Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][NH2:17])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37].C[N:39](C)C=O.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:15][N:39]=[N:17][N:16]=3)[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]
Reactant: CN(C)C=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
20 g (37 mmol) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide were added to 160 ml of N,N-dimethyl formamide. To this solution was added dropwise 23 ml of 6 N aqueous hydrochloric acid at a temperature of 15° C. Then a solution containing 5.1 g (74 mmol) of sodium nitrite in 20 ml de-ionized water was added slowly. The reaction mixture was allowed to warm up to 20° C. and was stirred for 1.5 hr. Then 160 ml of de-ionized water were added and the suspension was stirred for 1 hr. The solid was filtered off under suction, washed with 100 ml of de-ionized water and dried at 50° C., 2000 Pa for 17 hr. There were obtained 18.9 g (92% of theory) of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide with a HPLC purity of 89.6% (w/w).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]([F:18])([F:17])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[OH-].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:18][C:6]([F:5])([F:17])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2
Reactant: FC(F)(F)Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1cccc2c1CCN2
Temperature: -5 °C
Reaction time: 19 h
Yield: 20.5 %

Procedure:
0.57 g of sodium cyanoborohydride is gradually added to a solution of 0.87 g of 4-(trifluoromethoxy)indole in 12 ml of trifluoroacetic acid under argon, cooled to a temperature of about −5° C. The reaction mixture is allowed to warm up to 0° C. for 3 hours, and is then poured into 30 g of ice and alkalinized with 21 ml of a concentrated sodium hydroxide solution. After stirring for 19 hours, the mixture is diluted with 60 ml of ethyl acetate and then stirred at ambient temperature for 30 minutes. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×60 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is treated again with a mixture of 50 ml of water, 50 ml of ethyl acetate and 10 ml of a concentrated sodium hydroxide solution and stirred at ambient temperature for 30 minutes, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 3×50 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out with 95/5; 90/10; then 85/15 v/v cyclohexane/ethyl acetate mixtures, at a flow rate of 25 ml/min. 0.18 g of impure 4-(trifluoromethoxy)indoline is thus obtained in the form of a yellow oil which is directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(O[Cl:22])(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: CC(C)(C)OCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Yield: 91.9 %

Procedure:
To a solution of 5.0 g of 4-(3,5-difluorophenoxy)phenol in 50 ml of carbon tetrachloride, there was added dropwise 2.45 g of t-butylhypochlorite with vigorously stirring and ice-cooling. After completion of the addition, the reaction mixture was stirred at room temperature for 5 hours and concentrated, followed by addition of 200 ml of ethyl acetate. The obtained solution was washed with an aqueous solution of 5% wt. sodium dicarbonate, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.31 g of 2-chloro-4-(3,5-difluorophenoxy)phenol. Yield. 92%. nD25 : 1.5639
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CCOC(C)=O>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(Cl)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCCC2)c(Cl)c1

Procedure:
A suspension of Zn powder (620 mg, 9.48 mmol) and 1-(2-(2-chloro-4-nitrophenoxy)ethyl)pyrrolidine (320 mg, 1.19 mmol) in AcOH:H2O (3:1 mL) was heated at 55° C. for 2 h. After cooling the reaction to RT, any solid was removed by filtration and rinsed with AcOH and CH2Cl2. Once the combined filtrate was concentrated using a rotavap, the resulting residue was adjusted pH to 10 with NH4OH and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (10 mL), then dried over MgSO4. After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification. MS (ESI) 241 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](OCC)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(CO)CC1

Procedure:
Ethyl 1-(methylsulfonyl)piperidine-4-carboxylate 18 was reacted with lithium aluminum hydride in THF to give 19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9](I)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 5-bromo-1H-pyridin-2-one (2 g) and silver carbonate (4.3 g) in chloroform (40 mL) was added isopropyl iodide (11.5 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through silica gel (20 g) and the filtrate was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=98:2→90:10) to give 5-bromo-2-isopropyloxypyridine (2.41 g, yield: 97%).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+].O>C1COCC1.CCOC(C)=O>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH:4]=[O:5])[S:7][C:8]=2[CH:14]=1
Reactant: CON(C)C(=O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc2ccc(C(F)(F)F)cc2s1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To N-methoxy-N-methyl-6-(trifluoromethyl)-1-benzothiophene-2-carboxamide as a solution in THF (0.2 M) at −15° C. was added a solution of LiAlH4 in THF (0.5 M) dropwise via an addition funnel. After stirring at −15° C. for an additional 30 min, an aqueous 1 N KHSO4 solution was added cautiously via an addition funnel. H2O was added followed by EtOAc. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organic layers were washed with 1 N HCl, then washed with brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure to obtain the title compound as an oil that solidified under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][S:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH2:15][CH2:14][S:13][CH3:12])=[O:6]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CSCCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSCCCNC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-iodobenzoic acid (1.50 g, 5.70 mmol, Bosche Scientific) and 3-(methylthio)propylamine (0.72 mL, 6.84 mmol, Acros) in EtOAc (15 mL) followed by DIEA (1.19 mL, 6.84 mmol) and 1-propanephosphonic acid cyclic anhydride (3.99 mL, 6.27 mmol, 50% in EtOAc, Sigma Aldrich). The reaction was stirred at RT for 4 h, and then quenched with sat. NaHCO3. The layers were separated and the organic layer was washed with sat. NaHCO3, brine, then dried (MgSO4), filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 350.9 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, dd, J=7.6, 1.4 Hz), 7.30 (1H, dd, J=7.8, 1.4 Hz), 6.41 (1H, t, J=7.8 Hz), 6.32 (1H, br. s.), 3.54 (2H, q, J=6.7 Hz), 2.61 (2H, t, J=6.9 Hz), 2.09-2.17 (3H, m), 1.92 (2H, quin, J=6.8 Hz)
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[Br:11]Br.C([O-])(O)=O.[Na+]>O.[K+].[Br-]>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of KOH (4.2 g, 0.075 mol) in water (750 mL) was added 2-methoxypyridine 16-1 (16.4 g, 0.15 mol) followed by a dropwise addition of bromine (24 g, 0.15 mol) in 1N aqueous KBr (750 mL) and the resulting solution was stirred at room temperature for 5 hr. Solid NaHCO3 was added until basic and the solution was extracted with CHCl3 (3×500 mL). The organic layer was washed with 10% NaHSO3, then brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The resulting dark brown oil was predominantly the desired compound 16-2 and was used as such in the next step.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[C:6]2[CH:30]=[CH:31][C:32]([CH:34]([OH:36])[CH3:35])=[CH:33][C:5]=2[N:4]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:41](N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[C:6]2[CH:30]=[CH:31][C:32]([CH:34]([O:36][CH3:41])[CH3:35])=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1nc2cc(C(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1nc2cc(C(C)OC)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (Example 345, 151 mg, 0.3 mmol) in CH2Cl2 (15 ml) was added thionyl chloride (0.1 ml, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was dissolved with methanol (15 ml). The mixture was added triethylamine (0.08 ml, 0.6 mmol) and stirred at room temperature for 5 h. The solvent was removed and the residue was extracted with CH2Cl2 (50 ml). The organic layer was washed with water(10 ml), brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:6)/CH2Cl2:methanol(10:1) to afford 139 mg (89%) of the title compound as white solids.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(#N)C>CN(C)C=O.O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:23])[CH:29]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: Clc1cc(CBr)ccn1
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
0.028 g of sodium hydride is added to a solution of 0.1 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for 30 minutes. A solution of 0.1 g of 2-chloro-4-(bromomethyl)pyridine in 2 ml of dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction medium is placed on a cartridge 20 mm in diameter packed with 17 g of octadecyl-grafted 50 μm silica conditioned successively with acetonitrile and then with water. The elution is performed by gradient using the mixture (water/acetonitrile) of from 0 to 100% acetonitrile. The fractions containing the expected product are concentrated under reduced pressure. 0.130 g of crude product is thus obtained, which product is purified by a double chromatography using a cartridge packed with 10 g of 20-40 μm of conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate), (8/2) (v/v) at a flow rate of 5 ml/minute. The fractions between 30 and 75 ml are concentrated under reduced pressure. 0.1 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a white powder, the characteristics of which product are as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Br[C:15]1[C:16](=[O:22])[NH:17][N:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>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].O1CCOCC1>[Cl:21][C:19]1[CH:20]=[C:15]([NH:13][C:10]2[N:11]=[N:12][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)[C:16](=[O:22])[NH:17][N:18]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: Nc1ccc(-c2ccncc2)nn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]nc(Cl)cc1Nc1ccc(-c2ccncc2)nn1
Temperature: 130 °C
Yield: 41.1 %

Procedure:
A 25-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 6c (170 mg, 0.98 mmol), 4-bromo-6-chloropyridazin-3(2H)-one (411 mg, 1.97 mmol), cesium carbonate (956 mg, 8.61 mmol), and 1,4-dioxane (7 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (48 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.05 mmol) were added, and the reaction mixture was heated for 16 h in a 130° C. bath. After this time, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 41% yield (121 mg) of 6e as an off-white solid: mp 263-265° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 1.0.10 (s, 1H), 8.75 (dd, 2H, J=4.8, 1.8 Hz), 8.52 (s, 1H), 8.35 (d, 1H, J=9.3 Hz), 8.11 (dd, 2H, J=4.5, 1.5 Hz), 8.01 (d, 1H, J=9.3 Hz); MS (ESI+) 301.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:23][CH2:22][CH:21]3[CH2:24][CH:18]2[CH2:19][N:20]3C(OCC2C=CC=CC=2)=O)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.CCO>C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:18]12[CH2:24][CH:21]([NH:20][CH2:19]1)[CH2:22][CH2:23][N:17]2[C:4]1[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2c(c(N3CCC4CC3CN4C(=O)OCc3ccccc3)n1)CCCc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1nc2c(c(N3CCC4CC3CN4)n1)CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 82A was treated with EtOH (1.5 mL) and 20% Pd(OH)2/C (15 mg), then stirred at ambient temperature under an H2 atmosphere for 16 hours, then diluted with 5:1 CH2Cl2:EtOH, filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.65-1.86 (m, 2H), 2.01 (d, J=11.53 Hz, 2H), 2.20-2.27 (m, 3H), 2.40-2.49 (m, 1H), 2.62-2.69 (m, 2H), 3.20 (dd, J=11.53, 4.75 Hz, 1H), 3.32 (d, J=12.21 Hz, 1H), 3.46-3.58 (m, 2H), 3.76-3.81 (m, 1H), 4.50 (t, J=4.41 Hz, 1H), 4.71 (s, 2H), 7.20-7.24 (m, 1H), 7.31-7.39 (m, 2H), 7.71-7.75 (m, 1H); MS (M+H)+ m/z 322.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=2.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (160 mg, 500 μmol) and 1N NaOH (1.5 mL) in ethanol (25 mL) was heated at 80° C. for 18 h. The solution was cooled to ambient temperature, diluted with ethyl acetate, acidified with conc. HCl, and the layers separated. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the solvent was removed under reduced pressure to afford 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid. MS (m/z) 304.0 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[CH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[CH:15][C:16]([C:18]2[S:19][C:20]([C:29]([F:32])([F:31])[F:30])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:33][CH3:34])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([C:29]([F:30])([F:31])[F:32])=[C:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:33][CH3:34])[CH3:2]
Reactant: CCOC(=O)C=Cc1c(C)cc(C=CC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc1CC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)cc(CCC(=O)c2sc(C(F)(F)F)c3c2CCC(C)(C)C3)cc1CC
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2-ethyl-6-methyl-phenyl}-acrylic acid ethyl ester (630 mg, 1.25 mmol) in ethanol (25 mL), a suspension of Pd/C (400 mg, 10% Pd) in ethanol (15 mL) is added and the resulting slurry is stirred at 65° C. for 16 h under 8 bar of H2. The catalyst is filtered off and the solvent of the filtrate is evaporated. The residue is separated by CC on silica gel eluting with heptane:EA 4:1 to give 3-{4-[3-(5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2-ethyl-6-methyl-phenyl}-propionic acid ethyl ester (340 mg, contains traces of the corresponding isopropyl ester) as a colourless oil; LC-MS: tR=1.28 min, [M+1]=509.49.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][O:17]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH3:25])[CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cccc(CCCCc2ccccc2OCC2CO2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.83 g of 2-{2-[4-(3-methylphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran were treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified as described in Example 1(b), to give 1.25 g (yield 59%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:26])[F:27])=[CH:16][CH:17]=2)=[O:25])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 20 mg (37%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.30 (m, 1H), 7.55 (m, 2H), 7.80 (m, 2H), 8.12 (d, J=5 Hz, 1H), 10.08 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10][C:9]2=O)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[O:27]=[C:28]1[N:32](CO)[C:31](=[O:35])[CH2:30][N:29]1[CH2:36][C:37]#[CH:38]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:12]([CH:13]([CH3:14])[CH3:15])[C:11]([O:10][CH2:9][N:32]2[C:31](=[O:35])[CH2:30][N:29]([CH2:36][C:37]#[CH:38])[C:28]2=[O:27])=[O:16])=[CH:6][CH:7]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(Cl)cc2)C(C)C)C1=O
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (1.32 mmol) and dimethylaminopyridine in 5 ml of dry tetrahydrofuran is added a solution of (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol (1.26 mmol) in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred for about 20 hours, under dry air, and then diluted with ether followed by washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. After drying over calcium sulfate, solvent is evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 15% ether/hexane to give (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(4-chlorophenylamino)-3-methylbutanoate.