Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][NH:22][CH3:23]>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:23])[C:2]1[C:11]([CH:12]=[O:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: O=Cc1c(Cl)nc2ccccc2c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1C=O
Reaction time: 14 h

Procedure:
2-Chloro-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde (5.28 g) and 15 ml of dimethylamine are dissolved in 75 ml of toluene. This mixture is autoclaved for 14 hours at 123°-136° C. The mixture is cooled, evaporated to dryness, and partitioned between ethyl acetate and a saturated aqueous solution of potassium carbonate. The ethyl acetate layer is dried (magnesium sulfate) and evaporated to give an orange oil. Chromatography (silica, 10% ethyl acetate/hexanes) gives 4.20 g of 2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde as an orange solid; 1H NMR (chloroform-d): δ 9.73 (s, 1H), 7.78-6.96 (m, 8H), 3.10 (s, 6H) ppm.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][O:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[N:25][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1ccc(F)cc1
Agent: Cl
Product: O=c1[nH]c(COCCc2ccc(F)cc2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 80.2). Light brown solid. MS: m/e=318.1 [M+H+].
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15]1
Reactant: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccn(CCN)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 105.5 %

Procedure:
A mixture of 660 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate, 194 mg of hydrazine monohydrate, and 19 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then separated by filtration. The filtrate was concentrated under reduced pressure to obtain 430 mg of tert-butyl 1-(2-aminoethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C@@H:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[CH3:35]
Reactant: C[C@H](N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with (S)-1-amino-1-(2-pyridyl)-ethane (51 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 76 mg of the title compound. Optical Rotation [α]D=+63.90° (c=0.39 mg/ml; CH3OH)
Reaction SMILES: [O-2].[Mg+2].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][CH2:6][C:5]1=[O:22].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:6][C:5]1=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CN(C(=O)CCl)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 8.14 %

Procedure:
3 g. of magnesium oxide are added to a solution of 2.87 g. (0.01 mmoles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2 H-1,4-benzodiazepine-2-one in 30 ml. of chloroform, and a solution of 1.2 ml. (0.018 moles) of chloroacetyl chloride in 4 ml. of chloroform is added to the vigorously stirred mixture. After 3 hours of stirring at room temperature the magnesium salt is filtered off, washed with 20 ml. of chloroform, and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallized from acetone. 2.68 g. (8.14 %) of 1-methyl-4-chloroacetyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 197°-200° C.; Rf2 = 0.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:36][CH:35]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 45.6 %

Procedure:
The procedure is as in Example 1, but 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.14 g of tert-butyl (RS)-2-anilino-2-(4-methoxyphenyl)acetate and 0.72 cm3 of thionyl chloride are used as starting materials. The residue obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: cyclohexane/ethyl acetate (70/30 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from a mixture of diisopropyl ether/acetonitrile (50/50 by volume). 2.3 g of tert-butyl (RS)-2-(4-methoxyphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 206° C. are then obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=O)O.[BH4-].[Na+].B(F)(F)F.[OH-].[Na+].C1N2CCN(CC2)C1>C1(C)C=CC=CC=1.O.COCCOC>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:14][N:16]([CH3:17])[CH3:18]
Reactant: CN(C)C(=O)CC1(O)C(=O)Nc2ccc(I)cc21
Agent: C1CN2CCN1CC2
Agent: FB(F)F
Agent: [BH4-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: CN(C)CCc1c[nH]c2ccc(I)cc12
Temperature: -15 °C
Reaction time: 17 h
Yield: 10.9 %

Procedure:
A 3 L flask is charged with 2-(5-iodo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 6) (100 g, 0.277 mol), and 800 mL of DME. The supension is cooled to −15° C., and sodium borohydride (31.5 g 96%, 0.832 mol) is added to this mixture, which causes a raise of the temperature by 5C. To this, BF3-etherate is added dropwise during 30 minutes (157.6 g, 1.11 mol). Initially there is a strong exothermic reaction (requires slow addition of BF3-etherate) and evolution of a gas. The temperatureis maintained between −15 and −10° C. during the addition. The formed orange slurry is then allowed to warm slowly to ambient temperature (25-27° C.), and left stirring over night (17 h). To this mixture, then 4N NaOH (555 mL) is added and the mixture is heated under reflux for 50 minutes. Then DABCO (34.3 g) is added, and refluxing the mixture is continued for two additional hours. Then water (250 mL) is added, and the DME is removed on the rotavapor. The obtained orange slurry is then extracted with TBME (1000 mL, 2×600 mL), and the combined organic layers are washed with water (800 mL) and brine (700 mL), and concentrated on the rotavapor to about 600 mL. To the stirred residue, MnO2 (72.4 g), is added, and the exothermic oxidation causes a temperature rise of 20° C. Stirring is continued for one hour, and then the MnO2 is filtered off. Removal of the solvent from the filtrate gives a brown oil, which is dissolved in toluene. The toluene is extracted for three times with 4 N HCl (300 mL, 2×150 mL). After adjustment of the pH of the combined aqueous layers to about 10, the product is re-extracted with TBME (3×700 mL). The combined organic layers are washed with water (500 mL), and brine (500 mL), and after almost complete removal of the solvent on the rotavapor and standing over night at 4° C. some of the product crystallizes (39 g, 44.7%). Further concentration of the mother liquors and standing for two additional days gives another crop of the title product (9.5 g, 10.9%), while still about 20 g of material (about 22%) remains in the mother liquors. 1H-NMR (CDCl3, 300 MHz): δ 2.34 (s, 6H, NMe2); 2.59-2.66 (m, 2H, CH2NMe2); 2.85-2.92 (m, 2H, ArCH2); 6.90 (d, 1H, 3J=2.2 Hz, H-2); 7.03 (d, 1H, 3J=8.4 Hz, H-7); 7.38 (dd, 1H, 4J=1.3 Hz, H-6); 7.91 (d, 1H, H-4); 8.56 (br s, 1H, NH). 13C-NMR (CDCl3-D6, 75 MHz) δ 23.71 (ArCH2); 45.65 (N(CH3)2); 60.32 (CH2NMe2); 82.77 (C-5); 113.36 (C-6); 113.86 (C-3); 122.78 (C-2); 127.87 (C-4); 130.29 (C-7); 130.33 (C-8); 135.62 (C-9).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:14]([OH:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:16][CH2:15][CH2:14][OH:17])([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Yield: 74.5 %

Procedure:
20.25 g (0.1 mole) of 2,4-dinitrochlorobenzene, 124 g (2 moles) of ethylene glycol, 82.93 g (0.6 mole) of potassium carbonate, and 600 ml of xylene were placed in a reaction vessel to be stirred by heating for 12 hours. The reacted solution was isolated by filtration, and the filtrate was concentrated. 17.0 g of 2-(2,4-dinitrophenoxy) ethanol was yielded by column purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=O)[CH2:12]Br)[NH:9][CH:10]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[NH:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1c[nH]c(C(=O)CBr)c1
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)c[nH]3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrrole and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrrolyl)thiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].Cl.CCOCC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Temperature: 0 °C
Yield: 100.2 %

Procedure:
Dissolve [2-(2,4-difluoro-phenyl)-6-methoxynaphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (10.8 g, 21.5 mmol) in methylene chloride (200 mL). Add 2M HCl in ether (21.5 mL, 43 mmol) and concentrate in vacuo. Redissolve the foam in methylene chloride (200 mL) and cool to 0° C. under nitrogen. Slowly add boron tribromide (10.1 mL, 107 mmol) and stir at 0° C. for 30 minutes. Slowly pour into saturated aqueous sodium bicarbonate and extract with 20% WA in chloroform. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to yield 10.5 g (100%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.[Cl-].[C:40]([O:44][C:45](=[O:48])[CH2:46][Zn+])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.C1(C)C=CC=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]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:46][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:48])=[C:3]([F:10])[CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1F
Temperature: 50 °C
Yield: 74.5 %

Procedure:
Combined 4-bromo-3-fluorobenzonitrile (2.0 g, 10.00 mmol), Pd(dba)2 (0.287 g, 0.500 mmol), and 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.394 g, 1.000 mmol) in THF (60 mL) with nitrogen purge. Then (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (0.5M, 30 mL, 15.0 mmol) was added via syringe. The reaction mixture was heated in an oil bath at 50° C. for 18 hours and then was adsorbed onto silica gel (11 g) and purified by flash chromatography using an eluent of 1:1 heptane/EtOAc on an 80 g silica gel column (Single Step™) to give a residue. The residue was dissolved in toluene (0.5 mL) and purified by flash chromatography using a gradient eluent of heptane/EtOAc (0-25% EtOAc) on an 80 g silica gel column (Single Step™) to give the title compound (1.752 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9 H) 3.64 (d, J=1.26 Hz, 2 H) 7.36 (dd, J=8.97, 1.39 Hz, 1 H) 7.40 (d, J=7.07 Hz, 1 H) 7.42-7.45 (m, 1 H). MS m/z [M+H]+ 236.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[NH2:47][C:48]1[CH:53]=[CH:52]C=CN=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[CH:24]=[CH:52][CH:53]=[CH:48][N:47]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: Nc1ccccn1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccccn1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 2-aminopyridine was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].N.[Li]>C(OCC)C>[NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: N
Agent: [Li]
Solvent: CCOCC
Product: C[C@]12CCC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a stirred solution of 0.45 g of 4-aminoandrost-4,6-dien-3,17-dione in 20 ml of diethyl ether and 40 ml of liquid ammonia are added 0.28 g of lithium metal at small portions. The resulting blue reaction mixture is stirred for additional 30 minutes, quenched with absolute ethanol till the blue colour fades and allowed to reach the room temperature. The resulting residue is taken up with water, extracted with diethyl ether and purified as described in example 10. There are obtained 0.280 g of the title compound, m.p. 185°-187° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>Cl>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: COC(=O)c1cc(F)ccc1N
Agent: Cl
Product: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 16 g of 4-chloro-8-trifluoromethylquinoline, 11.62 g of methyl 2-amino-5-fluoro-benzoate and 70 ml of 2 N hydrochloric acid solution was heated to reflux and was allowed to stand overnight at room temperature. The mixture was iced and filtered and the product was empasted with a little water and was vacuum filtered. The recovered crystals were dissolved in methanol and triethylamine was added to the resulting solution until the pH was alkaline. The mixture was iced and filtered and the product was dried to obtain 11.2 g of methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate melting at 166° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:28][N:29]=1)=[CH:9]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][N:29]=1)=[CH:9]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
A mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (300 mg), 1N aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (2 mL) and ethanol (2 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (280 mg, yield 97%) as yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give yellow prism crystals. melting point 113-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:28][O:29][CH3:30])[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)[NH:11][N:12]=1>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:28][O:29][CH3:30])[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)[NH:11][N:12]=1
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C2CC(CCCOc3ccc(Cl)cc3Cl)=NN2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(-c2cc(CCCOc3ccc(Cl)cc3Cl)n[nH]2)cc1
Reaction time: 4 h

Procedure:
A large excess of manganese oxide was added to 4-{5-[3-(2,4-dichloro-phenoxy)-propyl]-3,4-dihydro-2H-pyrazol-3-yl}-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (0.259 mmol) in chloroform (20 mL). After stirring for 4 h the solution was filtered thorough Celite and concentrated in vacuo. The crude 4-{5-[3-(2,4-dichloro-phenoxy)-propyl]-2H-pyrazol-3-yl}-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide was used without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH:9]=[C:8]([F:21])[C:7]=1[N+:22]([O-])=O)=O.C(OCC)(OCC)OCC.C(O)CO>C(OCC)(=O)C>[F:21][C:8]1[C:7]2[N:22]=[C:3]([C:2]([F:26])([F:25])[F:1])[NH:5][C:6]=2[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: O=Cc1ccc(Oc2cc(F)c([N+](=O)[O-])c(NC(=O)C(F)(F)F)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: OCCO
Product: O=Cc1ccc(Oc2cc(F)c3nc(C(F)(F)F)[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a mixture of 2,2,2-trifluoro-N-{3-fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}acetamide (1.25 g, 3.36 mmol), triethyl orthoformate (0.614 mL, 3.69 mmol), and ethylene glycol (0.749 g, 13.43 mmol) was added Bu4NBr3 (0.016 g, 0.034 mmol). The homogeneous reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed 1×NaHCO3, once in brine and then dried (Na2SO4), filtered and concentrated with no further purification necessary. Residue (0.400 g) was re-dissolved in ethyl acetate (5 mL) and hydrogenated using 10% palladium on carbon (0.080 g) under an atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through Celite and the filtrate concentrated. The residue was re-dissolved in acetone and MP-Fosic acid resin (1.26 g, 1.92 mmol) was added. The mixture was stirred for 16 hours, filtered and the filtrate was concentrated. Chromatography on silica using 40% ethyl acetate/hexanes eluted the product to give 0.153 g of 4-{[4-fluoro-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}benzaldehyde as an off-white solid.