Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1>C(O)C(C)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([NH:11][C:8]2[NH:9][CH2:10][CH2:6][N:7]=2)[CH:3]=1
Reactant: Nc1cc(Br)c2[nH]cnc2c1
Solvent: CC(C)CO
Product: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Yield: 157.9 %

Procedure:
4-bromo-6-aminobenzimidazole (0.4 g, 1.9 mmol) and ISA (1.2 g, 8.9 mmol) was dissolved in isobutanol and stirred at reflux for 12 h. Column chromatographic separation of the reaction mixture (NH3 sat'd 20% MeOH/EtOAc) provided 0.41 g (1.5 mmol, 78%) of the product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.24 g (32%) of the product as a light brown solid: mp 217-218° C.; Anal. Calc. for C10H10N5Br.1.0C4H4O4 requires C, 42.44; H, 3.56; N, 17.68. Found: C, 42.28; H, 3.58; N, 17.40.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:1][C:2]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenylbenzoate 94 mg were added 4-iodoanisole 0.20 g, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added to it, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, 4-iodoanisole 0.20 g, cesium carbonate 0.23 g, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added to it, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-methoxyanilino)-4-phenylbenzoate.
Reaction SMILES: CC([O-])=O.[Na+].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1.Cl.[OH:19][NH2:20]>O.CCO>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[N:20][OH:19])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: NO
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCOc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
NaOAc (3.78 g, 46.2 mmol) in H2O (30 mL) was added to a soln of 7-bromo 4-chromanone (3.5 g, 15.4 mmol) and hydroxyl-amine hydrochloride (1.75 g, 23.1 mmol) in EtOH (70 ml). The reaction was heated at reflux for 2 h, cooled to room temperature, and concentrated. The residue was diluted with H2O and a precipitate was filtered to give 7-bromochroman-4-one oxime obtained as the needle like crystals 3.5 g (98%). LCMS 244 (M+2H) RT=1.7 min (Condition 2); 1H NMR (DMSO-d6) 11.37 (s, OH, 1H), 7.76-7.70 (d, 1H), 7.09-7.13 (d, 2H), 4.16-4.20 (t, 2H), 2.79-2.83 (t, 2H).
Reaction SMILES: Cl.[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>O.CCOCC.[Zn]>[C:3]1([CH2:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a solution of 1 gm Hg2Cl2 in 30 ml H2O was added 1 ml of concentrated HCl followed by 24 gms powdered Zn (portion wise) with mechanical stirring. The resulting mixture was stirred together for 5 minutes, then the liquid phase was decanted off, and 15 ml H2O was added, followed by 36 ml concentrated HCl. This mixture was cooled to room temperature (the reaction to this point is exothermic), then 5.4 gms 11-benzoylundecanoic acid was added followed by 25 ml toluene. The resulting mixture was stirred and refluxed for 20 hours; 12 ml concentrated HCl was added during the first 6 hours of the reflux. The reaction mixture was cooled, the liquid was decanted, the phases were separated and the solid was three times triturated with 25 ml ether. The aqueous phase was 3×15 ml ether extracted; all organic phases were combined, washed with water and brine and dried over MgSO4. The drying agent was filtered off, and the solvents were removed in vacuo to give a solid residue. This residue was dissolved in ether, extracted with dilute NaOH, and the organic layer was discarded. The aqueous layer was acidified with concentrated HCl, then extracted with there. This ether solution was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to give 4.2 gms title product which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[O:4].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:19])[S-:18].C([NH+](CC)CC)C>C(Cl)Cl>[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:18])[S:19][CH2:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Reactant: O=C(CCl)CCl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Yield: 86.9 %

Procedure:
1,3-Dichloroacetone (2.0 g) was added to methylene chloride (100 ml) and thereto was added triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (5.0 g) (c.f. European patent publication No. 286089) while stirring at 2° to 5° C. After stirring for 60 minutes, the mixture was washed with 3N HCl and then with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of hexane - ethyl acetate - ether to give the title compound (4.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17]#[N:18])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][OH:29]>C(O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17](=[NH:18])[NH:28][OH:29])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(CC1CC1)(NC(=O)OCc1ccccc1)C(=N)NO
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To a solution of (1-Cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid benzyl ester (Example 66b, 795 mg, 3.08 mmol) in ethanol (10 ml) were added triethylamine (343 mg, 472 μl, 3.39 mmol) and hydroxylamine hydrochloride (214 mg, 3.08 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (640 mg, 71%) as a white solid. MS (ESI, m/z): 292.5 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield by reaction of 3.70 g (9.0 mmol) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester with 18 ml trifluoroacetic acid in 75 ml dichloromethane, MS m/e (%): 293.1 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[CH:13]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:17][NH2:18]>C(O)C>[CH:1]1([N:6]2[C:7]3=[CH:13][N:17]=[N:18][C:11]([NH2:12])=[C:8]3[CH:9]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN
Reactant: N#Cc1ccn(C2CCCC2)c1C=O
Agent: Cl
Solvent: CCO
Product: Nc1nncc2c1ccn2C1CCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-cyclopentyl-2-formyl-1H-3-pyrrolecarbonitrile (0.525 g, 2.79 mmol) and hydrazine dihydrochloride (0.35 g, 3.35 mmol) in ethanol (30 mL) was heated at reflux for 2.5 hours then cooled to ambient temperature and purified by preparative reverse phase HPLC to give the title compound as a hydroscopic glass contaminated with ammonium acetate (594 mg) (60% by weight as determined by 1H NMR, yield=337 mg; 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1H), 7.55 (d, 1H), 6.71 (d, 1H), 6.10 (bs, 2H), 4.94 (m, 1H), 2.15 (m, 2H), 1.89 (m, 4H), 1.70 (m, 2H); 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 19.46 min.; LC/MS: MH+ 203.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[Cl:1][C:2]1[C:3]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Temperature: 130 °C

Procedure:
To a nitrogen gas purged mixture of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.488 mmol), and (2-methoxyphenyl)boronic acid (96 mg, 0.64 mmol) in 2 M aqueous sodium carbonate (0.610 mL, 1.22 mmol) and DME (3.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.049 mmol). The reaction was sealed and heated at 130° C. for 30 minutes. The reaction was then diluted with EtOAc and passed through a column of Celite and sodium sulfate to remove water and solids. The reaction solution was concentrated under reduced pressure and the crude product purified by silica chromatography eluting with 1-20% ethyl acetatehexane to afford 4-chloro-5-(2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a solid. LRMS (ESI) calcd for C19H25ClN3O2Si [M+H]+: 390, found 390.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH2:32]O)[CH:31]=1)[C:26]([NH2:28])=[O:27]>C(#N)C>[Br:20][CH2:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:31]=1)[C:26]([NH2:28])=[O:27]
Reactant: NC(=O)c1cc(Cl)cc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: NC(=O)c1cc(Cl)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 2) Triphenylphosphine (1.27 g) was suspended in acetonitrile (50 ml), bromine (0.25 ml) was added, and the suspension was stirred for 30 min. 3-Chloro-5-(hydroxymethyl)benzamide (0.90 g) obtained in Step 1 was added to the reaction mixture, and the mixture was stirred at 85° C. for 2 hr. The reaction solution was quenched with water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1) to give 3-(bromomethyl)-5-chlorobenzamide (0.54 g).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br-].S(C)C.FC(F)(F)S([O-])(=O)=O.[Cl-].[NH4+].[O:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>ClCCl>[C:7]1([CH2:6][CH2:5][CH2:10][CH:9]2[CH2:8][CH2:7][C:6]3[C:31](=[CH:30][CH:29]=[CH:28][CH:5]=3)[O:27]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCc1ccccc1
Reactant: C1CCOC1
Agent: II
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: CSC
Solvent: ClCCl
Product: c1ccc(CCCC2CCc3ccccc3O2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A suspension of magnesium (0.304 g, 12.6 mmol) in dry tetrahydrofuran (5 ml) with a iodine crystal was added drop by drop and under inert atmosphere with a solution of 2-bromoethylbenzene (1.72 ml, 12.6 mmol) in dry tetrahydrofuran (12 ml). The reaction, started during the bromide addition, was left at room temperature for 2.5 h. After that a solution of CuBr.(CH3)2S (163 mg, 0.79 mmol) in tetrahydrofuran (2 ml) and a solution of 2-chromanemethyl trifluoromethanesulfonate (1.381 g, 4.67 mmol) in tetrahydrofuran (5 ml) were added successively at 0° C. and the mixture was left under stirring at 0° C. for 2.5 h. After this time, the mixture was poured slowly onto a mixture of dichloromethane (25 ml) and an ammonium chloride saturated aqueous solution (20 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (4×25 ml). The combined organic extracts were dried and the solvent was evaporated off under reduced pressure, to obtain a crude which was purified by chromatography through a silica gel column, eluting with hexane:dichloromethane, 9:1, to recover 0.990 g of the title product (85% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH:8]=1.O.[OH-].[Li+]>C(Cl)Cl.O1CCCC1.O>[CH2:3]([N:2]([CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=1)[CH3:1])[CH3:4]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CCNC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
N-methylethanamine (96 μL, 1.1 mmol) was added to a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.13 g, 0.28 mmol, prepared as in Example 5, Step A) in methylene chloride (2.6 mL). After stirring for 30 minutes, solvent was removed in vacuo. The ester was hydrolyzed by stirring with lithium hydroxide monohydrate (0.12 g, 2.8 mmol) in tetrahydrofuran (4 mL) and water (2 mL) for 1 hour. 1N HCl was added dropwise to adjust the pH to 7. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.043 g (58%); LC-MS: 264.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 8.03 (s, 1H), 3.75 (s, 2H), 2.51 (q, 2H), 2.22 (s, 3H), 1.05 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2>[Pd]>[CH3:15][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([NH2:12])[CH:10]=[CH:11][CH:2]=2)[CH2:7]1
Reactant: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Agent: [Pd]
Product: CN1CCc2cccc(N)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 250 mL 3-necked round bottom flask was added a solution of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline (4.85 g, 17.89 mmol) in CH3OH/Et3N(anhydrous) (150/15 mL). To the mixture was added Pd/C (4.5 g). Hydrogen gas was bubbled into the mixture The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 50 mL of Na2CO3 (10%). The resulting solution was extracted four times with 50 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 50:1 CH2Cl2/MeOH solvent system. This resulted in 2.57 g (89%) of 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine as a light yellow oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.CC(C)=O>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([C:29]([F:31])([F:32])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C(F)(F)F)n1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cn(C)nc6C(F)(F)F)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47.5 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with 3 mL of acetone yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.C([NH2:24])=O.C[O-].[Na+].CO>CN(C=O)C>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH:5]([C:3](=[O:2])[NH2:24])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: NC=O
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(C(N)=O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.66 g. 2.21 mmol) in anhydrous DMF (13 mL) was added formamide (370 μL, 9.32 mmol). The mixture was heated to 100° C. and a solution of sodium methoxide in MeOH (25 w/w. 330 μL, 1.44 mmol) was added with heating being continued for 2 h. The reaction mixture was cooled to RT, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (40 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (280 mg, 69%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:43][CH2:44][NH:45][C:46](=[O:48])[CH3:47])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(=O)NCCO
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (560 mg, 5.44 mmol) N-2-hydroxyethyl-acetamide and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.