Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9]O.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)COCCN1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)COCCN1CCBr
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a solution of 2-(3,3-dimethyl-morpholin-4-yl)-ethanol (7.2 g, 45 mmol) and CBr4 (16.4 g, 49 mmol, 1.1 equiv.) in THF (150 mL) was added dropwise a solution of PPh3 (12.9 g, 49 mmol, 1.1 equiv.) in THF (75 mL). The resulting slurry was stirred at room temperature for 19 hours, at which time the slurry was diluted with hexanes and filtered. The filtrate was concentrated in vacuo and the resulting oil was diluted with CH2Cl2. The solution was then washed twice with NaHCO3 (aqueous, saturated) and brine. The aqueous layers were back-extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was distilled (65° C., 0.5 torr) to provide 4-(2-Bromo-ethyl)-3,3-dimethyl-morpholine (5.4 g, 54%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 3.69 (t, 2H), 3.28 (s, 2H), 3.28 (t, 2H), 2.70 (t, 2H), 2.58 (t, 2H), 0.99 (s, 6H); LC/MS found 222.02 (M++H, C8H17BrNO requires 222.05).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:30]2=[O:31])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 6-(pyridin-4-yl)hexanoate (2.0 eq., prepared in Synthetic Example 13) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-4-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 168.8 to 169.6° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=[C:25]([F:27])[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Product: Fc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-amino-5-fluorobenzotrifluoride were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.75 (s, 1H), 9.32 (d, 1H, J=1.2 Hz), 8.13 (d, 1H, J=3.6 Hz), 7.99 (d, 1H, J=12.3 Hz), 7.77 (s, 1H), 7.21 (d, 1H, J=2.4 Hz), 7.13 (dd, 1H, J=2.1 and 8.7 Hz), 7.03 (d, 1H, J=9.0 Hz), 6.80 (d, 1H, J=8.7 Hz), 4.21 (s, 4H); LCMS: purity: 97%; MS (m/e): 425 (MH+).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:11](O)([CH3:14])([CH3:13])[CH3:12].OS(O)(=O)=O>C1C=CC=CC=1.O>[C:11]([C:3]1[CH:2]=[CH:10][C:6]2[CH2:7][CH2:8][S:9][C:5]=2[CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc2c(c1)CCS2
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc2c(c1)SCC2
Temperature: 60 °C
Yield: 19.8 %

Procedure:
To a solution of 5-hydroxy-2,3-dihydrobenzothiophene (500 mg, 3.28 mmoles) in 20 mL benzene in a sealable tube was added t-butanol (729 mg, 9.84 mmoles, 3.0 eq) and 0.4 mL concentrated H2SO4. The tube was sealed and the reaction mixture heated at 60° C. for 24 hours. The reaction mixture was cooled, diluted with water (50 mL) and extracted 2×25 mL ether. The combined extracts were washed with sodium bicarbonate (1×25 mL), H2O (1×25 mL) and brine (1×25 mL). The organic layer was then dried over Na2SO4, filtered and concentrated to give 220 mg crude product. Purification by flash chromatography (90/10, hexane/EtOAc) afforded 125 mg pure product (18%) mp 90°-93° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
Using the method of Example 12, 7-amino-2-nitro-3-phenylbenzofuran is reacted with acetic anhydride to provide yellow solid 7-acetamido-2-nitro-3-phenylbenzofuran, m.p. 224°-226° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:19]([F:28])([F:29])[C@H:20]([O:27][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
To 5 ml of a methylene chloride solution containing 0.56 g of 4-benzyloxybenzoic acid chloride was slowly added a solution of 0.38 g of (R)-(+)-1-trifluoromethylheptanol and 0.23 g of triethylamine in 5 ml of methylene chloride under ice-cooling. The mixture was allowed to warm to room temperature and stirred at that temperature for 12 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride phase was washed successively with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual crude product was purified by silica gel column chromatography to obtain 0.53 g of (R)-(+)-4-benzyloxybenzoic acid 1-trifluoromethylheptyl ester.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([C:9]2[C:10]3[CH:11]=[N:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:15]=3[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=3)[CH:8]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc2c(ccn2Cc2ccc(F)cc2)cn1
Reactant: O=C(Br)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(cn1)c(C(=O)c1ccc(F)cc1)cn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
To a stirred solution of ethyl 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (4.0 g, 13.4 mmol) in dichloromethane (60 mL) were added aluminum chloride (3.6 g, 26.8 mmol) and 4-fluorobenzoyl bromide (3.2 mL, 26.8 mmol). The resulting mixture was stirred for three days at ambient temperature. It was quenched with ice-water (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (2×100 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as a solid (2.2 g, 39% yield). 1H NMR (CDCl3) δ ppm 9.62 (s, 1H), 8.23 (s, 1H), 7.85-7.87 (m, 2H), 7.74 (s, 1H), 7.12-7.18 (m, 4H), 7.03-7.06 (m, 2H), 5.43 (s, 2H), 4.51 (q, 2H, J=7.2 Hz), 1.47 (t, 3H, J=7.2 Hz). LCMS (APCI, M+H+): 421.1.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH:33]=O)([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:4])[CH3:5])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)C(N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Formula 201 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl: W and Z are —N═: X and Y are —C═: To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-pteridin-4-one (1.10 g, 3.19 mmol) and (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Seki et. al. Chem. Pharm. Bull. 1996, 44, 2061) (0.59 g, 3.19 mmol) in dichloromethane (80 mL) is added sodium triacetoxyborohydride (1.01 g, 4.79 mmol). The resultant mixture is maintained at ambient temperature for 4 hours, at which time it is quenched with brine (75 mL) and stirred vigorously for 10 minutes. The aqueous layer is extracted with dichloromethane (50 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester which is used in the subsequent step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:12]([CH3:13])[CH3:11])=[O:8]
Reactant: CNC
Reactant: O=C(Cl)c1cncc(Br)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Into a 100 mL round bottomed flask were added 5-bromonicotinoyl chloride (0.531 g, 2.41 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine in THF (5 mL, 10.0 mmol) was added dropwise, and the reaction mixture was stirred at rt under N2 for 6 h after which it was concentrated under vacuum. The crude residue was partitioned between EtOAc and water. The layers were separated, and the organic phase was washed 3× with water, then treated with brine, dried (Na2SO4), filtered and concentrated to afford 5-Bromo-N,N-dimethyl-nicotinamide as a brown oil (0.4951 g, 89%). MS: m/z 229/231 [MH+].
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]([CH2:26][C:27](OC=C)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(COC)OC>[C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([O:17][C:27](=[O:28])[CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=COC(=O)COc1ccccc1
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1
Solvent: COCCOC
Product: O=C(COc1ccccc1)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@H]1O
Yield: 88 %

Procedure:
226 mg (0.90 mmol) of 6-O-benzoylglucal are dissolved in 1 ml of dimethoxyethane and stirred with 1 ml of vinyl phenoxyacetate and 220 mg of lipase Fp at room temperature for 3 hours. Filtration and flash chromatography (silica gel; hexane and ether/hexane 1:1) result in 6-O-benzoyl-3-O-phenoxyacetylglucal in 88% yield (304.5 mg, 0.79 mmol).
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CCOCC>[CH2:18]([N:20]([CH2:21][CH3:22])[S:13]([C:2]([F:17])([F:1])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14])[CH3:19]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Under a blanket of nitrogen, a mixture of 55 g (0.180 moles) of perfluorobutane sulfonyl fluoride and 70.7 g (0.970 moles) of diethylamine was heated at reflux for nine hours. The reaction mixture was dissolved in 600 ml of ether and percolated through a column of 60 g of acidic alumina. The ether was stripped and the product was distilled at 56°-58° C. at 2.0 mm. Yield 41.6 g (65%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:30]>CO.[OH-].[OH-].[Pd+2]>[ClH:30].[CH3:23][N:19]([CH2:20][CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCCN(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-propyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (50 mg) in methanol (4 mL) was added 20% Pd(OH)2/C (10 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (2 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (44 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (27 mg, 65%) as a colorless powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C)C=O>[C:12]([CH:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: CCOC(=O)CCCBr
Reactant: N#CCc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCC(C#N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2.9 g, 71.8 mmol) was slowly added to a solution of (2,3-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) and ethyl 4-bromobutanoate (12.7 g, 65.3 mmol) in N,N-dimethylformamide (100 mL) at 0° C. After 30 min, the reaction mixture was warmed to ambient temperature. After 3 h, water was added and the mixture was extracted with ethyl acetate (2×). The organic extracts were washed with saturated aqueous ammonium chloride, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 267.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Br[CH2:13][S:14]([OH:17])(=[O:16])=[O:15].[Na]>O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][S:14]([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)CBr
Reactant: Oc1ccc(Cl)cc1Br
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)COc1ccc(Cl)cc1Br

Procedure:
To a solution of 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is added 16.0 g of sodium hydroxide and 100g of bromomethanesulfonic acid, sodium salt. The procedure of Example 1, part B, is followed to give about 74.5 g of 2-bromo-4-chlorophenoxymethanesulfonic acid, sodium salt, m.p. above 315°.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[ClH:15]>C1COCC1.O1CCOCC1>[ClH:15].[N:10]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)CN1CCCC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 19.6 grams (101 mmol) of t-butyl bromoacetate in 150 mL of THF was cooled in an ice bath and treated dropwise over about 0.5 hour with a solution of 14.4 grams (202 mmol) of pyrrolidine in 75 mL of THF, to produce a white precipitate. The bath was removed and the reaction slurry stirred for two hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to yield a clear liquid over an orange-colored solid. The liquid was cooled in an ice bath, then treated with 40 mL (80 mmol) of 4N HCl in dioxane and stirred for 15 hours. The solvents were removed in vacuo, and the residue was triturated with diethyl ether, then filtered to yield 12.9 grams of the desired acid as an off-white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8]1.[NH3:27]>CO>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:27])=[O:2])[CH2:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Reactant: N
Solvent: CO
Product: NC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Temperature: 100 °C
Yield: 74 %

Procedure:
4-[(R)-3-(4-Phenoxy-phenoxy)-pyrrolidin-1-yl]-butyric acid methyl ester (200 mg, 0.563 mmol) was taken into 7N Ammonia in methanol solution (5 mL) in a pressure tube. The tube was sealed and heated to 100° C. with stirring and left to react for 48 h. The reaction was concentrated to dryness, and purified by flash silica chromatography (20:1 silica ratio, eluted with a gradient of 10% methanol in dichloromethane to 15% methanol in dichloromethane) to provide the title product (141 mg, 74%); LCMS; m/z 341 (M+1); 1H NMR (400 MHz, DMSO) δ 1.62-1.68 (m, 2H), 1.75-1.78 (m, 1H), 2.06-2.10 (m, 2H), 2.22-2.25 (m, 1H), 2.35-2.43 (m, 3H), 2.59-2.68 (m, 2H), 2.80-2.84 (m, 1H), 4.80-4.83 (m, 1H), 6.69 (s, 1H), 6.89-6.93 (m, 4H), 6.94-6.98 (m, 2H), 7.05-7.09 (m, 1H), 7.24 (s, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:63])[C@@H:22]([NH:52]C(OCC1C=CC=CC=1)=O)[CH2:23][S:24][CH2:25][C@H:26]([O:40][C:41](=[O:51])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][O:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:52][C@@H:22]([CH2:23][S:24][CH2:25][C@H:26]([O:40][C:41](=[O:51])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][O:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:21](=[O:63])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)NCCCCCCCC
Temperature: 32 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-14-(benzyloxycarbonylamino)-18-(octylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazatriacontylphosphonic acid diethyl ester (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 32° C. overnight then cooled to room temperature, diluted with DCM and concentrated. The crude material was dried under high vacuum for 2 hours then purified by reverse phase high performance liquid chromatography (HPLC) with a C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to afford (14R,18R)-14-amino-18-(octylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazatriacontyl phosphonic acid as a white solid. 1H NMR (DMSO-d6): δ 8.57 (t, 1H), 7.42 (m, 2H), 4.78 (m, 1H), 4.01(m, 2H), 3.0-3.6 (m, 18H), 2.88 (m, 4H), 2.52-2.81 (m, 5H), 1.68 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H), 1.12-1.24 (m, 20H), 0.82 (t, 6H). LRMS [M+H]=745.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:11][CH:12]3[CH:16]([CH2:15][N:14]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([C:31]([F:33])([F:34])[F:32])[N:25]=4)[CH2:13]3)[CH2:17]2)=[O:9])[CH:7]=1
Reactant: Cc1cc(Cl)nc(C(F)(F)F)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and 4-chloro-6-methyl-2-trifluoromethyl-pyrimidine. MS (ESI): mass calculated for C21H19F4N7O, 461.42; m/z found 462.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.04-7.87 (m, 1H), 7.81-7.63 (m, 1H), 7.29-7.18 (m, 1H), 7.17-7.08 (m, 1H), 6.31-6.03 (m, 1H), 4.13-2.84 (m, 10H), 2.44 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-c2[nH]c3ccc(Cl)cc3c2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(O)cc3)[nH]c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a solution 150 mg (0.34 m mol) of 2-(4-acetyloxylphenyl)-3-(4-methylsulfonylphenyl)-5-chloroindole prepared in Example 94 in 10 ml of THF was added the solution of 20 mg of NaOH in 10 ml of 95% ethanol. The reaction mixture was stirred at room temperature for 4 h, and the solvent was removed. To the residue 10 ml of 0.5N HCl was added and the resulting precipiptate was filtered off, washed with water, dried, recrystallized from 95% ethanol to afford 123 mg of the title compound as white needle crystal, yield 90.7%, m.p. 271-273° C. Analysis via Nuclear Magnetic Resonance provided the following information: 1HNMR (300 MHz, DMSO)δ:3.23 (s, 3H, SO2CH3), 6.78-7.92 (m, 11H, Ar—H), 9.78 (s, 1H, OH), 11.83 (s, 1H, N—H); Anal. Calcd for: C21H16NO3SCl: C 63.39, H 4.05, N 3.52; Found: C 63.31, H 4.24, N 3.51.