Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([Br:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:36][C:14]1[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Br)cn1
Temperature: 25 °C
Reaction time: 63 h
Yield: 67 %

Procedure:
To an ethanol (2 ml) solution of t-butyl[5-bromo-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (130 mg, 0.227 mmol) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added saturated sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (72 mg, 0.152 mmol, 67%) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(=O)CC.CN1C(=O)N(C)CCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1C[O:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:5][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:39](=[O:40])[CH2:38][CH3:37]
Reactant: C1CCOC1
Reactant: CCC(=O)N(CC(=O)OC)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: CCC(=O)C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Under argon atmosphere, at −78° C., to a stirred solution of methyl-2-[tert-butoxycarbonyl-(propanoyl)-amino]-acetate (0.856 g, 3.5 mmol) in dry THF (4 mL) was initially added DMPU (0.89 g, 7.0 mmol) followed by LHMDS (1M solution in THF, 8.75 mL, 8.75 mmol) over a period of 10 min. After stirring at −78° C. for 1.5 h, the reaction mixture was quenched with saturated NH4Cl solution and extracted with AcOEt (3×15 mL). The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo affording a crude product, which was purified by typical silica gel column chromatography, eluting with petroleum ether/AcOEt (90:10) to give pure product (0.694 g, 81%) as colorless crystals. MS (ESI) m/z: 268 [M−Na]+. 1H NMR (CDCl3): δ 1.13 (t, J=7.2 Hz, 3H), 1.47 (s, 9H), 2.57-2.87 (m, 2H), 3.82 (s, 3H), 5.07 (d, J=7.1 Hz, 1H), 5.73 (d, J=4.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:20])[NH:13][O:14][C:15](OCC)=[O:16])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:15](=[O:16])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)ONC(=N)c1ccc(CC(C(=O)OC)c2cccc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(-c2noc(=O)[nH]2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
A mixture of 3-[4-(N-ethoxycarbonyloxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid methyl ester (30 mg, 68 μmol), sodium carbonate (2.0 g), dimethylformamide (10 ml), and water (10 ml) was stirred at room temperature for 2 days. The reaction mixture was evaporated, and the residue solved in potassium hydrogen sulfate solution and ethyl acetate. The organic layer was evaporated and gave after lyophilization 22 mg of the desired product (85% yield). MS m/z: 379.1 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[C:13]([O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
TEA (1.2 ml, 8.6 mmol, 5.0 eq) was added to a solution of paracetamol [4147] (0.26 g, 1.7 mmol, 1.0 eq) in dry THF under argon atmosphere. At 0° C., nicotinoyl chloride hydrochloride [296] (1.53 gm, 8.6 mmol, 5.0 eq) was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 24 h. After 24 h, organic solvent was evaporated under vacuum and residue was dissolved in dichloromethane (50 ml) and washed with a 10% solution of NaHCO3 (15 ml) and then with brine (10 ml) followed by drying of organic layer over anhydrous sodium sulfate. Evaporation of the solvents provided white solid which was purified by silica gel column chromatography (4% MeOH: DCM, 100-200 mesh silica) to give the product 4-acetamidophenyl nicotinate [297] (0.34 g, 78%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH2:18][C:19]5[S:20][CH:21]=[CH:22][C:23]=5[C:16]=4[N:15](COCC[Si](C)(C)C)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:17]4[CH2:18][C:19]5[S:20][CH:21]=[CH:22][C:23]=5[C:16]=4[NH:15][N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: c1cc2c(s1)Cc1c(-c3ccc(N4CCOCC4)cc3)n[nH]c1-2
Temperature: 100 °C
Yield: 75 %

Procedure:
6-(4-Morpholin-4-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen (0.21 g, 0.4 mmol) was dissolved in MeOH and treated with concentrated HCl (0.14 mL, 4.3 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Morpholin-4-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.1 g, 0.3 mmol) as brown solid in 65% yield.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc2ccccn2n1
Product: Clc1cc2ccccn2n1
Temperature: 25 °C

Procedure:
A stirred solution of pyrazolo[1,5-a]pyridin-2-ol (27-1; 0.9 g, 0.0067 mol) in POCl3 (10 mL) was heated in a sealed tube at 145° C. for 6 h. The reaction mixture was cooled to room temperature, poured into ice cold water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated sodium chloride, dried over sodium sulphate and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36-8.34 (d, J=7.2 Hz, 1 H), 7.44-7.42 (d, J=9.2 Hz, 1 H), 7.17-7.13 (m, 1 H), 6.78-6.74 (m, 1 H), 6.43 (s, 1 H). MS (M+1): 152.8.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[OH-].[Na+].Br[CH:31]([OH:33])[CH3:32]>C(O)(C)C.CCOC(C)=O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:32][CH2:31][OH:33])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CC(O)Br
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 105.4 %

Procedure:
To a solution of Intermediate 11 (1.5 g, 4.08 mmol) in isopropanol (20 mL) is added 3M aq. NaOH (5 mL) followed by bromoethanol (2.90 mL, 40.8 mmol). The reaction mixture is stirred at rt for 15 h, and is then diluted with EtOAc. The org. solution is washed with 1M aq. NaOH followed by brine, dried over Na2SO4, filtered and concentrated. The crude compound is purified by CC (eluting with Heptane/EA 4:1) to give the title compound as a yellow oil (1.77 g); LC-MS: tR=1.16 min; [M+H]+=412.09. 1H NMR (CDCl3) δ1.26 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 2.16 (t, J=5.5 Hz, 1H), 3.76 (q, J=7.0 Hz, 4H), 4.01 (m, 4H), 7.23 (s, 1H), 7.90 (d, J=5.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl.O>[C:23]([NH:15][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccsc1C(N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(Cc1ccccc1)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred two-phase mixture of 10 g (0.047 mol) of α-(3-methyl-2-thienyl)benzeneethanamine and 7.4 g (0.07 mol) of sodium carbonate in 150 ml of dichloromethane and 200 ml of water at 0° C. was added dropwise 7.6g (0.07 mol) of ethyl chloroformate. The resulting mixture was allowed to warm to ambient temperature and stirred vigorously overnight. The layers were separated, aqueous phase extracted with CH2Cl2 (2×50 ml), organic layers were combined and washed with 1N aqueous hydrochloric acid, brine, and dried. The crude N-carbethoxy-α-(3-methyl-2-thienyl)benzeneethanamine thus obtained was purified by silica gel chromatography to give 13.3 g of a pale yellow oil. A solution of 7.5 g (0.026 mol) of the oil in tetrahydrofuran (50 mL) was added dropwise to a stirred solution of 22 ml (0.075 mol) of a 3.4M solution of sodium bis (2-methoxyethoxy)aluminum hydride in toluene (Red-AL) dissolved in 150 ml of tetrahydrofuran at ambient temperature. The mixture was stirred overnight and quenched by dropwise addition of isopropanol until bubbling had ceased followed by dropwise addition of water until a white precipitate formed. After stirring for 30 minutes longer, the clear yellow solution was decanted and concentrated to dryness giving the crude product as an oil. The oil was dissolved in 50 ml of isopropanol, chilled to 0° C., and made acidic with hydrochlorinated isopropanol. The resulting white solid was collected by filtration and freeze-dried from water to give 1.8 g of white solid product (mp 214°-216° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 42.6 %

Procedure:
A mixture of 3-amino-N-phenylbenzamide (2.0 g, 9.4 mmol), diphenylcarbamoyl chloride (2.2 g, 9.4 mmol) and triethylamine (2.6 mL, 19 mmol) in ethanol (10 mL) was heated to reflux for 4.5 hours. The mixture was cooled and concentrated, water was added, the slurry was acidified with 1 N HCl and the solid was collected, washed with water, dried and recrystallized from acetone/hexanes, to give a colorless solid (1.63 g, 42%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 36 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 97/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1052.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:28].[CH3:29][N:30]([CH2:32][CH2:33][Cl:34])[CH3:31].O>CN(C)C=O>[ClH:34].[ClH:28].[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[CH:6][C:7]1[S:8][C:9]2[N:10]([CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH2:11][CH2:12][CH2:13][C:14]=2[N:15]=1
Reactant: COc1cccc(C=Cc2nc3c(s2)NCCC3)c1OC
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C=Cc2nc3c(s2)N(CCN(C)C)CCC3)c1OC
Temperature: 90 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
2-(2,3-Dimethoxystyryl)-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine (1.0 g, 3.3 mmole) and powdery potassium carbonate (1.37 g, 9.92 mmole) were suspended in dimethylformamide (20 ml). To the suspension was added N,N-dimethylaminoethyl chloride hydrochloride (0.57 g, 3.97 mmole) and the mixture was heated with stirring at 90° C. for 4 hours. Water was added to the mixture and an organic substance was extracted with a chloroform-methanol mixed solvent. The extract was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. The resulting oily compound was neutralized with hydrochloric acid and recrystallized from diethyl ether-ethanol to obtain the title compound (870 mg, yield: 54.4%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][O:19]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]([CH:51]([CH3:53])[CH3:52])[CH:54]([CH3:55])[CH3:56])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12)C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12)C(C)C
Yield: 109.6 %

Procedure:
To a solution of Intermediate 103d (100 mg, 0.13 mmol) in MeOH (2 mL) was added pyridinium p-toluenesulfonate (65 mg, 0.26 mmol) and the reaction mixture was heated to reflux temperature for 3 h. The volatiles were concentrated in vacuo and the resultant residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (97 mg, 99%). LCMS (Method 2): Rt 3.39 min, m/z 681 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[N:20]1[CH2:25][CH:24]=[C:23]([C:26]#[N:27])[CH2:22][CH2:21]1.Cl.C(O)=[O:30]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[N:20]1[CH2:21][CH:22]=[C:23]([C:26](=[O:30])[NH2:27])[CH2:24][CH2:25]1
Reactant: Cc1cc(N2CC=C(C#N)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=CO
Agent: Cl
Product: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 96% formic acid (5 mL) was dissolved 8-(2,4-dichlorophenyl)-2-methyl-4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)quinoline (1.0 g), and hydrogen chloride gas was bubbled into the solution under ice-cooling to saturate the solution therewith. The reaction mixture was stirred at room temperature for 4 hours and then distilled under reduced pressure to remove the solvent. The residue was separated with chloroform and a saturated aqueous sodium hydrogen-carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform-methanol=10:1) and then recrystallized from tetrahydrofuran to obtain the title compound (174 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]1([NH:33][CH2:34][CH2:35][NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:36][CH2:35][CH2:34][NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCCNc1ccccc1
Product: O=C(NCCNc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N1-phenylethane-1,2-diamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(phenylamino)ethyl)terephthalamide. MS (Q1) 505.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:16]([Br:17])=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:23][C@H:22]2[CH3:24])=[O:20])[S:14][N:13]=1>>[Br:17][C:16]1[C:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][S:14][C:15]=1[NH:18][C:19]([C@@H:21]1[CH2:23][C@H:22]1[CH3:24])=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc(F)cc2)c1Br
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Using a similar procedure to that of Preparation VI-3, but using 1.3 equivalents of 4-fluorophenylboronic acid to 1 equivalent of (R,R)—N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropanecarboxamide and stirring the reaction mixture at 70° C. for 1 day affords (R,R)—N-[4-bromo-3-(4-fluorophenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. ES-MS: m/e 357.0 (m+1).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH:49]([CH3:51])[CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[N:45]=[C:44]([C:46]([NH:48][CH:49]([CH3:51])[CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)NC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 57.9 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.10 g), 6-bromo-N-isopropyl-2-pyridinecarboxamide (1.13 g) and tetrakis(triphenylphosphine)palladium(0) (0.160 g), the title compound (1.67 g) was obtained as a colorless amorphous powder.
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[N:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][C:13]=2[O:23]C)=[CH:10][CH:11]=1.CO>C(Cl)Cl>[Cl:5][C:6]1[N:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][C:13]=2[OH:23])=[CH:10][CH:11]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
BCl3 (1 M in DCM, 91 mL, 91 mmol) was added to a solution of 3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine (Intermediate 2-1, 8.6 g, 30 mmol) in DCM (150 mL) at 0° C. and the reaction was stirred for 5 h at RT. MeOH (50 mL) was added to the reaction at 0° C., then the reaction was warmed to RT and the solvent was evaporated under reduced pressure. The crude material was treated with hot CH3CN then cooled to 5° C. The mixture was filtered and 2-(6-chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (7.6 g, 86%) was afforded as yellow solid. MS [M+H]: 273.2; 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.5, 2.0 Hz, 1H), 6.59 (t, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Br:10]Br>Br>[CH3:9][C:5]1[N:6]=[CH:7][NH:8][C:4]=1[C:1](=[O:3])[CH2:2][Br:10]
Reactant: BrBr
Reactant: CC(=O)c1[nH]cnc1C
Agent: Br
Product: Cc1nc[nH]c1C(=O)CBr
Reaction time: 1.25 h

Procedure:
A solution of 1.57 g (12.6 mmol) of 5-acetyl-4-methylimidazole in 15 ml of concentrated hydrobromic acid was warmed to 50° and a solution of 2.01 g (12.6 mmol) of bromine in 15 ml of concentrated hydrobromic acid was added over 0.75 hour. The mixture was stirred at 50° for 1.25 hour, then concentrated. The residue was triturated with isopropyl alcohol and the white solid was collected by filtration. This amounted to 2.78 g (78%) of 1-(4-methyl-5-imidazolyl)-2-bromoethanone hydrobromide: nmr (D6DMSO) (δ): 9.40 (s, 1H); 4.87 (s, 2H); 2.65 (s, 3H). This material was converted to its free base by stirring for 15 minutes in 50 ml of saturated sodium bicarbonate solution to give, after collection by filtration and drying, 1-(4-methyl-5-imidazolyl)-2-bromoethanone as a white powder.