Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(OC2CN3CCC2CC3)nn1
Agent: N
Product: c1cc2cc(-c3ccc(OC4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 7A (200 mg, 0.8 mmol) was coupled with 5-indolylboronic acid (161 mg, 1 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (35 mg, yield, 14%). 1H NMR (300 MHz, CD3OD) 61.50-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.00-2.16 (m, 1H), 2.29-2.37 (m, 1H), 2.78-3.05 (m, 5H), 3.44-3.55 (m, 1H), 5.26-5.35 (m, 1H), 6.56(dd, J=3.3, 1.1 Hz, 1H)), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH2:23]([O:30][C:31]([N:33]([CH2:35][C:36](O)=[O:37])[CH3:34])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N>C(Cl)Cl.C(N(CC)CC)C>[CH2:23]([O:30][C:31](=[O:32])[N:33]([CH2:35][C:36](=[O:37])[NH:1][CH2:2][C:3]1[C:4]2[C:9](=[CH:8][C:7]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)NCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, (Benzyloxycarbonyl-methyl-amino)-acetic acid, 1-hydroxybenzotriazole, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide and triethylamine in methylene chloride is stirred at room temperature. The reaction is quenched by addition of water, and the mixture is eluted through silica gel to give {[(6-Benzenesulfonylamino-naphthalen-1-ylmethyl)-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O.C(Cl)Cl>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]([OH:10])=[O:2]
Reactant: COC(=O)CCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)CCC(=O)O
Reaction time: 4.5 h
Yield: 84.7 %

Procedure:
4,4-Dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 1.0 eq.) was treated with a solution of NaOH (4.0 g, 100 mmol, 2.1 eq.) in water (5 mL). The homogeneous solution was allowed to stir for 4-5 hours. The reaction was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The aqueous layer was acidified with 6M HCl to pH˜1.5 and extracted with ethyl acetate (50 mL×3). The combined ethyl acetate fractions were dried over MgSO4, filtered and evaporated to provide 4,4-dimethyl-pentanoic acid (5.35 g, 41.1 mmol, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH3:25]>>[CH3:23][N:24]([CH3:25])[C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:28][CH:27]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cc1
Yield: 10 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-(N,N-dimethylamino)benzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(4′-dimethylamino-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (19 mg, 10%): m/z (ES+) 408 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[S:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[CH3:17][NH:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[S:16])[N:18]([CH3:17])[NH2:19])[CH:5]=[C:6]([Cl:13])[C:7]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CCN(CC)c1c(Cl)cc(N=C=S)cc1Cl
Reactant: CNN
Solvent: CCO
Product: CCN(CC)c1c(Cl)cc(NC(=S)N(C)N)cc1Cl

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.2 g (0.0080 mole) of 3,5-dichloro-4-diethylaminophenyl isothiocyanate with 0.37 g (0.0080 mole) of methylhydrazine in 75 ml of ethanol produced a quantitative yield of 4-(3,5-dichloro-4-diethylaminophenyl)-2-methyl-3-thiosemicarbazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:23]=[CH:22][CH:21]=[C:18]([C:19]4[N:24]=[N:25][NH:26][N:20]=4)[CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-n2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1cccc(-c2nn[nH]n2)c1
Yield: 82.9 %

Procedure:
In a 250 ml two-neck flask, 80 ml of N,N-dimethyl formamide (DMF), 2.92 g (6.85 mmol) of 3-(3,6-dibromo-9H-carbazol-9-yl) benzonitrile, 0.98 g (15.08 mmol) of sodium azide (NaN3), 0.81 g (15.08 mmol) of ammonium chloride (NH4Cl), and a stir bar were added. The reaction was carried out with reflux under a nitrogen atmosphere for 24 hours. After the completion of reaction, 20 ml of 10% hydrochloric acid (HCl) was added and a filtering was conducted. The crude product was purified by column chromatography to obtain 3.21 g of a white solid product of 3,6-dibromo-9-(3-2H-tetraazol-5-yl-phenyl)-9H-carbazole (yield: 82.9%).
Reaction SMILES: C1C2C(C[O:15][C:16]([CH2:18][S:19]([NH:22][N:23]3[CH2:27][CH:26]([C:28]4[CH:33]=[CH:32][C:31]([CH:34]5[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[N:25]([CH2:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[C:24]3=[O:47])(=[O:21])=[O:20])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.CCCCCCC=CCCC>CN(C=O)C>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH:26]3[CH2:27][N:23]([NH:22][S:19]([CH2:18][C:16]([OH:17])=[O:15])(=[O:21])=[O:20])[C:24](=[O:47])[N:25]3[CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)=[CH:29][CH:30]=2)[CH2:36][CH2:35]1
Reactant: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)OCC3c4ccccc4-c4ccccc43)CC2c2ccc(C3CC3)cc2)cc1
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(CCN2C(=O)N(NS(=O)(=O)CC(=O)O)CC2c2ccc(C3CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1-[[(9H-fluoren-9-ylmethyloxy)carbonylmethyl]sulfonylamino]-3-[2-(4-methoxyphenyl)ethyl]-4-(4-cyclopropylphenyl)-2-imidazolidinone (2.0 g, 0.0031 mol) in DMF (15 mL) at room temperature is added 1,8-diazabycyclo[5.4.0]undec-7-ene (0.35 mL). The reaction is stirred for approximately one hour, diluted with ice-cold 0.1 N HCl and extracted with ethyl acetate. The organic phase is washed with brine, dried (sodium sulfate) and concentrated. The residue is warmed in approximately 20 mL of ether and diluted slowly with approximately 20 mL of hexanes. The liquid is decanted and the resulting material is dried under vacuum to afford 1.08 g of the desired compound. 1H NMR (CDCl3) δ 8.03 (bs, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.05 (m, 2H), 6.84 (m, 2H), 4.51 (t, J=8.4 Hz, 1H), 4.30 (s, 2H), 4.01 (t, J=8.7, 1H), 3.81 (s, 3H), 3.66 (m, 1H), 3.51 (m, 1H), 2.95 (m, 1H), 2.64 (m, 1H), 1.93 (m, 1H), 1.02 (m, 2H), 0.74 (m, 2H). MS 652 (MH+). Anal. calcd. for C23H27N3O6S¼C4H10O: C, 58.58; H, 6.04; N, 8.54. Found: C, 58.37; H, 6.01; N, 8.35.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]Cl)[CH:2]=1.NC(N)=[S:13].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][SH:13])[CH:2]=1
Reactant: ClCCCc1cccnc1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: SCCCc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-pyridyl)-1-propylchloride (3 g; 19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 mL of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the crude thiol on a silica gel column eluting with 50% ethyl acetate in hexane delivered 1.2 g of 3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. 1H NMR (300 MHz, CDCl3): δ 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H) 8.42 (m, 2H).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=S)#[N:2].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.[NH2:33][CH:34]([NH:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[C:35]([Cl:38])([Cl:37])[Cl:36]>CN(C=O)C.C(OCC)(=O)C>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]([NH:39][CH:34]([NH:33][C:4](=[N:3][C:1]#[N:2])[NH:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:35]([Cl:38])([Cl:36])[Cl:37])=[O:48])=[CH:42][CH:43]=1
Reactant: Cc1ccc(C(=O)NC(N)C(Cl)(Cl)Cl)cc1
Reactant: N#CNC(=S)Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(NC(=NC#N)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A solution of Example 44A (200 mg, 0.932 mmol) in DMF (7 mL) at 23° C. was treated with EDCI (250 mg, 1.30 mmol) followed by diisopropyethylamine (0.180 mL, 1.03 mmol). The mixture was stirred for 30 minutes, then treated with a solution of Example 38A (262 mg, 0.932 mmol) as a solution in DMF (2 mL) along with additonal diisopropyethylamine (0.360 mL, 2.06 mmol). The solution was stirred for 10 hours, poured into ethyl acetate (25 mL), and washed with water (25 mL). The aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic portions were washed with water (3×20 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography (elution with 5% ethanol/hexanes) provided 146 mg of the desired product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of p-toluidine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][N:11]([CH3:13])[CH3:12])=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NN(C)C
Agent: N#N
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Reaction time: 1.5 h
Yield: 5.3 %

Procedure:
To a solution of 3-(N′,N′-Dimethyl-hydrazino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.72 mmol) in 1,2-dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (0.228 g, 1.08 mmol). The reaction mixture was stirred for 1.5 h at reflux. Then, the solvents were removed and the residue was purified by preparative tlc (8:2 Hexane/EtOAc) to obtain 0.017 g (5%) of 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): δ 7.62 (m, 2H), 7.40 (m, 3H), 7.23 (d, 1H), 3.87 (s, 3H), 2.52 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:19])[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2ccc(C(F)(F)F)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2ccc(C(F)(F)F)cc2n1
Reaction time: 8 h

Procedure:
2-Methyl-7-(trifluoromethyl)quinolin-4-ol (1 g, 4.4 mmol) was heated in phosphoroxychloride (3 ml) for under reflux for one hour. The mixture was poured on ice and left at 4° C. overnight. The mixture was extracted with ethylacetate, the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 1.1 g (4.4 mmol, quantitative) which were used directly in the next step.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])(=O)=O.[I:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[I:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: Oc1cccc(I)c1
Reactant: COCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOCCOc1cccc(I)c1
Temperature: 68 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 1-[(methanesulfonyl)-oxy]-3,6,9-trioxadecane (11.6 g, 47.9 mmol) in dry DMF (145 ml) was added 3-iodophenol (10.6 g, 48.2 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction was immersed in an oil bath which was warmed to 68° C. over a period of 0.5 hr. The reaction was stirred at this temperature under an N2 atmosphere for 16 hrs and then at 82° C. for an additional 2 hrs. At the end of this period, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into ethyl acetate (500 ml), washed with water (200 ml), 1N aqueous sodium hydroxide (200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide a light brown oil. Flash column chromatography (silica, 1:3 to 1:2; EtOAc:hexane) provided 1 -(3-iodophenoxy)-3,6,9-trioxadecane as a light yellow oil (10.8 g, 37.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+:11]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S-:8])=[CH:4][CH:3]=1.[Na+:11]
Reactant: Sc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [S-]c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
Sodium p-chlorothiophenoxide was prepared from p-chlorothiophenol (4.3 g) in methanol (10 ml) and sodium methoxide (5.4 g of a 30% sodium methoxide solution) by evaporation in a rotary evaporator. The resulting salt was dissolved, together with 3,4-dimethoxy-4'-fluorobenzophenone (7.8 g) in dimethylformamide (30 ml), and the solution was heated at 100° C. for 3 hours. Then, the reaction mixture was poured into water, and the crystals which precipitated were recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[CH3:23][CH2:24][O-:25].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:25][CH2:24][CH3:23])[C:5]2[O:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1
Reactant: CC[O-]
Reactant: Cc1cc(-c2ccccc2)nc2oc3c(Cl)nc(Cl)nc3c12
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1oc1nc(-c3ccccc3)cc(C)c12
Yield: 46.1 %

Procedure:
0.2 g (0.6 mmol) 2,4-dichloro-9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo-[3,2-d]pyrimidine and 0.12 g (1.8 mmol) sodium ethylate are added by stirring into 50 ml absolute ethanol at room temperature for 24 h. Then, the precipitate is sucked off, washed with about 40 ml water and dried. Following flash chromatography, 94 mg (46%) 2-chloro-4-ethoxy-9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I.S(=O)(=O)(O)[O-].[Na+]>CN(C=O)C>[I:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: II
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 5-nitro-1H-indole (5 g, 30.86 mmol) in DMF (50 mL) was added KOH (5 g, 92.58 mmol), followed by addition of I2 (15.7 g, 61.74 mmol). The reaction mixture was stirred at RT for 2 h and then added 10% aqueous sodium bisulfate (50 mL) solution. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to obtain the title compound as a pale yellow solid (8.0 g. 91%). MS (ESI, pos. ion) m/z: 286.9 (M−1)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([OH:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([O:20]C)=[O:19])[NH:9][C:8]=2[CH:24]=1>CO.CCOCC>[Cl:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([OH:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([OH:20])=[O:19])[NH:9][C:8]=2[CH:24]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 M NaOH (0.2 mL, 0.500 mmol) was added to a solution of methyl 5-({6-chloro-5-[4-(1-hydroxyethyl)phenyl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoate in MeOH (2.5 mL). Additional 2.5 M NaOH (0.250 mL, 0.625 mmol) was added and the reaction was stirred at rt overnight. The reaction mixture was diluted with Et2O (50 mL) and washed with 10 mL of 1 M aqueous HCl. The aqueous phase was extracted with Et2O. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to afford the desired product. LC-MS: calculated for C23H19ClN2O4 422.86, observed m/e 423.8 (M+H)+ (Rt: 1.74 min). 1H NMR (500 MHz, CD3OD): δ 7.85 (d, 1H), 7.47 (s, 1H), 7.44-7.36 (m, 6H), 7.30 (s, 1H), 4.87 (m, 1H), 2.61 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[N+:7]([C:10]1[N:14]=[C:13]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17](F)[CH:16]=2)[NH:12][N:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:7]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:21]([S:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:22]=2)[NH:12][N:11]=1)([O-:9])=[O:8]
Reactant: FC(F)(F)CS
Reactant: O=Cc1ccc(-c2nc([N+](=O)[O-])n[nH]2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc([N+](=O)[O-])n[nH]2)cc1SCC(F)(F)F
Temperature: 5 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
0.8 g of 2,2,2-trifluoroethylmercaptan was added dropwise under cooling with ice to a mixture of 1.6 g of 4-(3-nitro-1,2,4-triazolyl)-2-fluorobenzaldehyde, 1.3 g of potassium carbonate and 50 ml of N,N-dimethylformamide, followed by stirring at from 0 to 10° C. for 4 hours. The mixture was concentrated under reduced pressure, 200 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.8 g of 4-(3-nitro-1,2,4-triazolyl)-2-(2,2,2-trifluoroethylthio)benzaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:13])[CH2:2][NH:1][S:24]([C:23]2[C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=3[S:21][CH:22]=2)(=[O:25])=[O:26])=[CH:7][CH:8]=1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: NCC(O)COc1ccc(Cl)cc1
Product: O=C1CCCc2c(S(=O)(=O)NCC(O)COc3ccc(Cl)cc3)csc21

Procedure:
From 1-amino-3-(4-chloro-phenoxy)-propane-2-ol (58 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (70 mg), a yield (45 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:9][CH:10]([CH2:21][N:22]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH3:23])[CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:8])=[O:6])[CH:2]=[CH2:3].Cl.[OH2:31]>C(OCC)(=O)C>[CH2:27]([O:26][C:24]([N:22]([CH2:21][CH:10]([CH2:9][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:8])[C:11]([OH:13])([OH:31])[CH3:12])[CH3:23])=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)N(C)CC(CN(C)C(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)CC(CN(C)C(=O)OCC=C)C(C)(O)O
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-(N-allyloxycarbonyl-N-methylamino)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-3-(t-butyldimethylsilyloxy)butane (123 g) in ethyl acetate (1.2 l) was added 6N-aqueous hydrochloric acid (240 ml) at ambient temperature. After stirring at the same temperature for 2.5 hours, to the mixture was added water (1 l) and the organic layer was separated. The organic layer was washed successively with 1N-aqueous sodium hydroxide (1 l), saturated aqueous ammonium chloride (500 ml), and brine (500 ml). After the solution was dried over magnesium sulfate, removal of the solvents gave a residue. The residue was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (95:5-40:60, V/V) to give 1-(N-allyloxycarbonyl-N-methylamino)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-3-hydroxybutan-3-ol (83.18 g).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:14][C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cn(CCl)cc1C(F)(F)F
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC(C#N)(C#N)CCC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
0.23 g of 1-chloromethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole and 0.15 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.13 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of [(3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (47), hereinafter) shown by below formula.