Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH2:31]([N:35]1[CH:39]=[C:38]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)(=[O:20])=[O:21])=[CH:15][CH:14]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:37]=[N:36]1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=S(=O)(NCCCN1CCCC1)c1ccc(Nc2ncc3ccc(Br)cc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Cn1cc(-c2ccc3cnc(Nc4ccc(S(=O)(=O)NCCCN5CCCC5)cc4)nc3c2)cn1

Procedure:
Pd(dppf)2Cl2CH2Cl2 (0.05 eq) was added to a 0.05M mixture of 4-(7-bromoquinazolin-2-ylamino)-N-(3-(pyrrolidin-1-yl)propyl)benzenesulfonamide (eq), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3 eq), 2.0M potassium carbonate/water (2 eq) in DME. The mixture was microwaved at 120° C. for 10 min
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[C:17]([N:24]5[CH2:29][CH2:28][CH:27]([CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:26][CH2:25]5)[CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[N:12][N:13]=[C:7]2[CH:6]=1)[CH2:3][OH:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][CH2:30][CH:27]1[CH2:26][CH2:25][N:24]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[N:15]=[C:14]([C:11]2[N:8]4[CH:9]=[CH:10][C:5]([CH:2]([OH:1])[CH2:3][OH:4])=[CH:6][C:7]4=[N:13][N:12]=2)[CH:23]=[CH:22]3)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Reaction time: 1 h
Yield: 119.5 %

Procedure:
To tert-butyl (1-(2-(7-(1,2-dihydroxyethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (2 mg, 0.004 mmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was then stirred for 1 hour, then concentrated and purified by flash column chromatography (DCM/MeOH/NH4OH 20:1:0.1), affording the final product as a white solid (0.002 g; quantitative yield). MS ESI (+) m/z 419 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[C:15]([CH3:25])[CH:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH3:25])[CH:14]=[C:13]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: COc1ccc2nc(C)cc(-c3c(C)[nH]c4ccc(C)cc34)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 10 part a, using 2,5-dimethyl indole and 4-chloro-6-methoxy-2-methylquinoline.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](OC)=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](=[O:39])[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]
Reactant: C1CCNC1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 47.9 %

Procedure:
Following the general procedure outlined in Example 193, pyrrolidine (0.18 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (100 mg, 0.22 mmol) were reacted to give the desired product 52 mg (48%). LC-MS: 494.4 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CS(O)(=O)=O>C(Cl)Cl>[C:11]12([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([O:9][CH3:10])[C:5]=3[OH:8])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: COc1cc(Br)ccc1O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1O
Temperature: 54 °C
Yield: 75.3 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (2.00 g, 9.85 mmol), 1-adamantanol (1.50 g, 9.85 mmol), and MeSO3H (0.8 mL) in CH2Cl2 (8 mL) was stirred with heating at 54° C. (oil-bath) for 18.3 h. The resulting solution was quenched with H2O (30 mL) and extracted with EtOAc (120 mL). The extract was washed with 5% NaHCO3 and brine and dried. The residue obtained on concentration was purified on silica gel (4% EtOAc/hexane) to give 2.5 g (76%) of 2-(1-adamantyl)-4-bromo-6-methoxyphenol as a white solid, mp 157-159° C. IR 3510, 2903, 2850, 1413, 1217 cm−1; 1H NMR δ (CDCl3) 1.76 (bs, 6H, AdCH2), 2.07 (bs, 9H, AdCH and AdCH2), 3.87 (s, 3H, OCH3), 5.90 (s, 1H, OH), 6.86 (d, J=2.4 Hz, 1H, 5-ArH), 6.95 ppm (d, J=2.4 Hz, 1H, 3-ArH).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+].[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:33][CH2:32][CH:29]5[CH2:31][CH2:30]5)=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNCC3CC3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in cyclopropylmethylamine (3 ml) and the reaction stirred at room temperature for 18 hours. The excess amine was evaporated under vacuum and the residue purified by preparative HPLC. After evaporation of the solvent this gave N-cyclopropyl-4′-(5-{[(cyclopropylmethyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+:14].[Cs+]>CO>[C:1]([O-:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cs+:14]
Reactant: OC(=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: [O-]C(=S)c1ccccc1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a solution of thiobenzoic acid (50.0 g, 361.8 mmol) in methanol (362 mL) was added Cs2CO3 (130 g, 398 mmol) in portions over 5 min. The resulting mixture was stirred 10 min until all solids were dissolved. The resulting solution was concentrated on the rotovap. The solid residue was diluted with 500 mL of acetone and the white solid (CsHCO3) was filtered off. This process was repeated two times to ensure all CsHCO3 was removed. The acetone was then concentrated to afford cesium thiobenzoate (Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664) as a yellow solid (81.5 g, 83%); 1H NMR (300 MHz, CD3OD) δ 7.25-7.38 (m, 3H), 8.09 (dd, J=1.4, 8.2 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>>[C:20]1(=[O:30])[N:24]([CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:8]([F:18])[CH:7]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1

Procedure:
N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline is reacted with potassium phthalimide to provide N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline (Formula IV, R1═R3 is H; X is O; one R2 is H and the other R2 is F; and n is 1).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].S(=O)(=O)(O)O.[CH:30](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:30]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH3:24]
Reactant: NC=O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidin-6-one sulphate (1.5 q) (prepared by the addition of concentrated sulphuric acid to an ethanolic solution of the free base) and formamide (15 ml) was heated in an oil bath (temp. 190°-200° C.) for 70 minutes. When cool the mixture was filtered and the collected solid was washed with ethanol to give a crude product (1.1 g), m.p. 254°-259° C., which was recrystallised from ethanol to give the title compound, 0.72 g, m.p. 263°-265° C.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[C:6](OCC)(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[CH2:3]=[C:2]=[CH:1][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(=O)OCC
Reactant: C#CC[Mg]Br
Solvent: CCOCC
Product: C=C=CC(=O)CCCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.50 moles of propargyl-magnesium bromide in 340 ml. of ether at -78° C. is added a solution of 65.2 g. (0.50 moles) of ethyl valerate in 100 ml. of ether during 60 minutes. The solution is stirred at -78° C. for 30 minutes and then hydrolyzed by pouring onto a mixture of ice and ether. The ether layer is washed with brine, treated with hydroquinone, dried over magnesium sulfate, and concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8](=[O:21])[CH2:9][NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(/C=C/c1cccnc1)NCC(O)c1cccc(O)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)NCC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30.3 %

Procedure:
To a solution of (E)-N-[2-(3-hydroxyphenyl)-2-hydroxyethyl]-3-(3-pyridyl)-2-propenoic acid amide (568 g, 2 mmol) in dimethylformamide (4 ml), pyridinium dichromate (1.28 g, 1.7 eq.) was added under ice-cooling and stirred at room temperature for 10 hours. Then, water (4 ml) was added. Tar materials were filtered out on Celite and water (4 ml) was added to the filtrate and extracted with ethyl acetate. The solvent was distilled out under reduced pressure and the residue was solidified in ethanol to yield the titled compound (171 mg, 30%).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C@@H:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4].Cl>C1COCC1.O>[CH2:3]([O:5][C@@H:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Lithium hydroxide (27 mg, 1.15 mmol) was added to a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (167 mg, 0.38 mmol) in THF/water 4:1 (5 mL). The reaction mixture was stirred at room temperature overnight and 1 M HCl (2 mL) was added. The THF was removed under reduced pressure. The aqueous phase was diluted with water and extracted three times with CH2Cl2 in a Phase Separator. The combined organic layers were evaporated. The residue was purified by preparative HPLC to give the product as a colorless oil (129 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)O)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A cold solution of 6-methoxypicolinic acid (1.8 g, 11.8 mmol) in tetrahydrofuran (0.3M, 40 mL) was treated with lithium aluminum hydride (11.8 mL, 11.8 mmol) at 0° C. This mixture was stirred at 0° C. for 30 minutes, poured into a beaker containing aqueous saturated Rochelle's salt and stirring at ambient temperature continued for 1 hour. The product was extracted from EtOAc, dried (phase separator silicone treated filter paper) paper, concentrated (1.13 g, 69% yield) as a clear oil.
Reaction SMILES: [K+].[Br:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Br:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5g, 1-benzoyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C20H18BrN4O3: 441.06; found 441.07. HPLC retention time: 1.43 minutes (column B).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12 h

Procedure:
To a solution of (S) isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 μL, 0.24 mmol) and 2-bromobenzenesulfonyl chloride (51 mg, 0.2 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC using the following conditions:
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.[H-].[Na+].[P:29](Cl)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH:26][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Nc1c(-c2cc(Cl)cc(C(F)(F)F)c2)c(C(F)(F)F)nn1-c1ncccn1)OCC
Reaction time: 12 h
Yield: 23 %

Procedure:
To a mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.766 g, 2.00 mmol) and NaH (0.054 g, 2.20 mmol) in tetrahydrofuran at 0° C. is added diethyl chlorophosphate (0.414 g, 2.40 mmol). The mixture is allowed to reach room temperature (20-25° C.) and further stirred for 12 hours. The reaction was diluted with water and extracted with ethyl acetate; the organic layer separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (125 mg; 12%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CCN4CCCCCC4)cc1)OCO3)C2
Yield: 63.8 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (34 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=1[NH2:27])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>>[CH2:24]([O:23][C:21](=[O:22])[C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:13][C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])[C:3]([OH:28])=[O:2])=[C:16]([NH2:27])[CH:17]=1)[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(SC[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c(N)c1
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)c1ccc(SC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c(N)c1

Procedure:
200 mg (0.487 mmol) of N-tert-butoxycarbonyl-3-(4-alloxycarbonyl-2-aminophenylthio)-L-alanine methyl ester (96.7%) was added to a system consisting of 2 to 5 ml of an organic co-solvent (see following table) and 20 ml buffer solution (0.1M sodium chloride; 3 mM sodium phosphate pH 7.0) under vigorous stirring. Alcalase 2.4 L [a subtilisin Carlsberg from Novo Nordisk, amount see following table] was added and the pH maintained at 7.0 under vigorous stirring by the controlled addition (pH-static) of 0.1N sodium hydroxide solution. The reaction was monitored by the consumption of titrating agent, and the formation of the product confirmed by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Cl)ccn2)cn1
Temperature: 90 °C
Yield: 77.3 %

Procedure:
5-Chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (1.177 g, 4.31 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.166 g, 5.60 mmol) were dissolved in DMF (16.16 ml), cesium carbonate (4.21 g, 12.93 mmol) was added, followed by water (5.39 ml). Argon was bubbled through the mixture for 5 minutes, and then palladium tetrakistriphenylphosphine (0.249 g, 0.215 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated in a 90° C. oil bath under a balloon of argon for 4 hours. The reaction mixture was then cooled to RT and diluted with a 4:1 mixture of ethyl acetate and THF. The solution was extracted with 10% aqueous LiCl (2×150 mL) and brine (100 mL), dried (MgSO4), evaporated under reduced pressure and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as a tan solid (1.062 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 6.52 (dd, 1H), 5.49 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 319.1 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25][C:26](=[O:28])[CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([O:24][CH2:23][C@@:20]23[C@@H:19]4[C@H:10]([C@H:11]5[C@@:15]([CH2:17][CH2:18]4)([CH3:16])[C@@H:14]([O:25][C:26](=[O:28])[CH3:27])[CH2:13][CH2:12]5)[CH2:9][CH:8]=[C:7]2[CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Reaction time: 96 h

Procedure:
To a solution of 3β,17β-diacetoxy-19-hydroxyandrost-5-ene (14.4g) in pyridine (370ml) at 25° is added p-toluenesulfonyl chloride (38.1g) and the solution is left at 25° for 4 days. Water is then added, and the mixture is extracted with ethyl acetate, and the organic extract is washed successively with water, 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and water, and then dried (Na2SO4) and evaporated in vacuo. The residue is crystallized from methylene chloride-hexane to give the compound of this Example (11), mp. 135°-137°; mass spectrum m/e 484, 372, 312.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([CH2:27][O:28][C:29]2[C:30]([O:39][CH2:40][CH2:41]O)=[CH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:41][CH2:40][O:39][C:30]2[C:29]([O:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1cc2ccccc2cc1OCc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (2.29 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.552 g), stirred for 15 minutes and treated with the mesylate (4.3 g) prepared from 2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethanol. The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3:1 plus 2% ethyl acetate) to provide, after crystallization from dichloromethane-methanol, 3.0 g of alpha-oxo-4-[[2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 115°-117° C.