Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:23]=[C:22]([NH:24][CH2:25][C@H:26]4[O:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)[C:21]4[C:16](=[N:17][CH:18]=[CH:19][N:20]=4)[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl>CC(=O)OCC>[NH:28]1[CH2:29][CH2:30][O:31][C@H:26]([CH2:25][NH:24][C:22]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[CH:13][CH:12]=3)[N:23]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(N4CCC(O)CC4)cc3)cc3nccnc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC1CCN(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CNCCO4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
(R)-tert-butyl 2-((7-(4-(4-hydroxypiperidin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (112 mg, 0.21 mmol) was dissolved in 20 mL EA, then 15 mL 5M HCl in EA was added in. The mixture was stirred at room temperature overnight, concentrated, treated with ammonia, purified by preparative TLC to give 40 mg reddish solid. MS: (m/z): 421 (M+H)+
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:81])[CH2:77][CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][CH2:77][N:76]([CH3:81])[CH3:75])=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.207 mmole) of 3-(dimethylamino)propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0651 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methyl-benzamide (I-189) as a white solid
Reaction SMILES: BrC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11](OCC)=O.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:11]([CH2:10][C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Product: CCOC(=O)Cc1ccc(C)cc1
Temperature: 160 °C
Reaction time: 10 h
Yield: 88 %

Procedure:
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 88% of theory.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH3:24])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH3:24])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[O:39])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC(C)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1c(OCCCS(=O)CC2COC(C)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 50.3 %

Procedure:
The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 38 (0.30 g, 0.00066 mol) and m-chloroperbenzoic acid (0.113 g, 0.00066 mol). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.157 g (50%) of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.NO.[N:21]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OCC)(=O)C.O.ClCCl.C(N(CC)CC)C.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:21]2)[CH:3]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1.03 g of 2-(4-bromopyridin-2-yl)-1-p-tolylethanone obtained in step 13.1 are placed in a round-bottomed flask with 0.99 g (14.2 mmol) of hydroxylamine monohydrochloride, 3 mL (37 mmol) of pyridine and 100 mL of ethanol. The reaction medium is stirred overnight and then concentrated under reduced pressure. The residue obtained is then taken up in 200 mL of ethyl acetate and 200 mL of water. The organic phase is recovered, dried over sodium sulfate and then concentrated under reduced pressure. 1.10 g of compound are recovered and dissolved in a round-bottomed flask containing 0 660 mL (4.74 mmol) of triethylamine and 30 mL of dichloromethane. The reaction medium is then cooled to about 5° C. and 0.200 mL (1.42 mmol) of trifluoroacetic anhydride is added dropwise. The medium is then stirred at room temperature for 3 hours, followed by hydrolysis with 100 mL of water. The medium is then stirred for 10 minutes, followed by filtration through a hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction column). 1.2 g of silica are then added to the filtrate, followed by concentrating under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5). 0.746 g (77%) of expected compound is recovered in the form of a white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.CN(C=O)C>C(Cl)(Cl)Cl>[CH:21]1([C:5]2[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:8]([C:7](=[O:17])[C:6]=2[C:18]([OH:20])=[O:19])=[CH:9][C:10]([F:16])=[CH:11][C:12]=3[F:14])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1c(C2NCc3ccccc32)n(C2CC2)c2c(F)cc(F)cc2c1=O
Temperature: 120 °C
Yield: 67 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 180 mg of isoindoline, and 1.5 ml of anhydrous DMF was heated at 120° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. The residue thus obtained was dissolved into 20 ml of chloroform. The solution was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 123 mg of the target compound.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O-])([O-])=O.[Na+].[Na+].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[NH:6][CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: C=CCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCCNS(=O)(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1.03 g (12.0 mmol) pent-4-enylamine, 8 ml DCM and 5 ml 10% aqueous Na2CO3 at 0° C. are added dropwise 2.25 g (12.0 mmol) 3-chlorosulfonyl-propionic acid methyl ester. After stirring for 2 h at 25° C. the phases are separated and the organic phase is dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:2) gives the 3-pent-4-enylsulfamoyl-propionic acid methyl ester. This ester is dissolved in 2 ml DMF and heated to 65° C. in the presence of 1.58 g (11.5 mmol) K2CO3 and 0.716 ml methyl iodide for 5 h. The mixture is diluted with EtOAc and washed with water, dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc, hexane 1:4) gives the 3-(methyl-pent-4-enyl-sulfamoyl)-propionic acid methyl ester. Hydrolysis of this ester with LiOH in water/MeOH gives the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[S:14][C:10]=2[CH:9]=1.[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>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.CCO>[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:24][N:23]=1
Reactant: CC(C)Nc1nc2ccc(Br)cc2s1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)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: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(C)C)sc4c3)cnc2Cl)cc1
Temperature: 80 °C
Yield: 22.6 %

Procedure:
A reaction tube was charged with Pd(Ph3P)4 (13.6 mg, 11.8 μmol), 2.0 M aqueous sodium carbonate (235 μl, 471 μmol), 6-bromo-N-isopropylbenzo[d]thiazol-2-amine (63.9 mg, 235 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol) and 0.9 mL EtOH. The tube was sealed and the mixture was heated at 80° C. for 3 h. The mixture was concentrated and the crude material was purified by silica gel chromatography 0-10% MeOH/CH2Cl2 and reverse phase chromatography to provide N-(2-chloro-5-(2-(isopropylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (26 mg, 23%) as an off-white solid. MS (ESI pos. ion) m/z calc'd for C22H21ClN4O3S2: 489.0/491.0. found 488.9/491.0.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[CH3:19][C:18]([Si:15]([CH3:17])([CH3:16])[O:9][CH2:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20]
Reactant: Cc1ccc(CCO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Reaction time: 2 h

Procedure:
To a solution of compound 21A (2.00 g, 15.9 mmol) in DMF (50 mL) was added imidazole (1.62 g, 23.9 mmol), followed by tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol). After 2 h at 25° C., the reaction was poured into diethyl ether (300 mL) and washed with water (1×100 mL), 1 N HCl (1×100 mL), water (1×100 mL), brine (1×50 mL) and dried over anhydrous MgSO4. Crude compound 204A was analyzed by LCMS and NMR and determined to be pure enough to be carried on directly to the next step. HPLC: 100% at 4.347 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10–90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C=O)C>[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:11])=[CH:30][CH:29]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of commercially available 5-bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) in 30 mL of anhydrous DCM was added a catalytic amount of DMF followed by oxalyl chloride (1.95 mL, 22.3 mmol) and stirred for 2 h at room temperature. A mixture of aluminum trichloride (3.68 g, 27.6 mmol) and phenethyl acetate (3.38 mL, 21.23 mmol) in 15 mL DCM was cooled in an ice-bath and the acid chloride was transferred to it using a canula. The mixture was stirred at room temperature for 4 h. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic solution was washed with brine (25 mL) and dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 5:1 hexane:EtOAc followed by 10:1 hexane:EtOAc gave intermediate BF (2.1 g, yield 26%). 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.31 (t, J=6.9, 6.6 Hz, 2H), 3.01 (t, J=6.9, 6.6 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:17].Br[CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:3]1[CH:4]=[C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)c(Br)c1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1ccccc1CNc1ccc(C(C)C(=O)OC(C)(C)C)cc1Br
Temperature: 120 °C
Yield: 48.5 %

Procedure:
A mixture of tert-butyl 2-(4-amino-3-bromophenyl)propanoate (6.50 g, 21.7 mmol), methyl 2-(bromomethyl)benzoate (4.97 g, 21.7 mmol), diisopropylethylamine (2.80 g, 21.7 mmol), and ethanol (180 mL) was heated at 120° C. in a sealed vial overnight. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography (92:8 hexanes/ethyl acetate) to afford methyl 2-((2-bromo-4-(1-tert-butoxy-1-oxopropan-2-yl)phenylamino)methyl)benzoate (4.72 g, 48%) as thick oil: 1H NMR (500 MHz, CDCl3) δ 7.98 (m, 1H), 7.47 (m, 2H), 7.37-7.31 (m, 2H), 7.01 (dd, J=8.4, 2.0 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.03 (br t, J=6.1 Hz, 1H), 4.75 (d, J=6.2 Hz, 2H), 3.92 (s, 3H), 3.43 (q, J=7.2 Hz, 1H), 1.38 (s, 9H), 1.37 (d, J=7.2 Hz, 3H); ESI MS m/z 450 [(M+2)+H]+.
Reaction SMILES: F[C:2](F)([F:29])[CH2:3][CH2:4][CH2:5][CH:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([CH2:27][OH:28])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)[OH:7].C[N+]1([O-])CCO[CH2:34][CH2:33]1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:29][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:26]3[C@H:25]4[C@H:24]([CH2:14][CH2:11][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C:17]([CH:18]=[C:19]([CH:27]=[O:28])[CH2:20][CH2:21]2)=[CH:16][CH2:15]4)=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(CO)CC[C@@]43C)[C@@H]1CC[C@@H]2C(O)CCCC(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Tetrapropyl ammonium perruthenate is added to a solution of (17β)-17-(5,5,5-trifluoro-1-hydroxypentyl)-androsta-3,5-diene-3-methanol and 4-methylmorpholine N-oxide in CH2Cl2 (2.0 ml) at RT. After 1 h the reaction is flash chromatographed to yield the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5]1.CO>CN(C)C=O>[C:1]([CH2:5][C:6]1([OH:4])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by reacting potassium cyanide (20.7 mmol) with (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (13.8 mmol) in 60 ml 5:1 methanol: dimethylformamide mixture under stirring. The reaction was stirred for 12 hours at 25° C. and quenched with saturated ferrous sulfate solution. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate, organic layer was washed with brine and dried over sodium sulfate. Evaporation of organic solvent under vacuum and silica gel chromatographic purification afforded the titled product in 44% yield. M.P. 88-90° C. and MS (M+1)=373 (MH+, 100%) for M.F.=C19H24N4O4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:24]3)=[C:15]([Cl:25])[CH:14]=2)=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(Cl)c2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(Cl)c2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-2-chloro-phenyl]-piperazin-1-yl}-benzoic acid was synthesized by the coupling of N-(3-tert-Butyl-phenyl)-3-chloro-4-piperazin-1-yl-benzamide and 4-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H30ClN3O3 (m/e) 491, obsd 490 (M−H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:19](=[O:22])[CH:20]=[CH2:21])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)CCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCC(=O)OCC
Reaction time: 3 h

Procedure:
A mixture of ethyl-6-hydroxyhexanoate (49.44 grams, 0.31 moles), methylene chloride (200 mL), and triethylamine (36.26 grams, 0.36 moles) was cooled in an ice bath. Acryloyl chloride (29.87 grams, 0.33 moles) was added dropwise over 60 minutes. The mixture was stirred for 3 hours and filtered. The solution was concentrated under vacuum and diluted with ethyl acetate (300 mL). The mixture was washed with saturated aqueous sodium bicarbonate and water, and then dried over magnesium sulfate. The solvent was removed under vacuum to give a crude oil that was purified by vacuum distillation. A slightly yellow oil (ethyl-6-acryloxy-hexanoate) was collected at 90-92° C. at 0.70 mm Hg (51.27 grams). A portion of this oil (40 grams) was further purified by column chromatography over silica gel using 10 volume percent ethyl acetate in hexane to give the product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Cu]I>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])=[CH:3][C:4]=1[CH3:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Br)cnc1Cl
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(C(=O)OCC)c1cnc(Cl)c(C)c1
Temperature: 96 °C
Reaction time: 36 h

Procedure:
To a flask were added 5-bromo-2-chloro-3-methylpyridine 156-1 (4.13 g, 20 mmol), CuI (380 mg, 2.00 mmol), Cs2CO3 (18 g, 60 mmol), 2-picolinic acid (480 mg, 4.00 mmol). The flask was evacuated and backfilled with argon 3 times. Anhydrous dioxane (40 mL) was added to the flask, followed by diethyl malonate 156-2 (6 mL, 40 mmol). The mixture was stirred at 96° C. for 36 hours under argon. After cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The organic portion was dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash chromatography, eluted with 20% ethyl acetate in hexanes to give diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate 156-3 as colorless oil. MS m/z 286.1 (M+1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>O1CCCC1>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:12])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCCO)c(C)c1
Reaction time: 0.5 h

Procedure:
To 40 parts of tetrahydrofuran are added 1.5 parts of ethanolamine and 2.5 parts of triethylamine. Into this solution, 10 parts of tetrahydrofuran containing 5 parts of 2,4-dimethylbenzenesulfonyl chloride is dropped with stirring. After the dropping, the resultant mixture is stirred as it is for 30 minutes. Subsequently, the salt is removed by filtration, and the filtrate is freed from the solvent to form a solid. This solid is recrystallized from isopropyl ether to obtain 3.6 parts of N-2-hydroxyethyl-2,4-dimethylbenzenesulfonamide, m.p. 70°-72° C.