Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:9])=[C:4](F)[CH:3]=1.BrC1C=CC(/C(=N\NC2C=CC=CC=2)/C)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:9])=[N:10][N:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C/C(=N\Nc1ccccc1)c1ccc(Br)cc1F
Agent: C/C(=N/Nc1ccccc1)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of (E)-1-(1-(4-bromo-2-fluorophenyl)ethylidene)-2-phenylhydrazine and (Z)-1-(1-(4-bromo-2-fluorophenyl)ethylidene)-2-phenylhydrazine (24 g, 78.18 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL), potassium carbonate (57 g, 413.04 mmol, 5.30 equiv). The resulting solution was stirred for 2 days at 100° C. in an oil bath. The resulting mixture was cooled to room temperature with a water/ice bath, then concentrated under vacuum. The residue was dissolved in water (200 mL). The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined and dried over anhydrous sodium sulfate, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20), the resulting mixture was washed with petroleum ether (1×10 mL) to yield 6-bromo-3-methyl-1-phenyl-1H-indazole as a yellow solid. 1HNMR (400 MHz, CDCl3, ppm): δ 2.64 (3H, s), 7.30-7.87 (8H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24][CH2:23]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To a 100-mL round-bottomed flask was added 4,6-dichloro-2-(methylthio)pyrimidine (2.0 g, 10.25 mmol, Sigma-Aldrich) and 4-(n-boc-amino)-piperidine (2.053 g, 10.25 mmol, Sigma-Aldrich) in DCM (25 mL) followed by Et3N (2.139 mL, 15.38 mmol). The reaction was stirred at RT for 5 h, then diluted with DCM (100 mL). The mixture was washed with water, brine, dried MgSO4, filtered and concentrated to give crude tert-butyl 1-(6-chloro-2-(methylthio)pyrimidin-4-yl)piperidin-4-ylcarbamate (3.80 g, 100%) as a white solid. MS (ESI, pos. ion) m/z: 359.0 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1.OS(O)(=O)=O>>[Cl:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)ccc(Cl)c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(Cl)ccc(Cl)c21
Temperature: 25 °C

Procedure:
80 g of a mixed acid containing 33% of HNO3 are added dropwise at 5° to 10° C. in the course of 2 to 4 hours to a solution of 110.0 g of 1,4-dichloroanthraquinone in 600 ml of 96% strength H2SO4. The mixture is allowed slowly to warm to room temperature, and is then stirred for a further few hours, and the precipitated 1,4-dichloro-5-nitroanthraquinone (112.6 g) is filtered off with suction. The mother liquor is stirred into 2 liters of water. The solids are then filtered off with suction, and the press cake is washed with water until neutral and dried at 100° C. 12.7 g of 1,4-dichloro-6-nitroanthraquinone are isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[C:18]1([NH:26][CH2:27][CH2:28][NH2:29])[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:29][CH2:28][CH2:27][NH:26][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cccc(C)c1NCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: Cc1cccc(C)c1NCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N-(2,6-xylyl)ethylenediamine in DME. ES-MS m/e (%): 349 (M+H+, 100), 228 ([M+H—C8H11N]+, 65).
Reaction SMILES: [OH:1][C:2]1([C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[F:25][C:26]1[C:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29](F)=[O:30]>ClCCl>[F:25][C:26]1[C:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[C:28]([C:29]([N:4]2[CH2:3][C:2]([C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])([OH:1])[CH2:5]2)=[O:30])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (200 mg, 0.92 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (228 μL, 1.38 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (prepared according to the procedures described in Reference 1) (363 mg, 0.92 mmol). The mixture was stirred at rt for 16 h, after which the volatile materials were removed in vacuo. The residue was purified by column chromatography (50% hexanes:50% ethyl acetate) to provide 1,1-dimethylethyl {(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a colorless film (333 mg, 0.56 mmol, 61% yield). 1H NMR (400 MHz, CDCl3) δ 8.47 (br s, 1H), 7.40 (dd, 1H), 7.32 (d, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.74 (br d, 1H), 4.22 (d, 1H), 4.15-4.07 (m, 2H), 3.96 (br s, 1H), 3.77 (m, 1H), 1.43 (s, 9H), 1.18 (d, 3H); MS (EI) for C23H25F3IN3O4: 536 (M−tert-butyl+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>>[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CCCc1ccccc1N
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Product: COC(=O)CCCc1ccccc1Nc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Heat 259.8 mg (0.771 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 228 mg of 4-(2-aminophenyl)butanoic acid methyl ester (85% strength, approx. 1.0 mmol) to 150° C. overnight. After cooling, concentrate under reduced pressure, add dichloromethane to the residue and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 50:1→10:1). The product thus obtained is purified further by preparative RP-HPLC. 33.1 mg (8.7% of theory) of the target product are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)=O.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>O1CCCC1>[OH:2][CH2:3][C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2csc(CO)c2c(=O)n1-c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a solution of 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (0.2 g) in tetrahydrofuran (4 mL) was added diisobutylaluminum hydride (1.01 mol/L toluene solution, 1.5 mL) under ice-cooling, and the mixture was stirred for 1 hour. To the reaction mixture was added ethyl acetate, and the mixture was stirred for 10minutes. To the mixture was added 1 mol/L hydrochloric acid, 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=1/1) to give the title compound (0.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH2:20][CH2:21][OH:22])=[CH:13][C:12]=3[F:23])[C:3]=12.[OH-].[K+].[CH3:27]I>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:24])[CH:9]=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH2:20][CH2:21][O:22][CH3:27])=[CH:13][C:12]=3[F:23])[C:3]=12
Reactant: Cn1cc(-c2cc3c(cc2F)CCN3CCO)c2c(Br)ccnc21
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCN1CCc2cc(F)c(-c3cn(C)c4nccc(Br)c34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of 2-(6-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoroindolin-1-yl)ethanol (D41) (150 mg, 0.384 mmol) in DMSO (3 mL) was added potassium hydroxide (64.7 mg, 1.153 mmol) followed by methyl iodide (0.036 mL, 0.577 mmol). The reaction mixture was stirred at RT for 1 hour, after which an additional 0.5 eq of methyl iodide (0.012 mL) was added. The reaction mixture was stirred for an additional hour. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution (20 mL). The aqueous layer was extracted with DCM (3×40 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated. The crude was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford title compound (106 mg). LCMS (A): m/z (M+H)+ 404/406, C19H19BrFN3O requires 403/405 (acidic).
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][CH2:40]Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:39][CH2:40][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 0.5 h

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (3 grams) was added to about 40 ml of dry dimethylformamide (DMF) and stirred for about 30 minutes. Then 4.0 ml of chloromethyl pivalate in 5 ml of DMF was added. The mixture was stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: O1CCCCC1[N:7]1[C:19]2[CH:18]=[C:17](O)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.BrC1C=C(N2C(C)=CC(C)=N2)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>[Cu]I.C(OCC)(=O)C.O.O1CCOCC1>[CH:9]1[C:8]2[NH:7][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc2c3ccccc3n(C3CCCCO3)c2c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cc1cc(C)n(-c2cccc(Br)c2)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
In another step, 2-[3-(3,5-Dimethylpyrazol-1-yl)-phenoxy]-Netrahydropyranyl) carbazole was synthesized. To a 100 mL sealed tube was added with N-tetrahydropyranyl-2-hydroxycarbazole (880 mg, 3.0 mmol), N-(3-Bromophenyl)-3,5-dimethylpyrazole (826 mg, 3.30 mmol), Cesium carbonate (2.9 g, 3 mmol), copper(I) iodide (57 mg, 0.3 mmol), N, N-dimethylglycine (93 mg, 0.9 mmol) and 1,4-dioxane (8 mL) in glove box, and the mixture was stirred at 90° C. for 3 days. After cooling to rt, the mixture was treated with water (75 mL) and ethyl acetate (40 mL), and the water phase was extracted with ethyl acetate (3×30 mL). The organic extracted phase was combined, washed with brine (3×30 mL), dried with magnesium sulfate and concentrated. The resulting crude product was purified with an silica gel chromatography with hexane/ethyl acetate=3:1 as eluent to give an white colloidal solid. (1.12 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl
Yield: 93 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (4.06 g, 20 mmol, commercially available) and thionyl chloride (5 mL) was heated under reflux for 3 h. Evaporation of all volatiles afforded 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (4.4 g, 93%) as yellow oil, which was used without further purification in the next reaction. To a mixture of an aqueous solution of 2-picolylamine (0.182 g, 1.68 mmol) in water (2 mL) and ethyl acetate (4 mL) were added sodium hydrogen carbonate (362 mg, 4.2 mmol) in one portion. Then, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.31 g, 1.4 mmol) in ethyl acetate (2 mL) was added dropwise with vigorous stirring under ice-bath cooling keeping the temperature at 0° C. After addition, the reaction mixture was stirred at room temperature for 18 h. The resulting solution was then diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were then washed with brine, dried over sodium sulphate) and concentrated to afford the title compound (0.38 g, 93%) as a white solid. MS: m/e: 294.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1ccc(CBr)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-chloro-4-methoxybenzene (1.0 g, 4.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (550 mg, 3.9 mmol), and triethylamine (585 μL, 4.2 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with water (2×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (929 mg, 81% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.76 (s, 3H), 4.41 (s, 2H), 6.00 (s (br), 1H), 6.89 (dd, 1H, J=2.5 Hz, 8.6 Hz), 7.07 (d, 1H, J=8.6 Hz), 7.52 (d, 1H, J=8.6 Hz); M+297.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21].C(Cl)(=O)C(Cl)=O.[CH:30]1[CH:31]=[CH:32][N:33]2[CH2:39][C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[NH:36][CH2:35][C:34]=12.CCN(C(C)C)C(C)C>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:9]([N:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[CH2:39][N:33]2[CH:32]=[CH:31][CH:30]=[C:34]2[CH2:35]1)=[O:11]
Reactant: COc1cc(-c2ccccc2C(F)(F)F)c(OC)cc1C(=O)O
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2C(F)(F)F)c(OC)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Yield: 36.5 %

Procedure:
The title compound was prepared in the manner of Example 31, Step A using 2,5-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid of Step A (1.63 g, 5 mmol), oxalyl chloride (700 μL, 8 mmol), N,N-dimethylformamide (10 μL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.93 g, 5 mmol) and Hünig's base (1.78 ml, 10 mmol). Flash chromatography over silica gel using a solvent gradient from 30% ethyl acetate in hexane to 100% ethyl acetate provided the title compound (0.900 g) as a solid. Recrystallization from acetonelhexane yielded white needles, m.p. 210–213° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:12]>O1CCCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:9][C:8]([NH2:12])=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: N
Reactant: N#Cc1cc(F)c(F)cc1F
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(N)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
515 g of 2,4,5-trifluorobenzonitrile in 2000 ml of tetrahydrofuran are introduced into an autoclave and heated to 100° C. 250 ml of liquid ammonia are then pumped in at such a rate that the temperature remains in the range from 100 to 105° C. The mixture is then stirred at this temperature for 8 h and then cooled. The pressure reaches a maximum of 22 bar gauge. After the ammonia has been blown off, the solvent is removed using a rotary evaporator. The residue is stirred into 500 ml of water and placed on a suction filter. After filtering with suction, the residue is again slurried with 200 ml of water and filtered with suction. Drying in a vacuum at 40° C. gives 482 g (95.4% of theory) of 4-cyano-2,5-difluoroaniline having a melting point of from 99 to 100° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:32])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2cccc(C)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2cccc(C)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2,5-dioxo-4-(3-methylphenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile (829 mg) in DMF (1.5 mL) is added potassium carbonate (320 mg) and methyliodide (480 μL). The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over MgSO4 and concentrated to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:52])([F:51])[F:50])[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1>>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]([F:50])([F:51])[F:52])=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Oc1ccc(-c2ccccc2C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 71 %

Procedure:
Prepared according to Preparation 22 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 291 mg, 0.63 mmol) and 3-pyridazin-4-yl-2′-(trifluoromethyl)biphenyl-4-ol (Preparation 9, 200 mg, 0.63 mmol) to afford the title compound as a solid (339 mg, 71%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36](C)=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:38])[NH:34][C:33]=2[CH:40]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (52.2 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)[CH2:14][OH:15])[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To an ice-cold solution of 1.18 g (2.68 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-(4,4-difluoro-cyclohexyl)-acetic acid in 20 ml tetrahydrofuran was added 0.15 g (4.01 mmol) lithium aluminium hydride. After removal of the cooling bath the reaction mixture was stirred for 1.25 h at room temperature. The reaction mixture was poured onto 100 ml aqueous saturated potassium sodium tartrate solution, the phases were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining oil was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (39%). MS (Turbo Spray): m/z=427.1 [M+H].