Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.C(N(CC)C(C)C)(C)C.[C:42]([C:46]1[CH:47]=[C:48]([NH:74][S:75]([CH3:78])(=[O:77])=[O:76])[C:49]([O:72][CH3:73])=[C:50]([NH:52][C:53]([C:55]2[N:56]([CH3:71])[C:57]3[C:62]([CH:63]=2)=[CH:61][CH:60]=[CH:59][C:58]=3[CH2:64][N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[O:54])[CH:51]=1)([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O.C(OCC)(=O)C.O>[C:42]([C:46]1[CH:47]=[C:48]([NH:74][S:75]([CH3:78])(=[O:77])=[O:76])[C:49]([O:72][CH3:73])=[C:50]([NH:52][C:53]([C:55]2[N:56]([CH3:71])[C:57]3[C:62]([CH:63]=2)=[CH:61][CH:60]=[CH:59][C:58]=3[CH2:64][N:65]2[CH2:66][CH2:67][N:68]([C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH2:69][CH2:70]2)=[O:54])[CH:51]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CCN(C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
61 mg 1-methyl-piperidine-4-carboxylic acid are dissolved in 1 ml N,N-dimethylformamide and combined with 137 mg O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) and 138 μl N,N-diisopropyl-ethylamine (DIEA). The mixture is stirred for 20 minutes, then 150 mg 1-methyl-7-piperazin-1-ylmethyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are added and the mixture is stirred for 12 hours. Then it is divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried on magnesium sulphate. Then the solvents are eliminated in vacuo and the residue is chromatographed on silica gel with dichloromethane/(methanol/ammonia 9:1) 99:1 to 90:10.
Reaction SMILES: BrC1C=CC=CC=1CN1[C:13]2[C:8](=[N:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)C=C1.C[O-].[Na+].C[N:24]([CH3:27])[CH:25]=O>CO.[Cu]Br>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[CH:13]=[CH:8][NH:9][C:27]2=[N:24][CH:25]=1
Reactant: COc1ccc2c(ccn2Cc2ccccc2Br)n1
Reactant: CN(C)C=O
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2[nH]ccc2c1

Procedure:
Under an argon atmosphere and in an anhydrous medium, 1 g (5.07 mmol) of the compound obtained in Step C is dissolved in a mixture of 25 ml of N,N-dimethylformamide and 22 ml of methanol; 6.86 g (126.75 mmol) of sodium methanolate and 1.43 g (10.30 mmol) of copper (I) bromide are added at room temperature. The mixture is heated at reflux for 3 hours. After removal of the solvents by evaporation, the residue is taken up in water and ethyl acetate and then filtered over Celite. The organic phase is washed with water, dried over magnesium sulphate and evaporated to yield a solid, which is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3). The title compound is obtained in the form of a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].ClCCl.CO>ClCCl.C(OCC)(=O)C.O>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]1[C:18]([O:20][CH3:21])=[O:19])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCOS(C)(=O)=O

Procedure:
A mixture of 1-tert-butyl 3-methyl 4-(3-hydroxypropyl)piperidine-1,3-dicarboxylate (Intermediate 133, 460 mg, 1.53 mmol) in dry dichloromethane (5 mL) and triethyl amine (0.3 mL, 2.14 mmol) was treated at 0° C. with a solution of methanesulfonyl chloride (0.14 mL, 1.83 mmol) in dichloromethane (5 mL). After 2 hours minutes the reaction was complete by TLC (dichloromethane:methanol 10:1). The reaction was diluted with ethyl acetate and water. The layers were separated. The organic layer was washed with 0.1N HCl, water, saturated sodium bicarbonate, dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[CH2:11][C:12](=[O:34])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:33])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1>CC(O)C.C1(C)C=CC=CC=1>[CH2:7]([S:8][CH2:11][C:12](=[O:34])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:33])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSCc4ccccc4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
Toluene-α-thiol (1.0 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of propan-2-ol (25 ml.) and toluene (30 ml.). 21-Bromo-3α-hydroxy-5α-pregnane-11,20 -dione (0.7 g.) was then added and the mixture was gently refluxed for 2 hr. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was purified by preparative t.l.c. (CHCl3) to give title compound (0.4 g.) as a white foam, [α]D + 89° (c 1.1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Agent: Br
Product: O=C(O)C1CCc2cc(O)ccc21

Procedure:
By demethylation of 2,3-dihydro-5-methoxy-1H-inden-1-carboxylic acid (IV) with hydrobromic acid at a temperature ranging from 130° C. to boiling temperature of the mixture, 2,3-dihydro-5-hydroxy-1H-inden-1-carboxylic acid (V) was obtained. This acid, by reaction with an aliphatic alcohol in the presence of a sulphonic acid as a catalyzer, led to the corresponding ester. A preferred aliphatic alcohol is methanol. p-Toluensulphonic acid is preferably used as a catalyzer in this esterification. It is convenient that this esterification be carried out at boiling temperature of the mixture. Thus, methyl 2,3-dihydro-5-hydroxy-1H-inden-1-carboxylate (VI) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[C:32]([Br:33])=[CH:31][C:30]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[CH:29]=[C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:31]=[C:32]([Br:33])[C:16]2=[N:15][C:14]=1[C:12]1[O:13][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:10][N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNC(=O)c1nc2c(Br)cc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Reaction time: 3 h
Yield: 18.4 %

Procedure:
To a solution of the product of example 2 (140 mg, 0.23 mmol) in acetonitrile (2 ml), carbon tetrachloride (213 mg, 1.383 mmol), triethylamine (117 mg, 1.1584 mmol) and triphenylphosphine (302 mg, 1.151 mmol) were added successively at room temperature. The mixture was stirred for 3 hours. The product was purified by column chromatography (CH2Cl2/MeOH=150/1) to give the titled compound (25 mg, 20% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12]C(Cl)=C(Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1C=C[S:23]C=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][S:23][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1ccsc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccsc1
Yield: 52 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-3-yl)propan-2-one (6.53 g, 37.4 mmol) with acetic acid (4.3 mL, 4.5 g, 75 mmol) and triethylamine (10.4 mL, 7.57 g, 74.8 mmol). Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product, a golden-yellow oil (3.85 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.77 (s, 2H) 4.70 (s, 2H) 6.98 (dd, J=4.8, 1.3 Hz, 1H) 7.14 (dd, J=1.8, 1.0 Hz, 1H) 7.32 (dd, J=4.9, 2.9 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>CO>[NH2:14][C@@H:10]([CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](C/C=C/c1ccccc1)C(=O)O
Solvent: CO
Product: N[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and the reaction vessel was flushed with nitrogen. Catalytic amount of palladium (10% on carbon) was added and the reaction vessel was placed under a hydrogen atmosphere. The mixture was stirred for 2 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-amino-5-phenyl-pentanoic acid 2 (51 mg, quant.) as a white powder: 1H-NMR (400 MHz, CD3OD) δ=7.42–7.25 (m, 5H), 3.71 (t, J=6.0, 1H), 2.69 (t, J=6.4, 2H), 1.85 (m, 2H), 1.70 (m, 2H). MS calcd. for C11H16NO2 (M+H+) 194.12. found 194.4. Step B: (S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.83–7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01–1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16. found 312.4. Step C: (S)-2-(3-Methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 0.07 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{1-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-4-phenyl-butyl}-3-methyl-benzamide 4 (18 mg, 0.04 mmol, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.56–7.48 (m, 2H), 7.36–7.16 (m, 7H), 6.96–6.87 (m, 4H), 4.48 (dd, J=6.2, J=13.7, 1H), 3.82 (s, 3H), 3.78–3.64 (m, 2H), 3.58–3.50 (m, 2H), 2.71–2.64 (m, 2H), 2.35 (s, 3H), 2.06–1.70 (m, 4H). MS calcd. for C28H34N3O3 (M+H+) 460.26. found 460.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(Cl)c1
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: -20 °C

Procedure:
Fuming nitric acid (150 mL) was slowly added, at −50° C., over a period of 50 minutes to N-(3-chloro-phenyl)-acetamide (45 g). The reaction mixture was allowed to warm up to −20° C. and then was poured into ice-water. The solid formed was collected by filtration, washed with water, and dried under reduced pressure. The residue was washed with dichloromethane and dried under reduced pressure to afford 14 g of N-(3-chloro-4-nitro-phenyl)-acetamide as a light pink solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1[C@@:19]2([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=1)[CH2:21][CH2:20]2.S(Cl)([Cl:30])=O>C(Cl)Cl.CN(C=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:30])=[CH:12][C:11]=2[C:18]2[C@@:19]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[C:2]([F:1])=[CH:7][CH:6]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of 66.15F (0.035 g, 0.10 mmol) in DCM (2.00 mL) and DMF (0.01 mL) at 0° C. was added thionyl chloride (0.01 g, 0.10 mmol). The reaction was then stirred at room temperature for 2 hours and was then concentrated in vacuo. The resulting product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.15G as a colorless oil (0.035 g, 95% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH2:17]([O:19][CH:20]([O:22][C@@H:23]1[C@@:53]2([CH3:54])[C:27](=[CH:28][CH2:29][C@@H:30]3[C@@H:52]2[CH2:51][CH2:50][C@@:49]2([CH3:55])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[C@H:35]([CH3:48])[CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][C@@H:25]([O:56][CH:57]([O:59][CH2:60][CH3:61])[CH3:58])[CH2:24]1)[CH3:21])[CH3:18]>O1CCOCC1.CCCCCC>[CH2:17]([O:19][CH:20]([O:22][C@@H:23]1[C@@:53]2([CH3:54])[C:27](=[CH:28][CH2:29][C@@H:30]3[C@@H:52]2[CH2:51][CH2:50][C@@:49]2([CH3:55])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[C@H:35]([CH3:36])[CH2:48][C:9]#[C:8][C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])([CH3:11])[CH3:10])[CH2:26][C@@H:25]([O:56][CH:57]([O:59][CH2:60][CH3:61])[CH3:58])[CH2:24]1)[CH3:21])[CH3:18]
Reactant: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Reactant: C#CC(C)(C)OC(C)OCC
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC#CC(C)(C)OC(C)OCC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.6 %

Procedure:
A stirred solution, cooled to 9° C., of 46.8 g (0.3 mol) of 3-(1-ethoxyethoxy)-3-methyl-but-1-yne in 1.0 liters of dioxane was treated dropwise under argon with 150 ml (0.3 mol) of 2M n-butyl lithium in hexane. The solution was stirred at 7°-9° C. for 2 hours and at room temperature for 2 hours. Thereafter, there was added to the mixture a solution of 67.0 g of (20S)-1α,3β-bis(1-ethoxyethoxy)-20-methyl-21-(p-toluenesulphonyloxy)-pregn-5-ene in 0.4 liters of dioxane and, while stirring, solvent was distilled off until the internal temperature was 93° C. The mixture was then stirred at 100° C. under argon for 64 hours. After cooling, carbon dioxide was conducted into the mixture. The mixture was poured into ice water, and the emulsion was extracted with ether. The extracts were washed with saturated sodium chloride solution, dried and evaporated. There were obtained 73.6 g of crude 1α,3β,25-tris(1-ethoxyethoxy)-cholest-5-en-23-yne.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]2[CH:7]=[CH:8][N:9]=[C:3]12.[H-].[Na+].Br[CH2:13][CH2:14][Cl:15]>CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:2]1[CH:6]=[CH:5][N:4]2[CH:7]=[CH:8][N:9]=[C:3]12
Reactant: ClCCBr
Reactant: c1cn2cc[nH]c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCn1ccn2ccnc12
Yield: 37.8 %

Procedure:
Under an argon atmosphere, to a solution of 1H-imidazo[1,2-a]imidazole.hydrochloride (85 mg) in DMF (3 mL) was added 60% sodium hydride (52.1 mg), and the mixture was stirred under ice-cooling for 1 hr. Then, a solution of 1-bromo-2-chloroethane (170 mg) in DMF (0.5 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (38 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.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.O1CCOCC1>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 120 °C
Yield: 53.6 %

Procedure:
The mixture of tert-butyl 3-bromo-5-nitro-1H-indole-1-carboxylate (341.2 mg, 1.0 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (309.2 mg, 1.0 eq), (PPh3)4Pd (O) (231.1 mg, 0.2 eq), Na2CO3 (2M, 1.5 mL, 3.0 eq) and dioxane (10 mL) was degassed and heated at 120° C. in a microwave-oven synthesizer for 2 h. The mixture was cooled to room temperature and filtered through a celite pad to remove Na2CO3 and catalyst. EtOAc was used to wash the celite pad. The solvent was removed and the crude was purified by silica gel with chromatography (0%˜20% MeOH/DCM) to obtain the desired product tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (184.1 mg, isolated yield 54%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:22][C:21]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:19]([C:18]([F:17])([F:30])[F:31])[CH:20]=2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 23.8 %

Procedure:
Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:9](=[O:11])[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])[CH3:20]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To 2-(2-fluoro-4-biphenylyl)-propionic acid (30.0 g, 0.123 mol) in ethanol (300 ml) was added conc. sulfonic acid (3.0 g). After the addition, the mixture was stirring at 50° C. for 5 h, then concentrated and extracted with benzene. The benzene extracts were washed with aqueous sodium hydrogen carbonate solution then with water, and dried over. The extracts were evaporated under reduced pressure to afford ethyl-2-(2-fluoro-4-biphenylyl)propionate (33.6 g, 0.123 mol) as oily residue.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:18])[CH:13]=[CH:14][C:15]=3[CH3:17])[C:10](O)([C:19]3[C:20]([OH:28])=[CH:21][C:22]4[O:26][CH2:25][CH2:24][C:23]=4[CH:27]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:18])[CH:13]=[CH:14][C:15]=3[CH3:17])[CH:10]([C:19]3[C:20]([OH:28])=[CH:21][C:22]4[O:26][CH2:25][CH2:24][C:23]=4[CH:27]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(F)c2c1N(C(c1ccccc1)c1ccccc1)C(=O)C2(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: Cc1ccc(F)c2c1N(C(c1ccccc1)c1ccccc1)C(=O)C2c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-4-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-one was obtained (61%) as a colorless solid: MS (ES+) m/z 465.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:25])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCC4=O)nn3C)nc12
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4=O)nn3C)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
A mixture of (E)-1-(5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-1-methyl-1H-1,2,4-triazol-3-yl)pyrrolidin-2-one (24 mg, 70.9 μmol, Eq: 1.00) and palladium on carbon 10% (7.5 mg, 7.1 μmol, Eq: 0.1) in methanol (15 ml) was stirred for 5 hours at 25° C. under hydrogen atmosphere. Additional catalyst (0.1 eq) was added and hydrogenation continued for another 6 hours until HPLC shows complete conversion. The catalyst was filtered off, the filtrate was evaporated affording 1-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-pyrrolidin-2-one (24 mg, 99.4%) as a colorless oil. MS: m/z=341.6 (M+H+)
Reaction SMILES: [CH3:1][C:2](/[CH:9]=[CH:10]/[CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH-].[K+].[BH4-].[Na+].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH2:13][CH:12]([CH3:19])[CH2:11]/[CH:10]=[CH:9]/[C:2]([CH3:1])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:25]
Reactant: CCO
Reactant: CCOC(=O)C=C(C)/C=C/CC(C)CCC=C(C)C
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)C=C(C)/C=C/CC(C)CCCC(C)(C)OCC
Reaction time: 2 h

Procedure:
To a solution of 2 g. of trans ethyl 3,7,11-trimethyldodeca-2,4,10-trienoate in 20 ml. of ethanol, cooled to 0° in an ice bath, is added a suspension of 2.32 g. of mercuric acetate in 50 ml. of ethanol over 15 minutes. The reaction mixture is stirred for two hours and then, with cooling, 1.22 g. of potassium hydroxide in 20 ml. of ethanol is added. Then 0.139 g. of sodium borohydride is added in small portions and stirring continued for 30 minutes. The solution is decanted, then concentrated to half volume, diluted with 100 ml. of water and extracted with ether (3 × 50). The ethereal phase is washed with water, dried over magnesium sulfate and the crude product chromatographed on silica using hexane:ether to yield trans ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate.