Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[Cl-].COC1N=C([N+]2(C)CCOCC2)N=C(OC)N=1.Cl.[CH3:36][S:37]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:49]1[CH:54]=[C:53]([O:55][CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[N:52]=[CH:51][N:50]=1)[CH2:44][CH2:43]2)(=[O:39])=[O:38]>O.C(O)C>[CH3:36][S:37]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([C:49]1[N:50]=[CH:51][N:52]=[C:53]([O:55][CH:56]3[CH2:61][CH2:60][N:59]([C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH3:7])[CH2:58][CH2:57]3)[CH:54]=1)[CH2:44][CH2:43]2)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: CC(O)CC(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Product: CC(O)CC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
3-hydroxybutanoic acid (61 μL, 0.66 mmol), diisopropylethylamine (102 μL, 0.571 mmol), and 4-(dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (235 mg, 0.849 mmol) were added to an ethanol (3 mL) suspension of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline hydrochloride (224 mg, 0.545 mmol) produced in Reference Example 27, and the mixture was stirred at room temperature for 3 days. To the reaction solution, water was added, followed by extraction with dichloromethane three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by thin-layer silica gel chromatography (dichloromethane:methanol=1:1, V/V). The obtained crude product was washed with diisopropyl ether to obtain the title compound as grayish white foam (174 mg, yield: 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>[Cu]I>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ccccn1
Agent: [Cu]I
Product: OCCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2-bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0° C. under N2, 3-butyn-1-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70° C. The reaction mixture was quenched at 0° C. with water, TEA was removed under low pressure, and the organic layer was extracted 3× using DCM, washed with Ammonia, water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH: from 99/1 to 95/5 as eluent) to afford 3.60 g of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield: 77%).
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:43][CH2:44][C:45]([OH:47])=[O:46]>>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Reactant: NCC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)O
Yield: 70.2 %

Procedure:
Starting from 3-(9-octadecenoyloxy)-11-eicosenoic acid (2.6 g) prepared by the method described in Preparation 8 and glycine (1.2 g), N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycine (2 g) was obtained as powders in a similar manner to that of Example 6.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].[ClH:14].[CH3:15][NH:16][CH3:17].[CH2:18]=O.Cl>C(O)C>[ClH:14].[CH3:15][N:16]([CH3:18])[CH2:17][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)=[O:3]
Reactant: CNC
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1cccc(C(F)(F)F)c1
Yield: 74.8 %

Procedure:
A mixture of 1-(3-(trifluoromethyl)phenyl)ethanone (25.0 g) (II), dimethylamine hydrochloride (13.0 g), paraformaldehyde (4.8 g), 31% w/w aqueous hydrochloric acid (0.5 mL) in ethanol (70 mL) was stirred at reflux temperature for 24 hrs, then cooled down and the solvent flushed with toluene (50 mL). The precipitated pale yellow solid was then filtrated, washed with toluene and dried to give the title compound (IV) (28.0 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[OH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1.N1CCCCC1>ClCCCC>[OH:24][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:14])[C:16]1=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N:3]([CH2:12][CH3:13])[CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: O=C1CC(O)c2ccccc21
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: CCCCCl
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc(C=C2C(=O)c3ccccc3C2O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of 56.6 g.(0.32 mole) of p-diethylaminobenzaldehyde, 47.36 g. (0.32 mole) of 3-hydroxy-1-indanone and 7 ml. of piperidine was then heated with magnetic stirring to 80°-100° C. for 1.5 hours (the mixture is a melt at the reaction temperature). The mixture was cooled in ice water, 90 ml. of 1-chlorobutane and seed was added. The product tended to come out as a gum; the solution was therefore heated, cooled (seeded) and muddy brown solid separated. The product was collected by filtration and the brown solid washed until bright orange; 43.62 g. 44% yield, m.p. 139°-141°, m.p. recrystallized material (1-chlorobutane) 142°-143° C. An extra 11% yield was obtained through concentration and refiltration of the filtrate; the latter fraction washed up as cleanly as the first. The IR spectrum and elemental analysis are those expected of the titled merocyanine derivative.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15](CC2C=CC=CC=2)[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[N:12]=1.Cl.[H][H]>C(O)C.CCOCC.[Pd]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[N:15]=1
Reactant: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Reactant: [H][H]
Agent: O=[Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: BrCCCCCOCCCc1nc2ccccc2[nH]1
Yield: 69.1 %

Procedure:
A solution of 2-[3-[(5-bromopentyl)oxy]propyl]-1-(phenylmethyl) benzimidazole (1.7 g) in absolute ethanol (20 ml) containing 1:9 conc. hydrochloric acid:ethanol (3.27 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal catalyst (300 mg) in ethanol (5 ml) until the uptake of hydrogen (101 ml) ceased. The mixture was filtered through hyflo and evaporated in vacuo to give an oil, which was dissolved in ether (150 ml) and washed with 8% sodium bicarbonate solution (100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (2:3→0:5) gave the title compound as a yellow oil (0.92 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=2)=[CH:15][CH:14]=1.O.CCOC(C)=O>N1CCCCC1.[Cu]I>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=3)=[N:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: OCCOc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: O
Product: OCCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 253 mg (0.22 mmol) tetrakis-triphenylphosphane-palladium and 42 mg (0.22 mmol) CuI are added to a solution of 2.9 g (11 mmol) 2-(4-iodo-phenoxy)-ethanol and 2.35 g (11 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine in 50 mL piperidine and the reaction mixture is stirred for 30 min at RT. The solvent is eliminated i.vac., the residue is combined with water and stirred with EtOAc. The product precipitated is suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Product: O=C(O)c1cc(NCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 90.3 %

Procedure:
According to the similar procedure to Synthesis Example 1, by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrophenylethyl bromide (900 mg, 3.92 mmole), 890 mg (50% yield) of 2-hydroxy-5-[2-(4-nitrophenyl)ethylamino]-benzoic acid was obtained as a pale yellow solid. Melting point 234-236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1
Yield: 45.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from dichloromethane-hexane to give 0.19 g of crystals, m.p. 219°-221° C.
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:20])[C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:34]1C=CC=C[CH:35]=1>C(OCC)(=O)C.CN>[CH3:20][C:13]1([CH3:21])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2][NH:34][CH3:35])[C:12]1=[O:22]
Reactant: CC1(C)C(=O)N([C@@H](CCO)c2ccccc2)c2ccccc21
Reactant: c1ccncc1
Agent: CN
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Reaction time: 16 h

Procedure:
1-[(1S)-3-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.15 g, 3.9 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.89 g, 4.6 mmol) was added. Stirred for 16 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A portion of the crude product (100 mg, 0.21 mmol) was immediately dissolved in methylamine (8M in ethanol, 10 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 0-15% methanol saturated with ammonia in chloroform) to give 3.3-dimethyl-1-[(1S)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one as a colorless oil. The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (1.0 equivalent). The white precipitate was collected and dried under vacuum to give 43 mg 3,3-dimethyl-1-[(1S)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH3:10]>COCCOC>[CH3:16][C:14]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[C:13]=1[C:12]([O:11][CH2:9][CH3:10])=[O:18]
Reactant: Cc1ccnc(N)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2cc(C)ccn12
Yield: 78 %

Procedure:
In this specific example of synthesis of ND-8454, a solution of 2-amino-4-picoline (10.0 g, 91.5 mmol) and ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 mL of 1,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered and solids (2-amino-4-picoline hydrochloride salt) was collected and washed with hexanes. The filtrate liquor was concentrated in vacuo and residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2×) and brine. The organic phase was collected, dried over sodium sulfate (Na2SO4), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 20% ethyl acetate:CH2Cl2 solvent system to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate as a tan solid. mp 59-61° C.; 1H NMR (300 MHz, CDCl3) 9.14 δ(d, J=7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J=7.1, 1.7 Hz, 1H), 4.40 (q, J=7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1.42 (t, J=7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calcd. for C12H15N2O2, 219.1155; found 219.1128. Retention time=1.4 minutes (mobile phase: 60% water:acetonitrile).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].S(Cl)([Cl:12])=O.[CH3:14]O>C(OCC)C>[CH3:14][O:5][C:4]([CH2:3][C@@H:2]([NH2:1])[C:7]([OH:9])=[O:8])=[O:6].[ClH:12]
Reactant: CO
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C[C@@H](N)C(=O)O
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A suspension of D-aspartic acid (10.0 g, 75.1 mmol) in 50 mL methanol is treated with thionyl chloride (8.94 g, 75.1 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min, then at RT for 2 h. The resulting clear solution is diluted with 200 mL diethyl ether with rapid stirring. A white precipitate is formed which is collected by vacuum filtration, washed with diethyl ether and dried to yield 10.7 g (78%) of D-aspartic acid b-methyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:25](O)=[O:26])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH2:15][CH3:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C@H:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C@@H:28]([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: CCC(CC(=O)OC)c1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.07 mmol) of (+/−)-methyl 3-(3-amino-4-chlorophenyl)pentanoate and 668.9 mg (2.48 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 1.7 ml of pyridine and 3.3 ml of DMF, and 1.02 g (2.69 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed with 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase initially cyclohexane, then cyclohexane/ethyl acetate 50:1). This gave 675 mg of the target product (66.6% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CNc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CNc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1
Yield: 53 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)[CH2:16][CH3:17]>P(Cl)(Cl)(Cl)=O>[CH2:16]([C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1)[CH3:15]
Reactant: CCC(=O)O
Reactant: Nc1cnccc1Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2cnccc2n1-c1ccccc1
Yield: 19.3 %

Procedure:
A mixture of N4-phenylpyridine-3,4-diamine (8.0 g, 37.2 mmol), propionic acid (2.7 g, 37.2 mmol) and phosphorous oxychloride (50 mL) was stirred at reflux for 10 h. The reaction was purified by silica gel chromatography using ethyl acetate to afford the product as a solid (1.6 g, 19%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Na].[SH2:22]>CN(C)C=O.O.C(O)(=O)C>[CH:7]1[N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:18]2[C:5](=[C:4]([NH2:20])[NH:3][C:2]([N:19]=2)=[S:22])[N:6]=1
Reactant: S
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
2.0 g of 2-chloroadenosine was dissolved in a solution of 20 ml of anhydrous hydrogen sulfide and 1.5 g of sodium metal in 80 ml of dimethylformamide, and the mixture was allowed to react at a temperature of 80°C for 5 hours under anhydrous conditions. The reaction mixture was then diluted with 80 ml of water and neutralized with acetic acid followed by concentration. The resulting concentrate was dissolved in 75 ml of a mixture of n-butanol and water (2:1 by volume), and 25 ml of acetic acid was added to the solution. After allowing the mixture to cool, the precipitated crystals were filtered to obtain 21 g (100% yield) of crude 2-thioadenosine. The product thus-obtained was dissolved in dilute aqueous ammonia and adjusted to a pH of 4 with acetic acid to obtain pure 2-thioadenosine having a melting point of 196° ~ 199°C (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1C)[CH2:9][CH2:8][CH2:7]2.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:23](=O)([O-])[O-:24].[Na+].[Na+]>>[C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:24][CH3:23])[CH2:9][CH2:8][CH2:7]2)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc2c(cc1CCN)CCC2
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Product: COc1cc2c(cc1CCNC(=O)c1ccccc1)CCC2

Procedure:
The procedure of Example 1 was followed in reacting 5-aminoethyl-6-methylindan with benzoylchloride, using sodium carbonate in place of triethylamine, to produce the desired product. After recrystallization from ether the product melted at 104°-106° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:15]C(N)=O>>[F:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:15][C:1](=[O:2])[CH2:4]2
Reactant: O=C(O)Cc1cc(F)ccc1C(=O)O
Reactant: NC(N)=O
Product: O=C1Cc2cc(F)ccc2C(=O)N1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
An amount of 200 mg (1.01 mmol) of 2-carboxymethyl-4-fluoro-benzoic acid and urea (72.47 mg, 1.22 mmol) were heated neat at 180-190° C. for 45 min. The mixture is cooled to room temperature followed by recrystallization from water and anhydrous ether to give 175 mg (80% yield) of brown solid. MS (ESI) m/z 179.15 (M+1).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:8]([F:14])([C:5]1[N:6]=[CH:7][N:3]([CH2:2][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:4]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)C(F)(F)F)n1
Yield: 9.4 %

Procedure:
1.74 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole and 1.20 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.04 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.25 g of {[3-(pentafluoroethyl)-1H-1,2,4-triazole 1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (34), hereinafter) shown by below formula.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[CH:11]=1)[C:7]#[N:8].[CH3:19]I>C1COCC1.CCOC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]([CH3:19])[C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH:11]=1)[C:7]#[N:8]
Reactant: CI
Reactant: N#Cc1cc(F)cc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(F)cc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
NaH (23 mg, 0.96 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.1 mL) was added. The slurry was cooled to 0° C. and compound 11 (185 mg, 0.864 mmol, 1.00 eq) was added as a solution in THF (2.1 mL). After stirring at 0° C. for 30 minutes methyl iodide (59.3 μL, 0.958 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 163 mg (83%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.71 (s, 2H), 7.32-7.27 (m, 2H), 7.19 (dt, J=11.7, 2.3 Hz, 1H), 3.35 (s, 3H); [M+1]+: 229.2.