Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[CH:18])[CH2:12][CH2:11]1>C(NCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1(C)C(C(P(C(C2C(C)=CC=CC=2)=O)C(C2C(C)=CC=CC=2)=O)=O)=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:18]#[C:17][CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(I)c1
Reactant: C#CCN1CCC(C)CC1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCNCC
Product: CC1CCN(CC#Cc2cccc(F)c2)CC1
Yield: 56.2 %

Procedure:
A mixture of 3-fluoroiodobenzene (8.88 g), 4-methyl-1-(2-propynyl)piperidine (6.80 g), palladium acetate (0.045 g), tri-o-toloylphosphine (0.24 g) and copper(I) iodide (0.1 g) in dry diethylamine (50 ml) was heated under reflux for 5 hours. The solvent was removed under reduced pressure and the residue was taken up in diethyl ether and washed with water. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. Distillation of the residue under reduced pressure gave an oil (5.20 g) of boiling point 105° C./0.07 mm Hg.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20]>O1CCCC1>[C:1]([CH:3]([CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: COC(=O)CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCCBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCC(NC(=O)OC(C)(C)C)C2)cc1

Procedure:
Pyrrolidin-3-yl-carbamic acid tert-butyl ester (250 mg, 1.35 mmol) and 1-(3-Bromo-propyl)-4-methoxy-benzene (375 μl, 2.15 mmol), potassium carbonate (550 mg, 4 mmol) and sodium iodide (50 mg, 0.33 mmol) are dissolved in acetonitril and stirred at reflux overnight. The reaction is filtered and purified by preparative HPLC-MS (MeOH/H2O+0.1% TFA). 2 M K2CO3 is added to relevant fractions to prevent cleavage of boc group during solvent evaporation. Methanol is removed under reduced pressure and the remaining aqueous phase is extracted with dichloromethane. The solvent is removed in vacuo. LC (method F): tR=1.61 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1.CI>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[C:19]=1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of dry diisopropylamine (11.0 g, 108 mmol) in dry THF under nitrogen was cooled with a −78° C. bath, and n-butyl lithium (2.50 M in hexane, 39 mL) was added. The reactant solution was warmed to ambient temperature, and then cooled to −78° C. again. A solution of 3,5-dibromopyridine (22 g, 93 mmol) in dry THF was added. After stirring at −78° C. for 30 min, CH3I (17 g, 120 mmol) was added, the mixture was warmed to ambient temperature and stirred over night. The reaction was quenched with water, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography to afford 3,5-dibromo-4-methylpyridine: 1H-NMR (400 MHz, CDCl3) ppm 8.55 (s, 2H), 2.55 (s, 3H);
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:38]5[CH2:39][CH2:40][C:36]([F:41])([F:35])[CH2:37]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC1(F)CCNC1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCC(F)(F)C4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 2.4 %

Procedure:
Using a procedure similar to that of Example 282, step 2, with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 3,3-difluoro-pyrrolidine as starting materials, 6.3 mg (2.4%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 725 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (s, 2 H), 3.2 (m, 2 H), 2.70 (m, 2 H), 2.20 (s, 2 H); ES-MS m/z 536.22 [M+H]+, HPLC RT (min) 2.52.
Reaction SMILES: [F:1][C:2]([F:28])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(C(C)C)CC)C>C1COCC1>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:2]([F:1])([F:28])[C:3]([F:4])([F:6])[F:5])[CH:11]=2)=[O:21])[CH:48]=[CH:49][CH:50]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Agent: CCN(CC)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 60 °C
Yield: 39.2 %

Procedure:
A stirred mixture of phenyl 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (199 mg, 0.50 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (100 mg, 0.34 mmol), N,N-diethylisopropylamine (88 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude product. Purification via preparative HPLC afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 39%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 7.55-7.61 (m, 7H), 7.36-7.40 (m, 2H), 7.18 (m, 1H), 6.95 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[C:8]([C:20]([OH:22])=O)[CH:7]=[C:6]2[O:23][CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:28]1([C:31]2[CH:32]=[CH:33][C:34]([NH:35][C:20]([C:8]3[CH:7]=[C:6]([O:23][CH3:24])[C:5]4[C:10](=[C:11]([N:13]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]5)[CH:12]=[C:3]([F:2])[CH:4]=4)[N:9]=3)=[O:22])=[CH:36][CH:37]=2)[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1
Reactant: COc1cc(C(=O)O)nc2c(N3CCN(C)CC3)cc(F)cc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(N3CCN(C)CC3)cc(F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
Into a 250 mL round bottom flask equipped with a nitrogen inlet and magnetic stirrer is added 2.01 g (6.3 mmol, 1.0 equiv.) of 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic acid hydrochloride salt. This material is dissolved in 20 mL of DMF and then 1.35 g (7.56 mmol, 1.2 equiv.) of 4-morpholinoaniline is added. To the stirred solution is quickly added simultaneously added 4.05 g (12.6 mmol, 2.0 equiv.) of TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate) and 1.7 g (12.6 mmol, 2.0 equiv.) of HOBT (1-hydroxybenzotriazole hydrate). At this point 3.25 g, 4.11 mL (25.2 mmol, 4.0 equiv.) is added via syringe over 5 minutes. The reaction is allowed to stir at room temperature for 18 hrs, then is concentrated on a rotary evaporator under high vacuum in order to remove the DMF. The residue is triturated with methanol and the crude solids are recovered by filtration. The material is then dissolved in methylene chloride and extracted with 10% sodium bicarbonate solution. The organic layer is dried and then concentrated. These residues are then purified by flash chromatography using a gradient of 5-10% methanol in methylene chloride as eluent. The material which is obtained from chromatography, is then crystallized from methanol to give the pure product as 2.83 g (93%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:24]([N:31]1[CH2:35][CH:34]2[CH2:36][NH:37][CH2:38][CH:33]2[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C(O)CCCC>[CH2:24]([N:31]1[CH2:35][CH:34]2[CH2:36][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:18]5[CH:23]=[CH:22][N:21]=[N:20][CH:19]=5)=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:38][CH:33]2[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Agent: Cl
Solvent: CCCCCO
Product: Fc1ccc(-c2nc3ccc(N4CC5CN(Cc6ccccc6)CC5C4)nn3c2-c2ccnnc2)cc1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
The mixture of 0.90 g (2.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)-imidazo[1,2-b]pyridazine and 1.7 g (8.3 mmol) of 5-benzyloctahydropyrrolo[3,4-c]pyrrole in 15 ml of pentanol is heated in a sealed tube at 150° C. for 18 hours. The reaction medium is poured into a 1N aqueous solution of hydrochloric acid and the aqueous phase is washed with ethyl acetate. The aqueous phase is then basified using aqueous sodium hydroxide and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The product is chromatographed on a silica gel column, elution being carried out with a mixture of aqueous ammonia, methanol and dichloromethane (0.2/2/98), to give 1.2 g of solid in the form of an amorphous white foam.
Reaction SMILES: [F:1][C:2]1([F:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([F:1])([F:12])[C:3]1=[O:11]
Reactant: O=C1Nc2ccccc2C1(F)F
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCl)c2ccccc2C1(F)F
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 3,3-difluoroindolin-2-one (836.6 mg, 4.95 mmol, 1 equiv) in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60% dispersion) (217.6 mg, 5.44 mmol, 1.1 equiv) was slowly added and the reaction was stirred as such until all bubbling had stopped. 1-bromo-3-chloropropane (1.46 ml, 14.85 mmol, 3 equiv) was added to the reaction mixture in one portion. The reaction was allowed to warm to ambient temperature and stirred as such for 16 h. The crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a yellow oil (1.22 g, quant); MS for C11H10ClF2NO m/z 247.01 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccs1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) boronic acid obtained in Example 116 and 2-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 58%. Melting point: 155-156° C. (hexane-ethyl acetate).
Reaction SMILES: C([NH:18][C@H:19]([C:32]([OH:34])=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH4+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[N:51]1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.ClCCl.C(NCC)C>[C:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:19]([C:32]([NH2:51])=[O:34])[NH2:18])=[CH:22][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: c1ccncc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C[C@H](N)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
N-Fmoc-O-tert-butyl-tyrosine (3.27 g, 7.12 mmol) was dissolved in dioxane (15 mL). Ammonium hydrogenocarbonate (732 mg, 9.26 mmol), di-tert-butyl-dicarbonate (2.02 g, 9.26 mmol) and pyridine (0.4 mL) were added and the mixture was stirred under nitrogen atmosphere at room temperature for 12 h. It was then diluted with ethyl acetate and the organic phase was washed with brine (2×), 5% sulfuric acid (1×) and brine again. It was dried over magnesium sulfate and concentrated. The crude thus obtained (3.17 g) was dissolved in dichloromethane (50 mL) and diethylamine (10 mL). The mixture was stirred at room temperature for 12 h, concentrated under reduced pressure and purified by flash chromatography with DCM/MeOH/NH4OH (95/5/1 then 90/10/1) to give 1.37 g of the desired compound (yield=81%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](CO)=[C:28]([CH3:34])[CH:27]=1>CCCCCC>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:1][Br:5])=[C:28]([CH3:34])[CH:27]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) were added to a solution of (4-bromo-2-methylphenyl)methanol (3.7 g, 18.4 mmol) which was synthesized according to the method described in literature (Dawson, M. I., et al., J. Med. Chem., 1984, vol. 27, pp. 1516-1531) under ice-cooling, the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture and the insolubles were removed by filtration. After the obtained filtrate was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/0-10/1) to give a crudely purified 4-bromo-1-(bromomethyl)-2-methylbenzene. Potassium cyanide (1.3 g, 20 mmol) was added to a solution of crude 4-bromo-1-(bromomethyl)-2-methylbenzene obtained in the above in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=6/1-3/1) to give (4-bromo-2-methylphenyl)acetonitrile as a pale orange solid (2.4 g, two-step total yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:36](=[O:37])[N:35]([CH3:38])[C:12]2[N:13]([CH3:34])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27]C2CCCCO2)[N:21]=1)=[CH:16][CH:15]=3.C(O)(=O)C.C1COCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:36](=[O:37])[N:35]([CH3:38])[C:12]2[N:13]([CH3:34])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOC5CCCCO5)n4)ccc3n(C)c21
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Temperature: 45 °C

Procedure:
A solution containing 311 mg (0.56 mmol) of compound A 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazol-3-yl}-1,9-dihydropyrido[2,3-b]indol-2-one, 2.7 ml of acetic acid, 1.3 ml of THF and 0.7 ml of H2O is heated at 45° C. for 16 h. The reaction medium is allowed to cool, adsorbed onto silica and purified by flash chromatography, elution being carried out with EtOAc/20% cyclohexane, then 100% EtOAc, and, finally, EtOAc/5% MeOH. The residue is taken up in MeOH and the product is filtered and then washed with MeOH.
Reaction SMILES: [CH2:1]([C:13]1[S:17][C:16]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[C:16]1[S:17][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1ccc(-c2ccsc2)s1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(-c2ccsc2Br)s1
Temperature: 0 °C
Yield: 97 %

Procedure:
5′-Dodecyl-3,2′-bithiophene (34.5 g, 103 mmol, 1 eq) prepared above was placed in a three-necked flask equipped with a dropping funnel and a reflux tube. The atmosphere in the flask was replaced by Ar, 500 ml of dehydrated DMF was added thereto, and the mixture was stirred. The reaction solution was cooled to 0° C., and N-bromosuccinimide (19.2 g, 108 mmol, 1.05 eq) dissolved in 100 ml of dehydrated DMF in a separate vessel was added dropwise to the reaction solution. After the completion of the dropwise addition, the mixture was stirred for one hr, was brought to room temperature, and was stirred for 6 hr. The solvent was removed by evaporation, and the residue was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel to give an objective substance 2-bromo-5′-dodecyl-3,2′-bithiophene as a light yellow liquid (which solidified a few hours after that) (about 41.5 g, yield about 97%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (d6-DMSO, TMS/ppm): 0.86 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.66 (m, 2H), 2.80 (t, 2H, J=7.32 Hz), 6.83 (d, 1H, J=2.93 Hz), 7.22 (d, 1H, J=5.34 Hz), 7.32 (d, 1H, J=3.90 Hz), 7.59 (d, 1H, J=5.37 Hz).