Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:15]([N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]=[CH:11]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCI
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cnc(-c2ccccc2)c1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
To the suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in 30 ml of anhydrous DMF is added a solution of 4-phenylimidazole (7.21 g, 50 mmol) in 30 ml of DMF at room temperature, the resulting mixture is stirred at 70° C. 1 h, and then cooled to room temperature followed by the dropwise addition of iodobutane (9.66 g, 52.5 mmol, 1.05 eq.). The mixture is stirred at room temperature for 1 h, heated to 70° C. and stirred for an additional 8 h. The reaction mixture is cooled to room temperature, poured into 200 ml of ice-water, extracted with ethyl acetate (100 ml×3). The combined organics are washed with water, brine, dried over anhydrous sodium sulfate, filtered, evaporated at reduced pressure and purified by flash chromatography on silica gel to obtain 9.08 g of 1-butyl-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d, J=7.6 Hz), 7.49 (1H, s), 7.36 (2H, t, J=7.6 Hz), 7.23(1H, m), 7.20 (1H, s), 3.95 (2H, t, J=7.2 Hz), 1.80 (2H, m), 1.36 (2H, m), 0.96 (3H, t, J=7.2 Hz); MS (+VE) m/z 201 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[C:12]#[CH:13].[OH-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[N:6]([CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: C#CCOCCBr
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCCn1c(Cl)nc2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
2-Chlorobenzimidazole (30.0 g) and 2-bromoethyl propargyl ether (41.0 g) are dissolved in N,N-dimethylformamide (300 ml), and thereto is added a 25% aqueous sodium hydroxide (40.0 g), and the mixture is stirred at 60° C. for 4 hours. Water (700 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is distilled under reduced pressure to give 2-chloro-1-[2-(propargyloxy)ethyl]benzimidazole (24.5 g) as a colorless oily substance, b.p. 158°-160° C./1.2 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C.[Cu]I>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3cccc4cccnc34)c2)cc1

Procedure:
This material was prepared according to the method described in Example 413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 ML). Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) nm/z: 367 (M+1). Anal. Calcd for C21H13F3N2O: C, 68.85; H, 3.58; N, 7.65. Found: C, 68.88; H, 3.59; N, 7.51.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C=O.[OH-].[Na+].[C:14](OCC)(=[O:16])C>CN(C)C=O>[OH:16][CH2:14][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCn1nnc2ccccc21

Procedure:
A slurry of benzotriazole (11.9 g) and 30% formalin (8.3 ml) was heated to reflux in 100 ml of 25% aqueous dimethylformamide. A trace of starting material remained. The solution was treated with 1.0 ml of 10% aqueous sodium hydroxide and heated to reflux again. An aqueous ethyl acetate extractive work up afforded 1-(hydroxymethyl)benzotriazole (8.65 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[Li]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)([OH:11])[CH3:10]
Reactant: [Li]c1ccco1
Reactant: CC(=O)c1cc(Br)ccc1N
Product: CC(O)(c1ccco1)c1cc(Br)ccc1N

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl)-ethanone and 2-furyl lithium generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 7.6 (m, 1H), 7.08 (dd, J=2.73, 10.91 Hz, 1H), 6.8 (d, J=2.73 Hz, 1H), 6.56 (d, J=8.18 Hz, 1H), 6.45-6.38 (m, 2H), 6.14 (s, 1H), 5.3 (s, 2H), 1.76 (s, 3H); MS (ES) m/z 280/282 ([M−H]−, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 100 °C
Yield: 66.9 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (0.5 g, 2.79 mmol) and [4-(methylsulfonyl)phenyl]boronic acid (0.57 g, 2.79 mmol) in 1,4-dioxane (10 mL) and MeOH (4 mL) was treated with 2M Na2CO3 (4 mL) and Pd(PPh3)4 (65 mg, 0.06 mmol). The reaction mixture was degassed with N2 and heated at 100° C. for 3 h. Most of 1,4-dioxane and MeOH was removed under reduced pressure. Water was added, and the mixture was extracted with EtOAc (50 mL×4). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid, which was triturated with CH2Cl2 to give 0.465 g (67%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. The filtrate was washed with 1 N HCl (25 mL), and the aqueous layer was separated and basified with 4N NaOH. The mixture was extracted with EtOAc (50 mL×2) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give additional 0.045 g (7%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.15 (d, 2H, J=8.5 Hz), 7.97 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 6.81 (s, 2H), 3.20 (s, 3H); LRMS (ESI), m/z 250 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:56])[CH:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41].CCOC(/N=N/C(OCC)=O)=O>>[CH2:40]([O:42][C:43](=[O:56])[CH:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)OCC
Yield: 22.9 %

Procedure:
Reaction of 3,3-bis(4-methoxy-phenyl)-prop-2-en-1-ol (216 mg, 0.8 mmol), triphenylphosphine (240 mg, 0.9 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (240 mg, 1.0 mmol) and diethylazodicarboxylate (0.11 mL, 0.9 mmol) in an identical manner to Example 1 gave the title compound (90 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:6]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:6]
Reactant: COCCN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCCN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In acetic acid (100 ml) was dissolved N-(2-methoxy-ethyl)-N-methyl-4-nitrobenzylamine (5.9 g), and to the mixture was added reduced iron (7.5 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate, and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4-((N-(2-methoxyethyl)-N-methylamino)methyl)aniline (3.4 g) as red oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12]C[C@H:10]1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:10]1[NH:15][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: N[C@@H]1CCCC[C@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@@H]1CCC[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of (1R,2R)-2-benzyloxycyclohexylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×35 mL). The solid was suspended in 80% acetone/EtOH (200 mL). The suspension was stirred at reflux for 30 seconds before the solid was filtered and dried in the vacuum oven (50° C.), affording the title compound (844 mg. 55%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.60 (d, 1H, J=11.2 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.39 (m, 1H), 2.94 (m, 2H), 2.85 (m, 1H), 2.74 (t, 2H, J=6.5 Hz), 2.24 (m, 1H), 1.90 (m, 3H), 1.64 (m, 2H), 1.14 (m, 4H). 13C NMR (D2O, 125 MHz) δ ppm 137.35, 129.28, 129.19, 128.90, 76.90, 70.35, 60.97, 48.12, 42.90, 29.59, 26.53, 23.64, 23.09, 21.63. [α]D=−68.9° (c=0.0026 in water). ES-MS 326 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming sulphuric acid (105 mL) was added dropwise to 4-fluoro-1-methyl-2-nitrobenzene (30 g, 0.194 mol) at −5° C.˜0° C. and a mixture of fuming sulphuric acid (54 mL) and fuming nitric acid (18 mL) was added dropwise to it at −5° C.˜0° C. over the period of 3 h. After complete addition, the reaction mixture was stirred for 3 hours at ambient temperature. TLC showed complete conversion of starting material to the product. The reaction mixture was poured into ice and extracted with dichloromethane. The combined organic layers was washed with water (600 mL), sat. sodium bicarbonate (600 mL) and brine (600 mL). It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=20:1) to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[CH3:34].[H-].[Na+]>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:11]3[CH2:12][CH:13]([CH3:14])[NH:8][CH:9]([CH3:31])[CH2:10]3)=[O:30])=[CH:17][CH:18]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=1)[CH3:34]
Reactant: CC(Br)c1cccc(C(F)(F)F)c1
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4cccc(C(F)(F)F)c4)c3)cc2)CC(C)N1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-(1-bromo-ethyl)-3-trifluoromethyl-benzene (64 mg, 0.25 mmol) in DMF (2 ml) was added NaH (12 mg, 0.47 mmol) at 0° C. The mixture was stirred overnight. LCMS showed that the reaction was completed, DMF and water were removed. TFA (2 mL) was added to the residue and stirred at room temperature for 3 hr. TFA was removed followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-Amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (30 mg, yield 25.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2F)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cccc(F)c32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(2-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.88 (s, 3H), 5.11 (s, 2H), 6.22 (d, 1H), 6.61-6.67 (m, 1H), 6.82-6.89 (dd, 1H), 7.26-7.43 (m, 10H), 7.52 (d, 1H), 7.92 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[OH:8][S:9]([O-:11])=[O:10].[OH-].[Ca+2:13].[OH-]>>[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[Ca+2:13]
Reactant: Oc1ccccc1
Reactant: O=S([O-])O
Agent: [Ca+2]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(O)cc1

Procedure:
While 1000 g of a phenol sulfonic acid aqueous solution at a concentration of 5% was stirred at room temperature, calcium hydroxide was gradually added to reach a pH of about 6. The mixture was continuously stirred for a while. Then, this was filtered with 0.4 micrometer glass filter to obtain a calcium phenolsulfonate aqueous solution, which was then spray-dried to obtain powders of calcium phenolsulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(O)cc2)c2cccc(Cl)c2C)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
300 mg of N2-(3-chloro-2-methylphenyl)-N-(4-hydroxybenzyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 2.00 mL of DMF, and 110 mg of potassium carbonate and 133 mg of ethyl bromoacetate were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 30:70) to obtain 370 mg of ethyl 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]phenoxyacetate.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[S:13](C)=O>O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[SH:13]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,3-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol) in 300 mL of DMSO was added powdered Na2S 9H2O (Aldrich, 24.0 g, 100 mmol). The mixture was stirred at ambient temperature for 24 h, then was diluted with 2 L of water. The mixture was clarified by filtration and the filtrate was acidified to pH 4 with con. HCl. The mixture was extracted 3× with Et2O (400 mL). The organic layers were combined and washed twice with a brine solution (400 mL), dried over Na2SO4. Removal of the solvent under reduced pressure gave 18.4 g product.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Br[C:10]1[N:11]=[C:12]([O:31][CH3:32])[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])=[N:14][C:15]=1[CH2:16][CH3:17]>C1COCC1>[CH2:16]([C:15]1[N:14]=[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])[C:12]([O:31][CH3:32])=[N:11][C:10]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH3:17]
Reactant: CCC(O)CC
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1OC(CC)CC
Temperature: 50 °C

Procedure:
To a stirred solution of 3-pentanol (88 mg, 1 mmol) in THF (1 mL) is added 60% sodium hydride (12 mg, 0.3 mmol) and after 0.5 h [4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane (41 mg, 0.1 mmol) is added. The mixture is heated to 50° C. for 12 h, cooled and partitioned between ethyl acetate and water. The organic layer is washed with water, brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by preparative TLC eluting with 50% ether in hexanes to give {4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane, a colorless oil (19 mg). NMR (CDCL3, 400 MHz) □0.98 (t, 6 H), 1.22 (t, 3 H), 1.78 (m, 4 H) 2.80 (q, 2 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 5.05 (quintet, 1 H), 6.8 (s, 1 H), 6.90 (d, 1 H), 7.37 (d, 1 H); MS 345 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([OH:30])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[ClH:32].[CH3:33]CO>>[CH2:1]([O:2][C:3](=[O:31])[C@H:4]([OH:30])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:18][CH:17]=1)[NH2:7])[CH3:33].[ClH:32]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)OC(C)(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1

Procedure:
A solution of (R)-3-[N′-t-butoxycarbonyl-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid methyl ester (20 g, 16 mmol) in HCl/EtOH (1.1 M, 200 mL) was stirred overnight and then concentrated in vacuo. The residue was dispersed in EtOAc (2×40 mL), and the precipitate was collected by filtration to give the title compound as an off-white solid HCl salt (8.8 g). LC-MS: 367 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (t, J=7.2 Hz, 3H), 3.05-3.03 (q, J=7.2 Hz, 2H), 4.06-3.95 (m, 4H), 4.42 (br, 1H), 6.46 (br, 1H), 7.62-7.40 (m, 7H), 9.42 (s, 3H).
Reaction SMILES: [Na].[C:2]([C:4]1[C:5]([S-:15])=[N:6][S:7][C:8]=1[NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].I[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[NH:9][C:8]1[S:7][N:6]=[C:5]([S:15][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[C:2]#[N:3])[CH3:14]
Reactant: CCOC(=O)Nc1snc([S-])c1C#N
Reactant: CCCCCI
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
A mixture of sodium, 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0 g, 20 mmol), 1-iodopentane (4.0 g, 20 mmol) and tetrahydrofuran (20 mL) was stirred at ambient temperature for 16 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel using 1:1 ethyl acetate-hexane as eluent. The filtrated was concentrated and the residue was recrystallized from cold aqueous methanol, affording 2.5 g (42%) (4-cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester as a colorless solid. An additional 0.5 g (8.4%) was obtained by concentration of the mother liquor and purification by radial chromatography (4 mm plate, 4:1 hexane-ethyl acetate). 1H NMR (400 MHz, acetone-d6) δ11.1 (bs, 1H), 4.32 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=7.2 Hz), 1.73 (p, 2H, J=6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J=7.6 Hz) ppm; MS (APCI, m/z): 312 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](I)[CH2:15][CH3:16]>>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:15][CH3:16]
Reactant: CCCI
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Product: CCCOc1cc(C(F)(F)F)ccc1C=O

Procedure:
Using 2-hydroxy-4-(trifluoromethyl)benzaldehyde and propyl iodide, 2-propoxy-4-(trifluoromethyl)benzaldehyde was obtained in the same method as in Production Example 283a).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Br:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Reactant: CC(Br)c1ncnc(Cl)c1I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Br)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g) then, 4-chloro-6-(1-bromoethyl)-5-iodopyrimidine (1.8 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.