Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:16][C:17]1[C:18]([N:24]2[CH2:25][CH2:26][N:27]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=3)=[O:13])[CH2:28][CH2:29]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CNS(C)(=O)=O)cc3)CC2)c(C)c1
Yield: 80.9 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (183 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (153 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (260 mg) was obtained.
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O.C(O)(CC)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CS(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([C:65]3[CH:70]=[C:69]([N:71]4[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]4=[O:78])[CH:68]=[C:67]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:66]=3[O:83][CH3:84])[CH:61]=2)[CH:56]=1)(=O)=O.[CH3:85][S:86]([NH2:89])(=[O:88])=[O:87]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:79]([C:67]1[C:66]([O:83][CH3:84])=[C:65]([C:60]2[CH:61]=[C:62]3[C:57](=[CH:58][CH:59]=2)[CH:56]=[C:55]([NH:89][S:86]([CH3:85])(=[O:88])=[O:87])[CH:64]=[CH:63]3)[CH:70]=[C:69]([N:71]2[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]2=[O:78])[CH:68]=1)([CH3:82])([CH3:81])[CH3:80]
Reactant: COc1c(-c2ccc3cc(OS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: O
Solvent: CCC(C)(C)O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.0018 g, 8.09 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0086 g, 0.018 mmol) and water (0.6 μL, 0.032 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, and the contents were heated to 80° C. and stirred at this temperature for 15 minutes. The reaction mixture was cooled down to room temperature. Potassium phosphate tribasic (0.094 g, 0.445 mmol), 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to the 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 5 area % at 210 nm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2 g, 12.7 mmol) in MeOH (64 mL) was added dropwise thionyl chloride (0.93 mL, 12.7 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to dryness to give trans-methyl 4-(aminomethyl)cyclohexanecarboxylate (2.5 g, 115%) as HCl salts.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][N:14]([CH3:16])C)=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:16]([NH:14][CH2:13][CH2:12][C:8]1[C:7]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][C:9]=1[OH:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)CCc1ccc(C(C)(C)C)cc1O
Product: CC(C)(C)c1cc(O)c(CCNCc2ccccc2)c(C(C)(C)C)c1

Procedure:
The product of Example 75 (0.143 g) was treated with 0.060 g (0.58 mmol) of benzaldehyde according to the procedure described in Example 3. The product was purified on a silica gel flash chromatography column eluted with 5% isopropanol in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:22][N:21]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1Cl

Procedure:
Prepared according to Method D, Step A from (3-chloro-2-fluorophenyl)(3-chloro-4-methoxyphenyl)methanone (2.04 g, 6.82 mmol), hydrazine hydrate (2.5 mL), dimethylaminopyridine (0.97 g) and pyridine (12.5 mL). The title compound was obtained as a white solid and recrystallized from ethyl acetate/hexane (1.74 g, 5.94 mmol, 87%).
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:22]([NH:26][CH2:27][C:28]#[N:29])[CH:23]([CH3:25])[CH3:24].C(OC(=O)C)(=O)C.C(#N)C>C1(C)C=CC=CC=1.CN(C)C(=O)C.O>[CH2:22]([N:26]1[C:15](=[O:17])[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:27]1[C:28]#[N:29])[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Reactant: CC(C)CNCC#N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cn1c(C#N)c(-c2ccccc2)c2cccnc2c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a suspension of 3-benzoylpyridin-2-carboxylic acid (2.27 g, 10 mmol) in toluene (20 ml) was added thionyl chloride (0.88 ml, 12 mmol) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 ml). The obtained solution was added dropwise to (isobutylamino)-acetonitrile (1.68 g, 15 mmol) in N,N-dimethylacetamide (20 ml) and the mixture was stirred at 70° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue and acetic anhydride (1.1 ml, 12 mmol) in acetonitrile (6.0 ml, 40 mmol) at 0° C. and the mixture was stirred at room temperature for 15 h. Water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 7-isobutyl-8-oxo-5-phenyl-7,8-dihydro[1,7]naphthyridine-6-carbonitrile (2.65 g, 87.5%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CCCCCC.C(O)C>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[C@@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(C)sc3c21
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NCC[C@H]1CCc2ccc3nc(C)sc3c21
Yield: 49.2 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide (1.00 g) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=90/10), injection weight: 500 mg×2). A fraction containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (492 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a stirring solution of 4-fluoro-2-hydroxy-benzoic acid (5.58 g, 35.7 mmol) in dimethyl formamide (72 mL, 0.5 M) was added N-bromosuccinimide (7.08 g, 39.3 mmol). The mixture was allowed to stir for 24 h at room temperature. Next, the mixture was diluted with 300 mL of ethyl acetate and washed successively with water (3 x 330 mL) and saturated aq LiCl (4×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 5-bromo-4-fluoro-2-hydroxy-benzoic acid (8.1 g, 96%) as a beige powder. Please note, the product may contain up to 20% of a dibrominated impurity which may be separated from the desired product after coupling with a benzylamine or upon methylation (Example 50): Rf 0.32 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 mHz) δ 8.00 (d, J=8.1 Hz, 1H), 7.05 (d, J=10.5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (E)-ethyl 3-(5-hydroxy-[1,1′-biphenyl]-2-yl)acrylate (652) (420 mg, 1.57 mmol) in ethanol (6 mL) was added Pd/C (42 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(5-hydroxy-[1,1′-biphenyl]-2-yl)propanoate (653).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-1 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and 1-bromohexane (0.201 ml) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (620 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33])#[N:21].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[C:23]([C:32]([F:33])([F:34])[F:35])[CH:24]=2)(=[O:30])=[O:29])[C:3]([C:9]([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1C(F)(F)F

Procedure:
Prepared from 40 mg (0.15 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 137 mg (0.51 mmol) of 4-cyano-3-trifluoromethyl-benzenesulfonyl chloride in 0.3 mL pyridine using procedure x. After the sulfonylation was complete, 3 mL methanol, 0.5 mL water and 71 mg sodium hydroxide were used. Yield: 10 mg of a yellow solid. LC-MSD, m/z for C21H12ClF3N5O3S [M+H]+=505.9, 507.9
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].O.CO>O1CCCC1>[OH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(O)ccc2n1CC(F)(F)F
Yield: 99.7 %

Procedure:
A mixture of 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid ethyl ester (Intermediate 1, step b, 8.5 g, 1.0 eq.), lithium hydroxide monohydrate (1.43 g, 1.15 eq.), water (45 mL), methanol (30 mL) and tetrahydrofuran (90 mL) was heated to reflux for 24 h. The volatiles were removed in vacuo and the resulting solution was acidified (pH ca. 2) with hydrochloric acid (1N). The precipitate was filtered and dried in vacuo to yield 7.65 g (99%) of the desired product as off-white solid. MS (m/e): 258.5 (M−H−, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)C>[NH2:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CO)nc1N
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Dimethyl 6-aminopyridine-2,5-dicarboxylate (395 mg) was suspended in a mixed solvent (16 ml) of tetrahydrofuran/ethanol (1/1), calcium chloride (834 mg) and sodium borohydride (85.5 mg) were added thereto under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was acidified with 1M hydrochloric acid, basified with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (296 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.O.[NH2:13][NH2:14]>>[NH:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[O:1])[N:3]=1)[NH2:14]
Reactant: O=c1[nH]c(=S)c2nc[nH]c2[nH]1
Reactant: NN
Solvent: O
Product: NNc1nc(=O)[nH]c2[nH]cnc12
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
2-Oxo-6-thioxo-1,2,3,6-tetrahydro-9H-purine (J. Am. Chem. Soc., 76, 5633 (1954)) (0.5 g, 2.97 mmol) was added to 80% hydrazine hydrate (5 ml), and the mixture was stirred for 10 minutes at 120° C. After completion of reaction, crystals that precipitated were collected by filtration, and washed with water. The crystals were recrystallized from water to obtain 0.31 g (yield 63%) of colorless powdery crystals (m.p.=278° C. (decomposed)).
Reaction SMILES: O[N:2]=[C:3]([NH2:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:24])=[NH:2])=[CH:5][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=NO)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N=C(N)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 88.5 %

Procedure:
To an acetic acid (80 mL) suspension of 10.0 g of N′-hydroxy-4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine were added 5.31 mL of acetic anhydride and 0.50 g of 5% palladium-carbon at room temperature, which was stirred at room temperature under hydrogen atmosphere for 12 hours and 50 minutes. After filtering off insoluble matter, the solvent was distilled off under reduced pressure. To the resultant residue was added 6 mol/L hydrochloric acid, followed by distilling off the solvent under reduced pressure before purification using silica gel column chromatography (silica gel: ODS-A from YMC, eluent; water). The eluate was concentrated to about 100 mL under reduced pressure and then adjusted to pH 12 using a 5 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water to provide 8.43 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:17]=2)[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>C(O)C.O.[Fe]>[CH3:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:17]=2)[CH:5]=1)[NH2:10]
Reactant: C=C(C)Cn1cc(-c2cc(C)cc([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=C(C)Cn1cc(-c2cc(C)cc(N)c2)cn1
Temperature: 70 °C

Procedure:
Iron (1.57 g, 28.2 mmol) and saturated aqueous ammonium chloride (11 mL) were added to a solution of 4-(3-methyl-5-nitrophenyl)-1-(2-methylallyl)-1H-pyrazole (2.42 g, 9.41 mmol) in ethanol (7 mL) and water (11 mL). The mixture was heated at 70° C. for 18 h, then allowed to cool to room temperature, passed through CELITE, washed with methanol, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)aniline. MS ESI calc'd. for C14H18N3 [M+H]+ 228. found 228. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.68 (s, 1H), 6.52 (s, 2H), 6.21 (s, 1H), 4.92 (s, 2H), 4.87 (s, 1H), 4.70 (s, 1H), 4.66 (s, 2H), 2.14 (s, 3H). 1.60 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](O)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.CN(C=O)C>ClCCl>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:26]([N:37]3[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:27])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Reactant: C1CNCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCCNCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
200 mg (0.398 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 120 mg (1.20 mmol) of homopiperazine and 230 mg (1.20 mmol) of WSC hydrochloride were stirred in 6 ml of dichloromethane at room temperature overnight. 0.8 ml of DMF was added and stirred at 60° C. for 5 hours. After concentration under reduced pressure, chloroform was added. After being washed with saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained substance was dissolved in 5 ml of dichloromethane. 2 ml of trifluoroacetate was added and stirred at room temperature for 30 minutes. After concentration under reduced pressure, ethyl acetate was added and the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the thin layer silica gel chromatography (dichloromethane/methanol=9/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]=2)=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C2=NS(=O)(=O)c3ccccc32)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from example 1, step c (100 mg, 0.25 mmol) was dissolved in 4 mL MeOH. NaBH4 (30 mg, 0.75 mmol) was added and the reaction was stirred at rt for ½ h. Additional NaBH4 was added as needed in order to push the reaction to completion. The reaction was carefully quenched with HOAc until the evolution of hydrogen ceased. The resulting solution was partitioned between dichloromethane (DCM) and H2O. The organic layer was dried over MgSO4 and concentrated to an orange oil that was used without further purification. MS: ESI (negative): 397 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:2][CH2:3][CH2:4][N:5]([CH3:19])[CH3:6])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: CN(C)CCCOc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Yield: 175.8 %

Procedure:
According to Example 34, the compound (100 mg) produced in Example 37 was reacted with dimethylaminopropylchroride hydrochloride (54 mg) to obtain the title compound (105 mg; 100%).