Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>CO>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)CBr)cc1S(N)(=O)=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
21.3 Grams (0.1 M) of 5-acetyl-2-methylbenzenesulfonamide was dissolved in 180 g of methanol, while the resulting solution was kept at 35°-40° C., 16.0 g (0.1 M) of bromine was added dropwise by taking 1.5 hours. The reaction mixture was stirred for 10 minutes after the dropwise addition, 80 g of water was added to the reaction mixture and the whole reaction mixture was stirred for further 30 minutes at room temperature. A part of methanolwater was removed by evaporation, then the crystals formed were collected by filtration, washed with water and dried to obtain 28.0 g of 5-bromoacetyl-2-methylbenzenesulfonamide in the form of white crystals. Melting point: 146.5°-147.5° C Yield: 95.9%.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([C:11]2[CH:36]=[CH:35][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>C(OCC)C>[Br:2][CH:25]([CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]1[CH:35]=[CH:36][C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: BrP(Br)Br
Reactant: COC(=O)CCCCC(O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Solvent: CCOCC
Solvent: O
Product: COC(=O)CCCCC(Br)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
At 0° C., 140 mg (0.51 mmol) of phosphorus tribromide were added to a solution of 500 mg (1.14 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-hydroxyoctanoate XVI in 5 ml of diethyl ether. The mixture was stirred at 0° C. for 1 h and at room temperature for another 16 h. Water was added, the mixture was extracted with cyclohexane and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclohexane(ethyl acetate 10:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:28]=[C:27]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:20][CH:21]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)CCc1ccc(Cc2ccccc2)cc1
Product: O=C(CCc1ccc(Cc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 59 %

Procedure:
This material was prepared from 5-(2-pyridyl)oxazole and 3-(4-benzylphenyl)propanoic acid (S40) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11h (95 mg, 0.59 mmol, 59%) as a light tan oil: 1H NMR (CDCl3, 500 MHz) 8.68 (app d, 1H, J=4.8 Hz), 7.88 (s, 1H), 7.84 (d, 1H, J=7.7 Hz), 7.81 (td, 1H, J=7.7, 1.8 Hz), 7.33-7.27 (m, 3H), 7.21-7.12 (m, 7H), 3.96 (s, 2H), 3.45 (t, 2H, J=7.7 Hz), 3.09 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 187.3, 157.1, 153.2, 150.0, 146.1, 141.1, 139.0, 138.0, 137.0, 129.0, 128.8, 128.5, 128.3, 126.9, 125.9, 124.1, 120.3, 41.4, 40.6, 29.2; IR (film) νmax 3025, 2920, 1694, 1601, 1574, 1516, 1494, 1468, 1426, 1381, 1283, 1151, 1118, 1064, 990, 963, 936, 913, 849, 784, 727, 696 cm−1; ESI-TOF m/z 369.1600 (C24H20N2O2+H+ requires 369.1597).
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([NH2:8])=[O:7].Br[CH2:16][C:17]([O:19]CC)=[O:18]>C(O)C>[C:6]([C:5]1[C:4]([I:14])=[C:3]([C:11]([I:12])=[CH:10][C:9]=1[I:13])[O:2][CH2:16][C:17]([OH:19])=[O:18])(=[O:7])[NH2:8]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(I)cc(I)c(O)c1I
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I
Yield: 93.7 %

Procedure:
0.436 g (19 mmol) of sodium is dissolved in 20 ml of ethanol. Then 9.78 g (19 mmol) of 3-hydroxy-2,4,6-triiodobenzamide and subsequently 3.5 g (21 mmol) of ethyl bromoacetate are added thereto. The mixture is heated for one hour to reflux and, after several hours of stirring in an ice bath, the resultant 3-carbamoyl-2,4,6-triiodophenoxyacetic acid ethyl ester is vacuum-filtered, washed with a small amount of ice-cold ethanol, and suspended in 80 ml of water. The mixture is brought to pH 12 by adding concentrated sodium hydroxide solution, stirred for 30 minutes at 60° C., the solution is treated with 1 g of active carbon, filtered, and brought to pH 1 by the dropwise addition of dilute hydrochloric acid. After several hours of stirring in an ice bath, the thus-formed precipitate is vacuum-filtered, washed with water, and dried, thus obtaining 10.2 g (89% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[Br:1][C:2]1[CH:16]=[N:15][C:5]2[N:6]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (300 mg, 1.1 mmol) in DMF (2.5 mL), under an inert atmosphere, was added sodium hydride (65 mg, 1.3 mmol) and the reaction mixture was allowed to stir at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.3 mmol) was added dropwise and then the resultant suspension was allowed to warm to room temperature. Water (0.5 mL) was added to the resultant suspension to quench the reaction, the solvent was removed in vacuo and the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% ethyl acetate in cyclohexane) to afford the title compound as an off-white crystalline solid (266 mg, 62%). 1H NMR (CDCl3, 400 MHz): 9.18 (d, J=1.2 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H), 0.94-0.98 (m, 2H), 0.08 (s, 9H). LCMS (Method B): RT=4.55 min, M+H+=(403, 405).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:34])[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[C:27](=[O:36])[NH:28][C:29]([CH3:35])=[CH:30][C:31]=1[CH:32]([CH3:33])[CH3:34])=[O:9]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 7 h
Yield: 50.1 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, ˜0.7 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (200 mg, 0.91 mmol) in DMSO (5.3 mL) was added PyBOP (550 mg, 1.05 mmol) and hunig base (366 ul, 2.10 mmol). The reaction mixture was stirred at 23° C. for 7 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 Ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (166 mg, 50% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.06 (d, J=2.4 Hz, 1H), 7.01-7.05 (m, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.49-3.57 (m, 1H), 3.02 (q, J=6.8 Hz, 2H), 2.80-2.84 (m, 2H), 2.61-2.69 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.23 (s, 3H), 1.86-1.90 (m, 2H), 1.66-1.70 (m, 4H), 1.21 (d, J=6.8 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+Na] 495.2; HPLC 95.7% purity.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C)C=O>[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:36][CH2:37]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(CC(O)CCN3C(=O)c4ccccc4C3=O)CC2)c1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a mixture of 2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione obtained in step 2 (0.30 g, 1.38 mmol) and potassium carbonate (0.48 g, 3.45 mmol) in N,N-dimethylformamide (3.0 ml), was added 1-(2,3-dimethylphenyl)piperazine hydrochloride (0.31 g, 1.38 mmol) at room temperature. The resulting reaction mixture was stirred at 110° C. for 18 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.26 g). The compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C(O)C>[CH3:7][C:2]([CH3:8])([N:1]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:14])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(N)CC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCO
Product: CC(C)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: 180 °C
Reaction time: 54 h
Yield: 33.2 %

Procedure:
An intimate mixture of of 3-amino-3-methyl butanoic acid (27.4 g, 0.234 mol) and phthalic anhydride (38.1 g, 0.257 mol) is heated at 180° C. for 1.5 hours. After cooling, the reaction mixture is dissolved in 40 ml of ethanol and kept in a refrigerator for 54 hours. The colorless crystalline precipitate thus obtained is collected by suction and dried at 50° C. for 3 hours in a vacuum oven to give 19.2 g of β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (58%).
Reaction SMILES: N1(CC2N=CC([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:27]4[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=4[Cl:38])=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:16])=CC=2)CCNCC1.N[C:40]1[N:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:53])[CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=1>C(Cl)Cl.CO>[CH3:51][N:50]([CH3:52])[CH2:49][CH2:48][N:47]([CH2:46][C:43]1[CH:42]=[CH:41][C:40]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:27]3[C:28]([Cl:38])=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:34][CH3:35])[C:32]=3[Cl:33])=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)=[O:16])=[N:45][CH:44]=1)[CH3:53]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)nc3)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Exam pie 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4]1)#[N:2].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1N.[NH4+].[OH-]>Cl>[CH3:8][N:5]1[CH2:6][CH2:7][CH:3]([C:1]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:2]=2)[CH2:4]1
Reactant: CN1CCC(C#N)C1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CN1CCC(c2nc3ccccc3[nH]2)C1
Temperature: 110 °C

Procedure:
To 240 g of concentrated hydrochloric acid was added 43.2 g (0.39 mol) of 3-cyano-1-methylpyrrolidine (the temperature rose to 90° C.). After the temperature began to fall the solution was heated to 110° C. for 4 h. The solution was cooled to 60° C. and 42 g (0.39 mol) of 1,2-diaminobenzene in 250 mL of 1N hydrochloric acid was added. The solution was heated to reflux for 20 h. The cooled solution was made basic with concentrated NH4OH and the resulting crystals were collected by filtration. The product was chromatographed on a 7.5×36 cm silica column eluting with 1 gallon of 10% NH4OH-90% ethanol. The eluent was collected in 500-mL portions. The first 6 fractions were discarded and fractions 7-14 were collected and concentrated. The residue was recrystallized from ethyl acetate. Yield: 18 g (23%). A 5-g sample was recrystallized three times from ethyl acetate. Yield: 1.6 g, mp 189°-193° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][OH:25])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1>N1C=CC=CC=1>[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.01 g (21 mmol) of 4-toluenesulfonyl chloride are added while stirring at room temperature to a solution of 4.48 g (20 mmol) of 2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The reaction mixture is then stirred at room temperature for 2 hours, then poured onto ice-water and the mixture is extracted with diethyl ether. The combined organic phases are washed while cold with 2N hydrochloric acid and then with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 6.5 g (85.8% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman in the form of a light-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Cl:11])(Cl)=[O:9].[S:12]([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])(=[O:15])(=[O:14])[NH2:13]>ClCCl>[Cl:11][C:8]([N:18]1[CH2:19][CH2:20][N:16]([S:12](=[O:15])(=[O:14])[NH2:13])[C:17]1=[O:21])=[O:9]
Reactant: NS(=O)(=O)N1CCNC1=O
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 17 h

Procedure:
A solution of 17.8 parts by vol. of triethylamine in 30 parts by vol. of dichloromethane was added dropwise over the course of 2 hrs. to a mixture of 100 parts by vol. of dichloromethane, 6.15 parts by vol. of (condensed) phosgene and 7.0 parts by wt. of 1-sulphamyl-2-oxo-imidazolidine at 20° C and the mixture was then left to stand for 17 hrs. The precipitate present was removed by filtration, the filtrate was concentrated by evaporation in vacuo and the residue was repeatedly extracted with ethyl acetate at 20° C. The ethyl acetate extracts were combined. On evaporation, they left a hard varnish. The IR spectrum showed a strong acid chloride band at 1,805 cm-1 (Nujol). Furthermore, it could be seen from the IR spectrum that the substance still contained considerable amounts of the starting product.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:29])=[CH:5][CH2:6][O:7][C:8]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]2[C:11]([C:12](=[O:28])[C:13]([CH3:27])=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15]2)=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C(O)C.O>[CH3:27][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[C:17]([C:18](=[O:20])[CH:19]=[CH:35][C:34]3[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=3)[C:8]([O:7][CH2:6][CH:5]=[C:4]([CH3:29])[CH3:3])=[CH:9][CH:10]=2)[O:15][C:14]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(3-methylbut-2-enyloxy)-8-acetyl-3-methylflavone (2.71 g, 0.0075 mol) and 4-chloro-benzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.9 g product m.p. 130-133° C., 1H-NMR (CDCl3) δ:1.69 (s, 3H), 1.72 (s, 3H), 2.19 (s, 3H), 4.65 (d. 2H), 5.31 (m, 1H), 6.97-8.42 (m, 13H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].O1[CH2:38][CH2:37]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:38]3[CH:37]=[CH:16][CH:15]=[CH:14][N:11]=3)=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-[4-bromo-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (100 mg, 0.209 mmol) produced in Example (99a), 2-(tributyltin)pyridine (0.08 mL, 0.25 mmol), cesium fluoride (68 mg, 0.448 mmol) and dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), followed by stirring for 3 hours at an external temperature of 90° C. under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 43 mg of the title compound as light yellow crystals.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46]C4CCCCO4)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:53]>C(OCC)(=O)C>[ClH:53].[ClH:53].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCCOC4CCCCO4)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(OCCCO)cc3)cc3ccsc23)CC1

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.29 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-[3-(tetrahydropyran-2-yl)oxypropoxy]phenyl]thieno[2,3-c]pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate thrice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and the resulting solution was extracted with ethyl acetate thrice. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.26 g of the free compound of the title compound as a colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26]CC3C=CC=CC=3)=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:37])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:34](=[O:36])[CH3:35])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (1R,3S,5R)-2-[2-(3-acetyl-5-benzyloxy-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (79.0 mg, 0.138 mmol), TFA (3 mL) and thioanisole (0.163 mL, 1.38 mmol). Solid. MS (LC/MS): 484 [M+H]+; tR (HPLC, conditions k): 3.18 min.
Reaction SMILES: Cl.C(O)(=O)C.[Br:6][C:7]1[C:8]([F:37])=[C:9]([F:36])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25]C(C)(C)C)[N:18]=1)[CH:14]=[C:13]([C:30]([O:32]CC)=[O:31])[C:12]2=[O:35]>O>[NH2:25][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:7]=3[Br:6])[C:12](=[O:35])[C:13]([C:30]([OH:32])=[O:31])=[CH:14]2)[C:22]([F:23])=[CH:21][C:20]=1[F:24]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a mixed solution of 3.5 ml of 4N hydrochloric acid and 3.5 ml of acetic acid was added 1.38 g of ethyl 8-bromo-1-[6-(t-butylamino)-3,5-difluoropyridine-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 5 hours. After adding 5 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 1.10 g of the title compound as a colorless powder.