Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].[I-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CBr
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A solution of 3-bromophenol (17.3 g, 100 mmol) in 30 ml of THF is added at ambient temperature to a 50% solution of sodium hydride dispersed in mineral oil (5 g, 125 mmol) in 50 ml of anhydrous THF. The mixture was stirred at ambient temperature for 30 minutes before successively adding a solution of methyl bromoacetate (10.4 ml, 110 mmol) in 33 ml of anhydrous THF and sodium iodide (3.75 g, 25 mmol). The reaction medium is stirred for 30 minutes at ambient temperature and then treated with 30 ml of water at 0° C. The raw product is purified by chromatography on silica (eluent petroleum ether:ether 100:10). 19.66 g of methyl 3-bromophenoxyacetate is obtained (yield=80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][C:12]([CH3:15])=[N:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]3[N:16]([CH3:25])[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1
Reactant: CC1=Nc2c(c(-c3ccccn3)nn2C)C(c2ccc(Cl)cc2C)SC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(Cl)ccc1C1SCC(C)Nc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6-dihydropyrazolo[3,4-e][1,4]thiazepine (0.120 g, 0.31 mmol), acetic acid (0.054 mL, 0.94 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38 mmol) in DCE (10 mL) was stirred at rt for about 16 h. Then more acetic acid (0.054 mL, 0.94 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38 mmol) were added and stirring was continued for another 24 h. The resulting mixture was concentrated in vacuo and partitioned between 5% aqueous sodium bicarbonate (40 mL) and ethyl acetate (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with water (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(4-chloro-2-methyl-phenyl)-1,7-dimethyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.100 g, 0.26 mmol, 84%) as a pale yellow solid as a mixture of two diasereomers (ratio 61:39): LC-MS (Table 1, Method e) Rt=8.51 min and 8.76 min, m/z 385 (M+H)+; Major isomer 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.33 (3H, d, J=6.4 Hz) 2.58 (3H, s) 2.62-2.72 (2H, m) 3.43-3.53 (1H, m) 3.84 (3H, s) 4.06 (1H, br s) 6.59 (1H, s) 6.99 (1H, dd, J=8.3, 2.1 Hz) 7.01-7.09 (1H, m) 7.11 (1H, d, J=8.3 Hz) 7.14 (1H, d, J=2.1 Hz) 7.58 (1H, td, J=7.9, 1.9 Hz) 7.77 (1H, d, J=8.0 Hz) 8.44 (1H, d, J=4.6 Hz); Minor diastereomer: 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.21 (3H, d, J=6.6 Hz) 2.55 (1H, dd, J=15.0, 8.0 Hz) 2.61 (3H, s) 2.95 (1H, dd, J=15.0, 4.3 Hz) 3.36-3.43 (1H, m) 3.86 (3H, s) 4.06 (1H, br s) 6.44 (1H, s) 6.96 (1H, dd, J=8.3, 2.1 Hz) 7.01-7.09 (1H, m) 7.06 (1H, d, J=8.0 Hz) 7.12 (1H, d, J=2.1 Hz) 7.56 (1H, td, J=7.9, 1.9 Hz) 7.76 (1H, d, J=8.0 Hz) 8.40 (1H, d, J=4.6 Hz).
Reaction SMILES: C([O-])=O.[NH4+].C([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C1C=CC=CC=1>C(O)C.C(O)(=O)C>[CH2:14]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH3:12]
Reactant: CCOC(=O)CNCCCCc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNCC(=O)OCC
Temperature: 80 °C

Procedure:
Ammonium formate (2 g, 31 mmol) was added to a solution of ethyl 2-[benzylpropylamino]acetate (1.05 g, 4.47 mmol) in ethanol (15 mL) and acetic acid (1 mL). The reaction vessel was then carefully flushed with nitrogen gas. Palladium on carbon (10%, 300 mg) was added in one portion, and the resulting mixture was heated at 80° C., under nitrogen for 3 h. The reaction mixture was allowed to cool to room temperature, and filtered through celite filteraid. The filtrate was concentrated in vacuo, (azeotroping with toluene (20 mL) to remove the acetic acid), to give ethyl 2-(propylamino)acetate as a yellow oil (quantitative crude yield). 1H NMR (CDCl3) δ 4.14 (q, J=7.1 Hz, 2H), 3.30 (s, 2H), 2.60 (dd, J=7.4 Hz, 2H), 1.50 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[C:13][Si](C)(C)C)[N:11]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[CH:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(Cl)cc3)c2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: ClCCl
Product: C#Cc1nc(C(=O)OCC)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-4-hydroxy-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.189 mmol) in EtOH/CH2Cl2 (1/1, 0.76 mL) was added Cs2CO3 (0.227 mmol) with stirring at r.t. After 16 h the mixture was partitioned between 1N HCl (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 0-20% EtOAc/CH2Cl2, to give the title compound (38 mg) as a white solid: MS (m/z) 357.0 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(=O)[O:34][C:32](=[O:33])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:32](=[O:33])[C:31]3[C:30](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:29]2=[O:34])=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(N)cc1)C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CC(C)CC(C[PH](=O)OCCc1ccc(N2C(=O)c3ccccc3C2=O)cc1)C(=O)OCc1ccccc1
Yield: 50.6 %

Procedure:
2-[(4-Aminobenzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester (prepared as described in Example 2/Step A) (242 mg, 0.60 mmole) and phthalic anhydride (133 mg, 0.90 mmole) in acetic acid (10 ml) were refluxed for 1 hour. The cooled reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 ml). This solution was washed with saturated sodium bicarbonate solution (3×20 ml) and dried with magnesium sulfate. Filtration and concentration gave a light yellow oil which was purified by chromatography (ethyl acetate) yielding 162 mg (51%) of 2-{[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)benzyl]methoxyphosphinoyl methyl}-4-methylpentanoic acid benzyl ester as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([O:19][CH3:20])[CH:4]=1.[CH2:21](O)[CH:22]=[CH2:23]>CO.C(Cl)(Cl)Cl>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[O:19][CH3:20])[CH:22]=[CH2:21]
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OCCCC(=O)O
Reactant: C=CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Yield: 72 %

Procedure:
A mixture of compound 51 (7.00 g 24.50 mmol), allyl alcohol (80 mL) and p-tosic acid (742 mg, 3.90 mmol) was heated at reflux under a N2 atmosphere for 4 hOURS, at which time TLC (2% MeOH/CHCl3) indicated that reaction had gone to completion. Excess allyl alcohol was evaporated in vacuo to afford the crude compound (52), which was partitioned between NaHCO3 (50 mL) and EtOAc (50 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL) and then dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (CHCl3) yielded the product as an orange-brown solid (5.78 g, 72%). MP=73-75° C. 1H NMR (250 MHz, CDCl3) δ 7.70 (s, 1H), 7.16 (s, 1H), 6.00-5.84 (m, 1H), 5.36-5.21 (m, 2H), 4.94 (d, J=6.3 Hz), 4.62-4.59 (m, 2H), 4.13 (t, J=6.2 Hz, 2H), 3.97 (s, 3H), 2.67-2.56 (m, 3H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR 5173.1 (C12), 154.7 (Cquat.), 147.3 (Cquat.), 139.6 (Cquat.), 133.2 (Cquat.), 132.4 (C14), 118.7 (C15), 111.1 (C6), 109.9 (C3), 68.6 (C9), 65.6 (C13), 62.7 (C1), 56.7 (C8), 30.9 (C11), 24.6 (C10). IR (cm−1) 3329.4, 3100.0, 2972.1, 1734.5, 1647.9, 1577.4, 1508.1, 1281.5, 932.8, 884.0, 815.8, 758.2, 662.2. MS (M+ —OH) 308. Anal. Calcd for C16H19NO7: C, 55.38; H, 5.89; N, 4.31. Found: C, 52.41; H, 5.86; N, 4.67.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[NH:3][CH:2]=1.CO[C:21]([CH3:23])=[CH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH:21]([CH3:23])[CH3:22])[C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[NH:3][CH:2]=1
Reactant: FC(F)(F)Oc1ccc(NCc2cnc[nH]2)cc1
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)N(Cc1cnc[nH]1)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (3H-imidazol-4-ylmethyl)-(4-trifluoromethoxy-phenyl)-amine (0.39 g, 1.5 mmol) in 1,2-dichloroethane (5 ml) were added successively 2-methoxypropene (0.16 g, 2.25 mmol), trifluoroacetic acid (0.26 g, 2.25 mmol) and sodium triacetoxyborohydride (0.48 g, 2.25 mmol). After stirring the mixture overnight at 60° C. 1 M sodium hydroxide solution (5 ml) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate=1:1) to yield a white solid (0.24 g, 53%); MS (ISP): 300.1 ((M+H)+.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Product: COc1cccc2c(NCc3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methoxyquinoline and 4-chlorobenzylamine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH2:27](O)[CH3:28]>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (15.8 mg, 0.047 mmol) was added 1.25M hydrogen chloride in ethanol (1.124 mL, 1.405 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=366.6 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.22 (t, J=7.1 Hz, 3H), 1.24 (d, J=6.9 Hz, 0.5H), 1.56 (d, J=6.5 Hz, 2.5H), 1.75-1.90 (m, 1H), 1.98-2.14 (m, 2H), 2.22-2.38 (m, 1H), 2.66 (t, J=7.4 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 3.00-3.21 (m, 3H), 3.30-3.41 (m, 2H), 3.45-3.54 (m, 1H), 3.69-3.79 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[N:18]([CH3:19])[CH:17]=[CH:16][C:11]3=[N:12][C:13]=2[C:14]#[N:15])[CH2:4][CH2:3]1.[CH3:21][Mg]Br.CCOCC.[BH4-].[Na+]>C1COCC1>[NH2:15][CH:14]([C:13]1[N:12]=[C:11]2[CH:16]=[CH:17][N:18]([CH3:19])[C:10]2=[CH:9][C:8]=1[N:5]1[CH2:6][CH2:7][C:2]([CH3:20])([OH:1])[CH2:3][CH2:4]1)[CH3:21]
Reactant: Cn1ccc2nc(C#N)c(N3CCC(C)(O)CC3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(N)c1nc2ccn(C)c2cc1N1CCC(C)(O)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(4-hydroxy-4-methylpiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (245 mg, 0.906 mmol) in THF (5 mL) at 0° C. was slowly added 3M methylmagnesium bromide in ether (1.21 mL, 3.63 mmol). The resulting yellow solution was stirred at 0° C. for 2.5 hours. The reaction was quenched with MeOH (5 mL) and stirred for 15 minutes at RT. Sodium borohydride (68.6 mg, 1.81 mmol) was added. The reaction was stirred for 1 hour, quenched with 1M HCl (5 mL), and then stirred for an additional 15 minutes. The mixture was subsequently diluted with EtOAc and washed with saturated aqueous NaHCO3 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C16H24N4, 289; found 289.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4](=[O:25])[C:3]1=[N:26]NC1C=CC=CC=1>C(O)(=O)C.O.[Zn]>[NH2:26][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4]1=[O:25]
Reactant: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2F)c2ccccc21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCN1C(=O)C(N)C(=O)N(c2ccccc2F)c2ccccc21
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of the intermediate 2 (5.8 g) in glacial acetic acid (50 ml) was added, dropwise, to a suspension of zinc dust (6.37 g) in glacial acetic acid (20 ml) cooled to 0°. The mixture was stirred at 23° for 3 h, then diluted with water (200 ml) and decanted from zinc. Solid sodium carbonate was added until pH=9 and the mixture extracted with ethyl acetate (2×300 ml). The combined organic extracts were washed with brine (300 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in gradient from CH-EA 2:1 to EA) to give the title compound as a white foam (2.8 g). M.P. 125°-6°. T.l.c. DCM-methanol (30:1), Rf0.38.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH3:32])(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1ccccc1S(N)(=O)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)NCCc1ccc(-n2nc(C)c(-c3ccccc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.93 (1H, d, J=8.3 Hz), 7.50-7.21 (12H, m), 6.29 (1H, br.s), 3.49-3.43 (2H, m), 2.81 (2H, t, J=6.5 Hz), 2.62 (3H, s), 2.33 (3H, s), 2.24 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C([Li])CCC.CCCCCC.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][OH:10])([OH:35])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCCc1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
To a solution of 2-bromophenyl ethyl alcohol (1.9 g, 9.6 mmol) in tetrahydrofuran (25 ml) was added 1.6 M n-butyl lithium solution in n-hexane (14 ml, 23 mmol) at −60° C. After stirring for 30 min a solution of 1-benzyl-4-piperidone (2.6 g, 14 mmol) in tetrahydrofuran (10 ml) was added over a period of 15 min at −40° C. The cooling bath was removed and the reaction mixture was stirred for 72 h at room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution (30 ml). Basification to pH 11 with 2 M aqueous sodium carbonate solution (50 ml) was followed by extraction with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Volatile impurities were removed by kugelrohrdistillation at 170° C. and 1-2 mbar. Flash chromatography of the residual crude product with dichloromethane/methanol as eluent gave the title compound (2.3 g, 53%) as dark brown oil. MS m/e: 312 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:21][C@H:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[CH3:23])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Na].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:3][CH:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:21][C@H:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)=[CH:26][CH:25]=4)[CH3:23])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccn2c(-c3nc(N[C@@H](C)c4ccc(N5CCNCC5)cc4)ncc3C#N)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1cccn2c(-c3nc(N[C@@H](C)c4ccc(N5CCNCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
39 mg of the 4-(8-acetylimidazo[1,2-a]pyridin-3-yl)-2-{[(1S)-1-(4-piperazin-1-ylphenyl)ethyl]amino}pyrimidine-5-carbonitrile [156-3] was dissolved in a mixture solvent of 1 mL of tetrahydrofuran and 1 mL of methanol, then 2.8 mg of sodium boronhydride was added thereto, and stirred at room temperature for 15 minutes. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with a mixture solvent of chloroform and methanol (chloroform:methanol=9:1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography, and 31.9 mg of 4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[(1S)-1-(4-piperazin-1-ylphenyl)ethyl]amino}pyrimidine-5-carbonitrile [156-4] was obtained as a two kinds of diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.C(O)(=[O:16])C>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:4]([O:12][C:5](=[O:16])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1

Procedure:
49 g (0.226 mol) of 4,5-dichloroisatin are suspended in 200 ml of acetic acid and 200 ml of acetic anhydride, treated over a period of 50 minutes at a temperature between 80° and 90° with 37.65 g (0.376 mol) of chromium trioxide and the mixture is subsequently cooled to 5°. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dichloroisatoic acid anhydride of melting point 280°-283°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:24][N:23]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=323.4 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20]2[O:21][C:22]([CH2:25][NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CN(C1C=CC=CN=1)C.[C:45](OC(=O)C)(=[O:47])[CH3:46].C(Cl)(Cl)Cl>ClCCl>[C:45]([N:26]([CH2:25][C:22]1[O:21][C:20]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1cc(CC(=O)OC)c(-c2ccc(CNCCCN3CCOCC3)o2)c(OCOC)c1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCOc1cc(CC(=O)OC)c(-c2ccc(CN(CCCN3CCOCC3)C(C)=O)o2)c(OCOC)c1
Reaction time: 20 h
Yield: 89.5 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-{5-[N-(3-morpholinopropyl)aminomethyl]furan-2-yl}phenylacetate (46 mg, 0.094 mmol) obtained in Example 247 was dissolved in dichloromethane (1.0 mL), and dimethylaminopyridine (20 mg, 0.16 mmol) and acetic anhydride (0.1 mL, 1.1 mmol) were added thereto and stirred for 20 hours. Chloroform was added to the reaction solution for liquid-liquid separation. The organic layer was washed with 2 mol/L hydrochloric acid, aqueous saturated carbonic acid solution and aqueous saturated sodium chloride solution in order, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (methanol/chloroform=1/9) to obtain methyl 2-{5-[N-acetyl-N-(3-morpholinopropyl)aminomethyl]furan-2-yl}-3,5-bis(methoxymethoxy)phenylacetate (45 mg, 89%).