Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6]C)=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added with magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (0.1 mm Hg--35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% sulfate/potassium bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30°--0.1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(-c3ccncc3)c2nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Cl)c(Cl)c(-c3ccncc3)c2[nH]c1=O
Yield: 16.9 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-(4-pyridyl)quinoxaline (Preparation 2, 110 mg, 0.327 mmol), 2M aqueous hydrochloric acid solution (1 mL) and 1,4-dioxane (7 ml) was heated under reflux for 2 hours, cooled, and concentrated under reduced pressure. The solid residue was triturated with water, collected by filtration and washed with water and diethyl ether to give the title compound (17 mg, 17%) as a white solid, mp >300° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:7][CH2:6]2)=O.[CH3:38][NH:39][CH3:40]>>[CH3:38][N:39]([CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][CH2:7][CH2:6]2)[CH3:40]
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: CNC
Product: CN(C)Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 8, Step G) using essentially the same procedure used in Example 8, Step H except using dimethylamine. MS (+ESI m/z): 542 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][C:4]=1[OH:14].Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[CH:5][C:4]=1[OH:14]
Reactant: COc1cc([N+](=O)[O-])cc(O)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(N)cc(O)c1OC
Yield: 107 %

Procedure:
A solution of 1.1 g of 2,3-dimethoxy-5-nitrophenol in 45 mL dry methanol with 200 mg of 10% Pd/C (Degussa) was hydrogenated under a hydrogen ballon overnight. The reaction was filtered through a bed of celite and evaporated and the residue was chromatographed over silica gel (ethyl acetate/hexanes 3:2 gradient to 100% ethyl acetate). The appropriate fractions were evaporated to dryness to yield an oil that was taken up in methanol to which methanolic HCl solution was added and the solvent evaporated to yield 1.0 g of the desired product 4,5-dimethoxy-3-hydroxyaniline hydrochloride. MS (m/e): 170 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N+:16]([O-:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1.[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CCCCCCCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:19][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:18][N:16]2[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cn2cncn2)=[N+](C)[O-])cc1
Reactant: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCCCC1CC(Cn2cncn2)(c2ccc(OC)cc2)N(C)O1

Procedure:
Derivative 3 (R=4-OCH3, n=7) is prepared by a procedure similar to that described in Example 1 by reacting 1-(4-methoxyphenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=4-OCH3) with 1-decene (2: n=7). The resulting diastereomeric mixture of cis- and trans-derivative 3 (R=4-OCH3, n=7) is flash-chromatographed on neutral silica gel using chloroform-methanol (99:1 by volume) as eluent. Isomer A has a melting point of 89°-91° C. (ethyl acetate).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20](B(O)O)=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.OO>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]([OH:1])=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(B(O)O)c2C1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(O)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
A 2M aqueous solution of sodium hydroxide (0.53 mL, 1.06 mmol) was added to a stirred solution of {5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronic acid (0.21 g, 0.53 mmol) and hydrogen peroxide (0.084 mL, 1.06 mmol) in THF (5.3 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 10% yield) as a colourless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)C12CC3CC(CC(C3)C1)C2
Yield: 56.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), adamantanecarbonyl chloride (1.1 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided adamantane-1-carboxylic acid (6,7,8,9-tetrahydro-dibenzofuran-2-yl)-amide (0.98 g). Mp 247-248° C.; Anal. Calcd. for C23H27NO2: C, 79.05; H, 7.79; N, 4.01; Found: C, 78.75; H, 7.73; N, 3.75.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]=1[C:4](N(OC)C)=[O:5].[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:3]=1[C:4](=[O:5])[CH3:24]
Reactant: COc1ccc(COc2cccc(F)c2C(=O)N(C)OC)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(F)c2C(C)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-N-methoxy-6-[(4-methoxybenzyl)oxy]-N-methylbenzamide (6.926 g, 21.70 mmol) in tetrahydrofuran (10 mL) was added 1N methyl magnesium bromide in tetrahydrofuran (43.40 mL, 43.40 mmol). The reaction mixture was stirred at reflux for 4 hrs. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3/1) to give 1-{2-fluoro-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a pale yellow solid (1.21 g, yield; 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1.O>CS(C)=O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of 4-amino-2,3-difluorophenol (1.59 g, 7.49 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.1 g, 8.98 mmol), and the reaction mixture was stirred for 2 hours. Chloride 301 (1.6 g, 4.99 mmol) was added and the reaction mixture was heated at 100° C. for 2 hours. The mixture was cooled down then poured into water (150 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc/Hexane (2/1, 100 mL) for 1 h, to afford title compound 302 (1.7 g, 79% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.70 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.71 (d, J=5.1 Hz, 1H), 6.72-6.61 (m, 1H), 5.90 (s, 1H), 5.64 (s, 2H), 4.16-3.96 (m, 4H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nnn(-c3ccc(C(C)C)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(-n2nnc(-c3ccc(O)cc3)n2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
4-Isopropylaniline (1.35 g) was added to a mixed solution of 50% ethanol (16 ml) and concentrated hydrochloric acid (2.6 ml). To the mixture was added a solution of sodium nitrite (0.69 g) in water (4 ml) over 10 min below 5° C. and stirring was continued for 10 min. To a solution of 4-methoxybenzaldehyde phenylsulfonylhydrazone (2.9 g) in pyridine (60 ml) was added dropwise the above solution of diazonium salt during 20 min at -10° C.~-15° C., and stirring was continued for 30 min at -10° C. and for 30 min at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The extract was washed succesively with 4 N hydrochloric acid, water, aqueous sodium carbonate,and water, dried, and evaporated to dryness. The residue was purified by column chromatography on silica gel with benzene-hexane (1/2-2/1) as an eluate to give 2-(4-isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.6 g,54%). To a solution of 2-(4- isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.3 g) in dichloromethane (10 ml) was added dropwise boron tribromide (10 ml,2.6M solution in dichloromethane) at -10° C. Stirring was continued for 1 h at -10° C. and for 1 h at room temperature. To the mixture was added water (20 ml), and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated to dryness. The residue was recrystallized from benzene to give 1.1 g (72%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:20][CH2:21][CH3:22]
Reactant: Cc1ccc(CC#N)cc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(CC#N)ccc1C
Yield: 61.2 %

Procedure:
To a solution of (3-hydroxy-4-methylphenyl)-acetonitrile (1.7 g, 11.5 mmol) in acetone (100 ml), K2CO3 (7.9 g, 57.5 mmol) and 1-bromo butane (6.1 ml, 57.5 mmol) were added. The suspension was refluxed for 24 h and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude was purified by flash chromatography (petroleum ether:EtOAc 9.5:0.5) affording the title compound (1.43 g, 61% yield) as colourless oil.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:31](O)(=O)C.C=O>CO>[CH3:31][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:16]=2[CH2:22]1
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NCC5CCOCC5)n3)CNCC4)cc2)o1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (134 mg, 0.33 mmol) was dissolved in methanol (3 mL). Acetic acid (0.019 mL, 0.33 mmol) was added followed by formaldehyde (0.025 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 15 minutes and MP—CNBH3 was added. The reaction was stirred overnight. The MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by HPLC yielding 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (23.00 mg, 15.8%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].N1CC[CH2:15][CH2:14][CH2:13]1.FC(F)(F)C(O)=O>CC(C)=O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:14]([CH3:15])([CH3:13])[CH2:2][C:1]2=[O:3]
Reactant: C1CCNCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1

Procedure:
In another exemplary reaction sequence shown in Reaction Scheme 15, 4-bromophenol is reacted with acetyl chloride (AcCl) to provide the corresponding ester, and the ester made to undergo a Fries rearrangement under Friedel Crafts conditions to provide 2-acetyl-4-bromophenol. 2-Acetyl-4-bromophenol is reacted with acetone in the presence of piperidine and trifluoroacetic acid (TFA) to give 6-bromo-2,2-dimethyl-chroman-4-one. The latter compound is reacted with the Grignard reagent of the formula R1MgX and then with acid to provide the 6-bromo-2,2-dimethyl-chromene derivative of Formula 17.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[NH:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[C:20]1([C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[N:16]=[C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][CH2:11]3)[NH:17][C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: N=C(N)N1CCN(c2ncccc2C(F)(F)F)CC1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1

Procedure:
4-(3-(Trifluoromethyl)pyridin-2-yl)piperazine-1-carboxamidine (300 mg, 1.10 mmol, Example 3(a)) reacted with benzil (231 mg, 1.10 mmol, Aldrich) under the conditions of Example 4(b). The crude product was purified by silica gel column chromatography (1:3 EtOAc/hexane) to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 450.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([O-:32])=O)=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH2:42][CH2:41][N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[O:32])=[CH:28][CH:27]=4)=[CH:14][N:15]3[C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CNc1cc(-n2cc(-c3ccc(C(=O)[O-])cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cc(-n2cc(-c3ccc(C(=O)NCCN4CCOCC4)cc3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Yield: 24 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU; 63 mg, 0.167 mmol) was added to a mixture solution of 4-(6-(4-methoxyphenyl)-1-(6-(methylamino)pyrimidin-4-yl)-1H-indol-3-yl)benzoate (50 mg, 0.111 mmol), 2-morpholinoethanamine (14.6 μL, 0.111 mmol) and diisopropylethylamine (DIPEA; 29 μL, 0.167 mmol) in THF (2 mL) at room temperature. 2 hours later, the mixture was added to saturated sodium bicarbonate aqueous solution and then extracted with methylene chloride. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: Cl.FC(F)(F)O[C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[C:15](O)(=O)[CH3:16]>>[NH:11]1[C:8]2[C:7](=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:16]=[CH:15]1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)O
Agent: Cl
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
Ketone 2 (1.84 gr, 8.75 mmol) and 4-trifluoromethoxy phenylhydrazine hydrochloride (2.00 gr, 4.76 mmol) were stirred at 100° C. in acetic acid (40 ml, 0.22M) for 1 hour under nitrogen atmosphere to give a 1:2 mixture of 4- and 6-trifluoromethoxy indoles (desired 6-substituted indole is slightly less polar by TLC). The reaction was cooled to room temperature, the acetic acid was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with water (1×) and brine (1×). The organic layer was dried with sodium sulfate, filtered and evaporated to afford 3 as a yellow oil after column chromatography (hexanes/ethyl acetate/1% acetic acid, 6:1); 1H-NMR (CDCl3, 500 MHz) δ 8.43 (br s, 1H), 8.16 (dd, 1H), 7.46 (d, 1H), 7.23 (t, 1H), 7.14 (t, 1H), 7.03 (d, 1H), 6.74 (d, 1H), 2.54 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:25][N:26]1[CH:30]=[C:29]([C:4]2[C:5]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:6]([CH:16]=[CH:2][CH:3]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:28]=[N:27]1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Product: Cn1cc(-c2cccc(C(=O)Nc3cccnc3)c2OCc2ccccc2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 100 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.7 mg, 0.29 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.09 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated and the residue was purified using MDAP to yield the title compound. 31 mg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[N+]([O-])(O)=O.[C:34](N1C(C)=CC(C)=N1)(=[NH:36])[NH2:35]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4][N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[C:34]([NH2:36])=[NH:35]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/OCCN)CC[C@]12O
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=NOCCNC(=N)N)CC[C@]12O
Yield: 58.9 %

Procedure:
A solution of 1.00 g of (E,E)-17β-[3-(2-aminoethoxyimino)-1-propenyl]-5β-androstane-3β,14β-diol (I-ao) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was ground with water and then with diethyl ether/ethanol to give 0.65 g of the title compound (I-as), as a nitrate, white solid.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][CH2:8][CH2:9][Cl:10]>>[Cl:10][CH2:9][CH2:8][CH2:7][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: ClCCCBr
Reactant: CC(C)C#N
Product: CC(C)(C#N)CCCCl

Procedure:
reacting isobutyronitrile with 1-bromo-3-chloropropane in the presence of a first base in a non-polar solvent at a temperature of about 15°to 65°C. to afford 5-chloro-2,2-dimethylpentanenitrile;