Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]C=1.[C-:16]1([CH2:21][N:22]2[C:26](=[O:27])[NH:25][NH:24][C:23]2=[O:28])[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-]1C=CC=C1.[Fe+2:34]>O1CCCC1>[C-:16]1([CH2:21][N:22]2[C:23](=[O:28])[N:24]=[N:25][C:26]2=[O:27])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:12]1[CH:13]=[CH:14][CH:15]=[CH:10]1.[Fe+2:34]
Reactant: Ic1ccccc1
Reactant: O=c1[nH][nH]c(=O)n1C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1N=NC(=O)N1C[c-]1cccc1
Reaction time: 2 h

Procedure:
With reference to EXAMPLE 1-1, 11 mg (0.034 mmol) of iodobenzene diacetate was added to a mixture of 10 mg (0.033 mmol) of 4-(ferrocenylmethyl)urazole and 0.5 mL of tetrahydrofuran-d8 at room temperature. The mixture was stirred for 2 hours to give the tetrahydrofuran solution of 4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione. A tetrahydrofuran (0.5 mL) solution of 5 mg (0.013 mmol) of cholecalciferol (VD3, manufactured by Solvay Pharmaceutical, Co.) was added to the resulting solution, followed by stirring at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:2) to give 8 mg (90%) of the titled cholecalciferol/4-(ferrocenylmethyl)-1,2,4-triazoline-3,5-dione adduct (VD3-FMTAD) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[C:8]([C:20]#[N:21])=[C:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]3=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](O)[CH3:32])=[CH:27][CH:26]=1.C([O-])(=[O:36])C.[K+].Cl>CC(C)=O.C(O)CCC>[C:20]([C:8]1[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:4]=[CH:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:36])=[CH:27][CH:26]=3)=[C:13]3[C:12](=[O:15])[C:11]4[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]=1[C:14]=23)#[N:21]
Reactant: Cn1c(=O)c(C#N)c2c3c(c(Br)ccc31)C(=O)c1ccccc1-2
Reactant: CC(O)c1ccc(N)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCO
Product: Cn1c(=O)c(C#N)c2c3c(c(Nc4ccc(CCO)cc4)ccc31)C(=O)c1ccccc1-2
Reaction time: 0.12 h

Procedure:
A mixture of 6-bromo-1-cyano-3-methyl-3H-dibenz[f,ij]isoquinoline-2,7-dione (2.0 g), p-aminophenylethanol (15 g), potassium acetate (2.0 g), a trace of cupric acetate, and butanol (10 ml) was heated gradually to about 80° C., held for 5-10 minutes, and then drained into 250 ml of 10% HCl. The solid product was collected by filtration, washed with water, dried in air, and recrystallized twice from nitrobenzene to remove a red impurity and traces of starting material. A yield of 0.65 g of product, which had a visible absorption maximum at 587 nm in acetone, was obtained, thus imparting a reddish-blue color to acetone. The structure is as follows: ##STR6##
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].[N:11]1[CH2:12][CH2:13][CH2:14][CH:15]=1.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>O1CCOCC1>[N+:1]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]2[N:11]([CH2:15][CH2:14][CH2:13]2)[C:16](=[O:19])[CH2:17][CH2:18]1)([O-:3])=[O:2]
Reactant: C=CC(=O)Cl
Reactant: C1=NCCC1
Reactant: O=[N+]([O-])Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1CCC(c2ccccc2)([N+](=O)[O-])C2CCCN12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
To a room temperature solution of 280 mg (2.042 mmol) nitromethyl-benzene in 3 ml dioxane was added a solution of 141 mg (2.042 mmol) 3,4-dihydro-2H-pyrrole (CAS: 638-31-3) in 0.5 ml dioxane. The mixture was stirred at room temperature for 10 min then at 60° C. for 2.5 hours then cooled to 5-10° C. and 198.2 ul (2.45 mmol) acryloyl chloride was added dropwise. The mixture was then warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate and ethylacetate. The aqueous phase was extracted two times with ethylacetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 511 mg of light yellow oil. The crude compound was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 40%) to provide 332 mg of an oil that was dissolved in 3 ml dioxane and 816 mg of amberlyst A-21 was added. The reaction mixture was heated to 70° C. overnight cooled to room temperature, amberlyst was filtered and washed with ethylacetate. The filtrate was concentrated in vacuo. The crude compound was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 100%) to provide 329 mg (y: 62%) of title compound as a colorless oil. (M+H+: 261.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17]I)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.N(CC)CC>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH3:17])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1
Reactant: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CI)[C@H]1O
Agent: [Ni]
Solvent: CO
Solvent: CCNCC
Product: C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 31.1 %

Procedure:
To the solution of iodide 95 (85 mg, 0.16 mmol) in methanol (1.6 mL) was added Et2NH (0.03 mL, 0.31 mmol) and Raney nickel (20 mg). The reaction mixture was stirred 1 d under H2 (1 atm), filtered on Celite and evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford title compound 96 (21 mg, 31%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[CH:9]([N:12]([CH2:16][CH2:17]Cl)[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:17][CH2:16][N:12]([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Nc1nnc(S)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCSc1nnc(N)s1)C(C)C
Yield: 78.1 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (4.0 g), diisopropylaminoethylchloridehydrochloride (6.0 g), and potassium hydroxide (3.4 g) were stirred in methanol (100 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 6.1 g of the aimed compound.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:27]([C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([NH2:10])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:18]=[CH:17][C:16]=1[OH:19])([CH3:30])([CH3:28])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CC(CS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CC(N)CS(C)(=O)=O)ccc1O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-benzyloxy-3-t-butylphenyl)-1-methanesulfonylmethylethylcarbamic acid benzyl ester (1.0 g, 1.96 mmol) and 20% palladium hydroxide/carbon (0.08 g) in methanol (16 ml) was stirred at room temperature in a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1), giving the titled compound (0.56 g, 99%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:20]([NH2:19])=[N:13][N:12]=3)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NNc1ccc(-n2ccnc2)nn1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nnc2ccc(-n3ccnc3)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
(6-Imidazol-1-ylpyridazin-3-yl)hydrazine (500 mg) were initially charged in a mixture of acetic acid (4 ml) and water (8 ml) with addition of sodium acetate (232 mg) at RT while stirring. Thereafter, the mixture was cooled to 0° C. and cyanogen bromide (330 mg) was introduced in portions. After stirring for 2.5 h, the mixture was left to stand overnight. After cooling to 0° C., the mixture was alkalized with 10 M sodium hydroxide solution and extracted repeatedly with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. 66 mg of the title compound were isolated.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([I:17])[C:14]([OH:18])=[C:13]([I:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].C([O:33][C:34](=[O:36])[CH3:35])C>CC(C)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10](=[O:20])[C:11]1[CH:12]=[C:13]([I:19])[C:14]([O:18][CH2:35][C:34]([OH:36])=[O:33])=[C:15]([I:17])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCC(=O)O)c(I)c1
Temperature: 50 °C
Yield: 49.7 %

Procedure:
A mixture of 2-n-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran 1.0 g (1.83 mmol) and potassiumcarbonate 0.56 g (4 mmol) in aceton (dry) 100 ml, α-brom ethylacetate 1.0 g (12 mmol) was added, and the solution was extracted with 100 ml water. The organic layer was evaporated to dryness and the yellow rest was dissolved in methanol 50 ml+1M NaOH 50 ml. The solution was heated to 50° C. for 15 h, extracted with 3×75 ml dichloromethane, and dried (MgSO4). Evaporating the solution and purification on silica gave 0.55 g (005).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([O:21]CC)=[O:20])[C:5]([CH3:18])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1.[OH-].[K+].CO>O>[C:19]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1)([OH:21])=[O:20]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)cc(Cl)c2c1C1(CCS2(=O)=O)OCCO1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
A mixture containing 1.19 g (3.2 mmol) of 8-chloro-6-ethoxycarbonyl-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide, 0.33 g (5.0 mmol) of potassium hydroxide, 8 ml of methanol and 2 ml of water was stirred under heat at 80° C. for 2 hours. After the completion of the reaction, 20 ml of water was added, and an aqueous layer was washed with methylene chloride. The aqueous layer was neutralized with 2 wt % hydrochloric acid and extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 0.92 g (yield 84%) of 6-carboxy-8-chloro-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:24])=O)[CH2:20][CH2:19][CH2:18][CH2:17]C1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:22](=[O:24])[CH:21]([CH:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc(Cc2ccc(Cl)cc2)o1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cc2ccc(Cl)cc2)o1)C(c1ccccc1)C1CCCC1
Reaction time: 16 h

Procedure:
5-(4-Chloro-benzyl)-oxazol-2-ylamine (42 mg, 0.20 mmol) and cyclohexyl-phenyl-acetic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (9.6 mg, 0.023 mmol, 12%). ESI-MS m/z calc. 408.9. found 409.4 (M+1)+ Retention time 3.76 minutes.
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:13][C:14](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([N:13]=[C:14]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 25.4 g. of n-hexyl isocyanate, there was obtained 11.1 g. of 1-n-hexylamidino-3-n-hexylurea having the structural formula ##STR62## as a white crystalline solid which melted at 75°-78° C. The solubility of this base in water at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25° C. it was soluble to the extent of 5 percent (w/v); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[N:11][OH:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:12][N:11]=[CH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=NO)c([N+](=O)[O-])cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=NOCc2ccccc2)c([N+](=O)[O-])cc1OC
Reaction time: 4 h

Procedure:
6-Nitroveratraldoxime (113 g, 0.5 mole) was dissolved in 2500 ml of dimethylformamide. To this solution was added sodium methoxide (27 g, 0.5 mole). The suspension was treated with benzyl chloride (63 g, 0.5 mole) and stirring was continued for an additional 4 hr. The orange suspension was diluted with 3 1. of water and the solid was filtered, m.p. 109°-113°, yield: 110 g (78%). A small amount of the material was recrystallized from toluene to give an analytical sample melting at 116°-117°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[CH2:51](N(C(C)C)C(C)C)C.[CH3:60][C:61]1([CH3:69])[CH2:67][CH2:66][C:65](=[O:68])[O:64][C:62]1=[O:63]>C(Cl)Cl>[CH3:51][O:64][C:62](=[O:63])[C:61]([CH3:69])([CH3:60])[CH2:67][CH2:66][C:65]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:68]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: ClCCl
Product: CCC(CC)N(CCN(C)C(=O)CCC(C)(C)C(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reaction time: 1 h

Procedure:
To a mixture of 220 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.20 mL of N-ethyl-N-isopropylpropan-2-amine and 5.0 mL of methylene chloride was added 100 mg of 2,2-dimethylglutaric anhydride under ice cooling, followed by stirring for 1 hour at the same temperature and then for a day at room temperature, and the reaction mixture was concentrated under reduced pressure. 200 mg of potassium carbonate and 10 mL of DMF were added to the obtained residue, 150 mg of methyl iodide was further added thereto under ice cooling, and the reaction mixture was stirred for 1 hour under ice cooling and then for a day at room temperature. Ethyl acetate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 260 mg of methyl 4-(2-{4-[({2-[(3-{[{2-[(5-methoxy-4,4-dimethyl-5-oxopentanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CC1(F)Cl
Product: CC1(C(=O)Cl)CC1(F)Cl
Yield: 95.7 %

Procedure:
In a distillation equipment, a mixture of 51 g (0.33 mol) of 2-fluoro-2-chloro-1-methylcyclopropanecarboxylic acid and 60 g (0.5 mol) of thionyl chloride is heated slowly with stirring, during which process excess thionyl chloride distils over first and the desired product later. In this manner, 54 g (97% of theory) of 2-fluoro-2-chloro-1-methylcyclopropanecarbonyl chloride are obtained in the form of a liquid of boiling point 82-85° C./ 100 mbar.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH3:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]#[N:21])=[O:14]>>[CH3:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]#[N:21])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: CC12CCC(N)(CC1)CC2
Product: CC12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Yield: 60.2 %

Procedure:
Using 4-amino-1-methylbicyclo[2,2,2]octane (75.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (110 mg), the same procedure was followed as in Example 1 to obtain (2S)-1-[[N-(4-methylbicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (84.0 mg).
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23]>C1COCC1.CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5](=[O:23])[CH:4]([NH:2][CH3:1])[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1Br
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC1C=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reaction time: 0.17 h

Procedure:
A solution of methyl amine (16.0 mL of a 1.1N THF solution, 17.6 mmole) in 50 mL of dry THF was cooled to 0°-5° C. in an ice-water bath. To this solution was added, over a ten minute period, a solution of crude rac-3-bromo-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-H1-benzazepin-2-one (3.36 g estimated to be 85% pure, 7.36 mmole), dissolved in 55 mL of THF. After 10 minutes, the reaction solution was diluted with 300 mL of EtOAc, washed with water and brine, and dried (sodium sulfate). Concentration and drying under high vacuum yielded 2.98 g of crude material, which was used as is in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH2:24])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate (5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane and then extracted with 10% hydrochloric acid. The hydrochloric acid extract was washed twice with dichloromethane and then it was made basic with ammonium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 3.7 g of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine as a white powder, m.p. 175-176° C. Analysis: Calculated for C15H20N6: %C, 63.36; %H, 7.09; %N, 29.55. Found: %C, 62.98; %H, 6.92; %N, 29.89. HRMS (EI) calcd for C15H20N6 (M+) 284.1749. found 284.1748.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]([CH2:19][CH2:20][CH2:21]O)=[CH:17][N:16]=[CH:15]2)=[CH:9][CH:8]=1)#[N:6]>C(Cl)Cl>[Cl:3][CH2:21][CH2:20][CH2:19][C:18]1[N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: N#Cc1ccc(Cn2cncc2CCCO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCCCl)cc1

Procedure:
To a solution of 5.2 g of thionyl chloride in 80 ml of methylene chloride is added 8.4 g of 1-(p-cyanophenylmethyl)-5-(3-hydroxypropyl)-1H-imidazole as a solid in portions. The rate of addition is regulated to control the foaming that occurs. When addition is complete, the solution is refluxed for 1.5 h, cooled in ice and filtered to obtain the hydrochloride salt of the title compound (c) as a buff-colored solid, m.p. 190°-191°. The salt is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic extracts are washed with water, dried over sodium sulfate and evaporated to yield the free base as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:1]2[CH2:2][CH2:3][C:4](=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)[CH2:5][CH2:6]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 0.15 g (0.6m mole) of 10,11-dihydro-5-(4-piperidylidene)-5H-dibenzo[a,d]cycloheptene, 0.096 g (0.55 m mole) of 4-pyridylacetic acid hydrochloride, 0.16 g (0.83 m mole) of DEC and 0.075 g (0.55 m mole) of HOBT in 5 mL of DMF and stir at room temperature for 18 hours under nitrogen. Concentrate under vacuo and partition between 100 mL each of EtOAc and 10% aqueous sodium hydrogenphosphate. Dry the organic layer over MgSO4 and concentrate under vacuo. The resulting residue is chromatographed on silica gel using 98% dichloro methane and 2% MeOH, saturated with ammonia as the solvent, giving the product as a white waxy solid, mp=162.8°-163.4° C.