Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.C1C2C(C[O:33][C:34](=O)[NH:35][CH2:36][CH:37]([O:47][Si](C(C)(C)C)(C)C)[C:38]([NH:40][C:41]3[S:42][CH:43]=[C:44]([CH3:46])[N:45]=3)=[O:39])C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.C(Cl)(=O)C>C1COCC1.O>[C:34]([NH:35][CH2:36][CH:37]([OH:47])[C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([CH3:46])[N:45]=1)=[O:39])(=[O:33])[CH3:2]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1csc(NC(=O)C(CNC(=O)OCC2c3ccccc3-c3ccccc32)O[Si](C)(C)C(C)(C)C)n1
Agent: [F-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Product: CC(=O)NCC(O)C(=O)Nc1nc(C)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Tetrabutylammoniumfluoride (0.28 mL, 1M in THF, 0.28 mmol) was added to a stirred solution of 9H-fluoren-9-ylmethyl (2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl)carbamate (Step 2) (0.10 g, 0.186 mmol) in THF (5 mL). The reaction mixture was kept at ambient temperature for 3 hrs before DIPEA (0.036 g, 0.28 mmol) and acetyl chloride (0.018 g, 0.22 mmol) were added. The reaction mixture was stirred for another 3 hrs at ambient temperature and water (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with a gradient consisting of 0-20% MeOH in DCM) to give the title compound as a colorless oil (0.04 g). 1H NMR (500 MHz, CD3OD) δ 6.71 (s, 1H), 4.38 (dd, 1H), 3.64 (dd, 1H), 3.48 (dd, 1H), 2.33 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:25]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (19.9 mg, 0.062 mmol) in 1,2-dichloroethane (0.5 mL) was added benzaldehyde (6.3 μL, 0.062 mmol) and stirred for 10 min at room temperature. This was followed by the addition of sodium triacetoxyborohydride (18.4 mg, 0.087 mmol) and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and was extracted with EtOAc (3×5 mL). The combined extracts were washed with brine and dried over Na2SO4. The crude product was purified by preparative thin layer chromatography eluting with 1:9 MeOH:CH2Cl2 to obtain 17.9 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.35 (br s, 1H); 8.16 (d, J=7.5 Hz, 1H); 7.86 (d, J=8.9 Hz, 1H); 7.38 (m, 2H); 7.25 (m, 5H); 6.76 (d, J=5.5 Hz, 1H); 4.16 (m, 1H); 3.5 (Abq, JAB=13.2 Hz, 2H); 2.91 (d, J=10.5 Hz, 1H); 2.76 (d, J=11.2 Hz, 1H); 1.23 (d, J=6.6 Hz, 3H). Mass spectrum 413.4 (ESI, M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:6]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:18][CH2:17]1)#[N:2].S(Cl)(Cl)(=O)=O.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:41]1[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([OH:45])=[O:44]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:6]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([N:41]2[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:42]2[C:43]([OH:45])=[O:44])(=[O:24])=[O:23])[CH2:18][CH2:17]1)#[N:2]
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)Cl)CC2)c2cc(C#N)ccc21
Reactant: O=C(O)[C@H]1CCCCN1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=S(=O)(Cl)Cl
Product: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)O)CC2)c2cc(C#N)ccc21
Yield: 86 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxamnide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonyl-indol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:13][CH2:14][C:15](OCC)=[O:16]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:15](=[O:16])[CH2:14][NH:13][C:10]2=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: O=C1CNC(=S)N1c1cc(Cl)cc(Cl)c1
Reaction time: 60 h
Yield: 82.8 %

Procedure:
3,5-Dichlorophenylisothiocyanate (5 g, 24.5 mmol) was added by portion to a suspension of the HCl salt of ethyl glycinate (3.4 g, 24.5 mmol) in a mixture of TEA (7.5 ml, 53.9 mmol) and dry DCM (40 ml) while cooling the flask in a water bath. After 60 h at RT, the solution was concentrated to dryness and partitioned between EtOAc and aqueous HCl. The organic layer was washed with water and concentrated. The obtained amorphous solid was washed with Et2O to yield 3-(3,5-dichlorophenyl)-2-thioxoimidazolidin-4-one as an orange solid (5.3 g). 1H NMR (CDCl3): 7.45 (1H, m), 7.25 (2H, m), 4.44 (2H, s).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:33])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1=[O:32])([CH3:10])([CH3:9])[CH3:8].[NH:34]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:35]([C:45](O)=[O:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>>[C:7]([O:11][C:12](=[O:33])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:45](=[O:46])[C@@H:35]([NH:34][C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C@@H:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1=[O:32])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CN1CCN[C@@H](CCCCNC(=O)OC(C)(C)C)C1=O
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2CCCCNC(=O)OC(C)(C)C)cc1

Procedure:
In substantially the same manner as in Reference Example 2, the title compound was synthesized using (S)-3-(4-t-butoxycarbonylaminobutyl)-2-oxopiperazine-1-acetic acid t-butyl ester oxalate and N-Z-Tyr(OMe)-OH.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[CH:2]1.C[Mg]Br.B(F)(F)F.[CH3:15][CH2:16]OCC.[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2([NH2:7])[CH2:16][CH2:15]2)=[CH:2]1
Reactant: N#Cc1ccoc1
Reactant: CCOCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: NC1(c2ccoc2)CC1
Reaction time: 0.25 h

Procedure:
To solution of 3-furonitrile (5 g, 53.71 mmol, 1.0 eq) in dry THF at r.t. under an argon atmosphere was added slowly titanium isopropoxide (18.9 ml, 64.4 mmol, 1.2 eq). The reaction mixture was stirred for 15 min. A solution of 1.0 Methyl magnesium bromide in THF (129 ml, 128 mmol, 2.4 eq) was added via syringe slowly to the mixture at 0° C. After addition, the reaction mixture was stirred at r.t. for 2 hour. BF3.Et2O (10.4 ml) was then added slowly to the mixture at 0° C. After completion of the addition, the reaction mixture was stirred at r.t. for 30 min. 10% NaOH solution was added slowly till the reaction mixture becomes basic and then extracted with EtOAC. The organic was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 35% EtOAC/pet ether as eluent. Yield: 2.5 g (38%). 1H NMR (400 MHz, CDCl3): δ 7.32 (m, 2H), 6.10 (s, 1H), 0.98-0.95 (m, 2H), 0.83-0.78 (m, 2H). LCMS: (ES+) m/z=123.7 (M)+
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: COc1ccc2[nH]ccc2c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2[nH]ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 4-bromo-5-methoxyindole (540 mg, 2.4 mmol) in dichloromethane (12 ml) was cooled to −40° C. under an atmosphere of nitrogen. Boron tribromide (4.8 ml of a 1M solution in dichloromethane, 4.8 mmol) was added dropwise then the mixture warmed to ambient temperature and stirred for 1 hour. The mixture was diluted with dichloromethane (5 ml) and washed with 2M aqueous hydrochloric acid (3 ml). The organic layer was separated, dried (MgSO4) and evaporated to give a dark oil. This was purified by silica column chromatography eluting with dichloromethane/ethyl acetate (8/2) to give 4-bromo-5-hydroxyindole (295 mg, 55%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]2[C:12]3([O:16]CCO3)[CH2:11][CH2:10][S:9][C:5]2=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:17][C:3]1[C:2]([C:23]([OH:25])=[O:24])=[CH:7][C:6]([CH3:8])=[C:5]2[C:4]=1[C:12](=[O:16])[CH2:11][CH2:10][S:9]2
Reactant: O=C=O
Reactant: Cc1cc(Br)c(C)c2c1SCCC21OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC2=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
46.38 g (0.15 mol) of 6-bromo-5,8-dimethylspiro[thiochromane-4,2′-[1,3]dioxolane] were dissolved in 500 ml of tetrahydrofuran and cooled to −65° C. 80 ml (0.2 mol) of 2.5 M n-butyllithium in hexane were subsequently slowly added dropwise such that the temperature did not exceed −55° C. The mixture was stirred for another 1 h, and 90 g of dry ice were then added a little at a time. The solution was subsequently allowed to warm to room temperature, 500 ml of hexane were added and the precipitate was filtered off with suction. The precipitate was taken up in 500 ml of water and made strongly acidic using conc. hydrochloric acid. The mixture was boiled under reflux for 1 h and then allowed to cool, and the precipitated product was filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:21][CH2:22]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(S(C)(=O)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc(Cl)c1O

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (24 mg, 0.061 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (23 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.89 (s, 1H), 8.54 (d, J=9.1 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 5.83-5.73 (m, 1H), 4.04 (s, 3H), 3.38 (s, 3H), 3.08 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.50-2.43 (m, 2H), 2.07-1.95 (m, 3H), 1.73-1.63 (m, 2H), 1.46-1.35 (m, 2H). ESI MS m/z 519 [M+H]+; HPLC>99% (AUC), tR=9.77 min.
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:13][NH:12][C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:30][CH2:31]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(CNC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([NH:14][C:15]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=2[Cl:27])=[O:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)=[O:37]>CN(C)C=O>[Cl:27][C:20]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=1[C:18]([NH:17][C:15](=[O:16])[NH:14][C:4]1[CH:3]=[C:2]([NH:1][C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[O:37])[CH:7]=[CH:6][C:5]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[O:28]
Reactant: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(NC(=O)Oc2ccc(Cl)cc2)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 9 %

Procedure:
100 mg (0.24 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]phenyl}acrylate (example 54 b) were reacted in 2 ml of dimethylformamide with potassium carbonate and 4-chlorophenyl chloroformate. The precipitate resulting after 4 hours was filtered off with suction. Preparative HPLC (column: Waters Xterra™MS C18, 5 μm, 30×100 mm, mobile phases: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B) resulted in 12 mg (9%) of the desired product.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(CC(C)C)N=C(C)C=1)=O.[OH-].[Li+].C(N1C(N2C[C@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)C[C@@H]2C(O)=O)=CC(C)=N1)C(C)C>>[CH2:29]([N:24]1[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]1)[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(C)C
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(C)C
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)n(CC(C)C)n1
Agent: [Li+]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(CC(C)C)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(2-isobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as colorless oil which was used in the next step without further purification. MS (ESI): m/z=460.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:17]([OH:20])[C:18]#[CH:19]>C(NC(C)C)(C)C.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.[Cu]I>[OH:20][CH2:17][CH2:18][CH2:19][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C#CCO
Reactant: CCOC(=O)C(C)(C)Oc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(CCCO)c1

Procedure:
10d (50 g, 175 mmol) is placed in the presence of 2-propynol (12 ml, 210 mmol) in 400 ml of diisopropylamine, under nitrogen. Pd(PPh3)2Cl2 (3.5 g) and CuI (500 mg) are added and the reaction medium is stirred at reflux for 5 h. The precipitate formed in the course of the reaction is filtered on celite and the reaction medium is dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 80:20). It is then placed in a solution of 250 ml of THF and 150 ml of EtOH in the presence of Pd/C under hydrogen at 6 bar. This mixture is stirred for 24 h. at ambient temperature. After filtration on celite, the reaction medium is dry concentrated and 12a is isolated in the form of a clear oil (32 g, yield=69%). TLC silica gel 60 F 254 Merck, heptane:AcOEt 80:20, Rf=0.56.
Reaction SMILES: II.[CH3:3][O:4][C:5](=[O:17])[C@H:6]([CH2:15]I)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:28].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC(N(C)C)=O.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:3][O:4][C:5](=[O:17])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH3:28]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: II
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c(C)cc(C#N)cc1C)NC(=O)OC(C)(C)C
Temperature: 23 °C

Procedure:
A 50 mL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer, heating mantel, and thermocouple was charged under nitrogen dry DMAc (2 mL), I2 (38.1 mg, 0.15 mmol) and zinc powder activated (washed with 10% HCl, rinsed with H2O and acetone) (393 mg, 6 mmol). The resulting mixture was stirred at 23° C. until the red color of I2 disappeared (2 minutes). A solution of Boc-β-iodo-L-alanine methyl ester (1 g, 3 mmol) in DMAc (2 mL) was added slowly, (temperature change from 21° C. to 29° C.) and the resulting mixture was stirred at 80° C. for 0.5-1 hour, then co cooled to 35° C. To the resulting mixture were added, successively, 4-bromo-3,5-dimethyl-benzonitrile (315 mg, 1.5 mmol) in DMAc (6 mL), P(o-tol)3 (36.5 mg, 0.12 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol). The resulting mixture was heated to 70° C., with stirring for 1 hour, then cooled to ambient temperature. The resulting mixture was diluted with EtOAc (15 mL) and filtered with STAND SUPER-CEL 815520. The EtOAc solution was quenched with 1 N HCl (40 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with H2O (2×50 mL) and then with 50% brine, dried over Na2SO4, filtered and evaporated to dryness in vacuo to yield a brown solid. The title compound was crystallized from EtOAc (5 mL) and heptane (40 mL) to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])C2)(=[O:18])[CH3:17].N1CCCCC1>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]2[C:27]3[C:26](=[CH:22][CH:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[CH:28]=3)[NH:25][C:24]2=[O:29])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=Cc1cccn1-c1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)C(c1cccn1-c1cc(Cl)cc(Cl)c1)C(=O)N2
Yield: 40 %

Procedure:
2.68 g (11 mmol) of 3-[N-(3,5-dichlorophenyl)pyrrole-2-carboxaldehyde are added to a solution of 2.12 g (11 mmol) of 5-acetylaminoindolin-2-one in 220 ml of ethanol containing 0.5 ml of piperidine. The reaction medium is heated under reflux for 3 hours. After cooling, the precipitate formed is drained, washed with twice 5 ml of ice-cold ethanol and dried under reduced pressure. 1.81 g (40%) of 3-[N-(3,5-dichlorophenyl)pyrrol-2-yl]-5-acetylaminoindolin-2-one are thus obtained in the form of a yellow solid whose characteristic is the following: melting point=267° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[N:7]2
Reactant: Clc1ccc2nccn2n1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc3nccn3n2)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), methyl 3-hydroxybenzoate (1978 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=90/10→20/80). The objective fraction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100) and precipitated from diisopropyl ether to give the title compound (1722 mg, 6.4 mmol, yield 64%) as a white solid.