Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C:62]1[C:63]([CH3:77])=[CH:64][C:65]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[N:66][C:67]=1[CH3:68]>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:60][CH2:61][C:62]2[C:67]([CH3:68])=[N:66][C:65]([NH:69][C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])=[CH:64][C:63]=2[CH3:77])=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (25 mg, 73 μmol), as prepared in step 15 of Example 1, in DMF (0.25 mL) was added BOP (52 mg, 116 μmol), a solution of DIEA (38 mg, 295 mol) in DMF (0.1 mL), and N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)](tert-butoxy)carboxamide (23 mg, 91 μmol) (Sanderson, P. E., et al. WO 97/01338 (1997)). After stirring at ambient temperature for 2 days, additional amine (7 mg, 28 μmol) BOP (16 mg, 36 μmol), and DIEA (9 mg, 70 μmol) were added, and the mixture was stirred for another 16 hours. The solvents were evaporated, and the resulting residue was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 10% citric acid, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%) to produce the title compound (18.5 mg, 44% yield) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50-7.41 (m, 5H), 7.24 (s, 1H), 6.98 (dd, J=8.8, 1.1 Hz, 1H), 6.55 (t, J=9.0 Hz, 1H), 5.33 (bs, 1H), 4.40 (d, J=4.7 Hz, 2H), 4.24-4.20 (m, 1H), 3.78-3.70 (m, 4H), 2.39 (s, 3H), 2.28 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calcd for C29H33ClF3N4O3 (M+H): 577.0. Found: 577.1.
Reaction SMILES: CN(C)[C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:15][Li].[Cl-].[NH4+]>C1COCC1>[C:8]1([C:5]2([C:3](=[O:4])[CH3:15])[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C(=O)C1(c2ccccc2)CC1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4.34 g of 27 is dissolved in 189 ml of THF, cooled to −10° C., and 21.5 ml of methyllithium solution (1.6 M in diethyl ether) is added in drops under nitrogen. It is stirred for 2 hours at this temperature, and the reaction mixture is then poured into saturated ammonium chloride solution. After extraction with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.7 g of title compound 28 is obtained as a yellowish oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 3H (20.5 g) and piperazine (37.0 g) in dimethylsulfoxide (200 mL) was heated to 110° C. for 24 hours, and the mixture was allowed to cool to room temperature. The mixture was poured into water (1 L), extracted three times with dichloromethane, and the combined extracts were washed with 2× water, and brine and filtered and concentrated to give the pure product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]2[C@@:17]3([CH2:28][O:29][C:4]=2[CH:3]=1)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[C:31](=[O:32])([O:33][CH2:34][CH3:35])[O:27][CH2:26][C@H:19]1[O:18][C@@:17]2([C:5]3[CH:6]=[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=4)[C:2]([Cl:1])=[CH:3][C:4]=3[O:29][CH2:28]2)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@@H:20]1[OH:25]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)OC[C@H]1O[C@]2(COc3cc(Cl)c(Cc4ccc(CC)cc4)cc32)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 30 (12 mg, 28.5 μmol) in 2,4,6-collidine (100 μL) at −30° C. was added a solution of ethyl chloroformate (4 μL, 41.8 umol, 1.5 eq.) in DCM (100 μL). The mixture was kept at −30° C. for 1.5 hours, warmed to ambient temperature, and stirred overnight, after which additional ethylchloroformate (4 μL) was added. The reaction mixture was quenched with methanol, evaporated, and purified via HPLC to give 31 (7.5 mg, 53% yield). 1H NMR (300 MHz, CD3OD) δ 7.14 (s, 1H), 7.07 (s, 4H), 6.83 (s, 1H), 4.68 (d, J=10.2 Hz, 1H), 4.57 (d, J=10.5 Hz, 1H), 4.36 (dd, J=2.1, 11.4 Hz, 1H), 4.21 (dd, J=5.1, 11.4 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.99 (s, 2H), 3.71 (d, J=9.6 Hz, 1H), 3.53-3.59 (m, 1H), 3.39 (t, J=8.7 Hz, 1H), 3.27-3.34 (m, 1H), 2.58 (q, J=7.5 Hz, 2H), 1.17-1.23 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([C:19](N2[C@@H](C3C=CC=CC=3)COC2=O)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To (S)-3-((3R,4S)-1-benzyl-4-phenyl-pyrrolidine-3-carbonyl)-4-phenyl-oxazolidin-2-one (9.96 g, 23.35 mmol) in THF (100 mL) in a three-necked flask equipped with a thermometer and addition funnel was added lithium aluminium hydride (48 mL, 1M in THF) dropwise so that the temperature did not exceed 40° C. while keeping the reaction vessel in a water bath. When addition was complete the water bath was removed and the reaction stirred at room temperature overnight. The reaction was carefully quenched with water (1.6 mL), NaOH (1.6 mL, 2N) and water (4.5 mL). After stirring for 15 minutes, the reaction mixture was filtered through a pad of celite and rinsed with THF (40 mL). The filtrate was concentrated to give a pale yellow oil, which was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (1:1) to give 3.38 g (55%) of ((3R,4S)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methanol.
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].C=O.[C:8]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:15]([O:17][CH3:18])(=[O:16])[CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][OH:2]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A three necked one-liter flask equipped with a drying tube, a thermometer and a stopper was flame-dried, cooled and then charged with sodium bicarbonate (2.1 g; 0.025 mole), paraformaldehyde (34.74 g; 1.1 mole) and 300 mL of dimethylsulfoxide (DMSO). The air in the flask was purged with dry nitrogen and methyl phenylacetate (150:18 g; 1 mole) was added in one portion. Residual ester was washed into the flask using dry DMSO (5 mL). The slurry was then stirred magnetically (initial temperature 22°-23° C.) and the temperature rose slowly over one hour to 33° C. The temperature remained at about 32°-33° C. for 1.5 hrs. at which time the reaction liquid was almost a clear solution. The temperature was then raised to 45°-46° C. over 30 min. and kept at this temperature for 12 hrs. The solution was then allowed to cool and left at room temperature for 9 hrs. The reaction mixture was clear and essentially colorless with only a small amount of a white solid appearing at the bottom of the flask. NMR analysis of the solution indicated approximately an 80% yield of methyl tropate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][CH3:23])[CH:19]=2)[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]>CN(C)C=O.CCOC(C)=O>[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][CH3:23])[C:19]=2[Cl:1])[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
N-Chlorosuccinimide (505 mg, 3.8 mmol) was added to a solution of 2-butyl-5-methoxy-1-indanone (825 mg, 3.8 mmol) in anhydrous dimethylformamide (3.8 mL) and the resulting solution was stirred under nitrogen and at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with 5% aqueous NaHCO3 (20 ml), water (3×50 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on EM silica gel 60 (2320-400 mesh, 2.75×29 cm), eluting with CH2Cl2, to afford 2-butyl-4-chloro-5-methoxy-1-indanone (148 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
In THF (50 ml) was dissolved 4-nitrobenzylchloride (5.00 g), and piperidine (6.20 g) was added to the mixture. The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/2) to give 1-(4-nitrobenzyl)piperidine (6.41 g) as pale yellow oil. 1H NMR (200 MHz, CDCl3) δ: 1.38-1.70 (6H, m), 2.30-2.45 (4H, m), 3.55 (2H, s), 7.51 (2H, d, J=8.8 Hz), 8.17 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])[CH:2]=C.S(C1C=CC(C)=CC=1)([O:14][CH2:15][CH2:16][O:17][CH2:18]COC)(=O)=O>>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:2][CH2:1][N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCN(CCO)CCO
Product: COCCOCCN(CCO)CCO

Procedure:
The title compound was prepared as described above for N-allyldiethanolamine in Example 1 except that 2-methoxyethoxyethyl tosylate was used (0.55 mol, 150.9 g) in a 0.5 mol preparation. The pure diol whose formula is shown below was obtained (49.8 g, 48%) on fractional distillation at 129°-131° C. (0.04 mm):
Reaction SMILES: C(N1C2C=C(OC)C([O:14]C)=CC=2C(C2C=CC=CC=2)=NC(CC2C=C(C=CC=2)C#N)C1=O)C.[CH2:34]([O:36][C:37]1[C:64]([O:65][CH3:66])=[CH:63][C:40]2[C:41]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[N:42][CH:43]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]#[N:53])[C:44](=[O:47])[N:45]([CH3:46])[C:39]=2[CH:38]=1)[CH3:35]>>[CH2:34]([O:36][C:37]1[C:64]([O:65][CH3:66])=[CH:63][C:40]2[C:41]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[N:42][CH:43]([CH2:48][C:49]3[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=3)[C:52]([NH2:53])=[O:14])[C:44](=[O:47])[N:45]([CH3:46])[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCN1C(=O)C(Cc2cccc(C#N)c2)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C#N)c1)C(=O)N2C
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1cccc(C(N)=O)c1)C(=O)N2C
Yield: 86 %

Procedure:
By replacing 3-[(1-ethyl-7,8-dimethoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIcp) in example IIcs by 3-[(8-ethoxy-7-methoxy-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)methyl]benzonitrile (IIdf) and proceeding in the same manner, the abovenamed product is obtained. Yield: 86%. M: 199–201° C. 1H-NMR (CDCl3, 300 MHz): d 1.52 (s, 3H, CH3), 3.39 (s, 3H, NCH3), 3.66–3.79 (m, 3H, —CH2Ph+CH+OCH3), 4.17 (q, 2H, CH2), 5.84 (m, 1H exchangeable —NH2), 6.24 (m, 1H exchangeable —NH2), 6.64 (s, 1H Ar), 6.74 (s, 1H Ar), 7.26–7.83 (m, 9H Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][C:7]=1[F:8].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[C:34]([CH3:40])=[N:33]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:37]([C:35]2[C:34]([CH3:40])=[N:33][N:32]([CH3:31])[CH:36]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccccc1-c1ccc(F)c(Cl)c1
Reactant: Cc1nn(C)cc1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.47 g of 3′-chloro-4′-fluoro-2-aminobiphenyl and 0.82 g of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added to a solution of 0.30 g of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid and 0.43 g of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 12 hours. The mixture was then washed successively twice with dilute hydrochloric acid, twice with aqueous sodium bicarbonate solution and once with water. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography using cyclohexane/methyl tert-butyl ether 1:2. This gave 0.56 g of the desired product as white crystals of m.p. 177-180° C.
Reaction SMILES: Cl[C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[N+]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.C(O)C.[Cu]>[O:24]([C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: NC1(Cl)C=C([N+](=O)[O-])C=CC1C(=O)O
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])c1ccccc1
Product: NC1(Oc2ccccc2)C=C([N+](=O)[O-])C=CC1C(=O)O

Procedure:
2-Chloro-4-nitroanthranilic acid (40.2 g, 0.2 mol) is stirred in nitrobenzene (250 mL) with 3-nitrophenol (31 g, 0.22 mol), potassium carbonate (42 g, 0.3 mole), copper bronze (1 g) and cuprous iodide (1 g) at 155° C. for 6 hours. The pure product is obtained by recrystallization in ethyl alcohol to give 2-phenoxy-4-nitroanthranilic acid. (See Goldberg, Walker, J. Chem. Soc. (1953), 1348).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31](O)=[O:32])[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[OH:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:34])([F:35])[C:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:32])[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[OH:4]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 107 mg (0.22 mmol) of (3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[2,3-b]pyridin-1-yl)acetic acid in 3 mL of DMF was added 108 mg (0.66 mmol) of N,N-carbonyldiimidazole. The mixture stirred for 5 minutes and then 63 mg (0.66 mmol) of methanesulfonamide was added. After 30 minutes, the reaction was monitored by LCMS indicating only starting material [MS m/z 485.29 (MH+)]. To the mixture was added sodium hydride and the mixture stirred for 1.5 hours. The mixture was monitored by LCMS indicating desired product [MS m/z 562.37 (MH+)]. TLC (ethyl acetate or methanol-dichloromethane) indicated a new product. The mixture was diluted with saturated aqueous ammonium chloride and extracted with five 10 mL portions of ethyl acetate. The combined organic layers were washed with two 7 mL portions of saturated aqueous ammonium chloride, two 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The oily residue was chromatographed on silica gel using dichloromethane to load the sample and then methanol-dichloromethane (1-10%) to afford some mixed factions and clean fractions. Fractions containing product were chromatographed on four prep. plate (1 mm, methanol-dichloromethane 15:85). The most polar band was recovered eluting from the silica gel with 20% methanol-dichloromethane. The material was triturated with ether-hexanes to afford 42 mg (33%) of the title compound as a tan solid. MS m/z 562.39 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4I)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.CO[CH2:29][CH2:30]OC>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4[C:30]4[CH:29]=[CH:6][CH:7]=[CH:2][N:3]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1
Reactant: COCCOC
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4I)CC3C2)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ccccn4)CC3C2)n1
Temperature: 160 °C

Procedure:
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone (51 mg, 0.11 mmol) and 2-tributylstannane pyridine (57 mg, 0.13 mmol) were combined and dissolved in degassed DME then purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 and then purged with bubbling for 5 minutes in a sealed vessel and then heated to 160° C. in microwave for 90 min. Reaction was filtered through celite, concentrated and purified on 16 g SiO2 with 0-3.5% NH3 MeOH/CH2Cl2. MS (ESI) mass calcd. for C24H24FN5O, 417.49; m/z found, 418.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.71-7.64 (m, 1H), 7.57-7.52 (m, 1H), 7.46 (dddd, J=8.2, 5.6, 2.8, 1.2 Hz, 1H), 7.37 (td, J=7.9, 5.5 Hz, 1H), 7.30-7.24 (m, 2H), 7.20 (ddd, J=9.0, 2.5, 1.5 Hz, 1H), 7.11 (tdd, J=8.4, 2.6, 1.0 Hz, 1H), 6.31 (s, 1H), 3.97 (dd, J=12.7, 7.8 Hz, 1H), 3.89 (dd, J=11.5, 7.7 Hz, 1H), 3.82-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.50 (dd, J=11.5, 4.6 Hz, 1H), 3.40 (dd, J=10.9, 5.4 Hz, 1H), 3.07 (d, J=7.2 Hz, 1H), 3.03-2.94 (m, 1H), 2.30 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([CH3:16])[N:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOCCOC.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)n1
Solvent: ClC(Cl)Cl
Solvent: COCCOCCOC
Product: Cc1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C)n1
Temperature: 165 °C
Yield: 126.4 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 2,6-dimethyl-pyridin-4-yl ester (0.50 g, 1.96 mmol) in diglyme (50 mL) was added 4-nitrophenyl piperazine (0.37 g, 0.76 mmol) and heated in the microwave at 165° C. for 40 minutes. The mixture was diluted with chloroform (100 mL) and washed with water (5×50 mL). The organic layer was separated, washed with brine solution (5×40 mL), dried over sodium sulfate and filtered. The solvent was evaporated, and the crude material was purified by column chromatography over silica gel (60-120 mesh) using 12% methanol in chloroform as eluent to afford 4-[4-(2,6-dimethyl-pyridin-4-yl)-1-(4-nitrophenyl)-piperazine (0.30 g, 49%) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH:32]=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:31]=[CH:30][N:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(-c2ccccc2)ccn1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccc2)ccn1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 4-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 403.16 g/mol.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c(-c3cccc(NCc4ccc(C(Cc5ccccc5)C(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-{[3-(3-benzoyl-8-methyl-quinolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid (0.04 g, 0.08 mmol), benzyl bromide (0.12 g, 0.8 mmol), and cesium carbonate (0.33 g, 1 mmol) in 5 mL of DMF was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were washed with water, dried over magnesium sulfate and concentrated. The crude ester was treated with LiOH followed by semi-preparative HPLC purification to give the title compound. MS (ESI) m/z 577.