Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:20])([F:19])[F:18])=[C:13]([CH:16]=1)[C:14]#[N:15].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:18])([F:19])[F:20])=[C:13]([C:14]#[N:15])[CH:16]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1cc(N)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Triethylamine (1.09 g, 10.8 mmol) was added to a stirred solution of 5-amino-2-(trifluoromethyl)benzonitrile (Intermediate 37, 1.0 g, 5.37 mmol) in DCM (40 mL), at 0° C., and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (1.10 g, 8.06 mmol) was added at 0° C. and the mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with DCM and washed with ice water, and saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/pet.ether to give the title compound (1.1 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9](F)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([OH:38])[CH:27]=[N:28][C:29]=1[O:30][CH2:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34].COC(C)(C)C>CS(C)=O>[Cl:7][C:8]1[C:9]([O:38][C:26]2[CH:27]=[N:28][C:29]([O:30][CH2:31][C:32]([F:36])([F:37])[CH:33]([F:35])[F:34])=[C:24]([Cl:23])[CH:25]=2)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: Oc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Potassium carbonate (3.02 g, 21.85 mmol) was added portionwise to a suspension of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 2.26 g, 9.09 mmol), 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-ol (Preparation 73, 2.25 g, 8.67 mmol) in DMSO (13.5 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. tert-butyl methyl ether (50.0 mL) was added and the mixture was washed with water (3×50.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was suspended with heptane (20.0 mL) and concentrated in vacuo. The resulting solid was suspended in heptane (20.0 mL) and heated to 90° C. until full dissolution. The mixture was cooled with stirring and the residual solid collected by filtration. The filtrate was concentrated in vacuo and the resulting solid was suspended in heptane (10.0 mL) and heated to 90° C. until dissolution. The mixture was again cooled with stirring and the residual solid collected by filtration. The two crops were combined to yield the title compound as a white solid (2.58 g, 5.29 mmol, 61%):
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.Br[C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][C:37]([CH2:41][C:42]1[N:46]3[N:47]=[C:48]([CH3:51])[CH:49]=[CH:50][C:45]3=[N:44][N:43]=1)=[CH:36][CH:35]=2>O1CCCC1.[Cl-].[Cl-].[Zn+2]>[NH:3]1[CH:2]=[C:6]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][C:37]([CH2:41][C:42]2[N:46]4[N:47]=[C:48]([CH3:51])[CH:49]=[CH:50][C:45]4=[N:44][N:43]=2)=[CH:36][CH:35]=3)[N:5]=[CH:4]1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5c[nH]cn5)cc4c3)n2n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To a solution of 4-bromo-1-trityl-1H-imidazole (103 mg, 0.24 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added ethyl magnesium bromide (3M in diethylether, 0.094 mL, 0.28 mmol, 1.2 equiv) and the reaction was stirred for 90 min. ZnCl2 (38 mg, 0.28 mmol, 1.2 equiv) was then added and the solution stirred for an additional 90 min. Tetrakis (triphenylphosphine)palladium (2 mg, 0.024 mmol, 0.10 equiv) and 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (100 mg, 0.28 mmol, 1.2 equiv) were added and the solution heated at 70° C. for 18 hours. The solvent was removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20 to return 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(3-trityl-3H-imidazol-4-yl)-quinoline. The trityl group was removed by stirring the compound in methanolic hydrochloric acid (0.5 N) for 3 hours. The volatiles were removed in vacuo and the residue stirred in ethanol and collected via filtration and dried to return the title compound (5.6 mg, 8% yield). Analytical data presented in Table 2.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([N:61]=[N:62][C:63]2[CH:76]=[CH:75][C:66]([O:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]O)=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53].O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][O:67][C:66]2[CH:65]=[CH:64][C:63]([N:62]=[N:61][C:58]3[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=3)=[CH:76][CH:75]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(OCCCCCCO)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCCCCCOc3ccc(N=Nc4ccc([N+](=O)[O-])cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
0.2 g of N,N'-dicyclohexyldicarbodiimide (DCC) was added at room temperature while stirring to a solution of 0.5 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.25 g of 6-[4-(4-nitrophenylazo)phenoxy]hexanol and 0.04 g of 4-dimethylaminopyridine (DMAP) in 25 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol 1:1) and two-fold recrystallization from acetone of the fractions which were pure according to thin-layer chromatography gave 0.4 g of 6-[4-(4-nitrophenylazo)phenoxy]hexyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate; m.p. (C-N) 72° C., cl.p. (N-I) 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=O)[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:9]2[N:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cnc2c(Cl)ncnc2c1
Temperature: 25 °C

Procedure:
To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL, 4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and the reaction was stirred at reflux for 1 hour. After cooling to RT, the reaction mixture was concentrated to provide the title compound. LC/MS (ESI+) m/z=200 (M+H).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])[CH3:8])[CH:4](C)C.[OH:10][CH2:11][C@H:12]([CH3:40])[O:13][C:14]1[CH:15]=[C:16]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=2)=[O:31])[CH:29]=1)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC1CCN1>CN(C=O)C.C(OCC)(=O)C>[OH:10][CH2:11][C@H:12]([CH3:40])[O:13][C:14]1[CH:29]=[C:28]([CH:27]=[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:3]3[CH2:4][CH2:9][CH:7]3[CH3:8])=[O:24])=[CH:20][CH:19]=2)[CH:15]=1)[C:30]([NH:32][C:33]1[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)O)cc3)cc(O[C@@H](C)CO)c2)cn1
Agent: CC1CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4C)cc3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
DIPEA (0.20 mL, 1.04 mmol) was added to a suspension of 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carbonyl}phenoxy)benzoic acid (0.11 g, 0.26 mmol), HATU (210 mg, 0.55 mmol) and 2-methylazetidine (37 mg, 0.52 mmol) in DMF (3 mL) and the mixture stirred at ambient temperature for 24 hours. Ethyl acetate (30 mL) was added and washed with water (3×20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% methanol in ethyl acetate, to give the desired compound (54 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:16])[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1c2c(c3cc(F)ccc31)C(=O)CCC2
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
The product of Stage (ii) (7.28 g), potassium carbonate (9.90 g), acetone (70 ml), and dimethylsulphate (5.1 ml) were vigorously stirred at room temperature overnight under nitrogen. The mixture was concentrated to one half of its volume and then stirred with water (350 ml) for 30 min. The mixture was filtered off, washed with water (50 ml), air-dried for 1 h, and dried in vacuo over phosphorus pentoxide to give the title compound as needles (7.59 g), m.p. 157.5°-158.5°.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+].[CH:24]([O:27][C:28]([O:30][CH:31](I)[CH3:32])=[O:29])([CH3:26])[CH3:25]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH:31]([O:30][C:28]([O:27][CH:24]([CH3:26])[CH3:25])=[O:29])[CH3:32])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3csc4cncn34)C[C@H]12
Reactant: CC(C)OC(=O)OC(C)I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(c2csc3cncn23)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a solution of 48 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 73 mg of 1-(isopropoxycarbonyloxy)ethyl iodide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and washed twice with 10 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give the title compound in a yield of 22 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9].O>C(O)C>[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:3][N:2]([CH3:4])[CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CN(C)N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNN(C)C)C(=O)c1cc(F)c(F)c(F)c1F

Procedure:
3.1 g of 1,1-dimethylhydrazine are added dropwise to a solution of16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate in 60 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 60 ml of H2O are added, the mixture is cooled with ice and the precipitate is filtered off with suction and washed with water/ethanol (1:1). 12.9 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2,2-dimethylhydrazino)-acrylate of melting point 81° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:20]([N:25]=[C:26]=[O:27])(=[O:24])[C:21]([CH3:23])=[CH2:22]>ClCCCl>[C:20]([NH:25][C:26](=[O:27])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)N=C=O
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Yield: 100.2 %

Procedure:
Into a three-necked flask purged with nitrogen gas, p-hydroxybenzophenone (1.98 g; 10 mmol) was charged, and chloroform (10 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give p-benzoylphenyl N-methacryloylcarbamate (3.1 g), which was recrysallized from a mixture of benzene and chloroform to give white granules. M.P., 96°-97° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:17])=[O:16])[C:10]=2[F:18])[CH2:5][CH2:4]1)[CH3:2].C(O)=O>[Pd].C(O)(C)C>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:17])=[O:16])[C:10]=2[F:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(S(C)=O)c2F)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=CO
Product: CCN1CCC(c2cccc(S(C)=O)c2F)CC1

Procedure:
Preparation according to Example 2. 1-ethyl-4-[2-fluoro-3-(methylsulfinyl)phenyl]-1,2,3,6-tetrahydropyridine (150 mg, 0.56 mmol), formic acid (0.1 ml, 2.8 mmol), palladium on carbon (0.1 g), isopropanol (20 ml). MS m/z (relative intensity, 70 eV) 269 (M+, 11), 254 (bp), 239 (84), 84 (13), 57 (11).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.O.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:19]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(-c2c(F)cnn2C)c(Cl)s1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 0.974 mmol)[prepared according to the procedure in Example 95] in acetonitrile (4.864 ml) and H2O (486 μl) was added selectfluor (449 mg, 1.27 mmol). The resulting solution was stirred at 70° C. in a sealed tube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) was added in one portion. After stirring 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM-THF and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) affording methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274, 276 (M, M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[F:29][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:37]([C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([C:32]([O:31][CH3:30])=[O:33])[CH:35]=2)=[O:38])=[CH:8][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH:10]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.200 g, 0.5 mmol) in CH2Cl2 (5 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.0901 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), and Et3N (0.0703 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 h and then quenched with H2O. The organic layer was separated, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.26 g (93%). LC-MS m/z 562 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.93 mmol) [prepared according to the procedure of Preparation 9], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (209 mg, 0.60 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (340 mg, 0.73 mmol) in Chloroform (15 mL). DIEA (0.81 mL, 4.65 mmol) was added and the mixture stirred overnight at room temperature. Upon completion, the reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (112 mg, 0.203 mmol, 22%): LC-MS (ES) m/z=553 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)#[N:35].C(O)C(N)(CO)CO.CN(C=O)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:43]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)=[O:44])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.1 %

Procedure:
To a solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate (37 mg, 0.084 mmol) in anhydrous DCM (2 ml) was added 4-cyanophenyl isocyanate (Aldrich, 45 mg, 0.31 mmol) and the reaction mixture was stirred at rt for 18 hrs. Then PS-trisamine resin (75 mg, Novabiochem, 3.5 mmol/g) and DMF (1 mL) were added and the resulting mixture was stirred at rt for 5 additional hrs. Removal of the resin by filtration followed by evaporation of the solvents gave 65 mg (97%) of the title compound as a pale yellow oil. HPLC, Rt: 5.7 min (purity: 74.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 2,2,2-trifluoro-ethylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=495.1 [M+H]+.