Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:12])[CH3:11]>ClCCl>[C:10]([C:7]1[S:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCCCc1cccs1
Solvent: ClCCl
Product: CCCCc1ccc(C(C)=O)s1

Procedure:
2-Butylthiophene (obtained by Friedel-Crafts acylation of thiophene with butyryl chloride followed by Wolf-Kizner reduction in accordance with EP-A 0 392 510) is acetylated with acetyl chloride in dichloromethane under AlCl3 catalysis. Customary work-up followed by purification by distillation affords 2-acetyl-5-butylthiophene, b.p. 92° C./0.8 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:14][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:13]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25 mL rb flask was charged with 1.111 g (2.97 mmol) of the product of Step B, 1.451 g (4.45 mmol) Cs2CO3, 10 mL DMF and finally 0.5 mL (3.71 mmol) of bromopinacolone. The reaction mixture was stirred at room temperature 1 h then partitioned between EtOAc and water. The organic layer was washed with water, brine, then dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8](Br)=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3].C(N)[CH2:19][NH2:20]>CN1CCCC1=O.O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([C:19]#[N:20])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3]
Reactant: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1Br
Reactant: NCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1C#N

Procedure:
A mixture of 4-bromo-2,5-diisopropylphenyl methyl sulfone (19.9 g) prepared in Example 10A and 7.2 g of cuprous cyanide was heated in 100 ml of N-methyl pyrrolidone at 195°C under nitrogen for 2 hours. The reaction mixture was poured into a stirred solution of 25 g of ethylenediamine in 500 ml of water. The mixture was filtered and the residual product extracted into tetrahydrofuran. The extract was washed with 5% HCl and finally with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed to give 4-cyano-2,5-diisopropylphenyl methyl sulfone. Further purification by recrystallization from n-hexane gave 4-cyano-2,5-diisopropylphenyl methyl sulfone having a mp of 134°-137°C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCCCCC>CN(C=O)C>[N+:24]([C:23]1[C:18]([S:17][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccnc1S
Reactant: ClCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccnc1SCCSc1ccccc1
Temperature: 60 °C
Yield: 66 %

Procedure:
3.44 g (20.0 mmol) (2-chloroethyl)(phenyl)sulfane and 5.53 g (40.0 mmol) potassium carbonate were added to a solution of 1.56 g (10.0 mmol) 2-mercapto-3-nitropyridine in DMF (30 ml) and heated for 4 h at 60° C. Then the mixture was diluted with EE and washed with brine. The organic phase was separated off, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 1.93 g (6.6 mmol, 66%) 3-nitro-2-(2-phenylsulfanyl-ethylsulfanyl)pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH2:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.[H-].[Na+].CS(C)=O>O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:12])[CH:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Temperature: 160 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
A mixture of 5-hydroxy-3-methylindole (4.7 g), 2-amino-4-chloropyridine (4.1 g), sodium hydride (1.3 g), and dimethyl sulfoxide (40 ml) was stirred at 160° C. for 15 hours. Water was added thereto; extraction was performed with ethyl acetate; and purification was performed by silica gel column chromatography (ethyl acetate, sequentially, ethyl acetate:methanol=20:1). The solvent was distilled off to yield the title compound as a brown solid (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].C[C:12]1(C)[CH2:14][CH:13]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: CC1(C)CC1B(O)O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(N)cccc1C1CC1
Temperature: 25 °C
Yield: 40578.6 %

Procedure:
To a degazed solution of 2-amino-6-bromobenzonitrile (851 mmol, 168 mg), 2,2-dimethylcyclopropylboronic acid (1.106 μmol, 126 mg) (Example 270b), and Cs2CO3 (2.979 mmol, 970 mg) in DME (3.4 mL) and water (850 μL) was added tetrakis(triphenylphosphino)palladium(0) (43 μmol, 50 mg) under nitrogen and the reaction mixture microwaved for 2 hours at 160° C. The reaction mixture was cooled to room temperature and extracted with EtOAc (3×5 mL). The combined organic layers was washed once with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel (EtOAc/hexanes 10%-40%) to give the desired product (71 mg, 45%) as a waxy, yellow solid. 1H NMR (400 MHz, CDCl3) δ 0.82 (m, 1H), 0.82 (s, 3H), 0.85 (m, 1H), 1.33 (s, 3H), 1.92 (m, 1H), 4.36 (br. s, 2H), 6.47 (d, J=8 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:6]=[C:7]([C:18]#[N:19])[N:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1.C([Li])CCC.CCCCCC.[CH2:31]=[O:32]>C1COCC1>[C:13]([O:12][C:11](=[O:17])[NH:10][N:8]1[CH:9]=[C:5]([CH2:31][OH:32])[CH:6]=[C:7]1[C:18]#[N:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Reactant: C=O
Agent: C[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nn1cc(CO)cc1C#N
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Under argon, a 1 M solution of methylmagnesium bromide in THF (13.3 ml) was added over 15 min to a solution of tert-butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (3.7 g, 12.09 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883, Intermediate AAE, Step 3) in THF (37 ml) cooled to −60° C. After 30 min, a 1.6 M solution of n-butyllithium in hexane (15.1 ml, 24.2 mmol) was added over 10 min to the reaction, and the resulting mixture was stirred between −60° C. and −40° C. for 1 h. Then, paraformaldehyde (1.09 g, 36.3 mmol) was added to the reaction, and the reaction mixture was slowly warmed to rt and stirred overnight. After quenching with sat. aq. ammonium chloride solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1→1:1) afforded 2.04 g (69% of th.) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)C(OC(C)(C)C)=O)[CH2:10][C:9]=2[CH:30]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:10][C:9]=2[CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of 8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (10.07 g) in dichloromethane (100 ml) was added trifluoroacetic acid (9.47 ml), and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (7.78 g).
Reaction SMILES: O[CH:2]=[CH:3][C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:15]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5]
Reactant: CCC1CC(C)(C(=O)C=CO)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCC1CC(C)(C(=O)/C=C/Cl)C1
Reaction time: 15 h

Procedure:
A solution of 5.8 g of 1-hydroxy-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one (prepared in Example 4A) in 100 ml of benzene was stirred under an argon atmosphere and 7 ml of thionyl chloride in 10 ml of benzene was added dropwise. The resulting solution was stirred for about 15 hr. Excess solvent was removed by distillation at atmospheric pressure and the residue was then distilled in vacuo to yield 4.2 g of the title compound having the following physical characteristics:
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=O.[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[NH:40])[NH2:39])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:33][CH2:34][N:35]([C:38]2[NH:40][C:3](=[O:24])[C:4]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=3)[N:39]=2)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C(C(=O)c1ccc(C#N)c(F)c1)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)[nH]c2=O)cc1
Yield: 3.5 %

Procedure:
A mixture of 3-(4-cyano-3-fluoro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-propionic acid methyl ester (1.8 g, 5.5 mmol), (1-carbamimidoyl-piperidin-4-yl)-carbamic acid tert-butyl ester (2.6 g, 9.2 mmol), DIEA (2.4 g, 18.3 mmol) in toluene (50 mL) was refluxed overnight. The solvent was concentrated in vacuo. The residue was suspended in MeOH and the solids were filtered to give 100 mg (4%) of the title compound. [M+H] Calc'd for C28H30FN5O4, 520. Found, 520.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[N:9]([CH3:13])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19](=[O:34])[C:20](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])[C:21]([CH3:23])=O>>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]([C:20]1[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[C:11]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][N:9]([CH3:13])[C:10]=2[NH:12][C:21]=1[CH3:23])=[O:34]
Reactant: COCCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: Cn1nc(C2CCCCC2)cc1N
Product: COCCOC(=O)C1=C(C)Nc2c(c(C3CCCCC3)nn2C)C1c1ccccc1[N+](=O)[O-]

Procedure:
Starting from 3-cyclohexyl-1-methyl-5-pyrazolamine and 2-methoxyethyl-2-(2-nitrobenzyliden)acetoacetate in about equimolar proportions.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C([Li])CCC.[B:22]([O:31]C(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:23][B:22]([OH:31])[OH:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCC(c2ccc(I)cc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1CCC(c2ccc(OB(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 20.2 %

Procedure:
To a mixture of 4-(4-methoxymethylcyclohexyl)-1-iodobenzene (297 mmol) and 250 ml of THF, was added dropwise 200 ml of a solution of n-butyl lithium (corresponding to 312 mmol) in hexane at −78° C. in 3.0 hours, and stirred at the same temperature for 1.2 hours. To the solution was added dropwise 100 ml of a solution of triisopropyl borate (594 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 270 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with heptane to give a white solid of 4-(4-methoxymethylcyclohexyl) phenyl boric acid (60.1 mmol).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][CH:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][CH:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.081 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mol). The reaction mixture was stirred at room temperature for 1 hour and then quenched by phenol. After removing solvent, the residue was purified by preparative LCMS (method B) to yield the desired product. 1HNMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 4.30 (t, J=7.4 Hz, 2H), 1.86 (m, 2H), 1.41 (m, 4H), 0.93 (t, J=7.0 Hz, 3H). LCMS calculated for C11H14BrN6O (M+H): 325.0; found: 325.0, 327.0.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].[Cl:26]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)Cl>[Cl:26][C:9]1[CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]2([CH3:6])[C:4]=1[S:3][CH2:1][CH3:2])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCSC1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 100.5 %

Procedure:
A solution of 1.5 g of 17-(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4,16-trien-3-one in 70 ml of dry dichloromethane is stirred with 609 mg of N-chlorosuccinimide at room temperature under a nitrogen atmosphere for 2.5 hours. The resulting solution is diluted with 140 ml of chloroform; the chloroform solution is washed with saturated NaHCO3 solution and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.65 g of a foam. The foam is dissolved in chloroform-hexane (4:1) and chromatographed on a 60 g-silica gel column. Elution with chloroform-hexane (4:1) gives 1.2 g of a tlc-homogenous material. Crystallization from acetone-hexane gives 815 mg of an analytical specimen of the title compound, melting point 240°-241° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]#[N:6].[OH-].[Na+].C([OH:33])(C)(C)C.CO>OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]([NH2:6])=[O:33]
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Reactant: CC(C)(C)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-chloro-4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]benzonitrile (Example 29; 0.122 g), NaOH (0.063 g), 30% hydrogen peroxide (2 drops), and tert-butanol (2 mL) is stirred at 80° C. for 4 h, after which it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The solids remaining suspended in the aqueous layer are collected, washed with water, dried under reduced pressure, and combined with the solids obtained from concentration of the organic layers. The solids are taken up in dichloromethane and methanol with warming and filtered through a cotton plug to remove insolubles. The filtrate is then concentrated and the residue is crystallized from dichloromethane/hexane to give 0.0745 g of the title compound; mp 254-256° C.; MS m/z 403, 405; IR (mineral oil) 1413, 1235, 1597, 800, 1328 cm-1. 1H NMR (DMSOd6) δ2.64, 3.05, 3.69, 7.17, 7.25, 7.37, 7.55, 7.79, 7.84, 7.89, 7.96, 8.80.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([Cl:39])[CH:33]=1.C([O-])(O)=O.[Na+].ClCCl>S(Cl)(Cl)=O>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[NH:38][C:14](=[O:15])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:31]([OH:40])=[O:30]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)nc2)nc2cc(F)c(F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)nc3)nc3cc(F)c(F)cc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by heating [2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexylacetic acid (200 mg, 0.46 mmol) in 5 ml thionylchloride to 80° C. for 4 h. The solvent was evaporated and the residue taken up in dichloromethane. 4-Amino-3-chloro-benzoic acid methyl ester (85 mg, 0.46 mmol) were added and the reaction mixture stirred at rt overnight. The crude product was worked up by addition of a solution of 1 M NaHCO3 and extraction of the aqueous layer with dichloromethane. Organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was taken up in methanol (3 ml) and 1N NaOH (1 ml) added. The mixture was stirred at rt overnight, the solvent evaporated and the product isolated via preparative HPLC. MS (ES+): 560 (M+H).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:13]([NH:15][C@H:16]([C:32](O)=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:47][CH:48]([CH2:57][CH:58]([CH3:60])[CH3:59])[CH:49]([OH:56])[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:56][CH:49]([CH:48]([NH:47][C:32](=[O:33])[CH:16]([NH:15][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:57][CH:58]([CH3:60])[CH3:59])[C:50]([O:52][CH:53]([CH3:54])[CH3:55])=[O:51]
Reactant: CC(C)CC(N)C(O)C(=O)OC(C)C
Reactant: O=C(NCCCC[C@H](NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)C(CCCCNC(=O)OCc1ccccc1)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Temperature: -10 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
N-[3-(1-naphthalenyl)-2-(1-naphthalenylmethyl)-1-oxopropyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysine, 4 g (6.6 mmol), 1.58 g (6.6 mmol) of [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride, and 1.79 g (13.2 mmol) of 1-hydroxybenzotriazole are combined in 80 ml of dimethylformamide. The [2R-(2R*,3S*)]-3-amino-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester, monohydrochloride is neutralized with 1.4 ml (10.1 mmol) of triethylamine. The solution is cooled to -10° C. and 1.36 g (6.6 mmol) of dicyclohexylcarbodiimide is added with stirring. The reaction mixture is kept cold for 8 hours while stirring under nitrogen, allowed to warm to room temperature overnight, filtered, the filtrate concentrated and the residue partitioned between ethyl acetate and water. The organic layer is separated and extracted with saturated solution of sodium bicarbonate, dried (sodium sulfate), filtered and concentrated. The residue is flash chromatographed over silica gel 60 (230-400 mesh), eluted with hexane-ethyl acetate (2:3), the eluates collected, dissolved in diethyl ether, filtered and the filtrate concentrated to afford 4.01 g (77%) of the title compound as a white amorphous solid.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH:13]([OH:34])[CH2:14][N:15](CC2C=CC=CC=2)[CH:16]([CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:10]=1[NH:37][CH:38]=[O:39])C1C=CC=CC=1.[H][H]>[Pd]>[CH3:26][C@@H:16]([NH:15][CH2:14][C@H:13]([OH:34])[C:12]1[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([NH:37][CH:38]=[O:39])[CH:11]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(NC=O)c2)cc1
Agent: [Pd]
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1

Procedure:
4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (120 gms, 0.23 M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-30° C. for 3 hrs. The catalyst was removed by filtration and the clear filtrate concentrated under reduced pressure below 40° C. to yield the title compound. (63 gms, 80%).