Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].N[CH2:20][CH2:21][SH:22]>>[S:22]1[CH2:21][CH2:20][N:2]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCS
Product: c1ccc2c(c1)C1CC(C3=NCCS3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g) and 2-aminoethanethiol (2.0 g) is stirred at 130° C for 4 hours. The reaction mixture is recrystallized from ethanol to give 11-(2-thiazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.5 g) as crystals melting at 160° to 161° C. IR (KBr), 1619 cm-1 (S--C=N).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Br:5][C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10](Cl)[N:11]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Br:5][C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10]([NH:4][CH2:3][CH2:1][OH:2])[N:11]=1
Reactant: NCCO
Reactant: N#Cc1ncc(Cl)nc1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(NCCO)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
0.061 g (1.00 mmol) of ethanolamine were added slowly at room temperature to a solution of 0.218 g (1.0 mmol) of the 3-bromo-5-chloro-pyrazine-2-carbonitrile and 0.264 g (2.0 mmol) of N-ethyldiisopropylamine in 15.0 ml of dioxane. The reaction mixture was stirred at room temperature for 18 hours. It was subsequently poured into 50 ml of an ice/water/sodium hydrogen carbonate mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 100:0 to 95:5 v/v gradient of dichloromethane and methanol as the eluent giving 0.131 g (0.539 mmol, 53.9% of theory) of the 3-bromo-5-(2-hydroxy-ethylamino)-pyrazine-2-carbonitrile as yellow solid; m.p. 158-160° C.; MS: 243 (M)+.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]([N:16]1[C:20]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:18]([CH2:25][OH:26])=[N:17]1)([CH3:15])([CH3:14])[CH3:13].CCCCCC.CCOC(C)=O>C(Cl)Cl.CCOCC>[C:12]([N:16]1[C:20]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][C:18]([CH:25]=[O:26])=[N:17]1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)Cc1cc(CO)nn1C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reaction time: 0.5 h

Procedure:
PCC (0.67 g, 3.12 mmol) and silica gel (0.50 g) were grinded together and dispersed in 10 ml of purified CH2Cl2 followed by treatment with ultrasound at 20° C. for 30 minutes. 1-tert-butyl-5-iso-butyl-3-hydroxymethylpyrazole (0.50 g, 2.08 mmol) was dissolved in 10 ml of purified CH2Cl2 and the solution was added thereto and treated with ultrasound for 15 minutes. The reaction progress and completion were confirmed using TLC (hexane:EtOAc=6:1). Upon completion of the reaction, ether was added to the reaction mixture and then the resulting mixture was filtered through a celite bed, and concentrated under reduced pressure. The concentrate was separated by column chromatography (hexane:EtOAc:CH2Cl2=3:1:1) to obtain the compound of the present invention.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:12]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=3[NH2:22])[C@@H:11]3[CH2:23][C@H:8]2[CH:9]=[CH:10]3)=[O:6])[CH2:3][CH2:2]1.[Cl:24][C:25]1[N:26]=[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[S:28][C:29]=1[CH:30]=O.C([O-])(=O)C.[NH4+]>>[CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:12]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]4[NH:21][C:30]([C:29]5[S:28][C:27]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[N:26][C:25]=5[Cl:24])=[N:22][C:15]=34)[C@@H:11]3[CH2:23][C@H:8]2[CH:9]=[CH:10]3)=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Reactant: Nc1ncc(Cl)c(N[C@H]2[C@@H](C(=O)NC3CC3)[C@@H]3C=C[C@H]2C3)c1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(NC1CC1)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 8.2 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid cyclopropylamide (200 mg, 0.6 mmol), 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (162.28 mg, 0.74892 mmol), and Ammonium acetate (92.439 mg, 1.1992 mmol) were reacted to produce 26.23 mg (8%) of the title compound. (300 MHz, DMSO-d6) 12.68 (s, 1H), 8.31 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.38-6.31 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 2.84 (s, 1H), 2.75 (s, 1H), 2.65 (m, 1H), 2.23 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.38 (d, J=8 Hz, 1H), 0.63 (m, 2H), 0.37 (m, 2H). MS=530 (M+H), HPLC: 2.90 min. (G Method)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2Cl)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.ClCCl>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
Combine 1-(4-fluorobenzyl)-2-chloro-1H-benzimidazole (22.1 g, 84 mmol) and ethyl 4-aminopiperidine-1-carboxylate (27.7 g, 161 mmol) and heat to 170° C. After 4 hours, partition the reaction mixture between aqueous 2.5 M sodium hydroxide solution and chloroform. Separate the layers and extract the aqueous layer twice with chloroform. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with dichloromethane and then 15% ethyl acetate/dichloromethane. Evaporate the product containing fractions, triturate with hexane, filter, and dry to give (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[S:5][C:6]=1[CH3:7]>[Ni].CO>[CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)sc1C
Agent: [Ni]
Solvent: CO
Product: Cc1nc(NC(=O)c2ccc(N)c(N)c2)sc1C

Procedure:
Prepared analogously to example 14b by hydrogenation of the product obtained in 77a using Raney nickel in methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:30][CH:31]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)[OH:32])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl.CCOC(C)=O>[CH3:57][S:58]([O:32][CH:31]([C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:34]=1)[CH2:30][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:47])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])(=[O:60])=[O:59]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (350.1 mg, 0.516 mmol) in CH2Cl2 (15 mL) was added DIPEA (450 μL, 2.58 mmol). The solution was cooled to 0° C. and MsCl (100 μL, 1.29 mmol) was added. After 45 minutes of stirring at 0° C., the reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (25 mL), brine (25 mL), 1N HCl (25 mL), and brine (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was put through a short plug of silica gel with 25% EtOAc/hexanes and concentrated. The product, 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl methanesulfonate, was used immediately in the next reaction without further characterization. Rf=0.33 (25% EtOAc/hexanes).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14]12([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[CH2:27]Br)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.Cl>CN(C=O)C.O>[C:14]12([C:24]3[CH:25]=[C:26]([CH2:27][S:3][C:4]4[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: COc1ccc(CBr)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
1.44 g (48 mmol) of sodium hydride (80% in oil) and 25 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 6.73 g (40 mmol) of methyl 4-mercaptobenzoate in 60 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. A solution of 16.1 g (48 mmol) of 3-(1-adamantyl)-4-methoxybenzyl bromide in 90 ml of DMF was then added and the mixture was stirred at room temperature for eight hours. The reaction medium was poured into water, acidified to pH 1 with hydrochloric acid and extracted with ethyl ether. The organic phase was separated out after settling had taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (40/60). After evaporation of the solvents, 16.75 g (99%) of the expected methyl ester, having a melting point of 143°-5° C., were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]([CH:36]2[CH2:37][CH2:38]2)[C:18](=[O:20])[CH2:17][O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=2)[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: c1ccc(CN2CCC(NC3CC3)CC2)cc1
Product: Cc1nc(OCC(=O)N(C2CC2)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 9 and 1-benzyl-N-cyclopropylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])(C)[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1.[CH:15]([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1>[CH3:1][O:2][CH:3]([CH3:14])[CH2:4][CH:5]([CH3:15])[CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([OH:12])[CH2:7]1
Reactant: COC(C)(C)CCC1CCCC(=O)C1
Reactant: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)CC(C)C1CCCC(O)C1
Reaction time: 16 h

Procedure:
3-(3-methoxy-3-methylbut-1-yl)cyclohexanone (1.4 g, 0.0051 mol) was dissolved in tetrahydrofuran (10 mL) and cooled to -78~C. under a nitrogen atmosphere with stirring. A solution of lithium tri-sec-butylborohydride (6.1 mL of a 1 M solution of tetrahydrofuran, 0.0061 mol) was added. The mixture was allowed to come to 20~C. over 16 hours and 10% NaOH (aq, 4.0 mL) was added, followed by 30% hydrogen peroxide (aq, 4.0 mL). The mixture was extracted with hexane. The extracts were dried Na2SO4) and concentrated to the residue which was purified by bulb to bulb distillation (air bath temp 175~C., 0.1 mm Hg) to yield 3-(3-methoxy-methylbut-1-yl)cyclohexanol as a mixture of diastereoisomers in the ratio of 94:6 (0.7 g). NMR(CDCl3)δ 1.1(s,6H), 1.2-1.8(m,13H), 3.2(s,3H), 4.1(brs,1H). IR (neat) 3410, 2990, 2960, 2870, 1460, 1370, 1110, 1090, 980 cm-1. MS (m/e) 43, 73, 109, 124, 143, 181, 201, 214.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:14][CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccc(F)cc2)C1
Solvent: O=CO
Product: Fc1ccc(CSC[C@@H]2CCNC2)cc1
Yield: 103.7 %

Procedure:
A solution of (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylthio)methyl]pyrrolidine (0.5422 g, 1.67 mmol) in 90% formic acid (5 ml) was stirred at room temperature for 23 h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (25 ml) and washed with 2N NaOH solution (10 ml). The aqueous layer was reextracted with more dichloromethane (25 ml) and the combined organic extracts were washed with saturated NaCl solution (10 ml), dried (Na2SO4) and evaporated in vacuo to leave 0.3903 g of the title compound as an oil. δH (360 MHz, CDCl3) 1.42 (1H, m), 1.94 (1H, m), 2.24 (1H, m), 2.45 (2H, m), 2.59 (1H, m), 2.92 (2H, m), 3.08 (1H, m), 3.69 (2H, s), 7.00 (2H, t, J=8.6 Hz), 7.25-7.29 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCCCC1C=CC=[C:32]2[C:33]([NH:35]C(=O)[C:31]=12)=O.O.NN>C(O)C.C(OC(=O)C)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:31][CH2:32][CH2:33][NH2:35])=[CH:14][C:13]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Yield: 18.8 %

Procedure:
To 4-(2-benzyloxy-4-ethylphenoxy)-3-fluoroaniline (500 mg, 1.48 mmol) in 25 ml of ethanol was added 3-bromopropylphthalimide (440 mg, 1.64 mmol). The mixture was refluxed for 2 days. The reaction mixture was diluted with ethylacetate and washed with water, saturated brine solution, dried over anhydrous Na2SO4 and concentrated. The crude obtained was passed through a silica gel column using 15% ethylacetate in petroleum ether as eluant. The LCMS of the obtained mixture showed 53% mass of the coupled product. This was taken in 25 ml of ethanol and added 7 ml of hydrazine hydrate and refluxed overnight. Ethanol was removed in vacuo and added 20% KOH solution (20 ml) to the residue. The aqueous fraction was then extracted with dichlormethane and the combined dichloromethane fraction was dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by column chromatography using 5% methanol in dichloromethane as eluant to obtain 110 mg (18.8% after 2 steps) of the N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Yield: 85 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol and 3-chloro-4-fluorobenzeneboronic acid were coupled together as described in Example 1 to give 2-[3-(3-chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as a white solid (7.10 g, 85%): δH (400 MHz, CDCl3) 1.74 (6H, s), 2.08 (1H, s), 7.21 (1H, t, J 7), 7.31 (1H, t, J 9), 7.40-7.44 (1H, m), 7.60 (1H, dd, J 7 and 2), 7.67 (1H, s), 8.01 (1H, d, J 7); m/z (ES+) 323 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[C:25](O)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: COC(=O)[C@H](CCCCN)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)NCCCC[C@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-lysine methyl ester (from Example 21 above) and hexanoic acid (Aldrich), the title compound was prepared. The reaction was monitored by tlc (Rf=0.38 in 60% CH2CH2 /10% hexanes/27% EtOAc/3% MeOH) and purification was by flash chromatography using 60% CH2CH2 /10% hexanes/27% EtOAc/3% MeOH as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.O.OC1C2N=N[NH:29]C=2C=CC=1.N.O1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C.CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]=2[C:19]([NH2:29])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc(-c3cccs3)nc2C(=O)O)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(-c2oc(-c3cccs3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylic acid in DCM (2 mL) and DMF (1 mL) was added hydroxybenzotriazole monohydrate (0.022 g, 0.14 mmol) followed by 0.5M ammonia in dioxane (1.3 mL, 0.65 mmol). A solution of 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.078 g, 0.41 mmol) in DMF/DCM (4:1, 0.5 mL) was added and the reaction stirred at room temperature overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxamide (0.0128 g, 0.04 mmol, 15%) as a white solid. 1H NMR (CDCl3) δ 3.85 (3H, s), 5.53 (1H, br. s), 7.00 (2H, d), 7.16 (1H, dd), 7.17 (1H, br. s), 7.48 (1H, dd), 7.74 (1H, dd), 8.32 (2H, d). LCMS (2) Rt: 2.90 min; m/z (ES+) 301.
Reaction SMILES: [C:1]1([C:11]([NH2:13])=[NH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:12][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[N:13][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N=C(N)c1cccc2ccccc12
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cccc3ccccc23)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=395.3 (M+H+), was prepared from naphthalene-1-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=1[C:16]1[C:15]([O:14][CH3:13])=[CH:20][CH:19]=[CH:18][C:17]=1[O:21][CH3:22]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: COC(=O)c1ccc(I)c(Br)c1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2c(OC)cccc2OC)c(Br)c1
Temperature: 85 °C
Yield: 55.9 %

Procedure:
Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate (J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of 2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2M aqueous solution of caesium carbonate for 15 minutes under argon, then add 984 mg (0.85 mmol) of Pd(PPh3)4 and heat for 2.5 h at 85° C. After concentration under reduced pressure, distribute the residue obtained in 600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL of water, dry over MgSO4 and concentrate at reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 2.79 g of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58]>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (1.0 g, 1.84 mmol), sodium hydride (60% in oil, 220 mg, 5.50 mmol), 15-crown-5 (400 mg, 1.82 mmol) and t-butyl bromoacetate (0.55 ml, 3.69 mmol) in tetrahydrofuran (20 ml) was refluxed under heating for 1 hour and 15 min. The reaction solution was diluted with ethyl acetate and filtered with CELITE. Under cooling with ice, water was added dropwise to the filtrate which was then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=20:1) to give the titled compound (946.6 mg, 78%) as a colorless oil.