Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([N:30]1[CH2:35][CH2:34][N:33]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:24])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)N3CCN(C(C)(C)C)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-tert-butylpiperazine.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH:5][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3.54 g of Fmoc-Asn-OH (10 mmol) and 5.2 g of triphenylmethanol (20 mmol) in 30 ml of acetic acid and 1.9 ml of acetic anhydride (20 mmol) is stirred at 50° for 15 minutes and then a solution of 0.05 ml of conc. sulfuric acid in 5 ml of acetic acid is added. After about one hour at 50° C. a solution forms, and after 11/2 hours a precipitate starts to form. After 3 hours, 200 ml of ice-cold water are slowly added to the suspension, while cooling in ice, the mixture is briefly stirred, and the precipitate is filtered off and thoroughly washed with water. The moist material is dissolved in ethyl acetate, and the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Before the product starts to crystallize out, the solution is diluted with 1,2-dichloroethane, concentrated again and filtered through 50 g of silica gel. The excess triphenylmethanol is eluted with 200 ml of 1,2-dichloroethane, and then Fmoc-Asn(Trt)-OH is eluted with 500 ml each of a 98:2 and of a 96:4 mixture, of 1,2-dichloroethane and methanol. The residue after evaporation to dryness is dissolved in 10 ml of tetrahydrofuran, 30 ml of ethyl acetate are added, the solution is concentrated to 20 g, and diisopropyl ether is added to crystallize; the Fmoc-Asn(Trt)-OH obtainable in this way melts at 210°-211° (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2Cl)C(=O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1

Procedure:
A solution of product from step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.20 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 ml) and washed with H2O (3×100 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]([OH:18])=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[N+:27]([C:30]1[CH:35]=[C:34]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[CH:33]=[CH:32][C:31]=1Cl)([O-:29])=[O:28]>>[CH3:22][O:21][C:19]([C:15]1[CH:16]=[C:17]([O:18][C:31]2[CH:32]=[CH:33][C:34]([S:36]([C:39]([F:41])([F:42])[F:40])(=[O:38])=[O:37])=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])[N:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[N:14]=1)=[O:20]
Reactant: COC(=O)c1cc(O)n(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])n(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Using procedure as in example 10, a reaction of methyl 1-[3,5-di(trifluoromethyl)phenyl]-5-hydroxy-1H-pyrazole-3-carboxylate (100 mg, 0.282 mmol), NaH (12 mg, 1.1 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (82 mg, 1 equiv.) afforded 1-(3,5-bis-trifluoromethyl-phenyl)-5-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-1H-pyrazole-3-carboxylic acidmethyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.76 (d, J=2.1 Hz, 1H), 8.58 (dd, J=2.1 & 8.2 Hz, 1H), 8.42 (s, 2H), 8.30 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 6.76 (m, 1H), 3.7 (s, 3H, OCH3). MS-EI m/z 607 [M+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:15][C:13]=1[NH2:14].C(N(CC)C(C)C)(C)C.O>C(#N)C>[NH2:8][C:7]1[C:2]([NH:14][C:13]2[CH:15]=[C:16]([O:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=3[F:32])[C:17]([O:19][CH3:20])=[CH:18][C:12]=2[Cl:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: COc1cc(Cl)c(Nc2ncccc2N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 130 °C
Yield: 19.4 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (0.12 g), 2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyaniline (0.26 g) and N,N-diisopropylethylamine (0.14 mL) in acetonitrile (3 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL)-methanol (4 mL). To the solution were added nickel(II) bromide (9 mg) and sodium borohydride (89 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=67/33−35/65) to give 3-amino-2-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]pyridine (62 mg). This material was dissolved in tetrahydrofuran (2 mL). To the solution were added sodium hydride (55%, 20 mg) and thiophosgene (0.012 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (28 mg).
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([OH:11])[C:8]([F:12])=[CH:7][C:3]=1C(O)=O>O1CCOCC1>[OH:11][C:9]1[C:8]([F:12])=[CH:7][CH:3]=[C:2]([OH:1])[N:10]=1
Reactant: O=C(O)c1cc(F)c(O)nc1O
Solvent: C1COCCO1
Product: Oc1ccc(F)c(O)n1
Yield: 98.3 %

Procedure:
2,6-Dihydroxy-5-fluoronicotinic acid (2.25 g) was dissolved in dioxane (25 mL) and refluxed for 15 minutes. After being cooled, the solvent was evaporated to obtain Compound 4a (1.65 g). Yield: 99%1 H-NMR (DMSOd6, δPPM): 7.26 (1H, dd, J=7.7 Hz, J=11.0 Hz), 5.45 (1H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:20][C@H:21]([OH:29])[C:22]2[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:20][C@H:21]([OH:29])[C:22]2[CH:27]=[N:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2ccc(Cl)nc2)cc1OC
Agent: [Ni]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2cccnc2)cc1OC

Procedure:
A solution of (R)-N-[1-(3,4-dimethoxyphenyl)-2-phenylethyl]-2-hydroxy-2-(2-chloropyrid-5-yl)-ethylamine (100 mg, 0.26 mmol) in ethanol (7 mL) with 5N sodium hydroxide (0.1 mL, 0.5 mmol) was degassed with argon prior to the addition of Ni(R) (100 mg). The mixture was hydrogenated at 40 Psi overnight and then the catalyst was filtered through Celite and washed with a small amount of ethanol. The filtrate was stripped and the product was purified by prep TLC on silica gel (eluent: 5% methanol in methylene chloride) to give the titled compound. 1H NMR (500 MHz, CDCl3)δ 8.47 (m, 2H), 7.58 (m, 1H), 7.01-7.32 (m, 6H), 6.79-6.84 (m, 3H), 4.53-4.67 (m, 1H), 3.89 and 3.88(s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.79-3.85 (m, 1H), 2.90-3.03 (m, 2H), 2.78 (m, 1H), 2.49-2.50 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(=O)N1c2ccc(-c3cccc(S(C)(=O)=O)c3)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(3-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 3-(methylsulfonyl)phenylboronic acid The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 553.11; the expected mass is 552.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[CH3:23][CH:22]([S:19]([NH:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH:8]=[CH:7][CH:6]=3)[CH:10]=2)[CH2:14]1)(=[O:21])=[O:20])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Product: CC(=O)NCc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1

Procedure:
The title compound was prepared from N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide and acetyl chloride in a similar manner to Example 12.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(O)=O>CCO>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([NH:1][NH:2]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C/NNc1cc(C#N)ccn1
Yield: 34.6 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH >8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233. Found, 233.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2B(O)O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.CCO.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.O.CO>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:19]2[CH:20]=[C:21]4[C:30](=[CH:31][CH:32]=2)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc2ccccc2c2cc(Br)ccc12
Reactant: OB(O)c1c2ccccc2cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccccc2c2cc(-c3c4ccccc4cc4ccccc34)ccc12

Procedure:
32.86 g (148 mmol) of anthracene-9-boronic acid, 37.2 g (124 mmol) of 6-bromophenanthrene-9-carboxylic acid and 220 ml of 2 M Na2CO3 solution are suspended in 1 l of toluene and 1 l of EtOH, the mixture is saturated with N2, 2.9 g (3 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is heated at the boil for 2 h. The mixture is poured into 3 l of a mixture of water/MeOH/6 M HCl 1:1:1, and the beige precipitate is filtered off with suction, washed with water, EtOH and toluene and dried. The content of product according to 1H-NMR is about 96% with an overall yield of 38.5 g (78%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanone (260 mg, 0.78 mmol) in THF (10 mL) at 0° C. were added portion wise LiAlH4 (26 mg, 0.68 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (IV-B-9) 101 mg (38%) as a white solid ES-MS m/e: 334.2 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (IV-A-9) 80 mg (30%) as a white solid ES-MS m/e: 334.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:33])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (106 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (114 mg, 57%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1
Yield: 97.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (100 mg, 0.26 mmol) in DME (5 ml)/2M Na2CO3 (450 μL, 0.90 mmol) was treated with phenylboronic acid (47 mg, 0.39 mmol) and Pd[PPh3]4 (30 mg, 0.026 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (98 mg, 98%). LC-MS m/e 387.16 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Cl)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Cl)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 32 (0.565 g, 1.31 mmol) and pyridine hydrochloride (1.2 g, 10.38 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]([C:14]([O:16]CC1C=CC=CC=1)=[O:15])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH:4]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]([C:14]([OH:16])=[O:15])[CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 24 h

Procedure:
A solution of the compound of example 52 (700 mg, 1.59 mmol) in ethanol (95%, 100 mL) was hydrogenated in the presence of a catalytic amount palladium (10% on charcoal). After 24 h of stirring, the reaction was complete. The mixture was filtered over a celite pad and the solvent was evaporated. The residue was distributed between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][CH:17]([CH3:22])[CH3:16])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)CC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(C)CC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 3-methyl-butyryl chloride (67 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-3-methyl butanamide (0.042 g).