Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](=[N:26]\[O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=O)/[C:3]1[NH:25][C:6]2=[N:7][CH:8]=[C:9]([Cl:24])[C:10]([C:11]3[S:15][C:14]([C:16]4([O:20][CH2:21][O:22][CH3:23])[CH2:19][CH2:18][CH2:17]4)=[N:13][CH:12]=3)=[C:5]2[CH:4]=1>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:10]([C:11]2[S:15][C:14]([C:16]3([O:20][CH2:21][O:22][CH3:23])[CH2:17][CH2:18][CH2:19]3)=[N:13][CH:12]=2)=[C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:31]4)[O:27][N:26]=3)[NH:25][C:6]2=[N:7][CH:8]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/OC(=O)C5CCCN(C(=O)OC(C)(C)C)C5)cc34)s2)CCC1
Solvent: Cc1ccccc1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Temperature: 25 °C

Procedure:
A solution of Example 22C (0.084 g, 0.136 mmol) in toluene (3 mL) was heated to 110° C. for 10 hours. The reaction was cooled to ambient temperature and concentrated to give the title compound, which was used without further purification. MS ESI(+) m/z 601.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>C1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1C#CCCCO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCCC#Cc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material and analogous starting material may be prepared as follows: 3.0 g of 2-(5-hydroxypent-1-yn-1-yl)-benzenesulfonamide and 4.7 ml of pyridine are dissolved at 45° in 200 ml of benzene. The solution is cooled to room temperature and 1.23 ml of acetyl chloride and 3.2 ml of triethylamine are added. The batch is stirred for 1 hour at room temperature under argon until the thin layer chromatogram no longer shows any starting material. The solvent is evaporated off at 15 torr and 40°. A mixture of ethyl acetate, water and 1N hydrochloric acid (100 ml) is added to the residue. In a separating funnel, after shaking, the organic phase is removed and washed with 0.1N hydrochloric acid and with saturated sodium chloride solution, dried (over magnesium sulfate) and concentrated by evaporation at 15 torr and 40°. The crude product is purified on 200 g of silica gel (Merck, ST 60, 40-63 μm) with hexane/ethyl acetate=1/1 as eluant to yield 2-(5-acetoxy-pent-1-yn-1-yl)-benzenesulfonamide in the form of white crystals. The melting point is 66°-68°. 1H-NMR (300 MHz, DMSO-d6): 7.87 (d, d, 1H); 7.45-7.60 (m, 3H); 7.20 (s, 2H); 4.13 (t, 2H); 2.57 (t, 2H); 2.02 (S, 3H); 1.86 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([CH:12]([CH2:24][CH2:25][CH2:26][CH:27]([OH:37])[CH2:28]OC1C=CC(F)=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])[CH3:10]>>[C:9]([CH:12]([CH2:24][CH2:25][CH2:26][CH:27]([OH:37])[CH2:28][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])[CH3:10]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Reactant: Fc1ccc(S)cc1
Product: CCOC(=O)CCCCCCC(CCCC(O)CSc1ccc(F)cc1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of 4-fluorothiophenol is substituted for the 4-fluorophenol of Example 1, Step E.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH:10]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:18]([O:3][CH2:4][C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
55% sodium hydride (1.30 g) was added under ice-cooling to a THF (87 ml) solution of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.77 g), and this suspension was stirred at room temperature for 30 minutes. After ice-cooling again, benzyl bromide (5.32 g) and tetrabutylammonium iodide (1.00 g) were added thereto and stirring was performed at room temperature for 3 hours. After adding a saturated ammonium chloride aqueous solution, extraction was performed with EtOAc. A residue which was obtained by washing with saturated brine, drying over anhydrous magnesium sulfate, and concentration was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[(benzyloxy)methyl]-3,6-dihydropyridine-1(2H)-carboxylate (6.16 g).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[C:22]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH:31]=3)[CH:23]=[C:24]([CH3:26])[CH:25]=2)[N:14]=1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[C:22]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH:31]=3)[CH:23]=[C:24]([CH3:26])[CH:25]=2)[N:14]=1
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnn(CCC(N)=O)c2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(OCCO)n2)cc(-c2cnn(CCC(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl (550 μL, 0.55 mmol) was added to a solution of 3-[4-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]propanamide (91 mg, 0.18 mmol) in THF (1000 μL). The reaction mixture was stirred for 18 h at room temperature then diluted with water and extracted with EtOAc (2×) and chloroform:IPA (3:1). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, triturated with dichloromethane:hexanes (1:1) and then purified by reverse phase HPLC (ACN/water with 0.1% formic acid modifier) to afford 3-[4-(3-{[4-(2-hydroxyethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]propanamide as a white solid. MS ESI calcd. for C19H23N6O3 [M+H]+ 382. found 382.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[H][H]>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:10][O:9][C:7]([CH:6]1[CH2:11][CH:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH2:13][CH:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:5]1)=[O:8]
Reactant: COC(=O)c1cc(OCCCCCCCl)cc(C(=O)OC)c1
Reactant: [H][H]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(OCCCCCCCl)CC(C(=O)OC)C1
Temperature: 25 °C

Procedure:
7.5 g (22.8 mmol) 5-[(6-chlorohexyl)oxy]isophthalic acid dimethyl ester (example 6) were dissolved in 75 ml ethyl acetate and charged into a steel autoclave. After addition of 3 g of a hydrogenation catalyst (5% Rh/Alox, Johnson Matthey Company) the vessel was closed and the compound was hydrogenated at a reaction temperature of 70° C. using a constant hydrogen pressure of 18 bar until no further hydrogen uptage was observed (approx. 4 hours). The reaction suspension was cooled to room temperature, filtered and concentrated under vacuum to dryness. The crude product was essentially a cis/trans mixture of 5-[(6-chlorohexyl)oxy]-1,3-cyclohexanedicarboxylic acid dimethyl ester. The pure cis-compound was isolated as a colourless oil by chromatography on silica gel using hexane/ethyl acetate (4:1) as eluent. (yield: 6.1 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[CH:4]2[CH:9]([CH:10]=[CH:11][C:2]([N:15]([CH3:14])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)[CH:18]=3)=[CH:3]2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: CNCc1cccc(Oc2cncc(C)n2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cncc(Oc2cccc(CN(C)C3=CC4C(Cl)=NNC(=O)C4C=C3)c2)n1
Yield: 1.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (225 mg, 0.867 mmol), N-methyl-3-[(6-methylpyrazin-2-yl)oxy]benzylamine (250 mg, 1.09 mmol), Pd2(dba)3 (95 mg, 0.104 mmol), xantphos (180 mg, 0.312 mmol) and NaOtBu (300 g, 3.12 mmol) in dioxane (6 mL) was heated at 80° C. for 3.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 4-chloro-6-{methyl-[3-(6-methyl-pyrazin-2-yloxy)-benzyl]-amino}-4a,8a-dihydro-2H-phthalazin-1-one (6 mg) as a yellow solid. 1H (400 MHz, d6-DMSO) δ: 2.27 (s, 3H), 3.24 (s, 3H), 4.83 (s, 2H), 6.88 (d, 1H), 7.03 (s, 1H), 7.07 (d, 1H), 7.12 (d, 1H), 7.32 (dd, 1H), 7.40 (t, 1H), 8.00 (d, 1H), 8.24 (d, 2H), 12.41 (s, 1H) ppm; m/z (M+1) 408.27.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>CN(C)C=O.O>[CH:13]1([CH2:12][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.05 g, 44.7 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (2.7 g, 68 mmol, 60% mineral oil suspension) at 0° C. in portions and then followed by bromomethylcyclopropane (6.5 mL, 67 mmol) dropwise at same temperature. The mixture was stirred at room temperature for 4 h and diluted with water (300 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/50 to 1/20) to give the product as yellow oil (7.38 g, 98.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH2:39])[CH:34]=[CH:35]2)=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH:39][C:2]3[N:7]=[C:6]([N:8]([CH3:26])[CH:9]4[CH2:10][CH2:11][C:12]5([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]5)[CH2:24][CH2:25]4)[CH:5]=[CH:4][N:3]=3)[CH:34]=[CH:35]2)=[N:30]1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (500.0 mg, 1.3 mmol) and 2,3-dimethyl-2H-indazol-6-amine hydrochloride (778.6 mg, 3.9 mmol) in n-BuOH (10 mL) was added DIPEA (1.04 g, 8.0 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a yellow solid (657 mg, 100%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH:23]([OH:24])[C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(C(O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a stirred solution of 2-bromothiazole (0.40 g, 24.4 mmol) in THF (60 mL) under nitrogen at rt was added 2M isopropylmagnesium chloride solution in THF (10 mL, 20 mmol). The mixture was stirred at rt for 1 h and then cooled to 0° C. Methyl 3-bromo-5-formylbenzoate (1.0 g, 4.1 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (60 mL×3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography to afford the title compound (0.90 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]([CH3:19])=[O:18]>O1CCCC1>[Br:9][C:10]1[C:15]([C:17]([OH:18])([CH3:19])[CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Brc1ccccn1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1Br
Temperature: -78 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
Lithium diisopropylamide (2M, 12.5 mL, 25 mmol) is dissolved in tetrahydrofuran (40 mL) and cooled to −78° C. 2-Bromopyridine (3.9 g, 25 mmol) is added dropwise and the reaction is stirred for 3 hr. before adding acetone (1 mL, dried over freshly activated molecular sieves) and allowing warming to room temperature. The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated. The residue is purified by flash column chromatography on silica, eluting with 20% hexane/tert-butyl methyl ether to give the title compound (1.4 g, 26%). 1H-NMR (d6-dimethyl sulfoxide): 8.23 (dd, J=1.9, 4.5 Hz, 1H), 8.19 (dd, J=2.0, 7.8 Hz, 1H), 7.44 (dd, J=4.5, 7.7 Hz, 1H), 5.43 (s, 1H), 2.12 (s, 1H), 1.46 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: CCOC(=O)CCN
Reactant: COCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CCCCOC)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.8 %

Procedure:
To a mixture of 4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}benzoic acid (400 mg) synthesized above, β-alanine ethyl ester hydrochloride (234 mg), 1-hydroxybenzotriazole monohydrate (233 mg), triethylamine (422 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (291 mg), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-80% ethyl acetate/hexane) to give the title object compound (489 mg, 97%) as a pale-brown oil
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27].[CH3:29][C:30]1([C:35]2(C=O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32][O:31]1>C(OCC)C>[CH:24]([C:35]1([C:30]2([CH3:29])[O:34][CH2:33][CH2:32][O:31]2)[CH2:37][CH2:36]1)=[CH:25][CH2:26][CH3:27]
Reactant: [Li]CCCC
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: CCC=CC1(C2(C)OCCO2)CC1
Reaction time: 1 h

Procedure:
7.2 g of propyltriphenylphosphonium bromide is dissolved in 100 ml of diethyl ether, and 7.5 ml of n-butyllithium solution (2.5 M in hexane) is added in drops under nitrogen at room temperature. It is stirred for 1 hour, and then 2.34 g of aldehyde 7 is added to 10 ml of diethyl ether. It is stirred for 1 more hour, quenched with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.8 g of title substance 197 is obtained as a colorless oil (1:3 E,Z-mixture that cannot be separated).
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1>C(N(CC)CC)C>[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To 100 ml of a dried dichloromethane solution containing 2.67 g of oxalyl chloride was added dropwise at -50° C. 20 ml of a dichloromethane solution containing 1.64 g of dimethylsulfoxide. The mixture was allowed to stand for 5 minutes. To the mixture was added dropwise over a period of 10 minutes, while maintaining the temperature at -55° C., 40 ml of a dried dichloromethane solution containing 5.84 g of 1-(5-isoquinolinesulfonyl)-4-hydroxypiperidine as obtained in Example 7, followed by stirring at that temperature for 20 minutes. To the resulting mixture was added 1.4 ml of triethylamine, and the mixture was stirred for 5 minutes. Then, the temperature of the mixture was raised to 15° C. The mixture was washed twice with 100 ml each of water and dried with anhydrous sodium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 150 g; solvent: chloroform) to obtain 5.16 g of 1-(5-isoquinolinesulfonyl)-4-piperidone.
Reaction SMILES: ClC1C=CC(OC)=C(NC([C:11]2[C:20](O)=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=O)C=1.[OH2:24]>[OH-].[Na+]>[CH:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[OH:24])[CH:12]=1
Reactant: O
Reactant: COc1ccc(Cl)cc1NC(=O)c1cc2ccccc2cc1O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2ccccc12
Temperature: 90 °C

Procedure:
By reference to manufacturing example 1 according to an embodiment described in Japanese Patent Laid-Open Publication No. Hei 11-272014, a naphthol pigment (a pigment red 238) is prepared. More specifically, 50 parts by mass (0.21 parts by mol) of 3-Amino-4-Methoxybenzanilide is dispersed into 1000 parts of mass of water, into which ice is added to set a temperature to 0° C. to 5° C. The resultant solution is agitated for 20 minutes after the addition of 60 parts by mass (0.58 parts by mol) of 35% HCl water solution, and then agitated for 60 minutes after the addition of 50 parts by mass (0.22 parts by mol) of 30% nitrite soda water solution. Subsequently, 2 parts by mass (0.02 parts by mol) of sulfamic acid are added to the solution to remove nitrite, and 50 parts by mass (0.37 parts by mol) of acetic acid soda and 75 parts by mass (1.12 parts by mol) of 90% acetic acid are further added to the solution, to thereby obtain a diazonium salt solution. Separately from this preparation, 68 parts by mass (0.21 parts by mol) of N-(5-chloro-2-methoxyphenyl)-3-hydroxy-2-naphthalenecarboxylic amide is dissolved in 1000 parts by mass of water in conjunction with 25 parts by mass (0.63 parts by mol) of caustic soda at a temperature of 80° C. or lower, to which 3 parts by mass (corresponding to 2.49 weight percent relative to the pigment) of minerite 100 is further added to obtain a coupler solution. The coupler solution is added to the above-described diazonium salt solution at a temperature of 10° C. or lower in order to induce a coupling reaction, and then treated by heat at 90° C. Subsequently, the resultant solution is filtered and rinsed, and then dried at a temperature of 100° C. Further, the resultant product having been dried is pulverized. As a result, 117 parts by mass (0.20 parts by mol) of a naphthol pigment is obtained. The obtained naphthol pigment has a volume average particle size D50 of 70 nm. This pigment is hereinafter referred to as “naphthol pigment A.”
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:5]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([O:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[F:10])[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reaction time: 5 h

Procedure:
3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester (2.81 g, 10.0 mmol) was dissolved in tetrahydrofuran (15 mL) and mixed with 2M lithium hydroxide (15 mL, 30 mmol). The suspension was stirred for 5 h. To the reaction was added water, then extracted with EtOAc. The aqueous layer was treated with 6M HCl (5 mL, 30 mmol) and then extracted with EtOAc (3×25 mL). The extract was dried (MgSO4), filtered and evaporated to 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid. Yield: 2.22 g, 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCCc2ccccc2)c2cccc(N)c2)cc1
Yield: 70.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(2-phenylethyl)amine (2.70 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.52 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (1.74 g) as a clear colorless oil.