Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)=[CH:26][CH:27]=2)[N:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccccc4)cc3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(-c2ccccc2)nn1Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Methyl 3-[4-({4-[(5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl]benzyl}oxy)phenyl]propanoate (220 mg, 0.5 mmol) was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (3 mL), and 1 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (155 mg, yield 73%) as colorless crystals. 1H NMR (CDCl3) δ: 2.22 (3H, s), 2.64 (2H, t, J=7.5 Hz), 2.89 (2H, t, J=7.5 Hz), 5.00 (2H, s), 5.35 (2H, s), 6.38 (1H, s), 6.87 (2H, d, J=8.5 Hz), 7.07-7.18 (4H, m), 7.23-7.32 (1H, m), 7.33-7.44 (4H, m), 7.76-7.83 (2H, m).
Reaction SMILES: Br.[N:2]1([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][N:2]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1)(=[O:23])[CH3:22]
Reactant: O=C(NN1CCCNCC1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCCN(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(1-homopiperazinyl)-4-fluorobenzamide hydrobromide (455 mg) in 1N aqueous solution of sodium hydroxide (3.2 ml) was added acetic anhydride (0.2 ml) at 0° C., and the solution was stirred at ambient temperature for 1.5 hours. The reaction mixture was extracted with a mixture of ethyl acetate and n-butanol. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:15) to give oil. The oil was crystallized when treated with ethyl acetate below 0° C. to give N-(4-acetyl-1-homopiperazinyl)-4-fluorobenzamide (137 mg).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[O:15]([CH2:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([CH2:22][C:23]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)COc1ccccc1
Temperature: 25 °C

Procedure:
2.53 grams (g) of L-proline and 20 milliliters (ml) of anhydrous pyridine are mixed in a flask cooled by an ice bath, and 3.42 g of phenoxyacetyl chloride is added dropwise over about a 20-minute period. The mixture is warmed by water bath to room temperature, and the solvent evaporated under reduced pressure (in vacuo), leaving a viscuous syrup. The syrup is dissolved in 15 ml water and the water is evaporated in vacuo. The residue is dissolved in 20 ml water, and the resulting solution is filtered, and subsequently treated with 10 ml of 2 N hydrochloride. The resulting precipitate, crude phenoxyacetyl-L-proline, is purified on a chromatographic column containing 80 g of silica gel. The column is eluted with a solvent mixture composed of equal volumes of isopropanol and toluene to provide phenoxyacetyl-L-proline.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][CH:14]([CH3:18])[CH2:15][CH:16]=O.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:16][CH2:15][CH:14]([CH3:18])[CH3:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 0.414 ml of 3-methylbutyraldehyde (3.75 mmol) were dissolved in 7.5 ml methanol at rt and then refluxed for 1.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and the reaction mixture was then refluxed for 1.5 h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 458 mg light yellow oil (78%). MS (ISP) 234.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=1.Cl.C(Cl)(Cl)Cl.CO>C(O)CCC>[F:20][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:30][CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(OCCO)cc1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Cl
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCO)cc3)ncc2F)c1
Temperature: 25 °C
Yield: 18.6 %

Procedure:
To a solution of N-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}prop-2-enamide (0.05 g) and 2-(4-aminophenoxy)ethanol (0.031 g) in 1-butanol (2 mL), was added HCl (0.3 mg). The reaction mixture was heated to reflux for 5 hr. Completion of reaction was monitored by TLC using chloroform:methanol (9:1) as mobile phase. After completion, the reaction mixture was allowed to cool at room temperature. The reaction mixture was quenched in water and neutralized with sodium bicarbonate. The mixture was extracted in ethyl acetate, organic layer washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 50° C. The obtained semisolid was purified by preparative HPLC to give 13 mg of N-{3-[(5-fluoro-2-{[4-(2-hydroxyethoxy)phenyl]amino}pyrimidin-4-yl)amino]phenyl}prop-2-enamide. M+1=410.1 1H NMR (DMSO-d6, 400 MHz) 3.671-3.694 (t, 2H, J=4.4), 3.880-3.906 (t, 2H, J=5.2), 4.83 (br, 1H), 5.741-5.771 (dd, 1H, J=2.8, 8.4), 6.237-6.284 (dd, 1H, J=2, 15.2), 6.460-6.527 (dd, 1H, J=10, 6.8), 6.749-6.771 (d, 2H, J=8.8), 7.253-7.293 (t, 1H, J=8), 7.426-7.447 (d, 1H, J=8.4), 7.473-7.492 (d, 1H, J=7.6), 7.527-7.550 (d, 2H, J=9.2), 7.998 (s, 1H), 8.062-8.071 (d, 1H, J=3.6), 9.071 (s, 1H), 9.381 (s, 1H), 10.206 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])CCC.[F:16][C:17]([F:31])([F:30])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[CH:21]=1)=[O:19]>CCOCC>[F:31][C:17]([F:16])([F:30])[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[CH:21]=1)[OH:19]
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
To a chilled (−78° C.) solution of 1.5 g (7.61 mmol) of 5-bromoindazole in 15 mL ether was added 9.2 mL (23.0 mmol) of a 2.5 M solution of n-butyllithium in hexanes. After 5 minutes, the cold bath was removed and the mixture stirred 6 hours at room temperature. The mixture was cooled to −78° C. and 3.5 g (15.4 mmol) of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone in 4 mL of a 1:1 mixture of ether-THF was added. The mixture was stirred overnight while warming to room temperature and was then quenched with aqueous ammonium chloride and extracted with ether. The organic layer was washed with water, brine, and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by CombiFlash chromatography using 0-90% EtOAc-hexanes (product eluted at 35% EtOAc) to afford 700 mg (26%) of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol as a pale yellow foam.
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26](=[O:34])[N:27]([CH2:29][C:30]([O:32]C)=[O:31])[CH:28]=5)[C:20]([CH3:35])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[OH-].[Li+]>O1CCOCC1>[F:36][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26](=[O:34])[N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH:28]=5)[C:20]([CH3:35])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)O)c1
Temperature: 60 °C
Yield: 99.6 %

Procedure:
To a flask containing methyl 2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate (0.13 g, 0.27 mmol) was added a mixture of 2M Lithium hydroxide (1 mL of 2 M, 2.0 mmol) and 1,4-dioxane (4 mL) and the reaction mixture was heated to 60° C. for 2 hrs. The reaction mixture was evaporated and the resulting residue was suspended between ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL). The organics were dried over sodium sulfate and evaporated to give the product (0.13 g, 98%). ESI-MS m/z calc. 483.12. found 484.5 (M+1)+ Retention time 1.59 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].[Se](=O)=[O:24]>O1CCOCC1.O>[CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18]([OH:24])=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22]
Reactant: O=[Se]=O
Reactant: CN1C(=O)NC(=O)C12Cc1cc3ccc(C=O)nc3cc1C2
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)O)nc3cc1C2

Procedure:
A mixture of (±)-2,3′-dimethyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione (500 mg, 1.78 mmol, described in Intermediate 16) and selenium dioxide (592 mg, 5.33 mmol) in dioxane (30 mL) and H2O (3 mL) are heated at reflux for 18 h. The reaction mixture is allowed to cool, filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]([C:28]2[S:32][N:31]=[CH:30][N:29]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18][O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:78]1[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=1.CC(C)([O-])C.[Na+]>O.CO.C(Cl)Cl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:21]1([CH:19]2[CH2:18][O:17][C:16]3[CH:27]=[C:12]([S:9]([NH:8][C:28]4[S:32][N:31]=[CH:30][N:29]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]=3[N:20]2[C:78]2[CH:83]=[CH:82][C:81]([C:84]([F:87])([F:86])[F:85])=[CH:80][CH:79]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)OCC(c2ccccc2)N3)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCC(c1ccccc1)N2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
A vial was charged with N-(4-methoxybenzyl)-3-phenyl-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE R, 93.6 mg, 0.189 mmol), xantphos (21.89 mg, 0.038 mmol), Pd2(dba)3 (17.32 mg, 0.019 mmol), toluene (1891 μL), 1-bromo-4-(trifluoromethyl)benzene (31.8 μl, 0.227 mmol), and sodium tert-butoxide (36.4 mg, 0.378 mmol). The vial was sealed and placed in a 130° C. heating bath for 10 min. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM (0.5 mL) and TFA (0.5 mL). The resulting mixture was stirred for 20 minutes, then concentrated. The product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give a yellow foam. The material was dissolved in MeOH/DCM and loaded onto a 1 g anion exchange column. The column was eluted with MeOH, then with 10% HCl/MeOH (prepared by dissolving 1 mL of conc. HCl in 9 mL of MeOH). The acidic fractions were concentrated, and the residue was concentrated from DCM to give 3-phenyl-N-(1,2,4-thiadiazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (52.2 mg, 0.101 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 7.71 (d, J=8.8 Hz, 2 H), 7.44 (d, J=8.4 Hz, 2 H), 7.37-7.23 (m, 6H), 7.16 (dd, J=3.3, 5.4 Hz, 2 H), 5.28-5.23 (m, 1 H), 4.60 (dd, J=2.4, 11.2 Hz, 1 H), 4.40 (dd, J=2.8, 11.3 Hz, 1 H). m/z (ESI) 519.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])N)=[CH:4][CH:3]=1.CO[CH:22](OC)[CH2:23][CH2:24][CH2:25][NH:26][CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[CH:22]=[C:23]2[CH2:24][CH2:25][NH:26][CH3:27]
Reactant: CC(C)CCN(C)C(=O)CN(N)c1ccc(Cl)cc1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CC(=O)N(C)CCC(C)C)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 2-(1-(4-chlorophenyl)hydrazinyl)-N-isopentyl-N-methylacetamide (Example 7) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([NH2:30])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH:32]([CH2:40][CH2:41]Br)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([N:30]4[CH2:41][CH2:40][CH:32]4[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(N)C(=O)N3CCCC3)ccc21
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(C(=O)N3CCCC3)N3CCC3C(=O)OC(C)(C)C)ccc21
Temperature: 55 °C
Reaction time: 30 h

Procedure:
0.8 g (1.86 mmol) of 2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidin-1-yl-carbonyl)-ethyl]-benzimidazole and 1.65 g ((5.5 mmol) of tert.butyl 2,4-dibromobutyrate are dissolved in 5 ml of ethanol, mixed with 0.2 g (1.86 mmol) of sodium carbonate and stirred under nitrogen for 30 hours at 55° C. After cooling, the white precipitate is filtered off and washed with ethanol. The filtrate is concentrated by evaporation, the residue is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate/ethanol/ammonia (20:1:0.01). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=O)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (125 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.
Reaction SMILES: [C:1]1([C:7](=NNC(N)=S)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:21].NNC(N)=S>CC(O)=O>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NN=C(c1ccccc1)c1cccc(Br)c1
Reactant: CO
Agent: NNC(N)=S
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cccc(Br)c1
Yield: 34 %

Procedure:
Phenyl(3-bromophenyl) ketone thiosemicarbazone (13) Into a round bottom flask containing the appropriate ketone (1.79 g, 6.84 mmol), 30 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes. To the warm ketone solution, thiosemicarbazide (0.600 g, 6.59 mmol) and 1% solution of HOAc (0.8 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 26 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (30% EtOAc/70% hex) to obtain 0.7739 g (2.32 mmol) of the product in a 34% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[C:9]([C:13]1[C:14](=[O:29])[CH2:15][CH:16]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:17][C:18]=1[OH:19])(=[O:12])[CH2:10][CH3:11]>C(OC(=O)C)(=O)C>[C:9]([C:13]1[C:18](=[O:19])[CH2:17][CH:16]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([N+:1]([O-:4])=[O:2])[C:21]=2[CH3:28])[CH2:15][C:14]=1[OH:29])(=[O:12])[CH2:10][CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of fuming nitric acid (2.17 ml), glacial acetic acid (1.98 ml) and acetic anhydride (1.94 ml) was added dropwise to a solution of 2-propionyl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (10 g, 34.9 mmol) in acetic anhydride (23.3 ml) at 5°. Stirring was continued at 5° for 1 hr, then at 20° for 2 hr and 50° for 10 min. The mixture was then cooled and poured into ice water. The aqueous solution was extracted with methylene chloride. The organic layer was washed with water; saturated sodium bicarbonate solution and then further water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 2-propionyl-3-hydroxy-5-(3-nitro-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a pale yellow solid (9.59 g, 83%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.15 (3H,t), 2.18 (3H,s); 2.24 (3H,s); 2.38 (3H,s); 2.4-4.1 (7H,m); 6.88 (1H,s); 18.20 (1H,s).
Reaction SMILES: [Li+].[OH-].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1.C(O)(C(F)(F)F)=O>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1Cc2cc(OCCCNc3ccccn3)ccc2CC(CC(=O)O)C1=O
Reaction time: 0.02 h
Yield: 126.6 %

Procedure:
1.0 N LiOH (0.80 mL, 0.80 mmole) was added to a solution of methyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (207.5 mg, 0.52 mmole) in THF (2.6 mL) and H2O (1.8 mL) at RT. The initially cloudy solution became homogeneous within 1 min. After 18 hr, the reaction was acidified with TFA (0.12 mL, 1.56 mmole) and concentrated. ODS chromatography (20% CH3CN/H2O containing 0.1% TFA), concentration, and lyophilization gave the title compound (252.4 mg, 83%) as a light yellow, hygroscopic solid: HPLC (PRP-1®, 20% CH3CN/H2O containing 0.1% TFA) K′=2.4; 1H NMR (400 MHz, CD3OD) δ 7.83-7.93 (m, 1 H), 7.76-7.83 (m, 1 H), 7.00-7.11 (m, 2 H), 6.83-6.91 (m, 1 H), 6.80 (dd, J=8.4, 2.6 Hz, 1 H), 6.76 (d, J=2.6 Hz, 1 H), 5.30 (d, J=16.5 Hz, 1 H), 4.05-4.18 (m, 2 H), 3.94 (d, J=16.5 Hz, 1 H), 3.77-3.90 (m, 1 H), 3.57 (t, J=6.8 Hz, 2 H), 3.03 (dd, J=17.0, 4.2 Hz, 1 H), 2.99 (s, 3 H), 2.83 (dd, J=17.0, 9.1 Hz, 1 H), 2.72 (dd, J=17.0, 13.5 Hz, 1 H), 2.44 (dd, J=17.0, 4.7 Hz, 1 H), 2.11-2.23 (m, 2 H); MS (ES) m/e 384 (M+H)+. Anal. Calcd for C21H25N3O4.1.5 CF3CO2H.1.5 H2O: C, 49.57; H, 5.11; N, 7.23. Found: C, 49.65; H, 4.95; N, 7.15.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].CO.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1nc(-c2cccc(NC(=O)OC(C)(C)C)c2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(CCC(=O)O)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 100-mL round bottomed flask was charged with methyl 3-[3-(3-tert-butyloxycarbonylaminophenyl)-1,2,4-oxadiazol-5-yl]propionate (4.04 g, 11.6 mmol), lithium hydroxide (1.39 g, 58.2 mmol), methanol (15 mL), water (15 mL) and THF (15 mL). The resulting solution was then stirred for 2 h at room temperature. The solvents were then removed under reduced pressure and the residue dissolved into water (60 mL). The resulting solution was cooled to 0° C. and acidified to pH 5 by the addition of 2 N hydrochloric acid. The mixture was then extracted with ethyl acetate (4×50 mL) and the combined extracts dried over sodium sulfate. Filtration and concentration under reduced pressure afforded an 83% yield of 3-[3-(3-tert-butyloxycarbonylaminophenyl)-1,2,4-oxadiazol-5-yl]propionic acid as a white solid. m.p. 143-144° C.; 1H NMR (DMSO-d6) δ (ppm) 12.42 (bs, 1H), 9.60 (s, 1H), 8.24 (s, 1H), 7.57 (m, 2H), 7.42 (t, 1H,J=7.9 Hz), 3.26 (t, 2H,J=6.9 Hz), 2.84 (t, 2H,J=6.9 Hz), 1.49 (s, 9H); m/z=332 (M−H).