Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCOCC1.O.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>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]3)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=C1CCc2cc(Br)ccc2C1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCc2cc(-c3ccc([N+](=O)[O-])cc3)ccc2C1
Yield: 50.6 %

Procedure:
Pd(PPh3)4 (0.0736 g, 0.06 mmol) was added to a solution of 6-bromo-2-tetralone (1.5 g, 6.66 mmol) in 50 mL of 1,4 dioxane-H2O (3:1) mixture under argon atmosphere, followed by cesium carbonate (6.49 g, 19.99 mmol) and 4-nitrophenyl boronic acid (1.32 g, 7.99 mmol). The reaction mixture was degassed for 5 min. The reaction mixture was refluxed for 4 h and solvent removed under reduced pressure. The residue partitioned between ethyl acetate and water. The separated organic layer was dried over sodium sulphate, filtered and removed under reduced pressure. The product was purified by flash chromatography using 18% ethyl acetate in hexane to afford title compound (0.9 g, 50%) as solid. 1H NMR (300 MHz, CDCl3): 8.31 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.5 (m, 2H), 7.27 (s, 1H), 3.66 (s, 2H), 3.16 (t, J=6.9 Hz, 2H), 2.61 (t, J=6.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[O:27])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(Sc2cnc(N)s2)cc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 92.6 %

Procedure:
To a mixture of 2-amino-5-(4-methanesulfonylaminophenylthio)thiazole (2.0 g) in chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (1.6 g) in chloroform (50 ml) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 2.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and the precipitates were collected by filtration. The solid was washed with aqueous sodium bicarbonate and water, dried in vacuo to give 2-amino-5-(4-methanesulfonylaminophenylsulfinyl)thiazole (1.95 g, yield: 92.6%).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=1.Cl>CCCCCC.O1CCCC1>[O:22]=[C:21]([CH2:20][O:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)COc1cccnc1
Reactant: COP(C)(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1cccnc1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (4.76ml. of a 2.1M solution in hexane) was added to a solution of dimethyl methylphosphonate (1.24g.) in dry tetrahydrofuran at -78°C. in an atmosphere of nitrogen. After 10 minutes, a solution of ethyl 3-pyridyloxyacetate (0.90g.) in dry tetrahydrofuran (5ml.) was added dropwise, and the mixture was stirred for 1 hour at -78°C. The reaction mixture was taken to pH 1-2 with 2N hydrochloric acid and the solvents were removed under reduced pressure. The residue was shaken with water (10ml.) and extracted with ether (3 × 10ml.). The extracts were discarded, and the aqueous solution was adjusted to pH 7-8 with sodium bicarbonate solution and extracted with chloroform (6 × 10ml.). The combined extracts were evaporated, to give dimethyl [2-oxo-3-(pyrid-3-yloxy)propyl]phosphonate as an oil, RF = 0.2 (10% methanol in ethyl acetate).
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([O:12][C:13]([NH:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:22]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C=O)C>C(#N)C>[C:8]([O:12][C:13]([NH:15][N:16]1[C:20]([C:6]#[N:5])=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:22][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:24]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nn1cccc1C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nn1c(C#N)ccc1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
A solution of chlorosulfonylisocyanate (541 μL, 6.22 mmol) in acetonitrile (5 mL) was added dropwise to a cooled (0° C.) solution of benzyl 3-{1-[(tert-butoxycarbonyl)amino]-1H-pyrrol-2-yl}azetidine-1-carboxylate (2.10 g, 5.65 mmol) in acetonitrile (15 mL). The mixture was stirred at 0° C. for 30 min and was warmed to rt. After 1 h, the mixture was recooled (0° C.) and DMF was added dropwise. The reaction was allowed to warm to rt. After 30 min, the mixture was poured onto crushed ice (100 g) and was allowed to warm to rt. The aqueous mixture was extracted with EtOAc (3×75 mL) and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to obtain 800 mg (36%) of the desired product, which was used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:19][CH3:20])=[N:7][N:6]=[CH:5]2
Reactant: CCN(CC)CCN
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-diethylethane-1,2-diamine (0.25 mL, 1.81 mmol) were added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 323(M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:27]=[CH:28][C:16]([F:15])=[C:17]([C:29]([F:31])([F:32])[F:30])[CH:18]=1)[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
In accordance with the above reaction formula (1), the compound of the present invention was prepared. First, after 4.2 g (0.039 mole) of benzylamine and 3.1 g (0.039 mole) of pyridine were dissolved in 50 ml of toluene, 11.0 g (0.039 mole) of 2-(4-fluoro-3-trifluoromethylphenoxy)butanoic chloride was gradually added dropwise to the solution under stirring at room temperature. After dropwise addition, the mixture was further stirred for 3 hours at room temperature, and the reaction mixture was then washed with a diluted hydrochloric acid, diluted sodium hydroxide and water with the order. After the toluene layer was dehydrated with anhydrous sodium sulfate, toluene was distilled out under reduced pressure. Resulting crude crystal was recrystallized from toluene to give 12.8 g (Yield: 92 %) of N-benzyl-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic amide having a melting point of 75 to 76 ° C. as colorless needle crystals. Elemental analysis
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=O)=[CH:2]1.C[S:30](C)(=O)=O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[S:30])=[CH:2]1
Reactant: CS(C)(=O)=O
Reactant: O=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21
Solvent: O
Product: S=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21

Procedure:
3-(1H-indol-3-yl)-3,3′-biindolin-2-one (728 mg, 2 mmol), crystalline P2S5.2C5H5N (228 mg, 0.6 mmol) and dimethylsulfone (3.05 g) were heated (165-170° C.) for 20 min. The melt was allowed to cool and then heated in water for 10 min. The solid formed was collected, 766 mg (94%), mp>260° C. 1H NMR (300 MHz, DMSO-d6) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 72.7 (s), 111.2 (d), 124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7 (s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s), 143.0 (s), 143.5 (s), 145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C24H17N3S; C, 75.96; H, 4.51; N, 11.07. Found C, 76.10; H, 4.46; N, 11.00.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[CH3:18][C:15]1([CH3:19])[CH2:16][CH2:17][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([C:37]4[C:38]([F:42])=[CH:39][CH:40]=[C:41]5[C:36]=4[CH:35]=[CH:34][NH:33]5)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=2)[CH2:14]1
Reactant: CC1(C)CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)C1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC1(C)CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)C1

Procedure:
4-(2-chloro-6-((3,3-dimethylpyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.28 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 70.2 mg of 144 following reverse phase HPLC purification. MS (Q1) 461.2 (M)+
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[CH:18][CH:17]=4)=[C:13]([CH:14]=C)[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.C[OH:32]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[CH:29][CH:30]=4)=[C:13]([CH:14]=[O:32])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(-c2ccc(CN3CC(=O)N(C)C3=O)cc2)ccc2c1nnn2CC1CC1
Reactant: CO
Solvent: ClCCl
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-{4-[1-(cyclopropylmethyl)-4-ethenyl-1H-benzotriazol-5-yl]benzyl}-3-methylimidazolidine-2,4-dione [(Example 19, Step 1), 328 mg, 0.817 mmol] in methanol (8.2 mL) and dichloromethane (24.5 mL) was cooled to −78° C. Ozone was bubbled through the mixture until saturated and then removed. Oxygen was bubbled through the solution for 15 minutes and then treated with polymer-bound triphenylphosphine (0.27 g, 3 mmol/g). The mixture was warmed to ambient temperature and stirred for 14 hours. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated in vacuo and purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound: 1H NMR (400 MHz, CDCl3) 10.39 (s, 1H), 7.86 (d, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.8 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.39 (d, 2H, J=8.2 Hz), 4.67 (s, 2H), 4.62 (d, 2H, J=6.8 Hz), 3.83 (s, 2H), 3.09 (s, 3H), 1.40-1.46 (m, 1H), 0.67-0.72 (m, 2H), 0.51-0.55 (m, 2H) ppm. LRMS m/z (M+H) 404.2 found, 404.2 required.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-fluorophenyl)boronic acid to afford an off-white solid. HPLC (Condition 4) tR=5.48 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, J=3.90 Hz, 1H) 1.77-1.89 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.12-3.27 (m, 2H) 3.40 (m, J=7.40 Hz, 1H) 4.09-4.22 (m, 1H) 4.82 (d, J=3.52 Hz, 1H) 7.15-7.28 (m, 3H) 7.34 (d, J=1.00 Hz, 2H) 7.41-7.53 (m, 1H) 7.77-7.90 (m, 2H) 7.99 (d, J=2.30 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(Cl)n2)C1
Reactant: OB(O)c1ccccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(-c3ccccc3O)n2)C1
Yield: 49.1 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.120 g, 0.400 mmol), 2-hydroxyphenyl boronic acid (0.166 g, 1.20 mmol), palladium catalyst (0.013 g, 0.020 mmol), and 1 M aqueous Na2CO3 (0.80 mL, 0.80 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (66% ethyl acetate/hexanes) to give the title compound as an oil (0.070 g, 49%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]([C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CCc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Product: CCc1ccc(CN(CCc2ccc(O)c(C)c2)c2ncc(CC)cn2)cc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and 4-ethyl-benzyl bromide.
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH:22]([CH:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]4)[O:21][CH:20]3O)=[C:15]([F:35])[C:14]=2[F:36])=[C:9]([F:37])[C:8]=1[F:38])[CH3:5].C([SiH](CC)CC)C>O>[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][O:21][CH:22]([CH:25]4[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]4)[CH2:23][CH2:24]3)=[C:15]([F:35])[C:14]=2[F:36])=[C:9]([F:37])[C:8]=1[F:38])[CH3:5]
Reactant: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(O)O2)CC1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)CO2)CC1
Reaction time: 3 h
Yield: 36.1 %

Procedure:
Dichloromethane (30 ml) was added to 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-ol (12) (2.29 g) prepared in the tenth step. Triethylsilane (1.93 g) and a boron trifluoride-diethyl ether complex (2.37 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (30 ml) was added to give two layers. The organic layer was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=80/20 by volume) and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 5-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-2-(4-propylcyclohexyl)tetrahydropyran (13) (0.8 g) in 36% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH2:46][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:41]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 38.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.1 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]C)=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)Cn1ccnc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: CO
Product: O=C(Cn1ccnc1[N+](=O)[O-])N(CCO)CCO
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
A mixture of 4.00 g (21.6 mmol) of methyl 2-nitroimidazole-1-acetate and 4.0 g (38.0 mmol) of diethanolamine in 60.0 ml of methanol was stirred four days at room temperature. After removing the excess diethanolamine, the product was dissolved in 10 ml of methanol and chromatographed through a column of silica gel (70-230 mesh). Elution with 10% methanol in methylene chloride afforded 5.38 g (96%) of product as a hard gum that crystallized after several days to a cream colored hygroscopic solid on silica gel with 20% methanol in methylene chloride (Rf 0.47) and analyzed correctly for C9H14N4O5. The solubility of SR-2555 in 0.9% saline solution was over 300 mg/ml.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-imidazole (1.06 g, 15.6 mmol) and 2-(4-bromophenyl)ethanol (2.19 g, 10.9 mmol) in THF (20 mL) at room temperature was added tert-butylchlorodimethylsilane (1.81 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with hexanes. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give (4-bromophenethoxy)(tert-butyl)dimethylsilane 65 which was used in the next step without further purification.
Reaction SMILES: C([Li])CCC.C([O:10]O)(C)(C)C.[F:12][C:13]([F:27])([F:26])/[CH:14]=[C:15](/[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])\[CH3:16]>O1CCCC1.C(OCC)(=O)C>[C:20]1([S:17]([C:15]2([CH3:16])[CH:14]([C:13]([F:12])([F:26])[F:27])[O:10]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C/C(=C\C(F)(F)F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(S(=O)(=O)c2ccccc2)OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 15.2 mmol n-butyllithium solution (1.6 M in hexane) in 20 ml tetrahydrofuran at −78° C. was added dropwise 15.2 mmol tert-butyl hydroperoxide solution (5.5 M in nonane) and the mixture was stirred at −78° C. for 10 min, then warmed to −50° C. and re-cooled to −78° C. A solution of 10.1 mmol ((E)-4,4,4-trifluoro-but-2-ene-2-sulfonyl)-benzene in 6 ml tetrahydrofuran was then added dropwise and stirring continued for a further 30 min at −78° C. and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1 M hydrochloric acid and with brine. The organic phase was then dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a colourless oil (yield 49%). EI-MS (m/e): 251.1 ([M−CH3]+, 6%), 250.1 ([M−O]+, 20%), 126.1 (PhSOH+, 61%), 125.0 ([M−PhSO2]+, 100%), 78.2 (PhH+, 21%), 77.2 (Ph+, 44%), 43.3 (CH3CHCH3+, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=CC(OC[CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCN(C)C)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1 H) 8.14 (m, 1 H) 8.10 (m, 1 H) 8.00 (m, 1 H) 7.89 (t, J=8.0 Hz, 1 H) 7.69 (s, 1 H) 7.28 (d, J=8.08 Hz, 1 H) 7.20 (d, J=8.08 Hz, 1 H) 4.68 (t, J=5.0 Hz, 2 H) 3.80 (t, J=5.0 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 3.13 (s, 6 H) 1.33 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C23H25ClN3O3S, 458; found, 458.