Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=CC(S(O)(=O)=O)=CC=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.[C:30](=[O:33])([O-])[O-].[Na+].[Na+].S(O)(=O)(C1C=CC=C(N)C=1)=O>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:33][CH3:30])=[CH:4][C:3]=1[S:17]([OH:20])(=[O:18])=[O:19]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Reactant: O=C([O-])[O-]
Agent: Fc1nnnc(F)c1F
Agent: Nc1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(N)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
31.9 g of 2-amino-5-hydroxy-naphthalene-1,7-disulphonic acid are dissolved in 400 ml of water to give a neutral solution. 300 g of ice are then added, and 8.8 ml of trifluorotriazine are allowed to run in, a pH of 4.0-4.5 being maintained with 15% strength sodium carbonate solution. The mixture is subsequently stirred for 5 minutes, a neutral solution of 17.3 g of m-sulphanilic acid is then added, and a pH of 5.0-5.5 is maintained with 15% strength sodium carbonate solution. During the acylation, the temperature is allowed to rise to 15°-20°. A diazo compound obtained by the customary route by diazotisation of 20.3 g of 1-amino-4-methoxy-benzene-2-sulphonic acid is added to the resulting solution of the reaction product of the formula ##STR17## at 5°-10°, the pH simultaneously being kept at pH 7.0-7.5 by sprinkling in sodium bicarbonate. When the coupling has ended, the dyestuff of the formula ##STR18## is salted out, filtered off with suction, dried and ground. The red dyestuff powder dissolves readily in water and dyes cotton a clear scarlet (colour code number 6) by a process customary for reactive dyestuffs.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)[C:6]([F:27])=[CH:5][C:3]=1[NH2:4].[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>>[F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:12]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:13]=3[N:14]=2)[C:6]([F:27])=[CH:5][C:3]=1[NH:4][C:31]([NH:30][CH2:28][CH3:29])=[O:32]
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2cc(F)c(N)cc2F)nc2c1CCN(C)C2
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)cc1F
Yield: 11 %

Procedure:
Method as example 85 using (S)-2,5-difluoro-4-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline and ethyl isocyanate as starting material. The solvent was removed in vacuo and purified twice by flash chromatography using 0-20% DCM/MeOH as eluent yielding the title compound (6.2 mg, 0.013 mmol, 11%).
Reaction SMILES: [F:1][C:2](F)([C:6](F)(F)[C:7](F)(F)[C:8](F)(F)[C:9](F)(F)[C:10](F)(F)[C:11](F)(F)F)[C:3]([OH:5])=[O:4].[OH-].[K+:27]>>[C:3]([O-:5])(=[O:4])[CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F-:1].[K+:27]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCC(=O)[O-]
Product: [F-]

Procedure:
82.8 g of perfluorooctanoic acid (0.197 mol) are neutralized with a 20% aqueous KOH-solution to a pH of 6 and the salt mixture formed by octanoate and KF is dried for 24 hours at 100° C./1 mbar. Thereafter 70 ml of tetraglyme are added. After addition of 100 g of perfluoro-(3,6-dimethyl-1,4-dioxanyl-2-oxy)-propionic acid fluoride, the mixture is stirred for 15 hours and the product mixture is treated as in Example 1. By distillation there are obtained 102 g (62.2% of the theory, calculated on used perfluorooctanoic acid) of the compound of the formula ##STR12## having a boiling point of from 210° to 222° C., the structure of which is confirmed by the analysis and by spectroscopic data.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[O:35][CH3:36])=[N:26][N:25](COCC[Si](C)(C)C)[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[OH-].[Na+]>Cl(O)(=O)(=O)=O.CO>[CH3:1][N:2]([CH3:45])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[O:35][CH3:36])=[N:26][NH:25][C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: COc1ccc(F)cc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A solution of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone from Step 5 in 5% of perchloric acid in methanol (1 mL) was stirred for 45 minutes at room temperature. Sodium hydroxide solution (2M) was then added to the solution slowly until pH ˜8. Ethyl acetate was then used for extraction and the organic layers were combined and concentrated to dryness, which was then redissolved in methanol (1 mL) and sodium carbonate (2M, 1 mL). The mixture was stirred at room temperature for 15 hours before being diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Mass triggered reverse phase HPLC purification afforded (4-(2-(dimethylamino)ethyl)piperazin 1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (25.6 mg, 64% yield from 12) as white solids. 1H NMR (500 MHz, CD3OD) δ 2.42 (s, 6H), 2.49 (br, 2H), 2.59 (m, 4H), 2.69 (m, 2H), 3.54 (br, 2H), 3.81 (br, 2H), 3.85 (s, 3H), 7.17 (m, 2H), 7.40 (dd, J=3.0, 9.5 Hz, 1H), 7.44 (d, br, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.72 (br, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.80 (d, J=2.5 Hz, 1H). MS: m/z 503.2 (M+H+).
Reaction SMILES: BrC1([O:12][C:13]2C=[CH:17][CH:16]=[CH:15][CH:14]=2)COC(C)(C)OC1(C)C.NC1C=CC=CC=1.C1(NC2C=CC=CC=2)C=CC=CC=1.[Br:39][C:40]1[CH:52]=[CH:51][C:50]2[C:49]3[C:44](=[CH:45][C:46](Br)=[CH:47][CH:48]=3)[C:43](CC)(CC)[C:42]=2[CH:41]=1>>[Br:39][C:40]1[CH:41]=[C:42]2[C:50]([C:49]3[CH:48]=[C:47]([CH2:46][CH3:45])[C:14]([CH:13]=[O:12])=[C:15]([CH2:16][CH3:17])[C:44]=3[CH2:43]2)=[CH:51][CH:52]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC1(C)OCC(Br)(Oc2ccccc2)C(C)(C)O1
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Nc1ccccc1
Product: CCc1cc2c(c(CC)c1C=O)Cc1cc(Br)ccc1-2
Yield: 93 %

Procedure:
The convergent synthesis of AF-452-6OH (compound 9 in Scheme 1) was accomplished in two parallel sequences followed by a converging sequence: (i) a 4-step sequence to the protected 3-O-alkylated diphenylamine intermediate, (ii) a 3-step sequence to the tris(7-bromofluorene(triazine intermediate 7 and (ii) a 2-step sequence to AF-452-6OH (8). Briefly, the first sequence was started with tris-1,1,1-(hydroxymethyl)ethane, which was first protected as an acetonide derivative, i.e. 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (compound 1) in either reaction as indicated in Scheme 1, as reactions (i) or (ii). A Mitsunobu reaction of 1 with 3-bromophenol furnished the corresponding bromophenoxy-methyltrimethyl-1,3-dioxane (2) in 85% yield [Scheme 1, reaction (iii)]. The same compound could also be obtained in 59% yield from a copper-catalyzed reaction between 3-bromoiodobenzene and 1 [Scheme 1, reaction (iv)]. Compound 2 was aminated with aniline to produce the diphenylamine intermediate 3 [Scheme 1, reaction (v)]. In the second sequence, 2,7-dibromo-9,9-diethylfluorene (4) was first monoformylated to form 7-bromodiethylfluorene-2-aldehyde (5), which was then converted to the nitrile intermediate (6) in 93% yield [Scheme 1, reactions (vi) and (viii), respectively]. A less satisfactory conversion of the aldehyde intermediate 5 to the nitrile intermediate 6 via an hydroxyl-imine intermediate was also conducted [49% yield, Scheme 1, reaction (vii)]. The nitrile intermediate 6 was subsequently and catalytically trimerized in trifluoromethanesulfonic acid to afford the tribromo-1,3,5-triazine intermediate (7) in 95% yield [Scheme 1, reaction (ix)]. Covalently joining the triazine (7) component with the diphenylamine component (3) with the assistance of a Pd-catalyzed amination gave the precursor chromophore protected as an acetonide 8, [Scheme 1, reaction (x)]. Removal of the acetone protecting groups from 8 was accomplished by mixing and stirring 8 together with Dowex-50Wx2 (acid-form) resin, and the desired product, AF-452-6OH (9), was obtained in 90% yield [Scheme 1, reaction (xi)].
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]([O:55][P:56]([O:63][CH2:64][C:65]([CH3:71])([CH3:70])[CH2:66][C:67](O)=[O:68])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:54])([CH3:53])[CH3:52].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:51]([O:55][P:56]([O:63][CH2:64][C:65]([CH3:71])([CH3:70])[CH2:66][C:67]([O:29][C@H:10]([C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C@@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:68])([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CC(=O)O
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](OC(=O)CC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 68 h
Yield: 80.7 %

Procedure:
To a solution containing the compound of Example 1 (0.10 g, 0.14 mmol), the product from Example 10D (0.045 g), and 4-(dimethylamino)pyridine (0.017 g) in DMF (1.4 mL) was added EDAC (0.027 g), and the mixture was stirred at room temperature for 68 hours. Additional product from Example 10D (0.045 g) and EDAC (0.027 g) were added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the concentrate was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with ethyl acetate and ending with 5% methanol in ethyl acetate, to give the title compound (0.115 g, 81% yield).
Reaction SMILES: C(OC(=O)C[NH:11][C:12]([O:14][CH2:15]Cl)=[O:13])C1C=CC=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27]N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC(OC(Cl)C)=O.[Cl:37][C:38]1[C:39]([F:78])=[C:40]([C@@H:44]2[C@:48]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=3[F:58])([C:49]#[N:50])[C@H:47]([CH2:59][C:60]([CH3:63])([CH3:62])[CH3:61])[NH:46][C@H:45]2[C:64]([NH:66][C:67]2[CH:75]=[CH:74][C:70]([C:71]([OH:73])=[O:72])=[CH:69][C:68]=2[O:76][CH3:77])=[O:65])[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[CH2:18]([O:25][C:26]([CH2:27][CH:15]([O:72][C:71](=[O:73])[C:70]1[CH:74]=[CH:75][C:67]([NH:66][C:64]([C@H:45]2[C@H:44]([C:40]3[CH:41]=[CH:42][CH:43]=[C:38]([Cl:37])[C:39]=3[F:78])[C@:48]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=3[F:58])([C:49]#[N:50])[C@H:47]([CH2:59][C:60]([CH3:62])([CH3:63])[CH3:61])[NH:46]2)=[O:65])=[C:68]([O:76][CH3:77])[CH:69]=1)[O:14][C:12](=[O:13])[NH2:11])=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C(CNC(=O)OCCl)OCc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)OC(CC(=O)OCc2ccccc2)OC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 23, chloromethoxycarbonylamino-acetic acid benzyl ester was prepared from amino-acetic acid benzyl ester and 1-chloroethyl chloroformate (Aldrich) in the presence of pyridine in methylene chloride. It was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid and cesium carbonate in dimethylformamide to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid benzyloxycarbonylmethyl-carbamoyloxymethyl ester as a white solid. MS (ES+) m/z calcd. for C42H41Cl2F2N4O8 [(M+H)+]: 837, found: 837
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:23])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH3:23])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-methyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Yellow solid. MS (m/e): 262.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.Cl.[C]=O.[C:15]([O:18][CH:19]([CH2:24][CH2:25][S:26][CH3:27])[C:20]([O:22][CH3:23])=O)(=[O:17])[CH3:16]>O1CCCC1.C1(C)C=CC=CC=1>[C:15]([O:18][CH:19]([CH2:24][CH2:25][S:26][CH3:27])[C:20]([O:22][CH3:23])=[S:8])(=[O:17])[CH3:16]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: Cl
Agent: [C]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 17.8 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising Pd(Pφ3)4 plus 10 mole percent HCl co-catalyst was added. Toluene was included as an internal standard Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 45.25 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 21.7 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 17.8 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog. When this run was repeated without the HCl co-catalyst (run length 44 hours), the yields of the above ester and thioester were3 93 percent.and 4.48 percent, respectively.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]1([OH:10])[CH2:9][CH2:8]1>CC(O)C.O>[Br:1][CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4][Cl:3]
Reactant: OC1(CCCCl)CC1
Reactant: BrBr
Solvent: CC(C)O
Solvent: O
Product: O=C(CCBr)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (2.0 mL, 39 mmol) was added slowly to a solution of 1-(3-chloro-propyl)-cyclopropanol (5.0 g, 34 mmol) in i-PrOH (80% in water, 30 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr then diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×30 mL) and the organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude 1-bromo-6-chloro-hexan-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (7.0 g, 40 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (9.5 g, 40 mmols), potassium carbonate (5.5 g, 40 mmols) and N,N-dimethylformamide (100 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of tert-butyl 2-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.2 g, 96.6%).
Reaction SMILES: [I-].[C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Zn+])#[N:3].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16](Cl)=[O:17]>C1COCC1.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=2[C:2]#[N:3])=[O:17])[CH:19]=[CH:20][N:21]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: N#Cc1c(F)cccc1[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1C(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 2-cyano-3-fluorophenylzinc iodide (0.5 M, 31 mL, 15.5 mmol) in THF was added 2-chloro-isonicotinoyl chloride (3 g, 17.05 mmol), followed by Pd(PPh3)2Cl2 (0.33 g, 0.465 mmol). The resulting mixture was stirred at room temperature for 4 hours and diluted with ethyl acetate (80 mL) and H2O (40 mL). The organic phase was separated, washed with H2O (3×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 20-50% EtOAc in hexane to afford of the title compound (3.6 g, 88%).
Reaction SMILES: N=C=N.[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:20]=[C:21]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[CH2:22][CH2:23][C:24](O)=[O:25].C(Cl)Cl.CCO>C(Cl)Cl.CN(C=O)C>[O:25]=[C:24]([N:11]1[CH2:12][CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:23][CH2:22][C:21]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)=[O:20]
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Agent: N=C=N
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCC(=O)N1CCc2ccccc2C1c1ccccc1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
1.98 g (˜2.0 mmol) of PS carbodiimide resin were added to a solution of 209 mg (1.0 mmol) of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in a mixture of DCM and DMF (82 ml, 40:1 vv) and the mixture was shaken for 16 h at RT. Then the resin was filtered off and it was washed with DCM and MeOH. The filtrate was concentrated to small volume under vacuum. Column chromatography (DCM/EtOH 40:1) of the residue produced 287 mg (0.6 mmol, 62%) of 4-oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 467.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=12.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH3:16][N:17]([CH3:19])[CH:18]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1ccc2nccn2c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)c1ccc2nccn2c1
Yield: 74.4 %

Procedure:
In 200 l of N,N-dimethylformamide, 33.17 g of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone was stirred at 80° C. for 1 hour, together with 45.4 g of N,N-dimethylformamide dimethyl acetal. After cooling, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (eluted with chloroform-methanol=97:3) to obtain 32.46 g (74.5%) of 4-dimethylamino-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one.
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC1C(F)=C(F)C=CC=1CBr.C[O:30][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=O>C(O)C>[CH3:6][NH2:7].[CH3:6][NH:7][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=[O:30]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)c(F)c3F)cc2)C1
Agent: Fc1ccc(CBr)c(F)c1F
Solvent: CCO
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)c(F)c3F)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,3,4-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid (94% of theory) which, thereupon, by treatment with methylamine in ethanol at 50° C. yields the (RS)-5-oxo-1-[4-(2,3,4-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide. Yield: 99% of theory as a white solid; MS: m/e=379 (M+H)+.