Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:12]=2)=[CH:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2ncn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(Br)cc2)n1
Product: C[Si](C)(C)CCOCn1ncnc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186 %

Procedure:
To a solution of 5-(4-bromophenyl)-1H-1,2,4-triazole (5.40 g, 24.1 mmol) in DMF (48.2 mL, 24.1 mmol) at 0° C. was carefully added NaH (1.16 g, 28.9 mmol). The resultant mixture was stirred for 30 minutes prior to the addition of (2-(chloromethoxy)ethyl)trimethylsilane (6.38 mL, 36.2 mmol). The reaction mixture was stirred 0° C. for 15 minutes before removal of the ice bath and the mixture was allowed to warm to ambient temperature stirring for 2 hours. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to provide 10.09 g as a pale yellow oil which solidified upon standing. Purification by normal phase chromatography on silica eluting with 0-50% EtOAc/Hexanes provided 3-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole and 5-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (7.94 g, 93%) as a mixture of two regioisomers. LCMS (APCI+) m/z 354, 356 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=CC(S(CC(C2C=CC=CC=2)=O)=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N=[N+]=[N-].Cl[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][C:38]([NH:40][C:41]2[CH:46]=CC=CC=2)=O)(=[NH:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:38]2[N:40]=[C:41]([CH3:46])[NH:36][SH:34](=[O:35])([C:31]3[CH:30]=[CH:29][CH:28]=[CH:33][CH:32]=3)[C:37]=2[CH:7]=1
Reactant: O=C(CS(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: N=S(=O)(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=N
Solvent: ClC(Cl)Cl
Product: CC1=Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1

Procedure:
Following the procedure of (D) but using 83.8 g. (0.30 mole) of 4-chloro-2-(phenylsulfinyl)acetophenone, 500 ml. of chloroform, 250 ml. of concentrated sulfuric acid, and 472 ml. of a 1.4 N chloroform solution of hydrazoic acid, 79.7 g. of a mixture of 4-chloro-2-(phenylsulfonimidoyl)acetanilide and 7-chloro-3-methyl-1-phenyl-1,2,4-benzothiadiazine-1-oxide is obtained. This mixture is stirred and heated under reflux conditions in 450 ml. of 10% sodium hydroxide solution for 3.5 hours. After the mixture is cooled, it is extracted with 500 ml. of chloroform, and the extract is dried and concentrated to give 68.7 g. of a viscous oil. This is extracted with 500 ml. of anhydrous ether. The extract is filtered and cooled in ice. While the extract is cooling in ice, it is treated in a dropwise manner with a slight excess (to pH 4.0) of ethereal hydrogen chloride to give 55.2 g. of product, melting point 217°-219°C after filtration and drying.
Reaction SMILES: [NH2:1][CH:2]([CH3:22])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:20][CH3:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C@H:2]([C:3]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH2:20][CH3:21])[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:4])[CH3:22])=[O:33])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(CNC(=O)C(C)N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(CNC(=O)[C@H](C)NC(=O)Cc3ccc(C#N)cc3)ccc21
Yield: 14 %

Procedure:
A solution of the compound obtained in Step 2 (242 mg, 0.82 mmol), 2-(4-cyanophenyl)acetic acid (198 mg, 1.23 mmol), HATU (468 mg, 1.23 mmol) and TEA (0.343 mL, 2.46 mmol) in DMF (3 mL) was stirred at room temperature for 16 hr. To the reaction solution was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: ethyl acetate) to give the title compound (50.3 mg, 0.115 mmol, 14%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11](O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(C(=O)O)c(-c3ccc(Nc4nc5cc(F)cc(F)c5[nH]4)cc3)c12
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3cc(F)cc(F)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a suspension of 4-amino-5-{4-[(5,7-difluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (75.0 mg, 0.178 mmol) in DMF (3 mL) was added tert-butylamine (0.021 ml, 0.196 mmol), benzotriazolyloxytris(dimethlyamino)phosphonium PF6 (86.6 mg, 0.196 mmol), and 4-methylmorpholine (0.039 ml, 0.356 mmol). The reaction was stirred for 3 hr at rt and then purified directly by HPLC using 25-85% acetonitrile in water to afford the desired product (75.3 mg, 89%). 1H-NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.02 (s, 1H), 7.80-8.02 (m, 3H), 7.38 (dd, J=6.7, 2.0 Hz, 2H), 7.00 (dd, J=8.9, 2.2 Hz, 1H), 6.85 (ddd, J=10.7, 10.7, 2.4 Hz, 1H), 6.54 (s, 1H), 4.96-5.21 (br s, 1H), 1.16 (s, 9H); ES-MS m/z 477.1 (MH)+; HPLC RT (Method B) 2.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.NC(N)=O.[C:13](=[O:18])([O:15][CH2:16][CH3:17])N.C(O)C>ClC1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(N)=O
Agent: NC(N)=O
Solvent: Clc1ccccc1
Solvent: CCO
Product: CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Following the procedure described in Example 1, 638 g of 4-chloroaniline, 240 g of urea, 89 g of ethyl carbamate, 625 g of ethanol (approximately 96%) and 1400 g of chlorobenzene were reacted for 6.5 hours at 200° C. in the pressure apparatus described in Example 1. After the apparatus had been cooled and vented, the reaction mixture was removed. Excess ethanol was removed by fractional distillation at atmospheric pressure. The mixture (while being stirred) was then exposed to hydrogen chloride gas at room temperature, filtered and subjected to fractional distillation in vacuo. Chlorobenzene was separated off at 15 mbar. Subsequent distillation at 0.2 mbar yielded 785 g (78.6% of the theoretical yield) of N-(4-chlorophenyl)-carbamic acid ethyl ester melting at from 68° to 70° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].CN1CCCC1=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=1)[CH:20]=[CH2:21]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCN(CC=C)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98.6 %

Procedure:
A mixture of 3-fluoro-4-nitroaniline (1.56 g, 10 mmol), 1-methylpyrrolidinone (10 mL), diallylamine (1.94 g, 20 mmol) and potassium carbonate (1.38 g, 10 mmol) was heated to 115-125° C. for 9.5 h. The mixture was diluted with water, and extracted with ethyl ether. The combined extracts were washed with water, washed with saturated brine solution, and dried over magnesium sulfate. The extract was concentrated to give N,N-diallyl-6-nitro-1,3-benzenediamine as an orange oil (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC.O.Cl>[CH3:15][C:13]([CH3:14])([CH3:16])[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:8]=1)=[O:17]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(C(=O)C(C)(C)C)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1.43 g (6-methoxy-1H-indazol-3-yl)-2,2-dimethylpropan-1-one from the Step C above in 45 mL anhydrous DMF was added 1.13 g ethyl bromoacetate and 2.41 g cesium carbonate. The mixture was stirred under nitrogen at room temperature for 2.5 days. It was diluted with ether and cold water with 15 mL 1 N HCl. The aqueous layer was separated and extracted with ether three times. The combined ether extract was washed with water (5×) and saturated brine, dried over anhydrous Na2SO4 and evaporated to give a crude product. It was purified by SGC with 20-40% EtOAc in hexanes to give title compound as solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=8.9 Hz, 1H), 6.985 (dd, J=2.1 & 8.9 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 5.15 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 1.50 (s, 9H), 1.28 (t, J=7.1 Hz, 3H). LC-MS: 3.93 min. (m/Z=319.3).
Reaction SMILES: BrCCC1C(Cl)=CC(Cl)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1CCBr.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>CN(C)C=O>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:20])[CH:16]=1)[O:12][CH2:5][CH2:6][N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29]
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 101.88 g (0.38 mole) of 2-bromoethyl-3,5-dichlorophenyl ether and 70.3 g (0.38 mole) of potassium phthalimide in 800 ml of dimethylformamide was stirred overnight at 85° C. The reaction mixture was filtered and dimethylformamide removed from the filtrate in a rotary evaporator to yield a white solid. The solid was triturated with diethyl ether and the mixture filtered. The solid was dried in vacuo. Recrystallized from methylene chloride-hexane, the product melted at 133+-136° C. Yield overall was 41.7%.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:23]3[C:28](CC1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)C.[C:30]([NH:34][Si:35]([CH3:38])([CH3:37])Cl)([CH3:33])([CH3:32])[CH3:31]>CCOCC>[CH3:37][SiH:35]([N:34]([CH2:2][CH2:3][CH:4]1[C:5]2[NH:14][C:22]3[C:17]([C:16]=2[C:23]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:38]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: CCn1c2c(c3ccccc31)-c1ccccc1C2
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[SiH](C)N(CCC1c2ccccc2-c2c1[nH]c1ccccc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
8.02 mL of n-BuLi 2.5 M in hexane (20.04 mmol) were added dropwise at 0° C. to a solution of 4.30 g of N-ethyl-5,6-dihydroindeno[2,1-b]indole (Mw=233.31, purity 98.9%, 18.22 mmol) in Et2O. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for two hours. The dark brown solution obtained was added at 0° C. to a solution of 4.32 g of (tert-butylamino)dimethylchlorosilane (Mw=165.74, purity 83.7% wt., d=0.887, 21.86 mmol) in Et2O. The final mixture was allowed to warm up to room temperature and stirred for three hours. Then the solvents were evaporated under reduced pressure to give a residue (8.73 g) which was extracted with 50 mL of toluene. The extract, a sticky brown solid (7.48 g), was washed with pentane obtaining 4.32 g of a light brown powder, which was analyzed by 1H-NMR. The 1H-NMR analysis showed a purity of 96.6% wt. in the desired ligand together with a 3.4% wt. of starting N-ethyl-5,6-dihydroindeno[2,1-b]indole. Yield=63.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(C(C)C)CC)(C)C.CCOCC>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)c(=O)c1ccccc1n2CCCCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1ccc2c(c1)c(=O)c1ccccc1n2CCCCCC(=O)O
Reaction time: 3 h
Yield: 86 %

Procedure:
6-(2-Amino-9-oxo-9H-acridin-10-yl)hexanoic acid (370 mg: 1.14 mmol) was dissolved in anhydrous pyridine (10 ml) and acetic anhydride (100 μl) followed by diisopropylethylamine (350 μl). The mixture was stirred for 3 hours. The solution was evaporated to dryness under vacuum and the gummy residue dissolved in dichloromethane. The solution was washed with 1.0M hydrochloric acid and then brine. The organic phase was dried with anhydrous magnesium sulphate, filtered and the solvent removed by rotary evaporation to leave a sticky solid. Trituration with ether gave a solid which was dried under vacuum to give 360 mg (86%) of 6-(2-acetamido-9-oxo-9H-acridin-10-yl)hexanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][OH:7].[H-].[Na+].Cl[C:16]1[C:25]2[C:20](=[C:21]([OH:26])[CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:27])[CH:17]=1>CN1CCN(C)C1=O>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[C:18]([CH3:27])[CH:17]=[C:16]2[O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: COc1ccc(CO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(COc2cc(C)nc3c(O)cccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzyl alcohol (1.68 g) in 1,3-dimethyl-2-imidazolidinone (10 ml) was added sodium hydride (60% in oil, 400 mg) portionwise in an ice-water bath under a nitrogen atmosphere. The mixture was stirred for 30 minutes and then 4-chloro-8-hydroxy-2-methylquinoline (770 mg) was added thereto. The reaction mixture was stirred at 150° C. for 3 hours and cooled to ambient temperature followed by partition into ethyl acetate and water. The organic layer was washed with water twice, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether to give a pale yellow powder (812 mg) of 8-hydroxy-4-(3,4-dimethoxybenzyloxy)-2-methylquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 2-(3,4-dichlorophenyl)acetic acid (1 g, 4.9 mmol), N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (940 mg, 4.9 mmol), hydroxybenzotriazole (660 mg, 4.9 mmol), and triethylamine (2.5 g, 25 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=10:1) to afford 2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (880 mg, yield 72.7%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[CH:11]=[C:10](Br)[S:9][C:8]=3[C:13]3[CH:17]=[C:16](Br)[S:15][C:14]=3[C:4]=2[CH:3]=1.[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[CH:19]1[C:31]2[N:30]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[S:6][C:5]5[C:7]6[CH:11]=[C:10]([C:35]7[CH:34]=[CH:33][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:37][CH:36]=7)[S:9][C:8]=6[C:13]6[CH:17]=[C:16]([C:35]7[CH:36]=[CH:37][C:32]([N:30]8[C:29]9[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=9[C:23]9[C:31]8=[CH:19][CH:20]=[CH:21][CH:22]=9)=[CH:33][CH:34]=7)[S:15][C:14]=6[C:4]=5[CH:3]=4)=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: Brc1cc2c(s1)c1cc(Br)sc1c1cc(Br)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2cc3c(s2)c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc2c2cc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)sc32)cc1
Temperature: 95 °C

Procedure:
Under a nitrogen atmosphere, 2,5,8-tribromobenzo[1,2-b:3,4-b′:5,6-b″]trithiophene (33) (500 mg, 1.04 mmol) obtained in Example 4, 4-(N-carbazolyl)phenyl boronic acid (1.34 g, 4.66 mmol) and tripotassium phosphate hydrate (3.96 g, 18.6 mmol) were suspended in DMF (40 mL) and degassed by Ar bubbling for 30 minutes. Pd(PPh3)4 (179 mg, 0.155 mmol) was added and heated at 90-100° C. for 18 hours. After completion of the reaction, water (30 mL) was added. A precipitated solid substance was obtained by filtration, washed with water (50 mL) and acetone (10 mL) and dried under reduced pressure. Vacuum sublimation purification was performed to obtain a light yellow substance (47.7 mg, 5%). MS (MALDI-TOF,1,8,9-trihydroxyanthracene matrix) m/z=966.34
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.C(=O)([O-])[O-].[K+].[K+].[F:23][CH2:24][CH2:25][CH2:26]I>C(#N)C.O>[F:23][CH2:24][CH2:25][CH2:26][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: FCCCI
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCN(CCCF)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
187 a) To a suspension of 1-(3-nitro-phenyl)-piperazine; hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) was added 1-fluoro-3-iodo-propane (0.85 g, 4.5 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. 1-(3-Fluoro-propyl)-4-(3-nitro-phenyl)-piperazine was isolated as a viscous orange oil (0.886 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.71 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H), 4.54 (ddd, J=47.2, 5.9, 5.9 Hz, 2H), 3.32-3.27 (m, 4H), 2.65-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=268 (MH)+. 187 b) 3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenylamine was prepared from 1-(3-fluoro-propyl)-4-(3-nitro-phenyl)-piperazine (0.20 g, 0.75 mmol) in a manner analogous to Example 111a. Product isolated as a tan waxy solid (0.18 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.04 (t, J=8.1 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 6.26 (s, 1H), 6.21 (d, J=7.9 Hz, 1H), 4.62-4.44 (m, 2H), 3.60 (br s, 2H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.53 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=238 (MH)+. 187 c) {3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenyl}-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (220.0 mg, 0.7148) and 3-[4-(3-fluoro-propyl)-piperazin-1-yl]-phenylamine (180.0 mg, 0.7585 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (60.0 mg, 0.110 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.264 g, 73%). MP=157-169° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.7 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.46 (br s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.64-4.48 (m, 2H), 3.30 (br s, 4H), 3.11 (s, 3H), 2.93-2.40 (m, 6H), 2.08-1.90 (m, 2H). MS=509 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10](F)=[CH:9][N:8]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CCOC(COc1ncc(F)cn1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1ncc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)cn1)OCC
Temperature: 190 °C
Reaction time: 14 h
Yield: 37.6 %

Procedure:
2-(2,2-Diethoxyethoxy)-5-fluoropyrimidine (168 mg, 0.73 mmol) and potassium tert-butoxide (93 mg, 0.83 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (80 mg, 0.33 mmol), and stirred at 190° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=1:2) to obtain 6-{[2-(2,2-diethoxyethoxy)pyrimidin-5-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (56 mg, yield: 37%) as a pale brown amorphous solid.