yellow oil which is purified by chromatography (Biotage 12Si, I=7.5 cm, ethyl acetate/ethanol 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][Cl:9])=[CH:4][CH:3]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1.Cl>C(O)C>[ClH:9].[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1ccc(C=CCCl)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C=CCN2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5 grams of p-methylcinnamyl chloride in 50 milliliters of ethanol is added dropwise to a solution of 8.93 grams of isoindoline in 50 milliliters of ethanol, following which the mixture is stirred overnight at room temperature. After completion of the reaction, the reaction mixture is concentrated followed by adding chloroform to the residue and filtering the insolubles off. Next, the solvent is distilled off, and the residue is purified by silica gel column chromatography to obtain an oily product, which is transformed into a hydrochloride in a customary manner and recrystallized from a methanol-ether mixture to obtain 4.1 grams (yield 47.8%) of N-(p-methylcinnamyl)-isoindoline hydrochloride as crystals having a melting point of 213°-214° C. (decomposition).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([NH:19][S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[O:18])[CH:5]=2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH:37]=[O:38])[CH:29]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([NH:19][S:20]([N:23]([CH3:24])[CH3:25])(=[O:22])=[O:21])=[O:18])=[CH:7][CH:8]=3)[N:3]3[CH:37]([OH:38])[C:30]4[C:31]([C:2]=23)=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=4)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(O)n1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 85 °C

Procedure:
To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (4.3 g, 10 mmol), 4-methoxy-2-formylphenylboronic acid (2.5 g, 14 mmol) and LiCl (11.05 g, 25 mmol) in EtOH/toluene (1:1, 80 mL) was added Pd(PPh3)4 (1.12 g, 1.0 mmol) and then 1M Na2CO3 (aq.) (30 mL, 30 mmol). The reaction solution was flushed with nitrogen and heated at 85° C. for 18 h and cooled to rt. The reaction was diluted with EtOAc (200 mL), washed with 0.5N aqueous HCl (100 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated to yield 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide which was used without further purification. LCMS: m/e 482 (M−H)−, ret time 1.63 min, column A, 2 minute gradient.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)=O.[CH2:21]([NH2:23])[CH3:22]>>[CH2:21]([NH:23][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)[CH3:22]
Reactant: CCN
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3ccccc3)c2n1
Product: CCNc1ncc2ccc(=O)n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of 2-methanesulfinyl-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one (81 mg, 0.28 mmol) and 1.5 mL of aqueous ethyl amine was stirred at room temperature for 10 minutes then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 54 mg (72%) of 2-ethylamino-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 193-195° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][CH:10]=1)=[O:5])C.O.[NH2:21][NH2:22]>C(O)C>[NH:21]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:11]([C:8]2[NH:7][C:6]([C:4]([OH:3])=[O:5])=[CH:10][CH:9]=2)=[N:22]1
Reactant: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) and hydrazine hydrate (0.7 g) in ethanol was heated at 80° C. for 24 hours. The resulted precipitate was collected by vacuum filtration, washed with water and dried to give 80 mg of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:25]1([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1COCC1>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]1[C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:35]
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O)c1ccccc1
Temperature: 0 °C
Yield: 67.1 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.363 g, 11.86 mmol) was dissolved in toluene (7 mL) and cooled to 0° C. LHMDS (12.45 mL, 12.45 mmol) in THF was added. After 2 min 2-phenylpropanoyl chloride (0.855 mL, 5.93 mmol) was added. After 2 min the cooling bath was removed and after 5 min 1:1 acetic acid:water (3 ml) was added. The water phase was separated after hard stirring and the organic phase was dried with MgSO4 and the solvent was evaporated. Purification by flash column chromatography (0-25% EtOAc in heptane) yielded tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1-carboxylate (1.319 g, 67.1%). MS (ES−) m/z 330.1 (M−H)−
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(N[C@H](C(N[C@H](C(OCC1C=CC=CC=1)=O)CC(=O)N)=O)CCC(=O)OCC1C=CC=CC=1)=O)C.Cl.[NH2:46][C@H:47]([C:49]([NH:51][C@H:52]([C:65]([NH:67][C@H:68]([C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:74])[CH2:69][C:70](=[O:72])[NH2:71])=[O:66])[CH2:53][CH2:54][C:55](=[O:64])[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:50])[CH3:48].[NH:83]([C:116]([O:118][C:119]([CH3:122])([CH3:121])[CH3:120])=[O:117])[C@H:84]([C:97]([NH:99][C@H:100]([C:113](O)=[O:114])[CH2:101][CH2:102][C:103](=[O:112])[O:104][CH2:105][C:106]1[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=1)=[O:98])[CH2:85][CH2:86][C:87](=[O:96])[O:88][CH2:89][C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CN(C=O)C.CCN(CC)CC>[NH:83]([C:116]([O:118][C:119]([CH3:122])([CH3:121])[CH3:120])=[O:117])[C@H:84]([C:97]([NH:99][C@H:100]([C:113]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:65]([NH:67][C@H:68]([C:73]([O:75][CH2:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:74])[CH2:69][C:70](=[O:72])[NH2:71])=[O:66])[CH2:53][CH2:54][C:55](=[O:64])[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:50])[CH3:48])=[O:114])[CH2:101][CH2:102][C:103](=[O:112])[O:104][CH2:105][C:106]1[CH:107]=[CH:108][CH:109]=[CH:110][CH:111]=1)=[O:98])[CH2:85][CH2:86][C:87](=[O:96])[O:88][CH2:89][C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
Boc-Ala-Glu(OBzl)-Asn-OBzl (28.2 g; 46 mmol) was treated with 1.1 liter of 4N HCl in THF for 1 hour. Evaporation of the solvent and excess acid left an oil which was evaporated twice more with fresh THF. The residual oil turned into a solid when treated with a large volume of ether. The solid HCl.H-Ala-Glu(OBzl)-Asn-OBzl was stirred with Boc-Glu(OBzl)-Glu(OBzl)-OH (25.6 g, 46 mmol), HOSu (10.6 g, 92 mmol) and DCC (10.9 g, 53 mmol) in DMF (540 ml) at 0° for 1 hour and then at 25° for 48 hours. Et3N was added to maintain the reaction slightly basic over the entire period of time (~16 ml Et3N total). The insoluble by-products formed were filtered off and the filtrate evaporated to dryness. The crude product was dissolved in CHCl3, washed with water (3×), dried over Na2SO4 and evaporated to dryness. The product solidified when treated with petroleum ether. Recrystallized from i-PrOH: Yield, 28.9 g (59.8%); mp 169°-175°; [α]D25 =-11.78° (c 1, DMF).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[CH:18][C:12]=3[N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:28][C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.[Cu]I>[CH3:26][N:25]([CH3:27])[CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:12]3[N:11]=[C:10]([C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:30]5[C:31]6[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=6[N:33]=[C:29]5[CH3:28])[CH:7]=4)=[O:9])[NH:14][C:13]=3[CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3c2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)cc3[nH]2)ccn1
Temperature: 130 °C
Yield: 14.1 %

Procedure:
A mixture of (2-bromo-pyridin-4-yl)-[6-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-methanone (0.46 mmol, 1.0 mol eq.) [Example 102 (Method 1, Step 3)], 2-methyl benzimidazole (0.56 mmol, 1.2 mol eq), CuI (0.047 mmol, 0.5 mol eq.), (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.093 mmol, 0.2 mol eq.) in 2 mL of DMF was heated at 130° C. for 48 h under nitrogen. The reaction was diluted with 50 mL EtOAc and 50 mL brine. The organic layer was separated and dried over Na2SO4, filtered and evaporated to dryness. HPLC purification gave the title compound (31 mg, 14%). HRMS m/z 480.2502 (M+H)+. 1H NMR (400 MHz, DMSO-d6): 8.96 (1H, d), 8.65 (1H, s), 8.30 (1H, d), 7.74-7.63 (3H, m), 7.31-7.29 (2H, m), 7.17 (1H, d), 6.93 (1H, s), 4.16 (1H, bs), 3.77-3.74 (2H, m), 2.80-2.71 (2H, m), 2.70 (3H, s), 2.20 (6H, s), 1.89-1.85 (2H, m), 1.57-1.48 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=1)(=[O:29])=[O:28]
Reactant: Cn1c(CCCCCO)nnc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(CCCCCOS(C)(=O)=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of 5-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-1-pentanol (127 mg, 0.52 mmol) in DCM (5 ml) was added trietylamine (0.62 mmol) and methansulfonyl chloride (0.57 mmol). The solution was stirred at r.t. for 2 h and quenched with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give the title compound as light yellow oil (195 mg). MS (m/z): 324[MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.Br[C:22]1[C:27]([C:28]#[N:29])=[N:26][CH:25]=[CH:24][N:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[CH:8][C:9]([NH:12][C:24]2[N:23]=[CH:22][C:27]([C:28]#[N:29])=[N:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: COC/C=C/c1cnc(N)cc1NC1CCN(C)CC1
Reactant: N#Cc1nccnc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NC1CCN(C)CC1
Temperature: 90 °C
Yield: 3.3 %

Procedure:
A solution of (E)-5-(3-methoxyprop-1-enyl)-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.090 g, 0.32 mmol), 2-bromo-cyanopyrazine (0.060 g, 0.32 mmol), BINAP (0.007 g, 0.02 mmol), sodium tert-butoxide (0.043 g, 0.45 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.013 g, 0.01 mmol) in dioxane (3 mL) was stirred at room temperature under nitrogen for 10 min, then heated for 30 min at 90° C. under microwave irradiation. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/9), to give the title compound as a yellow solid (0.004 g, 3%).