Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:16]1[CH2:15][CH2:14][N:13]([C:5]2[C:6]3[S:12][CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:3]([N:2]([CH3:19])[CH3:1])[N:4]=2)[CH2:18][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)c1nc2c(c(N3CCNCC3)n1)SCCC2
Product: CN(C)c1nc2c(c(N3CCN(Cc4ccccc4)CC3)n1)SCCC2

Procedure:
2-Dimethylamino-4-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine obtained in Example 11 was reacted with benzyl bromide in the same manner as described in Example 3 to obtain 4-(N-benzylpiperazino)-2-dimethylamino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine which was then recrystallized from dichloromethane-diethyl ether. Colorless prisms. Melting point: 106° to 108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Reactant: C#CCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(Cl)c2)c1

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenyl-phosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 min.
Reaction SMILES: C(O)(=[S:3])C.[OH-].[K+].Br[CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:18].O>C(O)C>[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:18])[CH:8]([SH:3])[CH2:16]2
Reactant: CC(O)=S
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1c2ccc(Cl)cc2CC1S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (18 mmoles) of thioacetic acid in 30 ml of ethanol is neutralized exactly, in a nitrogen atmosphere, by the dropwise addition of a 40% strength aqueous KOH solution, and 3.7 g (15 mmoles) of 2-bromo-5-chloro-1-indanone (Example 1 (a)) are added. The reaction mixture is stirred for 1 hour at room temperature and poured into 200 ml of water. The product which crystallizes after some time is filtered off and introduced, under nitrogen, into 35 ml of a 5% strength aqueous NaOH solution. After stirring for 1 hour at room temperature, the pH is adjusted to 1 with 2 N hydrochloric acid and the crystalline precipitate is filtered off. The resulting 5-chloro-2-mercapto-1-indanone decomposes at 173°-175° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1ccccn1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccccn3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-2-yl-boronic acid to give the title compound as yellow solid. MS: 500.0 (MH+).
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH2:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:26]([CH3:32])[C:27](OCC)=[O:28])=[O:18])[CH:13]([CH3:15])[CH3:14]>CN(C)C=O>[CH2:12]([N:16]1[C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:25]1[CH:26]([CH3:32])[C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccccc2C1C(C)C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine is prepared as described in Example 30, starting with 3.73 g (39.0 mmol) of guanidinium chloride in 20 cm3 of dimethylformamide and 3.94 g (35.1 mmol) of potassium tert-butoxide. The mixture is stirred for 45 minutes at a temperature in the region of 20° C., followed by dropwise addition of a solution of 1.13 g (3.90 mmol) of ethyl 3-(2-isobutylcarbamoylphenyl)-2-methylacrylate in 15 cm3 of dimethylformamide, and the mixture is stirred for 3 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed and the residue is dissolved in aqueous 2N hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is then taken up in 2N hydrochloric acid solution, filtered and then freeze dried. 862 mg of N-[2-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine are thus obtained in the form of a mixture of the diastereomers. The pH of the aqueous phase is adjusted to a value of 12 with potassium hydroxide and the precipitate thus obtained is filtered off*. The solid thus obtained is taken up in aqueous 2N hydrochloric acid solution and, after filtration and a freeze drying procedure, about 255 mg of one of the two diastereomers produced (diastereomer A) are obtained in the form of the hydrochloride enriched in a ratio of 9:1 (MS(ES): M+H, 303.1). *The first filtrate obtained is subjected to double extraction with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in aqueous 2N hydrochloric acid solution, filtered and then freeze dried; 78 mg of the second diastereomer (diastereomer B) are thus isolated in the form of the hydrochloride enriched in a ratio of greater than 10:1 (MS (ES): M+H, 303.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13](S(C)(=O)=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:24][CH:23]=2)[C:3]1=[O:40].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:41])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:26][CH:27]=2)[C:3]1=[O:40]
Reactant: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(c2ccc(NS(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a stirred solution of N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (40 mg, 0.06 mmol) in THF: H2O (6 mL) was added 2N NaOH (1.0 mL) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 0° C. for 10 min. Upon complete consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl) phenyl)methane sulfonamide (20 mg, 26%), as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1H), 8.12 (t, J=7.9 Hz, 1H), 7.78 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.64 (t, J=8.2 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 6.98 (d, J=8.2 Hz, 2H), 5.42 (s, 2H), 2.85 (s, 3H), 1.44 (s, 6H). MS: [M+Na]: m/z=537.3, [M+H]: m/z=515.2 HPLC: 95.7% (RT-2.37 min),
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18]
Reactant: CC=CCC1Cc2c(C)cccc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc2c1CC(CC=O)C2=O
Reaction time: 1.5 h
Yield: 94 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 12.0 g of (RS)-2-(2-buten-1-yl)-4-methyl-1-indanone in 220 ml of anhydrous dichloromethane and 45 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 6.6 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 160 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 10.6 g (94%) of (RS)-2-(2-oxoethyl)-4-methyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[CH:16]=[C:15]4[O:20][CH2:21][O:22][C:14]4=[CH:13][C:12]=3[C:11]2=[O:23])[CH2:4][CH2:3]1
Reactant: ClCc1ccccn1
Reactant: O=C1c2cc3c(cc2C(=O)N1CCC1CCNCC1)OCO3
Agent: Cl
Product: O=C1c2cc3c(cc2C(=O)N1CCC1CCN(Cc2ccccn2)CC1)OCO3

Procedure:
Compound I-36 was prepared according to the method in example 3, using 6-[2-(4-piperidyl)ethyl]-[1,3]dioxolo[4,5-f]isoindole-5,7-dione hydrochloride (compound II-1) and 2-chloromethylpyridine hydrochloride as the raw materials: 1H NMR (DMSO-d6): δ 1.12-1.19 (m, 3H), 1.48 (q, 2H, J=6.1 Hz), 1.67 (d, 2H, J=9.4 Hz), 1.94 (t, 2H, J=10.3 Hz), 2.76 (d, 2H, J=11.2 Hz), 3.54 (m, 4H), 6.27 (s, 2H), 7.24 (dd, 1H, J=6.8, 5.4 Hz), 7.38 (s, 2H), 7.42 (d, 1H, J=7.8 Hz), 7.74 (td, 1H, J=7.7, 1.4 Hz), 8.64 (d, 1H, J=4.2 Hz): m/z 394 [M+H]+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.C1C[O:16]CC1>>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:16])[CH:3]=2)[CH:8]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2cc(Br)ccc2c1
Product: Oc1ccc2cc(Br)ccc2c1

Procedure:
According to a known method described in a reference [L. C. Anderson et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 65, p.241, 1943], a solution of 2-amino-6-bromonaphthalene (223 mg) obtained from commercially available 2-bromo-6-hydroxynaphthalene (TCI) in anhydrous THF (10 ml) was added with 30% potassium hydride (191 mg, Ald) under ice cooling and stirred for 1 hour. The reaction mixture was cooled to −78° C. under argon atmosphere, added dropwise with-1.7 M solution of t-butyllithium in pentane (1.88 ml) over 10 minutes and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (0.92 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature and further stirred for 3 hours. The reaction mixture was added with water (3 ml) and 0.5 M aqueous sulfuric acid (4 ml) and extracted with diethyl ether (100 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-amino-2-naphthaleneboronic acid (402 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 13 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=4:1), a solution of the above compound in ethanol (0.5 ml), Intermediate 3 (119 mg), 2 M aqueous sodium carbonate (1.5 ml) and (Ph3P)4Pd (61 mg) were reacted and treated to obtain the title compound (Compound No. 011, 129 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)N(Cc2ccccc2)c2ccc(Cl)cc2)cc1)OCC

Procedure:
To a solution of 0.50 g of 4-diethoxyphosphinylmethyl-N-(4-chlorophenyl)benzamide in 10 ml of dry THF was added in portions 0.07 g of sodium hydride (60%, in oil) under ice-cooling with stirring. After stirring for 30 minutes under ice cooling, a solution of 0.23 g of benzyl bromide in 2 ml of dry THF was added. After stirring for 5 hours at room temperature, 30 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-benzyl-N-(4-chlorophenyl)benzamide. It was recrystallized from benzene-n-hexane to give 0.40 g of colorless columnar crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2Cl)[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].[F:25]C1C=C(C=CC=1F)C=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:25])[CH:18]=2)[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)c(F)c1

Procedure:
Compound D was prepared in analogy to Compound B with the procedure shown in Scheme 3 by using 3,4-difluoro-benzaldehye instead of 2-chloro-5-fluorobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH2:40])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH:40][C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:7])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC1(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-Methylcyclopropanecarboxylic acid (435 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (553 mg, 2.17 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide (464 mg, 68.4% yield) was obtained as a solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)OC2
Temperature: 130 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.70 g, 2.28 mmol), piperidine (2.0 ml, 20.2 mmol) and EtOH (4.0 ml) was heated under microwave irradiation at 130° C. for 30 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the pure title compound (0.31 g, 49%). The amine was converted into HCl salt and crystallized from MeOH/DEE (0.33 g). M.p. 217° C. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J1 8.0 Hz, J22.0 Hz), δ 7.39 (1H, d, J 1.6 Hz), δ 7.31 (1H, d, J 8.0 Hz), δ 5.31 (1H, t, J 5.2 Hz), δ 5.02 (2H, dd, J1 60.4 Hz, J2 15.6 Hz), δ 3.10 (3H, s), δ 2.77 (2H, m), δ 2.60 (4H, s, broad), δ 1.63 (4H, m), δ 1.49 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[CH3:30][N:31]([CH3:54])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:43][CH:42]=2)=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([N:51]2[CH2:50][CH2:49][N:48]([CH2:47][C:44]3[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][O:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]([CH3:30])[CH3:54])=[CH:37][CH:36]=4)=[CH:42][CH:43]=3)[CH2:53][CH2:52]2)=[O:28])[CH:5]=[C:6]([CH3:24])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)O)cc3Cl)nc2)cc1
Reactant: CN(C)c1ccc(OCCc2ccc(CN3CCNCC3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(CCOc6ccc(N(C)C)cc6)cc5)CC4)cc3Cl)nc2)cc1
Yield: 51.6 %

Procedure:
To a CH2Cl2 (5 mL) solution of (E)-3-[3-chloro-5-methyl-4-({5-[(4-methyl-benzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoic acid (200 mg) was added N,N-dimethyl-4-{2-[4-(piperazin-1-ylmethyl)phenyl]ethoxy}aniline (191 mg), DCC (151 mg), and DMAP (5.96 mg) at room temperature, then the resultant mixture was stirred over night. The mixture was evaporated. The residue was added AcOEt, then filtered off, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/0 and then AcOEt/MeOH=4/1) to afford (E)-3-[3-chloro-5-methyl-4-({5-[(4-methylbenzyl)oxy]-pyridin-2-yl}oxy)phenyl]-1-[4-(4-{2-[4-(dimethylamino)phenoxy]ethyl}benzyl)piperazin-1-yl]prop-2-en-1-one as a pale brown amorphous powder (184 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 65.7 %

Procedure:
25 g (0.13 mol) of 2,4-dichloro-1-nitrobenzene, 19.5 g (0.26 mol) of glycine and 18 g (0.13 mol) of potassium carbonate were heated in 200 ml of dimethylformamide at 120° C. for 3 h. The mixture was then poured into ice-water, acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: toluene/acetone/acetic acid=20:10:1) to yield 19.7 g (66%) of the product. Melting point 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[O:19]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][N:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:31]=3)[CH2:33][CH2:34]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: c1ccc(Oc2nccc(N3CCNCC3)n2)cc1
Agent: Cl
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4ccnc(Oc5ccccc5)n4)CC3)nc(N)c2cc1OC
Yield: 9.2 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.8 g, 3.3 mmole) and 2-phenoxy-4-piperazinopyrimidine dihydrochloride (1.2 g, 3.6 mmole) were heated under reflux in n-butanol (50 ml) overnight. The mixture was then evaporated in vacuo and the residue partitioned between chloroform/methanol/saturated aqueous sodium carbonate solution (300 ml:100 ml:50 ml). The chloroform/methanol layer was separated, dried (Na2SO4), evaporated in vacuo then the residue (1 g) chromatographed on silica gel (85 g). The column was eluted with chloroform, then chloroform containing 2.5% methanol by volume, appropriate fractions combined, evaporated in vacuo and the residue recrystallized from ethanol to give the title compound, (0.14 g) m.p. 253°-254° C.