Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[C:39]1([O:43][CH2:44][CH2:45][CH3:46])[CH2:42][NH:41][CH2:40]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C=O)C>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9]([NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([N:41]2[CH2:40][C:39]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]3[CH3:32])([O:43][CH2:44][CH2:45][CH3:46])[CH2:42]2)=[O:14])=[O:24])[N:3]=[CH:2]1
Reactant: CCCOC1(C2CCCCC2C)CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC1(C2CCCCC2C)CN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)C1
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To 97 mg (0.29 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 2 mL of DMF are added 94 mg (0.29 mmol) of 3-(2-methylcyclohexyl)-3-propoxyazetidine trifluoroacetate, 70 mg (0.37 mmol) of EDC and 45 mg (0.33 mmol) of HOBt. After 3 hours, the reaction medium is hydrolysed with aqueous 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is purified by preparative HPLC. 33 mg of 1-[2-(1H-imidazol-4-yl)ethyl]-3-{1-(4-methoxybenzyl)-2-[3-(2-methylcyclohexyl)-3-propoxyazetidin-1-yl]-2-oxoethyl}urea trifluoroacetate are obtained in a yield of 18%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:27][S:24]([CH2:23][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10])(=[O:26])=[O:25]
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2CS(C)(=O)=O)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2CS(C)(=O)=O)sc2ccc(F)cc12
Yield: 23.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methanesulfonylmethyl-phenyl)-amide (0.123 g) and 4-pyridineboronic acid (0.0462 g) in 1,2-dimethoxyethane (5 ml), ethanol (1 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.035 g) to obtain the title compound (0.029 g) as a yellowish foam. MS (ISN): 489.1 (M−H)−
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:29])[C:25]([O:27]C)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][O:22][CH2:21][C@:20]2([CH3:29])[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]1(C(=O)O)COCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
(3R,4R)-Methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylate (856 mg, 2.04 mmol) was stirred with 15% NaOH (5 mL) in THF (5 mL) and MeOH (5 mL) at 45° C. overnight. The mixture was then cooled to 0° C. and acidified with 2N HCl to pH ˜3. After extraction with ethyl acetate the organics were washed with brine, dried over MgSO4, and concentrated. The residue was triturated with ether to yield 726 mg (88%) of (3R,4R)-4-(4-(benzyloxy)phenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxylic acid as a white solid. MS: (M+Na)+=428.0; (M−H)−=404.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[CH2:15][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)CN1CCNCC1)C1CCc2ccc(OC)cc2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 6a (3.87 g, 8.68 mmol) was dissolved in 40 ml of dichloromethane and 40 ml of trifluoroacetic acid was added. The mixture was stirred for overnight, at which time the solution was concentrated to dryness, dissolved in saturated NaHCO3 solution and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to yield 2.91 g (97%) of 7a as yellow wax, which was used in the next reaction. 1H NMR (400 MHz, CDCl3) 0.93-0.96 (t, 3H, J=12 Hz), 1.62 (m, 3H), 1.85-1.97 (m, 3H), 2.56 (m, 1H), 2.81-2.88 (m, 5H), 2.98-3.34 (m, 9H), 3.81 (s, 3H), 6.60 (s, 1H), 6.65-6.68 (d, 1H, J=12 Hz), 6.96-6.98 (d, 1H, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])[C:4]=23)[CH2:19]1
Reactant: ClCCl
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
tert-Butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.150 g, 0.311 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse chromatography (Biotage SP4, C-18 25M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide hydrochloride (0.110 g, 78% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.16 (s, 1H), 7.44 (s, 1H), 3.99-3.96 (m, 2H), 3.91-3.87 (m, 1H), 3.71-3.64 (m, 2H), 3.57-3.53 (m, 1H), 3.36 (s, 3H), 2.44-2.39 (m, 1H), 2.06-2.02 (m, 1H), 1.31-1.29 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (84 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 88 mg (71% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide.
Reaction SMILES: IC.N1C2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=C1.[C:15](=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[C:23]2[C:6]([CH:5]=[CH:24][N:22]2[CH3:21])=[CH:7][CH:8]=1)=[O:13]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Iodomethane (2.3 mL, 36.9 mmol) was added to a suspension of indole-6-carboxylic acid (1.55 g, 9.62 mmol) and potassium carbonate (1.98 g, 14.3 mmol) in DMF (32 mL) under argon. The reaction was stirred at room temperature for 24 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 190 (MH)+.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].[K].[CH2:16]([NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23](Cl)[N:22]=1)[CH2:17][CH2:18][CH3:19]>C(#N)C.O.C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:23]1[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])[N:22]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Reactant: CCCCN
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [K]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCCCNc1nc(NCCCC)nc(NCCCC)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 150 mL of acetonitrile. The mixture solution was cooled to 0° C. The cooled solution was dropwise added with a solution of 14.6 g (0.2 mol.) of butylamine in 20 mL of water over one hour while stirring in such a manner that the temperature did not raise over 5° C. While further continuing the stirring, a solution of 20.0 g (0.2 mol.) of potassium hydrogenecarbonate in 100 mL of water was dropwise added to the solution at the same temperature. Thereafter, the reaction temperature was gradually raised and the stirring was continued at 45° C. for eight hours. After the completion of the conversion of the resulting product into 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was recognized by a high-performance liquid chromatography, the obtained produt was cooled and separated through filtration. After the filtrated cake was fully wahsed with a large amount of water, the obtained 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was suspended in 100 mL of water and added with 29.2 g (0.4 mol.) of butylamine and further reacted for six hours under heat-reflux. After cooling, the resulting product was added with 200 mL of toluene and vigorously stirred. Thereafter, the aqueous layer was separated. After the toluene layer was further washed thrice with each 150 mL of water, toluene was distilled off from the organic layer under heating and reduced pressure to obtain 28.2 g of 2,4,6-tris(n-butylamino)-1,3,5-triazine (yield: 96%).
Reaction SMILES: C([C:4]1SC(N2CCN(CC3C=CC(C(N4CCCCC4)=O)=CC=3)C2=O)=[N:6][C:5]=1C)(=O)C.[C:31]([C:34]1[S:38][C:37]([N:39]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH:46]=[C:47]([CH:52]=[CH:53][CH:54]=3)[C:48]([NH:50][CH3:51])=[O:49])[C:40]2=[O:55])=[N:36][C:35]=1[CH3:56])(=O)[CH3:32].COC(OC)([N:61](C)C)C.O.NN>>[CH3:51][NH:50][C:48](=[O:49])[C:47]1[CH:52]=[CH:53][CH:54]=[C:45]([CH2:44][N:41]2[CH2:42][CH2:43][N:39]([C:37]3[S:38][C:34]([C:31]4[NH:61][N:6]=[C:5]([CH3:4])[CH:32]=4)=[C:35]([CH3:56])[N:36]=3)[C:40]2=[O:55])[CH:46]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Reactant: CNC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Agent: NN
Solvent: O
Product: CNC(=O)c1cccc(CN2CCN(c3nc(C)c(-c4cc(C)n[nH]4)s3)C2=O)c1
Yield: 54 %

Procedure:
Following the procedure as described in Example 40, making variations as required to replace 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(piperidine-1-carbonyl)benzyl)imidazolidin-2-one with 3-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)-N-methylbenzamide to react with N,N-dimethylacetamide dimethyl acetal and further with hydrazine monohydrate, the title compound was obtained as a colorless solid in 54% yield: mp 259-261° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.62 (m, 2H), 7.42-7.34 (m, 2H), 6.32 (br s, 1H), 4.51 (s, 2H), 4.13-4.04 (m, 2H), 3.49-3.41 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 373.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].[C-]#N>CCCCCC.C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:16][C:17](=[O:18])[N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])([CH3:15])[CH3:14]
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Reactant: CNC1CCCCC1
Agent: [C-]#N
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CN(C(=O)NC(C)(C)c1cccc(Cl)c1)C1CCCCC1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
A solution of 1.2 g of N-methyl-N-cyclohexylamine in 5 ml of n-hexane was added to a solution of 0.01 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as shown in Synthesis Example 1) in 10 ml of benzene. The mixture was kept at room temperature for 6 hours and concentrated under reduced pressure to obtain crystals, which were recrystallized from n-hexane to give 2.8 g of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2.O>C(OCC)(=O)C.CCCCCC>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C)cc1
Reactant: Brc1ccc(-c2nnc(-c3cccnc3)nc2-c2ccc(Br)cc2)cc1
Agent: C1=CC2C=CC1C2
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2ccc(-c3cccnc3)nc2-c2ccc(Br)cc2)cc1
Temperature: 150 °C
Yield: 28 %

Procedure:
Into a 200 mL three-neck recovery flask, 2.4 g (5.0 mmol) of 5,6-bis(4-bromophenyl)-3-(3-pyridyl)-1,2,4-triazine, 60 mL of para-xylene, and 2.5 mL (23 mmol) of 2,5-Norbornadiene were put. This solution was refluxed at 150° C. for 20 hours under a nitrogen stream. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extract was washed with a saturated saline together with an organic layer and the organic layer was dried over magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was refined with silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized with chloroform/hexane, so that an objective substance, 0.68 g of yellow powder was obtained in a yield of 28%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3](N)[CH:2]=1.N([O-])=O.[Na+].[BrH:19]>O.[Cu](Br)Br>[Br:19][C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)oc1ccccc12
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)oc1ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine N-dibenzofuran-3-ylamine (2.0 g, 10.8 mmol), water (20 ml), and conc. hydrobromic acid (6 ml). Cool to 0° C. Add a solution of sodium nitrite (0.7 g, 10.8 mmol) in water (16 ml). After 15 minutes add the mixture above to a mixture of copper bromide (1.7 g, 12.3 mmol) in water (9.2 ml) and hydrobromic acid (4 ml). Warm to ambient temperature. After 18 hours, add water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:7]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:8]=[N:9]1
Reactant: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(C#C[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, copper(I) iodide (7 mg), bis(triphenylphosphine)palladium(II) dichloride (90 mg) and triphenylphosphine (34 mg) were added to a dimethylformamide (45 mL) solution that contained 4-iodo-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (4.51 g), trimethylsilylacetylene (2.26 g) and triethylamine (3.57 mL), and the obtained solution was then stirred at 75° C. for 4 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and a saturated saline. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=85:15 to 70:30), so as to obtain the title compound (3.46 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([CH3:11])[CH3:10])=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[Br:1][C:2]1[C:3]([CH:9]([CH3:11])[CH3:10])=[N:4][N:5]([CH2:7][Cl:14])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1nn(CO)cc1Br
Solvent: ClCCl
Product: CC(C)c1nn(CCl)cc1Br
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.29 g of 4-bromo-3-i-propyl-1H-pyrazole-1-ylmethanol was dissolved to 20 ml of dichloromethane. 2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.28 g of 4-bromo-3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:21]1[CH:25]=[CH:24][C:23]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)=[CH:22]1
Reactant: OB(O)c1ccoc1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: OCCCO
Solvent: O
Product: FC(F)(F)c1cc(-c2ccoc2)c2c(c1)ncn2-c1ccccc1
Yield: 53.6 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (0.5 g, 1.25 mmol), 3-furane boronic acid (0.2 g, 1.87 mmol), 1,3-propanediol (0.45 ml, 6.2 mmol), potassium carbonate (0.86 g, 6.2 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (15 ml) was stirred at reflux in a nitrogen atmosphere for 30 min. The cooled reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in diethyl ether to afford the title product as an off-white solid (0.22 g, 54%) m/z, 329.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:36]1([CH2:42][CH2:43][CH2:44]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:44][CH2:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3ccccc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and 3-phenylpropylbromide (0.175 ml) were added, and the mixture was stirred at 50° C. for 2 hr, and at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.
Reaction SMILES: CC(C1C=C(C(C)(C)C)C=CC=1S[C@@H]1CCC[C@H]1SCC(OC)=O)(C)C.[CH3:27][C:28]([C:31]1[CH:32]=[C:33]([S:41][C@@H:42]2[CH2:47][CH2:46]C[CH2:44][C@H:43]2[S:48][CH2:49][C:50]([O:52]C)=[O:51])[CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)([CH3:30])[CH3:29]>>[CH3:27][C:28]([C:31]1[CH:32]=[C:33]([S:41][C@@H:42]2[CH2:47][CH2:46][CH2:44][C@H:43]2[S:48][CH2:49][C:50]([OH:52])=[O:51])[CH:34]=[C:35]([C:37]([CH3:39])([CH3:38])[CH3:40])[CH:36]=1)([CH3:29])[CH3:30]
Reactant: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: COC(=O)CS[C@@H]1CCC[C@H]1Sc1ccc(C(C)(C)C)cc1C(C)(C)C
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method described in Example 5, except that the title product of Example 98 was substituted for the title product of Example 4. The structure was supported by NMR and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1.ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 93.7 %

Procedure:
Dissolve N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (1.8 g, 6.3 mmol) in tetrahydrofuran (50 mL) and dichloromethane (50 mL), add slowly 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol), stir the reaction at room temperature for 15 hrs. Collect the white solid formed by filtration (2.0 g), recover from the mother liquor to give another 1.0 g (total 3.0 g, 93.7% yield). MS: (M+1): 506.2.