Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:19][CH2:20][CH:21]([OH:44])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[N:38]([CH3:42])[CH:37]=[N:36][C:35]=2[N:34]([CH3:43])[C:32]1=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH2:11]([O:19][CH2:20][C:21](=[O:44])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[N:38]([CH3:42])[CH:37]=[N:36][C:35]=2[N:34]([CH3:43])[C:32]1=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOCC(O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOCC(=O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.03 h
Yield: 43 %

Procedure:
Dimethylsulfoxide (0.18 ml, 2.5 mmol) was added slowly by syringe to a stirring solution of oxalyl chloride (0.11 ml, 1.3 mmol) in dichloromethane (5 ml) at -780° C. After 2 minutes, a solution of 1-(11-octyloxy-10-hydroxyundecyl)-3,7-dimethylxanthine, prepared above (0.5 g, 1.0 mmol) in dichloromethane (15 ml) was added dropwise over 5 minutes. Stirring was continued at -78° C. for 45 minutes . Triethylamine (0.72 ml, 5.2 mmol) was added and the cold bath subsequently removed. After 20 minutes, water (25 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (20 ml) and saturated aqueous salt solution (20 ml), and then dried over sodium sulfate. The solvents were evaporated under vacuum to give a thick oil which was purified by chromatography (silica/dichloromethane-5% methanol) to obtain 205 mg of 1-(11-octyloxy-10-oxoundecyl)-3,7-dimethylxanthine (43% yield).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: CC(C)Br
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Br)ccc1OC(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
2-Bromopropane (3.39 mL, 36.2 mmol) was added to a suspension of 4-bromo-2-methoxy-phenol (5 g, 24.1 mmol), K2CO3 (6.67 g, 48.3 mmol) and DMSO (71 mL) at room temperature. The heterogeneous mixture was stirred at 55° C. for 2 hours, then cooled to room temperature and diluted with water. The reaction mixture was extracted with Et2O and the extract was washed successively with 10% aq. NaOH solution, water, then brine solution. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-1-isopropoxy-2-methoxy-benzene (5.83 g, 94%) as a pale yellow oil. ESI-MS m/z calc. 244.0. found 245.0 (M+1)+; Retention time: 1.93 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03-6.95 (m, 2H), 6.76 (dd, J=7.7, 1.1 Hz, 1H), 4.47 (dt, J=12.2, 6.1 Hz, 1H), 3.84 (s, 3H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:35])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)C(=N)N(C)C.Cl>ClCCl>[CH3:35][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]2[C:9]=1[CH:10]=[C:11]([CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=3)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:15])[F:16])[NH:1]2
Reactant: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC3(C)CCOc4ccc(S(C)(=O)=O)cc43)C(F)(F)F)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 7.9 %

Procedure:
To a chilled (0° C.) solution of 130 mg (0.25 mmol) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile in 5 mL of dichloromethane was added 105 μL (0.74 mmol) of trifluoroacetic anhydride. After 15 minutes, the reaction was concentrated in vacuo and the residue was diluted with diethyl ether and concentrated in vacuo, three times. The resulting oil was dissolved in 1 mL of DMSO and then 0.09 mL (0.74 mmol) of tetramethylguanidine was added and the mixture was warmed at 140° C. in a microwave oven. After 10 minutes, the mixture was cooled, poured onto crushed ice with 1N aqueous HCl and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparatory TLC (silica gel, 1:1 ethyl acetate-hexanes) to afford first 35 mg (27%) of the title compound as a single diastereomer (M−1=505) and second 10 mg (8%) of the title compound as the opposite diastereomer (M−1=505).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][N:5]2[CH:12]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[Cl:15][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:12]=[C:2]([CH3:1])[N:3]=2)[CH:6]=1
Reactant: Cc1cn2cc(CO)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn2cc(CCl)ccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.80 g of the 2-methylimidazo[1,2-a]pyridine-6-methanol prepared in the Preparative Example 16 was dissolved in 90 ml of chloroform, followed by the dropwise addition of 6.1 ml of thionyl chloride under stirring at room temperature. After 2 hours, the solvent was distilled off. Crude 6-chloromethyl-2-methylimidazo-[1,2-a]pyridine hydrochloride was obtained as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40]CO)[CH2:36][CH2:35]1.C(=O)([O-])[O-:44].[K+].[K+].O>CN(C)C=O>[OH:44][CH2:40][CH:37]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=4[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:32][CH3:33])[CH2:39][CH2:38]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: O=C([O-])[O-]
Reactant: OCCC1CCNCC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (62 mg), 4-piperidine ethanol (25 mg), and potassium carbonate (100 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (55 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:26]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
The mixture of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one (100 mg, 0.266 mmol), benzoyl chloride (37 mg, 0.266 mmol) and DIPEA (34 mg, 0.266 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. Then the mixture was concentrated and the residue was purified with preparative HPLC to give 29 mg of rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light orange solid. MS m/z 480 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:10]2[N:11]=[C:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][N:15]=[C:14]([CH3:24])[N:13]3[CH:25]=2)=[N:6][CH:5]=[N:4]1)[CH3:2].[Br:26]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:26][C:25]1[N:13]2[C:14]([CH3:24])=[N:15][N:16]=[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:11][C:10]=1[O:9][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][N:6]=1
Reactant: BrBr
Reactant: CCn1ncnc1COc1cn2c(C)nnc(-c3ccccc3)c2n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCn1ncnc1COc1nc2c(-c3ccccc3)nnc(C)n2c1Br
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-methyl-8-phenylimidazo[1,2-d][1,2,4]triazine (205 mg, 0.61 mmol) in a mixture of carbon tetrachloride (100 ml) and chloroform (50 ml) was added bromine (34.2 μl, 0.67 mmol) dropwise. The mixture was stirred for 1 h, the solvent removed in vacuo and the residue recrystallised from a mixture of diethyl ether and methanol to give the title compound (160 mg). δH (400 MHz; d6-DMSO) 1.35 (3H, t, J 7.2), 3.15 (3H, d, J 6.6), 4.31 (2H, q, J 7.2), 5.72 (2H, s), 7.58 (3H, m), 7.98 (1H, s), 8.42 (2H, m); m/z (ES+) 414/416 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 4-Bromo-2-iodophenol [207115-22-8] (0.9 g, 3.0 mmol), 4-Methoxyphenylacetylene (0.43 g, 3.3 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.4 g, 45%): Mp=192–194° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=9.1 Hz), 7.66 (s, 1 H), 7.37–7.32 (m, 2 H), 6.98 (d, 2 H, J=9.1 Hz), 6.82 (d, 1 H, J=0.8 Hz), 3.87 (s, 3 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10]C(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2.[C:27]([CH2:29]C(O)=O)#[N:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>O1CCOCC1.Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH2:29][C:27]#[N:28])[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1c1nnn2cnc3[nH]ccc3c12
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC1CCN(C(=O)CC#N)CC1c1nnn2cnc3[nH]ccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
tert-Butyl 4-methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (5.6 mg, 0.016 mmol) in 4 M hydrogen chloride-1,4-dioxane solution (1.0 mL) was stirred under cooling with ice for 1 hour and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and mixed with 2-cyanoacetic acid (2.7 mg, 0.0314 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (11.9 mg, 0.0314 mmol) and then with N,N-diisopylethylamine (0.0082 mL, 0.0471 mmol) and stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: chloroform/methanol=15/1 (v/v)) and further purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound as a pale yellow solid (0.62 mg, yield 12%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[N:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[OH-].[K+]>CO>[Br:13][C:14]1[CH:15]=[C:16]2[C:17]([CH:4]([C:3]3[C:6]([O:11][CH3:12])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=3[Cl:1])[OH:5])=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: COc1ccc(F)c(Cl)c1C=O
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(Cl)c1C(O)c1c[nH]c2ncc(Br)cc12

Procedure:
A solution of 2-chloro-3-fluoro-6-methoxybenzaldehyde (10.55 g, 55.82 mmol), 5-bromo-7-azaindole (10.0 g, 50.76 mmol) and KOH (4.0 g, 71 mmol) in methanol (200 mL) was stirred at ambient temperature for 12 h. The reaction mixture was quenched with water and the crystallizing solid was filtered and dried to give the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): □ δ=3.71 (s, 3H), 5.69 (d, 1H, J=6.3 Hz), 6.55 (d, 1H, J=4.5 Hz), 7.07 (dd, 1H, J=4.5, 4.2 Hz), 7.19 (s, 1H), 7.32 (t, J=8.0 Hz), 8.30 (s, 1H), 9.60 (s, 1H), 11.38 (s, br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][C@H:9](O)[C:8]2=[O:15])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10]/[C:9](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:8]2=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Reactant: CC1CN(Cc2ccc(F)cc2)C(=O)[C@@H](O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C3\O[C@@H](C)CN(Cc4ccc(F)cc4)C3=O)cc2F)cn1

Procedure:
9.06 mg of the title compound was obtained from (S)-4-(4-fluorobenzyl)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 5.
Reaction SMILES: [O:1]=[C:2]1[CH:23]=[CH:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([NH2:16])=[O:15])[CH3:13])=[CH:3]1.[O:26]=[C:27]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[C:29]([CH2:30][CH2:31][C@@H:32]3[C@@H:45]2[CH2:44][CH2:43][C@@:42]2([CH3:50])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[CH:37]([C:39]([NH2:41])=[O:40])[CH3:38])=[CH:28]1>>[O:1]=[C:2]1[CH:23]=[CH:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C:11]2=[C:12]([C:14]([NH2:16])=[O:15])[CH3:13])=[CH:3]1.[O:26]=[C:27]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[C:29]([CH2:30][CH2:31][C@@H:32]3[C@@H:45]2[CH2:44][CH2:43][C@@:42]2([CH3:50])[C@H:33]3[CH2:34][CH2:35][C:36]2=[C:37]([C:39]([NH2:41])=[O:40])[CH3:38])=[CH:28]1
Reactant: CC(C(N)=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C(N)=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C(N)=O)=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C(N)=O)=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The present invention utilizes as a starting material (A) 3-oxo-pregna-1,4-diene-20-carboxylic acid amide; (B) 3oxo-pregn-4-ene-20-carboxylic acid amide; (C) 3-oxo-pregna-1,4,17(20)-triene-20-carboxylic acid amide, and (D) 3-oxo-pregna-4,17(20)-diene-20-carboxylic acid amide and mixtures thereof to obtain the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[N+]([O-])([O-])=[O:12].[Ag+:15].[Na].S(C1[C:29]2[N:28]=NN[C:25]=2[CH:24]=[CH:23]C=1)(O)(=O)=O>>[Ag:15].[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[CH2:10]=[CH:2][N:28]1[C:29](=[O:12])[CH2:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)(O)c1cccc2[nH]nnc12
Reactant: [Ag+]
Agent: Cc1ccc2[nH]nnc2c1
Agent: [Na]
Product: C=CN1CCCC1=O
Product: [Ag]

Procedure:
28.8 g of 5-methylbenzotriazole silver salt obtained by reaction of 5-methylbenzotriazole and silver nitrate in water-alcohol mixed solvent, 16.0 g of poly (N-vinyl pyrrolidone) and 1.33 g or 4-sulfobenzotriazole sodium salt were dispersed with alumina ball mill. This solution was arranged to have pH of 5.5 and quantity of 200 ml.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OC)=[O:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH:19]([CH3:20])[CH3:21])[C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.5 ml (92.75 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.5 g (26.5 mmol) of the compound from Example 19 in 200 ml of absolute tetrahydrofuran at 0° C. and the mixture is stirred for 30 minutes at room temperature. After cooling again to 0° C., 200 ml of water are cautiously added dropwise and the mixture is extracted three times using 150 ml of ethyl acetate each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, φ4.5 cm, using ethyl acetate/petroleum ether 2:8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:8].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C:30]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([O:20][CH3:21])[CH:11]=1)=[O:8]
Reactant: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(C(F)(F)F)c1
Reactant: O=C(Cl)N1CCOCC1
Product: COc1cc(NC(=O)c2cc(Br)ccc2OC(=O)N2CCOCC2)cc(C(F)(F)F)c1
Yield: 85.8 %

Procedure:
Using 5-bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=1[C:24]#[N:25].[Cl:26]C1C=C(CC(O)=O)C=C(O)C=1>>[Cl:26][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=2[C:24]#[N:25])[CH:2]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 12 step (ii) and the product of example 18 step (iv).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:7]([CH2:10][C:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:7]([CH2:10][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 91.3 %

Procedure:
A mixture of diethyl [2-n-butyl-1-{(2-chloro-phenyl)methyl}-1H-imidazol-5-yl]methyl-2-benzylmalonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL) and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 118-120° C. (from acetone/diethyl ether as the hydrochloride salt).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([F:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.CN([CH:36]=[O:37])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:36]([NH:30][CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:31])([F:32])[F:20])[CH:23]=2)=[O:37])=[C:7]([F:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(C(=O)NCCc2cccc(C(F)(F)F)c2)c(F)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
880 mg (2.93 mmol) of trifluoro-methanesulfonic acid 4-tert-butyl-2-fluoro-phenyl ester and 1.13 g (5.86 mmol) of 2-(3-trifluoromethyl-phenyl) ethyl amine were dissolved in 15 ml DMF. Under argon at rt 19.7 mg (0.0.88 mmol) of palladium acetate and 36.2 mg (0.088 mmol) of dppp were added. The reaction mixture was evacuated and charged with carbon monoxide gas three times. The reaction mixture was heated to 80° C. under a carbon monoxide atmosphere for 1 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with 1N aqueous HCl solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (60 g silica gel; heptane/EtOAc 7:3) to yield 676 mg (63%) of 4-tert-butyl-2-fluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a yellow viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 8.28 (t, 1H), 7.60-7.55 (m, 4H), 7.47 (t, 1H), 7.28-7.22 (m, 2H), 3.51 (q, 2H), 2.94 (t, 2H), 1.27 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:16]>C(OC(C)C)(C)C.C(Cl)(Cl)Cl.O>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Br:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)OC(C)C
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
To a solution of 4-phenylbenzyl alcohol (1.00 g, 5.43 mmol) in a mixture of diisopropyl ether (10 mL) and chloroform (20 mL) was added phosphorus tribromide (0.98 g, 3.62 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol-hexane to provide 1.00 g of the title compound. Yield 75%.