Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=3[CH3:26])=[O:19])[CH2:10][CH2:9]2)=[CH:2]1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](=[O:44])[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=3[CH3:27])=[O:19])[CH2:12][CH2:13]2)[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(NCc2ccsc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccsc2)C(=O)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 79.8 %

Procedure:
Following general procedure E: a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (41 mg, 0.1 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.22 mmol), EDCI (39 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and DIPEA (0.05 ml, 0.3 mmol) in CH2Cl2 (2 ml) was stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 9:1) afforded 4-{[(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28]([OH:30])=O)=[CH:5][CH:4]=1.Cl.[CH3:32][NH2:33]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28](=[O:30])[NH:33][CH3:32])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Yield: 88.2 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and methylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 88.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[CH3:12][CH2:13][C:14](=O)[C:15](=[O:18])[CH2:16][CH3:17].C(O)C>S(=O)(=O)(O)O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:14]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH3:12])([O-:3])=[O:2]
Reactant: CCC(=O)C(=O)CC
Reactant: NNc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCC(=O)C(CC)=NNc1ccccc1[N+](=O)[O-]
Yield: 96.1 %

Procedure:
A mixture of 2-nitrophenylhydrazine (2.00 g), hexane-3,4-dione (1.80 g), sulfuric acid (2 drops) and ethanol (20 mL) was heated under reflux for 1 hr. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and dried to give the title compound (3.13 g, 96%) as brown crystals. melting point 96-97° C.
Reaction SMILES: Br.Br.[NH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:30])C=O>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[O:16][CH3:17])[C:6]1=[C:4]([CH3:5])[N:3]=[C:26]([NH:27][C:30]3[C:6]([CH3:4])=[CH:15][CH:10]=[CH:11][C:12]=3[CH3:13])[N:7]1[CH2:8][CH2:9]2
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1OC)C(C(C)N)=NCC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1OC)-c1c(C)nc(Nc3c(C)cccc3C)n1CC2

Procedure:
2.9 g 2,6-dimethylphenylisocyanide dichloride is added to a suspension of 5 g of 1-(1-aminoethyl)-3,4-dihydro-6,7-dimethoxyisoquinoline dihydrobromide in 100 ml dimethylformamide. 3.6 g of anhydrous potassium carbonate are then added. The suspension is stirred and warmed at 60° for 6 hours. The potassium carbonate is filtered off and washed with dimethylformamide. The washings and filtrate are concentrated in a vacuum, and the residue is chromatographed on silicagel using CHCl3 /CH3OH (95:5) as eluant to give the title compound as the free base; M.Pt. 234°-236°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:17]3=[O:32])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=[O:26])[C:17]3=[O:32])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Yield: 64 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (570 mg, 1.219 mmol) in DCM (15 ml), trifluoroacetic acid (939 μl, 12.19 mmol) was added, and the mixture was reacted for 1 hour at room temperature. The solvent was evaporated and crude 2-(5-(N-(2-morpholinoethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt was obtained (408 mg, 0.776 mmol, 64% yield).MS/ESI+ 411.8 [MH]+) and used without purification.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:14][C:15]1[CH:19]=[CH:18][O:17][C:16]=1[C:20](OC)=[O:21].Cl>C1COCC1>[CH3:14][C:15]1[CH:19]=[CH:18][O:17][C:16]=1[C:20](=[O:21])[CH2:2][C:1]#[N:3]
Reactant: COC(=O)c1occc1C
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)CC#N
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Following the method of Turner and Jacks (J. Org. Chem. 1989, 54, 4229), to a stirred solution of 9.4 ml (179 mmol) acetonitrile in 250 ml dry THF under argon at −78° C. was added dropwise 78.9 ml (78.9 mmol) lithium bis(trimethylsilyl)amide solution (1M in THF) and stirring continued for 30 minutes, after which a solution of 5.0 g (35.7 mmol) methyl 3-methyl-2-furoate in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) afforded 4.43 g (83%) 3-(3-methyl-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 149 (M+, 20), 109 ([M—CH2CN]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25](O)=[O:26])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][C:41]([NH2:45])([C:43]#[CH:44])[CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]([NH:45][C:41]([CH3:42])([CH3:40])[C:43]#[CH:44])=[O:26])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: C#CC(C)(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: C#CC(C)(C)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.14 g), carbonyldiimidazole (0.064 g) and 1,1-dimethylpropargylamine (0.06 g) using the method of example 115 step (i). Purification was by chromatography eluting with ethyl acetate/isohexane (2/3). Yield 0.03 g as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[C@H:4]([CH2:9][OH:10])[CH2:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][O:8][S:19]([CH3:18])(=[O:21])=[O:20])[C@H:4]([CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1C[C@@H](CO)[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C[C@@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To an ice cooled solution of 6.2 gm (43 mMol) 1-methyl-cis-3,4-di(hydroxymethyl) pyrrolidine and 14.5 gm(143 mMol ) triethylamine in 200 mL dichloromethane was added a solution of 14.7 gm (129 mMol) methanesulfonyl chloride in 20 mL dichloromethane. Once this addition was complete the reaction mixture was stirred for 15 minutes at 0° C. and then for 1.5 hours at ambient. The reaction mixture was then quenched with dilute aqueous sodium hydroxide solution and then was extracted with dichloromethane. The organic phase was dried over sodium sulfate and then concentrated in vacuo to give 9.6 gm of the desired compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nccc(N2CCOCC2)n1
Yield: 90.5 %

Procedure:
To a cooled (0° C.) suspension of 2,4-dichloropyrimidine (20)(1.0 g, 6.7 mmol) in ethanol (20 ml), which was stirred under an inert atmosphere, was added triethylamine (1.4 ml, 10.1 mmol) and then morpholine (0.59 ml, 6.7 mmol). The mixture was maintained at this temperature for 3 hours whereupon it was concentrated in vacuo, diluted with NaOH (20 ml, 1M) and extracted with EtOAc (3×20 ml). The organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to give a colorless solid. The crude residue was re-crystallised using EtOAc/Hexanes to give the title compound (1.21 g, 90%) as a colourless solid which required no further purification. m/z (LC-MS, ESP): 200 [M+H]+, R/T=3.26 mins
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[NH2:18]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC1=NS(=O)(=O)c2cnccc2N1
Temperature: 70 °C

Procedure:
3-Methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (1.0 g) was added to hydrazine hydrate (0.8 ml) and the mixture was heated to 70° C. for 30 min. After cooling, the reaction mixture was supplemented with methanol (10 ml) and the solvents were removed by distillation under reduced pressure. The residue was dissolved in NaOH 2M (20 ml), treated with charcoal, filtered, and the filtrate was adjusted to pH 6-7 with HCl 1M. The precipitate so obtained was collected by filtration, washed with water an dried (yield: 0.8 g); m.p. 290°-292° C. (Compound 1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][F:31])=[CH:24][CH:23]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[F:31][CH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:32]([OH:34])=[O:33])[NH2:8])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CCCc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N[C@@H](CC(CCCc1ccc(CCCF)cc1)C(=O)O)C(=O)O

Procedure:
Di-tert-butyl N-(tert-butoxycarbonyl)-4-{3-[4-(3-fluoropropyl)phenyl]propyl}-L-glutamate (40 mg, 0.07 mmol) was dissolved in 3 ml trifluoroacetic acid and stirred at room temperature for 1d. Then, 5 ml toluene were added and the solution was concentrated in vacuo. The product was purified by preparative HPLC. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH2:22])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:25]#[N:26])[K]>O>[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH:22][C:25]([NH2:26])=[O:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
C-(7-Benzenesulfonyl-chroman-4-yl)-methylamine HCl salt (75 mg, 0.22 mmol) was dissolved in 8 mL water and KOCN (36 mg, 0.44 mmol) was added. The reaction mixture was stirred at 100° C. for 30 minutes., then cooled, partitioned between EtOAc and water, and dried over MgSO4. After concentration, the product was precipitated from Et2O/hexanes. After formation of the HCl salt, 24 mg (32%) of (7-Benzenesulfonyl-chroman-4-ylmethyl)-urea was collected. MS: 347 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][C:35]2[N:39]=[CH:38][O:37][N:36]=2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][NH:7][CH2:6]1)[C:26]([C:28]1[N:32]([CH2:33][CH2:34][C:35]2[N:39]=[CH:38][O:37][N:36]=2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ncon1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ncon1)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (125 mg) was dissolved in dimethyl sulfoxide (5 ml), sodium hydrogen carbonate (463 mg) was added and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl (3S,5R)-3-[{[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) in dimethyl sulfoxide (5 ml) was added to the reaction mixture, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in trimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to basic silica gel chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for min. The solvent was evaporated under reduced pressure to give the object product (35 mg).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][NH:13][CH2:12]1.CCN(CC)CC>O>[CH3:10][C:11]1([CH3:16])[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:12]1
Reactant: Nc1cccc(F)n1
Reactant: CC1(C)CCNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCN(c2cccc(N)n2)C1
Temperature: 205 °C
Yield: 78.5 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol), 3,3-dimethylpyrrolidine hydrochloride (0.73 g, 5.35 mmol) and Et3N (1.08 g, 10.7 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-amine (0.67 g, 78%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.187 min.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Cc1ccccc1N
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccccc1C
Yield: 88.2 %

Procedure:
Ten grams of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved by heating in 50 ml of ethanol to 60°. Then 5.32 g of 2-methylaniline in 20 ml ethanol is added and the mixture heated at reflux for 4 hours with stirring. Crystals appear on cooling and the mixture is filtered and washed with ether to yield 11.36 g of α-cyano-β-(2-methylanilino)-N-ethoxycarbonylacrylamide, which is dissolved in tetralin and heated at reflux for 3 hours. After cooling, the mixture is filtered, washed with ether, to yield 5-cyano-1-(2-methylphenyl)uracil, m.p. 251.5°-2.52.5°.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13](Cl)[CH:14]=[CH2:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:15]([N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7])[CH:14]=[CH2:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 42 %

Procedure:
To a stirred mixture of phthalimide potassium salt (20 g, 108 mmol) and tetrabutylammonium bromide (1.04 g, 3.24 mmol, 0.03 equiv) in anhydrous DMF (75 ml) was added allyl chloride (8.84 ml, 108 mmol) at room temperature, and the mixture was stirred at room temperature for 22 h, resulting in a light-yellow suspension. The reaction was quenched by adding cold H2O (150 ml), and the mixture was stirred for 10 min (an ice bath was applied during this time to aid the precipitation). The resulting white suspension was filtered off, washed with H2O (3×50 ml), and air-dried to give N-allylphthalimide (8.5 g, 42% yield) as white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:47])([CH3:46])[CH2:10][NH:11][C:12](=[O:45])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:21]=2)=[N:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([CH3:47])([CH3:46])[CH2:10][NH:11][C:12](=[O:45])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:21]=2)=[N:15][CH:14]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl(3-(6-((6-((4-(3-bromopropoxyl)benzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (10 mg) in DCM (3 mL) was added TFA (0.3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give N-(3-amino-2,2-dimethylpropyl)-6-(6-(4-(3-bromopropoxyl)benzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamide (8 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:26])=[CH:23][N:22]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (3.0 mg, 0.022 mmol) were suspended in pyridine (2 mL), and 6-chloronicotinoyl chloride (158 mg, 0.897 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with ethanol to afford the entitled Compound 502 (138 mg, 73%) as a pale brown solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH:10]([CH2:16][C:17]([NH2:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C([NH:23]C1C2C=CC=CC=2C2C(CC(=O)NN=2)C1)(=O)C>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]3[CH:10]([CH2:16][C:17](=[O:18])[NH:19][N:23]=3)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CC(N)=O)C2=O
Reactant: CC(=O)NC1CC2CC(=O)NN=C2c2ccccc21
Product: CC(=O)Nc1ccc2c(c1)CCC1CC(=O)NN=C21

Procedure:
In a manner similar to that described in Preparation 1(d), 6-acetamido-1-oxo-1,2,3,4-tetrahydro-2-naphthylacetamide (1.55 g) was converted into 6-acetamido4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (0.2 g; mp 259°); ν(Nujol mull) 3330, 3215, 1655, 1610cm-1 ; M+ =257.