Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[S:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:16]1[CH2:17][CH2:18][S:13][CH2:14][CH2:15]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSCC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
TMSOTf (1.4 mL, 7.7 mmol) was added dropwise to a solution of tetrahydro-4H-thiopyran-4-one (0.88 g, 7.6 mmol) in DCM (80 mL) in the presence of molecular sieves at 0° C. (bath temp). A solution of ethyl 5-bromo-1H-indole-7-carboxylate (2 g, 7.4 mmol). in DCM (20 mL) was added and the reaction was stirred for 15 min. Triethylsilane (2 mL, 12.5 mmol) was added and the reaction was allowed to warm to room temperature overnight. Saturated aqueous Na2CO3 was added, the layers separated and the aqueous layer extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was washed with MeOH and dried in a vacuum oven, giving 2.07 g (76%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[CH2:11]2)=[CH:6][N:5]=1>O1CCOCC1.CO>[F:32][C:3]([F:2])([F:31])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)nc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)nc2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4 N HCl in dioxane (2.29 mL, 9.15 mmol) was slowly added to a solution of tert-butyl (1R,2R)-2-((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-ylamino)cyclohexylcarbamate (0.58 gm, 1.31 mmol) in dioxane (3.52 mL) and MeOH (0.44 mL). After 1 h of stirring the reaction mixture was concentrated and the residue was partitioned between EtOAc and sat. NaHCO3. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the product (1R,2R)—N1—((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-yl)cyclohexane-1,2-diamine (0.44 gm, 1.29 mmol, 99% yield) as a syrup. Anal. Calcd. for C16H24F3N5 m/z 343.2, found: 344.2 (M+H)+.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=O)[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[F:34][C:35]1[CH:46]=[CH:45][C:38]([N:39]([CH2:41][CH:42]([NH2:44])[CH3:43])[CH3:40])=[CH:37][CH:36]=1>C(Cl)Cl.O>[F:34][C:35]1[CH:46]=[CH:45][C:38]([N:39]([CH2:41][CH:42]([NH:44][C:23](=[O:25])[C@H:18]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH3:43])[CH3:40])=[CH:37][CH:36]=1
Reactant: CC[C@H](C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CC(N)CN(C)c1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccccc1)C(=O)NC(C)CN(C)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
1.9 g of N-methylpiperidine was added to a solution containing 4.8 g of N-phenoxycarbonyl-L-isoleucine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.5 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 1.1 g of the desired product in the form of a white crystal (yield: 13%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23])[CH3:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:12][CH3:13])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOc1ccccc1N=C=O
Product: CCOc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-ethoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.84 g, 81%). EI-MS m/z 318 (M+H)+
Reaction SMILES: CC(O)C.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][CH:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]>CO>[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][C@@H:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid (1.75 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-94%) dissolved in methanol (6 mL) was added into reaction mixture at 60-65. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2 to 3 hrs. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 10 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.08 g, % Y-29%, Purity by HPLC-99.1%, % Chiral purity by HPLC of R-isomer 76.7%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23][NH2:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:24][CH2:23][C:22]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:20]([C:19]([F:18])([F:32])[F:33])[CH:21]=2)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reaction time: 3 h
Yield: 62.9 %

Procedure:
Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) and 3,5-bis-trifluoromethyl-benzylamine (125 mg, 0.514 mmol) were dissolved in dry DCM (2 mL), acetic acid (0.1 mL) and NaBH(OAc)3 (180.6 mg, 0.856 mmol) was then added. After stirred for 3 hours the reaction mixture was diluted with DCM, washed with saturated NaHCO3 (cautiously), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to afford the title product 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester 124 mg (63%) as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:18])[N:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[F:1][CH:2]([F:18])[N:3]1[CH:7]=[C:6]([C:8](=[S:28])[NH2:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4]1
Reactant: NC(=O)c1cn(C(F)F)nc1-c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cn(C(F)F)nc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of the mixture (1.15 g, 4.51 mmol) obtained in step 3 in THF (18.8 mL) was added Lawesson's reagent (1.46 g, 3.61 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hr. After cooling to room temperature, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 7% ethyl acetate/hexane) to give a mixture (0.840 g, 68%, 1:1.92 mol/mol) of 1-(difluoromethyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide and 1-(difluoromethyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide as a pale-green powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[CH3:15][N:14]1[C:8](=[O:9])[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH:12][C:11](=[O:13])[CH2:16]1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: CNCC(=O)O
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N(C)CC(=O)N2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 14.0 g (79 mmol) of 6-methylisatoic acid anhydride, 7.04 g (79 mmol) of sarcosine and 80 ml of dimethyl sulphoxide is stirred at 110° C. for 3 hours. The red coloured solution is evaporated in a high vacuum. The residue is treated with 80 ml of ethanol, the product crystallising out. There is obtained 3,4-dihydro-4,6-dimethyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 200°-202° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26]C)[CH:20]=[CH:21][CH:22]=1.C[O-:32].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: CCCCOc1nc(N)c2nc(Br)n(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(CP(C)(=O)OC)c3)c2n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 69 (130.4, 0.26 mmol) in methanol (10 mL) was slowly added sodium methoxide (283.8 mg, 5.25 mmol). The mixture was heated to 70° C. for 3 hours at which time Dowex resin was added to quench any remaining methoxide. The resin was filtered off and the solvent evaporated. The product was stirred in 6N HCl over night (16 hr) after which time the solvent was evaporated to give 70 as a white solid, the crude product was carried through to the next step. LCMS: m/z for C20H28N5O4P++H observed 420.2 at 1.92 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.CN(C=O)C.[H-].[Na+]>O.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7][N:8]3[CH2:13][CH3:14])=[CH:3][C:2]=2[F:1])[CH2:22][CH2:21]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OC3CCN(C)CC3)cc21
Yield: 9.9 %

Procedure:
To a mixture of 280 mg of 6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 345 mg of N-methyl-4-piperidinol and 4 ml of DMF was added 200 mg of 50% sodium hydride while the former was stirred under ice cooling. After the resultant mixture was stirred for 2 hours at room temperature, 260 mg of acetic acid was added, followed by the addition of chloroform and water. The resultant mixture was thoroughly shaken and mixed. The chloroform layer was collected, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solid thus precipitated was collected by filtration, whereby 38 mg of the title compound was obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Br:19][C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[Cl:34])[C:21]=1[CH2:35]Br>C1COCC1>[Br:19][C:20]1[CH:25]=[C:24]([Br:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[Cl:34])[C:21]=1[CH2:35][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Fc1ccc(-c2nc(Br)cc(Br)c2CBr)c(Cl)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 1M solution of lithium bis(trimethlsilyl)amide (10.5 mL) at −78° C. was added tert-butyl acetate (1.77 mL, 13.2 mmol) dropwise. To this mixture a solution of 4,6-dibromo-3-(bromomethyl)-2-(2-chloro-4-fluorophenyl)pyridine (4.02 g, 8.77 mmol) (COMPOUND PS) in 9.2 mL of THF was added dropwise over 20 min. After stirring for 30 min at −78° C., the reaction mixture was quenched by the dropwise addition of 3 mL of methanol, then warmed up to rt and partitioned between 30 mL each of saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was extracted with 2×20 mL of ethyl acetate. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with warm Et2O. The mother liquor was purified by flash chromatography on a Biotage 40M column eluting with 97:3 hexanes-ethyl acetate. The two batches were combined to give the tert-butyl 3-[4,6-dibromo-2-(2-chloro-4-fluorophenyl)pyridin-3-yl]propanoate. Mass spectrum (ESI) 492.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([C:18](OC)=[O:19])=[N:13]3)=[CH:5][CH:4]=1.C([BH-](CC)CC)C.[Li+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH2:18][OH:19])=[N:13]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2c(Nc3ccc(OC)cc3)ccnc2n1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ccnc3nc(CO)ccc23)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 5-(4-methoxyanilino)-1,8-naphthyridine-2-carboxylate (1.0 g) and dry THF (100 ml) was stirred at 0° C. while lithium triethylborohydride (a 1M solution in THF, 6.5 ml) was added over 10 minutes. After stirring at 0° C. for 1 hour further lithium triethylborohydride solution (3 ml) was added. The mixture was stirred for a further 1.5 hours at 0° C. Water (100 ml) was added cautiously and the mixture was extracted with ethyl acetate. The ethyl acetate extract was extracted with 0.5M hydrochloric acid. The acid extract was washed with ethyl acetate, basified with sodium bicarbonate and extracted with dichloromethane:methanol (3:1) (2×200 ml) to give a residue which was triturated with methanol and filtered. The solid obtained was triturated with ethyl acetate and filtered to give 5-(4-methoxyanilino)-1,8-naphthyridin-2-ylmethanol, m.p. 275°-281° C.
Reaction SMILES: CC1C=C([N+]([O-])=O)C=CC=1N.C(NC1C=CC([N+]([O-])=O)=CC=1C)=O.C(Cl)C=C.[CH2:29]([N:32](C=O)[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])[CH:30]=[CH2:31]>C(O)=O>[CH2:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[CH3:42])[CH:30]=[CH2:31]
Reactant: C=CCN(C=O)c1ccc([N+](=O)[O-])cc1C
Agent: Cc1cc([N+](=O)[O-])ccc1N
Agent: Cc1cc([N+](=O)[O-])ccc1NC=O
Solvent: C=CCCl
Solvent: O=CO
Product: C=CCNc1ccc([N+](=O)[O-])cc1C

Procedure:
The particularly advantageous compound I-8 according to the invention can be prepared, for example, by formylating 2-methyl-4-nitroaniline using 95% strength formic acid, alkylating the resultant N-formyl-2-methyl-4-nitroaniline using allyl chloride under phase-transfer conditions and reducing the resultant N-allyl-N-formyl-2-methyl-4-nitroaniline. On the other hand, it is also possible to hydrolyze the intermediate N-allyl-N-formyl-2-methyl-4-nitroaniline to form N-allyl-2-methyl-4-nitroaniline, and to alkylate the latter using methyliodide to give the compound I-8 according to the invention. To this end, the intermediate N-allyl-2-methyl-4-nitroaniline can also be prepared by alkylating N-formyl-2-methyl-4-nitroaniline using allyl chloride. In addition, it is also possible to reduce the intermediate N-formyl-2-methyl-4-nitroaniline using a boron hydride in tetrahydrofuran to give the corresponding N-methyl derivative, which is subsequently alkylated using allyl chloride to give the compound I-8 according to the invention.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11]
Reactant: OCc1cc2ccccc2[nH]1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of crude (1H-indol-2-yl)methanol 17 (5.37 g, 36.53 mmol) in anhydrous CH2Cl2 (50 mL) at cold-bath temperature (˜10° C.) was added portionwise pyridinium chlorochromate (PCC) (9.44 g, 40.18 mmol). Reaction was stirred at ambient temperature for 2 hours. Reaction was diluted with CH2Cl2 and filtered through a pad of celite and washed with CH2Cl2. After evaporation of solvent, crude product was silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 1H-indole-2-carbaldehyde 18 (1.52 g, 29% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([N:41]3[CH2:42][CH2:43][N:39]([CH3:38])[C:40]3=[O:44])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: CN1CCNC1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1C(=O)OC(C)(C)C
Temperature: 180 °C
Yield: 60.8 %

Procedure:
In a 2 mL glass microwave reaction vessel are placed in (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.32 mmol), 1-Methyl-imidazolidin-2-one (35 mg, 0.35 mmol), CuI (123.4 mg, 0.35 mmol), trans-1,2-cyclohexane (0.005 mL, 0.35 mmol), K2CO3 (88 mg, 0.64 mmol) in dry dioxane (2 mL). The reaction vessel is sealed and heated under microwave irradiation at 180° C. for 20 min. After completion of the reaction, the solvent is diluted with EtOAc and washed with sat. NH3 (aq.), water, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:13].Cl[Si](C)(C)C.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:19][CH3:20])=[O:11])=[CH:4][C:3]=1[F:13]
Reactant: CCO
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)/C=C/c1ccc(Cl)c(F)c1
Reaction time: 20 h
Yield: 99.65 %

Procedure:
(E)-3-(4-Chloro-3-fluorophenyl)acrylic acid (17.3 g, 86.24 mmol) was suspended in ethanol (200 mL), and chlorotrimethylsilane (24.00 mL, 189.7 mmol) was added. The mixture was then agitated for 20 hours and evaporated, to give (E)-ethyl 3-(4-chloro-3-fluorophenyl)acrylate (19.65 g, 85.94 mmol, 99.65% yield) as an oil, which solidified later.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: CN(CC(=O)c1ccccc1)Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Into a 250 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-phenylethanone (4.3 g, 14.01 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of NaBH4 (1.5 g, 39.47 mmol, 2.82 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 20 mL of acetone. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:80˜1:20). This resulted in 3.4 g (79%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC=C(c1ccccc1)c1cc(Br)cnc1N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Brc1cnc2[nH]cc(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
1.093 g (3.582 mmol) of 5-bromo-3-(2-methoxy-1-phenylvinyl)-2-pyridylamine was dissolved in 60 ml of anhydrous 1,4-dioxane. 800 μl of 70% aqueous perchloric acid was added and the mixture heated to 100° C. for 13 hours. The mixture was then cooled to room temperature and 3 ml of triethylamine was added and the mixture evaporated to dryness. The resulting crude was crystallized from hot ethanol to afford 763 mg (2.79 mmol, 78% yield) of 5-bromo-3-phenylpyrrolo[2,3-b]pyridine as a beige-brown to brown crystalline solid. 1H-NMR (d6-DMSO) δ: 12.19 [1H] s, 8.44 [α] d, 8.34 [1H] d, 7.97 [α]d, 7.72 [2H] d(m), 7.45 [2H] t, 7.27 [1H] t(m). MS: m/z 273 [MH+].