Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:31])=[C:17]([CH3:30])[C:18]4[O:22][C:21]([CH2:24][C:25](O)=[O:26])([CH3:23])[CH2:20][C:19]=4[C:28]=3[CH3:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:32]([NH2:35])[CH2:33][CH3:34].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:31])=[C:17]([CH3:30])[C:18]4[O:22][C:21]([CH2:24][C:25]([NH:35][CH2:32][CH2:33][CH3:34])=[O:26])([CH3:23])[CH2:20][C:19]=4[C:28]=3[CH3:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CC(=O)O)O4)CC2)cc1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNC(=O)CC1(C)Cc2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.4 %

Procedure:
A solution of DMF (1.0 mL) containing {5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}acetic acid (50 mg, 0.118 mmol) synthesized in Example 141, propylamine (45 mg, 0.236 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.236 mmol), 1-hydroxybenzotriazol monohydrate (36 mg, 0.236 mmol) and triethylamine (60 mg, 0.590 mmol) was stirred at room temperature for 15 hours, and the reaction solution was distributed using water and ethyl acetate. The organic layer was washed with saturated saline and dried using anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 90:10-70:30) and crystallized from ethyl acetate-hexane to obtain 20 mg of the title compound (yield 36%). Melting point was 135 to 138° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25]([OH:27])=O)[C:10](=[O:28])[CH2:9]1)=[O:7].[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.ON1C2C=CC=CC=2N=N1.[ClH:56].CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>ClCCl.O>[ClH:56].[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25]([N:42]2[CH2:43][CH2:44][CH2:45][N:39]([CH3:38])[CH2:40][CH2:41]2)=[O:27])[C:10](=[O:28])[CH2:9]1)=[O:7]
Reactant: O=C(O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Reactant: CN1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CN1CCCN(C(=O)CN2C[C@@H](Cc3c[nH]c4ccccc34)N(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To an ice-cooled solution of (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(carboxymethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.15 g), 1-methylhomopiperazine (0.032 g) and 1-hydroxybenzotriazole (0.038 g) in dichloromethane (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.055 g). The mixture was stirred at the same temperature for 1 hour and then at room temperature for 16 hours. Water and aqueous sodium bicarbonate solution were added and then the resulting mixture was extracted with dichloromethane. The organic layer was washed successively with aqueous sodium bicarbonate solution, water and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue (0.13 g) was dissolved in dichloromethane (2 ml). To the solution was added 4N hydrogen chloride in dioxane solution (0.052 ml) under ice-cooling, and the mixture was stirred for 50 minutes at the same temperature. After concentration, ether was added to the residue and the resulting precipitates were collected by filtration, washed with ether, and dried to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-5-(1H-indol-3-ylmethyl)-1-[(4-methyl-1-homopiperazinyl)carbonylmethyl]-piperazin-2-one hydrochloride (0.13 g) as an amorphous solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:28][C:29]([F:46])([F:45])[C@H:30]([O:32][C:33](=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1)[CH3:31]>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:33]([O:32][C@H:30]([CH3:31])[C:29]([F:46])([F:45])[F:28])=[O:34])[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: C[C@@H](OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2)C(F)(F)F

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and (R)-carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 12. LC (method 6): tR=1.00 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: O[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[Cl:24][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1ccccc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6a (2.00 g, 7.54 mmol) in MC (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (1.90 g, 15.0 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/9). As the result, Compound 7a was obtained.
Reaction SMILES: [CH2:1]([O:17][C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC(OCC)=O>N1C=CC=CC=1>[CH2:1]([O:17][C:18]1[O:24][C:23](=[O:25])[C:22]2[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:21]=2[N:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Nc1ccc(C)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
4.0 g (10.0 mmol) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid are introduced into 20 ml of pyridine at 0° C. under a nitrogen atmosphere, and 4.93 g (45.4 mmol) of ethyl chloroformate are added dropwise to the resulting solution at 0° C. over the course of 20 min. After the reaction mixture has been stirred at 0° C. for 1 h and at room temperature for 2 h it is added to 30 ml of ice-water. The solid is filtered off and dried in vacuo. 3.3 g (8.2 mmol, 82%) of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one are obtained in the form of a pale yellow coloured solid with a melting point of 67° C. (literature: 72-73° C., WO 00/40569).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)([CH3:21])[CH3:20]>>[CH:19]([N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:28]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CC(C)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-isopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e) 404, obsd 405 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[C:39]5[CH:38]=[C:37]6[C:40]([CH3:48])([CH3:47])[C:41]7[C:46]([C:36]6=[CH:35][C:34]=5[C:33]5[C:28]4=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:45][CH:44]=[CH:43][CH:42]=7)=[CH:23][CH:22]=3)=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:49]([CH3:57])([CH3:56])[C:50]4[C:55]([C:7]3=[CH:6][C:5]2=1)=[CH:54][CH:53]=[CH:52][CH:51]=4.[B:58]1(B2OC(C)(C)C(C)(C)O2)[O:62][C:61]([CH3:64])([CH3:63])[C:60]([CH3:66])([CH3:65])[O:59]1.C([O-])(=O)C.[K+].ClCCl>O1CCOCC1>[CH3:65][C:60]1([CH3:66])[C:61]([CH3:64])([CH3:63])[O:62][B:58]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C:39]6[CH:38]=[C:37]7[C:40]([CH3:48])([CH3:47])[C:41]8[C:46]([C:36]7=[CH:35][C:34]=6[C:33]6[C:28]5=[CH:29][CH:30]=[CH:31][CH:32]=6)=[CH:45][CH:44]=[CH:43][CH:42]=8)=[CH:23][CH:22]=4)=[CH:17][CH:16]=2)[C:10]2[CH:9]=[C:8]4[C:49]([CH3:57])([CH3:56])[C:50]5[C:55]([C:7]4=[CH:6][C:5]3=2)=[CH:54][CH:53]=[CH:52][CH:51]=5)[O:59]1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(Br)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(B8OC(C)(C)C(C)(C)O8)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21

Procedure:
7.1 g (9.0 mmol) of 4-(7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)-4′-(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl, 2.5 g (9.85 mmol) of bis(pinacolato)diborane and 2.6 g (26 mmol) of potassium acetate are suspended in 500 ml of dioxane. 0.22 g (0.27 mmol) of 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex with dichloromethane is added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 150 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene. The yield is 6.8 g (8 mmol, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[N:6][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1C(=N)N
Product: Cc1ccccc1-c1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=358.9 (M+H+), was prepared from 2-methyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A solution of ethyl 3-[4-benzyloxyphenyl)-2-hydroxypropanoate (5.0 g, 16.6 mmol) (prepared in a similar manner as described in Ref: WO95/18125) in dry dimethyl formamide (5 mL) was added to a suspension of sodium hydride (0.1 g, 41.6 mmol) (60% dispersion in oil) in dry dimethyl formamide (3 mL) at 0° C. and stirring was continued for further 1 h. To the above reaction mixture n-butyl bromide (3.4 g, 24.0 mmol) was added at 0° C. and stirring was continued for 10 h at ca. 25° C. Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with water (50 mL), brine (25 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and and pet. ether (1:9) as an eluent to afford the title compound (0.7 g, 20%) as an oil.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:6]([Cl:18])=[CH:7][C:8]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:10]=1[NH2:11]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[NH:12][C:8]1[N:9]=[C:10]2[NH:11][C:2]([NH2:1])=[N:4][C:5]2=[C:6]([Cl:18])[CH:7]=1)[CH3:17]
Reactant: N#CBr
Reactant: CCOC(=O)Nc1cc(Cl)c(N)c(N)n1
Solvent: CCO
Product: CCOC(=O)Nc1cc(Cl)c2nc(N)[nH]c2n1
Reaction time: 3 h
Yield: 38 %

Procedure:
Cyanogen bromide (0.55 g, 5.2 mmol) was added to a stirred solution of ethyl 5,6-diamino-4-chloro-2-pyridinecarbamate (intermediate for the preparation of 1, 1.00 g, 4.3 mmol) in 20 mL of ethanol at room temperature. The solution was stirred for 3 h and then at 60° C. for 3 h. The precipitate was filtered and washed with diethyl ether to give (2-amino-7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-carbamic acid ethyl ester (0.55 g, 38%) as a yellow powder. 1H NMR confirmed the structure.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:10](O)=[O:11]>C1COCC1>[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11]
Reactant: NC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CCO)c1ccccc1
Temperature: 0 °C

Procedure:
To a well stirred suspension of LiAlH4 (1.3 g, 35.0 mmol) in THF (75 mL) in a round bottom flask fitted with a condenser was added 3-amino-3-phenyl-propionic acid (2.5 g, 15.0 mmol) in small portions at 0° C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 1.3 mL of water, 1.3 mL of 3N NaOH followed by 4.0 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et2O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO4, filtered and the solvent was removed in vacuo. 3-amino-3-phenyl-propan-1-ol was obtained as a white solid (2.30 g, 100%) which was used in the next step without further purification.
Reaction SMILES: O.O.[Sn](Cl)Cl.[OH:6][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1>>[OH:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cccc2c(O)ncc(Br)c12
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cccc2c(O)ncc(Br)c12

Procedure:
According to the method of Example 114, Step A, a reduction reaction with tin(II) chloride dihydrate was performed by using Intermediate 137 to obtain the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N:12]=1.[H-].[Na+]>C(#N)C>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:9])=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCCC1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2ccc(Cl)nc2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 4-propylpyrrolidin-2-one x1 (0.50 g, 3.93 mmol, 1 eq) and 2-chloro-5-(chloromethyl)pyridine x37 (0.64 g, 3.93 mmol, 1 eq) in acetonitrile (3 ml) is heated at 50° C. NaH (60% dispersion in oil, 158 mg, 3.93 mmol, 1 eq) and acetonitrile (5 ml) are added and the solution is stirred for 8 h at 50° C. The mixture is then poured on ice/water and the aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 99/1/0.1 (v/v/v)) to afford 790 mg of 1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 68 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using cyclopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 148 mg, 68%) which was obtained as a white solid. MS: m/e=350.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[O:25]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: COc1cccc(C(=O)NN)c1
Product: COc1cccc(C(=O)NNC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methoxybenzoyl)isonicotinohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.55 mmol of 3-methoxy-benzohydrazide. LC/MS [9.23 min; 507 (M+1)]
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Li+].CCOCC.O.Cl>C1COCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14][C:15]#[C:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(C#CSc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(SC#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate (590 mg, 1.6 mmol) and of lithium hydroxide (383 mg, 9.3 mmol) in THF is refluxed for 24 hours. The reaction mixture is poured into an Et2O/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution, and extracted once with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The solid obtained is crystallized from heptane and 440 mg (77%) of a white solid are obtained. m.p. (melting point)=193.5° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1.[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:19]([NH:31][C:17]([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CC(CSc2nc3ccccc3s2)C(=O)O1
Product: CCCCCCCCCCCCNC(=O)C(CSc1nc2ccccc2s1)CC(=O)O

Procedure:
A mixture of 6.5 parts of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic anhydride and 4.3 parts of dodecylamine is heated at 55° during 3 hours to give a mixture of the two isomeric mono-dodecylamides as a yellow oil.
Reaction SMILES: [NH:1]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:43]([NH:45][C@H:46]([C:66]([O:68]C)=[O:67])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:65])[NH:52][S:53]([C:56]1[C:63]([CH3:64])=[CH:62][C:60]([CH3:61])=[CH:59][C:57]=1[CH3:58])(=[O:55])=[O:54])=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1>[NH:1]([C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:43]([NH:45][C@H:46]([C:66]([OH:68])=[O:67])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:65])[NH:52][S:53]([C:56]1[C:63]([CH3:64])=[CH:62][C:60]([CH3:61])=[CH:59][C:57]=1[CH3:58])(=[O:55])=[O:54])=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
0.14 g (0.13 mmol) of the product (XV) was dissolved in 1.95 ml of dry dioxane and 0.65 ml of 1N NaOH was added thereto. The mixture was stirred at room temperature for 3 hours. After removing the dioxane by concentrating under reduced pressure, approximately 20 ml of water was added and a small amount of insoluble matter was filtered off. The filtrate was cooled and 10% citric acid at 0° C. was added thereto. The precipitate thus formed was filtered, washed with a small amount of water twice and then dried. Thus 0.10 g of Boc-Tyr(Bzl)-Ile-Gly-Ser(Bzl)-Arg(Mts)-OH was obtained. This product was stirred in 6.0 ml of dry dioxane and 6.0 ml of 4N HCl/dioxane for 3 hours to remove the Boc group. Thus 0.08 g of HCl.H-Tyr(Bzl)-Ile-Gly-Ser(Bzl)-Arg(Mts)-OH was obtained.