Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:13][Cl:14])([CH3:12])OC(C)C)=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([Li])CCC>O1CCCC1.CCCCCC>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([SiH:7]([CH2:13][Cl:14])[CH2:12][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)O[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1ccc(C[SiH](CCl)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g (32.8 mmol) of (1,1'-biphenyl-4-yl)(chloromethyl)methyl(2-propoxy)silane and 3.6 ml (32.8 mmol) of 4-bromofluorobenzene in 30 ml of dry tetrahydrofuran was cooled to -60° under nitrogen and stirred while 20.5 ml (32.8 mmol) of 1.6 molar n-butyllithium in hexane was added at a rate that held the mixture below 50°. After stirring at -70° for another 30 minutes, the solution was allowed to warm to room temperature and was worked up as in Example 8. The resulting crude product was subjected to distillation at 130°-150° (0.2 mm) to remove unreacted starting material, leaving the title compound as an oil: nD23 1.5128; nmr (CDCl3): 0.7 (3H, s), 3.1 (2H, s), 7.1 (2H, t), 7.2-7.8 (11H, m).
Reaction SMILES: [C:1]([C:8]([CH2:23][CH2:24][NH2:25])=[C:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:28]=1O.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:28]=1[O:11][C:10](=[O:12])[C:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[C:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:23][CH2:24][NH2:25]
Reactant: CC(C)(C)OC(=O)C(CCN)=C(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCN)=C(Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A solution of acid in Example 20a (195 mg, 0.57 mmol) in 8 mL anhydrous methylene chloride was treated with 2,4,5-trichlorophenol (112 mg, 0.57 mmol) and EDCI (160 mg, 0.85 mmol). The reaction mixture was stirred for 24 hours at ambient temperature under nitrogen atmosphere. The mixture was washed with 10% citric acid and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to yield a residue that was purified by flash chromatography on silica gel. Elution with EtOAc/hexane (1/5~1/1, v/v, with 1% HOAc) afforded the title compound (158 mg, 54% yield) as an oil: 1H NMR (CDCl3, 60 MHz) δ1.45 (s, 9H), 2.58 (q, 2H), 3.28 (q, 2H), 3.85 (q, 2H), 4.80 (br, 1H), 7.2 (s, 1H), 7.5 (s, 1H), 6.8-7.8 (m, 6H), 10.1 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:9]=[CH:10][C:11]=1[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([O:21]C)=O)=[O:4].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[C:19](=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]2[CH:10]=[CH:9][C:8]([CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]1=2)=[O:4]
Reactant: COC(=O)Cc1cc(C(C)C(=O)OC)ccc1Sc1ccccc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1ccc2c(c1)C(C(=O)OC)C(=O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
Methyl 2-[3-methoxycarbonylmethyl-4-(2-methoxycarbonylphenylthio)phenyl]propionate (prepared in Example 21, 78 mg, 0.19 mmol.), toluene (1 mL) and potassium t-butoxide (43 mg, 0.38 mmol.) were mixed, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was then extracted with ethyl acetate after addition of 2N hydrochloric acid. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off, to leave 78 mg of a pale yellow oil. The oil was subjected to moderate pressure silica gel column chromatography and eluted with ethyl acetate/hexane (1/4, v/v), to give 21 mg of the desired compound as a colorless oil (a mixture of 1:1 diastereomers). The following NMR data are those of the 1:1 diastereomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]2=[O:18].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>CC(O)C>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]=[C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]2=[O:18]
Reactant: ClCC1CO1
Reactant: O=c1c(-c2ccccc2)coc2c(O)cccc12
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)coc2c(OCC3CO3)cccc12

Procedure:
Following the procedure of Example 1a, the title compound was prepared from the reaction of 8-hydroxyisoflavone with epichlorohydrin, mp 141°-143° C. (i-PrOH).
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=N)OC>C(O)(=O)C>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=N)c1ccccn1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]c(-c4ccccn4)nc3c2)n2ccnc2)cc1
Yield: 40 %

Procedure:
To a stirred and cooled solution of 5.3 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 50 parts of acetic acid were added 3.3 parts of methyl 2-pyridinecarboximidate while still cooling. The whole was stirred for 8 hours at room temperature and then allowed to stand over weekend. The reaction mixture was evaporated. The residue was taken up in water and treated with activated charcoal. The whole was filtered and the filtrate was made alkaline with ammonium hydroxide. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo for 24 hours at 50° C., yielding 2.8 parts (40%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-(2-pyridinyl)-1H-benzimidazole; mp. 123.3° C. (compound 201).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:14]2=[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[NH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.Br[CH2:29][CH3:30].[Cl-].[NH4+]>CN(C)C=O>[CH2:29]([N:16]([C:4]1[CH:3]=[C:14]2[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4CCC3)cc1
Reactant: CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A suspension of sodium hydride (60%, 0.009 g) in N,N-dimethylformamide (2 ml) was added with ethyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.037 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with bromoethane (0.02 ml), the mixture was stirred at room temperature for 2 hours, and then added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to obtain the title compound (0.036 g, yield: 90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(Cl)Cl.O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of benzenesulfonic acid 3-hydroxy-5-methylphenyl ester (528 mg, 2.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step f of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. was added diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound as a colorless liquid (781 mg, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2H), 1.47 (s, 9H), 1.76 (m, 2H), 1.88 (m, 1H), 2.24 (s, 3H), 2.73 (t, 2H), 3.66 (d, 2H), 4.12 (m, 2H), 6.32 (s, 1H), 6.58 (s, 1H), 7.54 (t, 2H), 7.67 (t, 1H), 7.86 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[CH3:22])=[CH:7][N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4].I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[K+].O>CN1C(=O)CCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[CH3:22])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:4]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)cn2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
The compound of step 2 (1.79 g, 6.02 mmol), iodo-benzene (1.47 g, 7.22 mmol), potassium acetate (1.18 g, 12.03 mmol) and bis(triphenylphosphine)palladium(II) chloride (844 mg, 1.20 mmol) in NMP were heated at 100° C. for 10 min under argon. Then water (844 mg, 36.10 mmol) was added and heating continued for 12 h. The mixture was cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 729 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CC(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:59]=2)[CH:54]=[C:53]1[C:66](O)=[O:67])=O)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:66]([C:53]2[NH:52][C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[C:58]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:59]=3)=[O:67])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2ccc(NS(C)(=O)=O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
HATU (0.083 g, 0.218 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.045 g, 0.146 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.037 g, 0.146 mmol) and diisopropylethylamine (0.038 mL, 0.218 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer wa sdired over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.036 g, 45%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 9.53 (br. s., 1H), 8.94 (t, 1H), 7.78 (s, 1H), 7.52 (d, 1H), 7.48 (br. s., 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 6.91 (dd, 1H), 4.52 (d, 2 H), 2.87 (s, 3H). ES MS: m/z 547 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[NH:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C

Procedure:
To a solution of crude 2,4-dichloro-N-(4-chlorophenyl)benzenecarboximidamide (10.3 g, 34.6 mmol) in toluene (100 mL), ethyl bromopyruvate (4.3 mL, 34.6 mmol) and Na2CO3 (7.3 g, 41.6 mmol) were added. The resulting solution was heated at reflux for 3 h. The reaction mixture was cooled to rt. The solid was filtered off and the solvent was evaporated. The residue was purified by flash chromatography over silica gel (40% ethyl acetate in hexane) to give the product (7.5 g, 52% overall yield from 4-chroloaniline) as a light yellow solid: LC-MS m/z 395 (MH+), retention time 3.91 min (method 1); mp 143-144° C.; Rf=0.63 (50% EtOAc in hexane). 1H NMR (300 MHz, CDCl3) δ 1.39-1.43 (3H, t, J=7.2 Hz), 4.39-4.46 (2H, q, J=6.9 Hz), 7.04-7.08 (2H, m), 7.25-7.50 (5H, m), 7.89 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: COCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybutylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH2:3][C:4](O)=[O:5].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: N[C@H](CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
T a solution of (R)-3-amino-3-(3,4-dichlorophenyl)propanoic acid (10.0 g, 42.7 mmol, CASRN 909709-44-0) and THF (57.0 mL, 42.7 mmol) under a N2 atmosphere and cooled to 0° C. was added dropwise LiAlH4 (32.0 mL, 32.0 mmol, 1M solution in THF) at a rate that maintained the internal temperature at 20° C. (10 min addition). The reaction was stirred at 0° C. for 1 h, then warmed to RT and stirred overnight. The reaction was quenched with 2M HCl (20 mL) then 2M NaOH (30 mL) and brine (50 mL) were added sequentially. The white solids were removed by filtration through CELITE and rinsed with THF (100 mL) and EtOAc (50 mL). The organic phase was dried (Na2SO4), filtered and concentrated to afford 5.25 g (56%) of (R)-3-amino-3-(3,4-dichlorophenyl)propan-1-ol (172) as a light yellow oil which was used without additional purification: MS m/z (APCI-pos) M+1=220.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].[CH2:12](Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCCCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCNc1cccc(NC(C)=O)c1

Procedure:
3-Acetylaminoaniline (15 parts) was reacted with n-hexyl chloride (12.1 parts) at 100° to 110° C. for 4 hours in the presence of anhydrous sodium carbonate (5.3 parts) to obtain 3-acetylamino-N-hexylaniline. Thereafter, reaction was further continued at 120° to 130° C. for 4 hours with addition of n-amyl chloride (10.7 parts) and anhydrous sodium carbonate (5.3 parts) to obtain 3-acetylamino-N-n-hexyl-N-n-pentylaniline (coupling component). In the same manner as in Example 1, 2-cyano-4-nitro-6-chloroaniline was diazotized and coupled with the above coupling component to obtain 42.5 parts of a dye (6).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[OH-:14].[Na+].Cl>CS(C)=O.O>[F:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:14])[CH:7]=1
Reactant: [OH-]
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 1,5-difluoro-3-methoxy-2-nitro-benzene (20 g, 105 mmol) in dimethylsulfoxide (50 ml) is added a 10N aqueous solution of sodium hydroxide (31.5 ml) and the mixture is stirred at room temperature for 18 h and at 60° C. for 3 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (50 ml), acidified with 2N hydrochloric acid to pH 3 and extracted with ethyl acetate (3×100 ml). The combined organic layers are washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (15% ethyl acetate/hexane) to yield 5-fluoro-3-methoxy-2-nitro-phenol (12.0 g, 63.5 mmol, 60%).
Reaction SMILES: Cl.[C:2]1([C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C[O:21][C:22]1C=CC=C[C:23]=1N1CCN(CCO)CC1>>[C:2]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:23][CH2:22][OH:21])[CH2:16][CH2:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Reactant: O=C(c1cccc2ccccc12)N1CCNCC1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(CCO)CC1
Yield: 30 %

Procedure:
2-(4-Naphthoyl-piperazin-1-yl)-ethanol (39B) is prepared from 39A as described for 28A.
Reaction SMILES: C12BC(CCC1)CCC2.[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:18](Br)[N:17]([CH2:31][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[CH2:34])[C:13]=2[N:14]=[CH:15][N:16]=1.[OH-].[Na+]>O1CCCC1>[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]([C:13]=2[N:14]=[CH:15][N:16]=1)[CH2:31][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH2:34]3
Reactant: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 0.5 M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (141.3 ml) was added to a solution of (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (6.0 g) obtained in Reference Example 1 in tetrahydrofuran (42 ml) under a nitrogen atmosphere at room temperature, and stirred at room temperature for 2 hours. A 2 N sodium hydroxide aqueous solution (84.8 ml) was slowly added to the reaction mixture at room temperature, and degassed under reduced pressure. Under a nitrogen atmosphere, (tetrakistriphenylphosphine)palladium(0) (1.70 g) was added thereto, and the mixture was stirred at 66° C. for 12 hours. After the reaction mixture was cooled, the organic layer was separated and washed with a 20% ammonium chloride aqueous solution (60 ml). SH silica gel (6.0 g) was then added to the organic layer, and the result was stirred at 50° C. under a nitrogen atmosphere for 14 hours, and then filtered. SH silica gel (produced by Fuji Silysia Chemical Ltd.) (6.0 g) was added to the filtrate again, and the result was stirred under a nitrogen atmosphere at 50° C. for 14 hours, and then filtered. The solvent was distilled off from the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound (4.46 g) (yield: 88%) as a light-yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:36]2[C:37]([C:42]3C=CC=CN=3)=[N:38]OC=2C)C=1)=O.C(N)(C)C>>[CH:37]([NH:38][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:42])[CH3:36]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)no1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)on1
Yield: 88 %

Procedure:
As described for example 14e, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (21 mg, 0.36 mmol), to the title compound (95 mg, 88%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=361.2 [M+H]+.