Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:14])#[C-:12].C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:7][CH:12]=[N:11][C:13]=2[CH3:14])=[CH:4][C:3]=1[F:10]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 4-bromo-3-fluorobenzaldehyde (1.02 g, 5.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.05 g, 5.0 mmol), and K2CO3 (0.83 g, 6.0 mmol) in methanol (20 mL) was heated to reflux. After 2.5 hr the mixture was cooled to ambient temperature and the volatiles evaporated. The residue was partitioned between Et2O and H2O. The separated aqueous phase was extracted with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 10% to 20% EtOAc/hexanes eluant; SF25-80 g column) yielded 1.04 g (81%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (dd, J=8.3, 7.5 1H), 7.57 (dd, J=10.1, 2.0 1H), 7.42 (dd, J=8.5, 2.0 1H), 2.38 (s, 3H). MS (DCI+) m/z 256/258 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:5].O1CCOCCOCCOCCOCCOCC1.[OH-].[K+].[Cl-].[NH4+]>ClCCl>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH2:2][CH2:3][C:4]2=[O:5])=[CH:8][CH:9]=1
Reactant: O=C(CCBr)Nc1ccc(C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1CCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.30 g of 3-bromo-N-[4-(trifluoromethyl)phenyl]propanamide (Example 153A, 66.16 mmol, 1 equivalent) were initially charged in 161 ml of dichloromethane, 18.54 g of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6, 70.13 mmol, 1.06 equivalents) and 3.86 g of potassium hydroxide (68.81 mmol, 1.04 equivalents) were added and the mixture was stirred at RT overnight. Saturated aqueous ammonium chloride solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. This gave 25.0 g (86% of theory; purity about 49%) of the title compound which was reacted further without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[F:17].C([O-])([O-])=O.[Cs+].[Cs+].[C:24]([Si](C)(C)C)#[C:25][CH2:26][CH3:27].N#N>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC(N(C)C)=O>[C:24]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[F:17])#[C:25][CH2:26][CH3:27]
Reactant: CCC#C[Si](C)(C)C
Reactant: Fc1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CC(=O)N(C)C
Product: CCC#Cc1ccc2c(c1)c(F)nn2C1CCCCO1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (6.2 g, 20.7 mmol; Intermediate 39), DMA (20 mL), CuI (393.3 mg, 2.07 mmol), Pd(OAc)2 (465.0 mg, 2.07 mmol), dppf (1.1 g, 2.07 mmol), Cs2CO3 (10.8 g, 33.1 mmol), and but-1-yn-1-yltrimethylsilane (3.4 g, 26.9 mmol; Intermediate 35) sequentially while N2 was bubbled through the solution. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (350 mL) and H2O (300 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:30) to afford the title compound as a yellow solid (3.9 g, yield 69.1%). 1H NMR (DMSO-d6, 400 MHz): δ 7.76-7.71 (m, 2H), 7.49 (d, 1H), 5.79 (dd, 1H), 3.88-3.85 (m, 1H), 3.74-3.71 (m, 1H), 2.44 (q, 2H), 2.24-2.21 (m, 1H), 2.01-1.91 (m, 2H), 1.70-1.65 (m, 1H), 1.57-1.54 (m, 2H), 1.18 (t, 3H); LCMS: 273 (M+H)+.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O>C(O)(=O)C>[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:1]
Reactant: Br
Reactant: COc1cc(Br)c(O)c(CO)c1
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c(CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 30 minutes, at room temperature, 20 g of hydrogen bromide are introduced into a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 300 ml of anhydrous acetic acid. The reaction mixture is stirred for 5 hours at room temperature and the resulting solution is concentrated by evaporation. The black-brown oily residue, which crystallises slowly when left to stand at room temperature, is crystallised from ethyl acetate/cyclohexane (5:1) with the addition of a small amount of activated charcoal. 3-Bromo-2-hydroxy-5-methoxy-benzyl bromide is thus obtained [1H-NMR (360 MHz, CDCl3); 3.75 (s, 3H, OCH3), 4.53 (s, 2H, CH2BR), 5.45 (s, 1H, OH), 6.85 (d, 1H), 7.00 (d, 1H) ppm].
Reaction SMILES: [CH2:1]([CH:5]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:29]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=1)=[O:11])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(CCCC)CCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC(CCCC)CCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-(6-butyldecanoyl)-1-indolyl]butyrate obtained in Ex. 21 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]1-indolyl]butyrate to give 4-[3-(6-butyldecanoyl)-1-indolyl]butyric acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1>[CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)N1CCOCC1
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
In anhydrous tetrahydrofuran was dissolved 6.9 g of the compound obtained in step (c) above, and 3 g of triethylamine and then 3.3 g of ethyl chlorocarbonate were added to the solution at 0° C. The mixture was stirred for 20 minutes. Into the liquid reaction mixture was dropped 3.1 g of morpholine at 0° C., and the mixture was stirred for 30 minutes. The liquid reaction mixture was extracted with n-hexane, and the extract was washed with water and dried. The solvent was removed by distillation and the residue was purified by column chromatography using silica gel to obtain 5.6 g of the intended compound in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH2:16][CH2:17][CH3:18])[CH:8]=2)=[CH:4][CH:3]=1.[Br:21]Br>O1CCOCC1.C(OCC)(=O)C>[Br:21][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH2:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(C)=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Reaction time: 2 h

Procedure:
To a solution of the product from Step 7 (1.2 g, 4.2 mmol) in dioxane (20 mL) at room temperature was added dropwise bromine (0.25 mL, 5.0 mmol). After 2 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with an aqueous solution of sodium thiosulfate and dried over magnesium sulfate. Removal of the solvent gave a residue which was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=O.O.[NH2:22][NH2:23]>CCO>[CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:23][N:22]=1
Reactant: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2n[nH]c(=O)c3ccccc23)c(C)c1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2,4,6-trimethylbenzoyl-benzoic acid (5.0 g, 18.7 mmol) and hydrazine hydrate (2 mL) in 15 mL of EtOH was stirred at reflux for 8 hours. The solvent was then removed from the mixture. The residue was heated to melt for about 10 minutes and then solidified by cooling. The resulting yellow solids were triturated with ether and filtered. The solid was washed with 1 N NaOH and water, and dried to give 1.8 g of titled compound as yellow solids, m.p. 259-62° C.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[CH3:15][N:16]1[C:28]2[C:27]3[N:26]=[C:25](SC)[N:24]=[CH:23][C:22]=3[CH2:21][CH2:20][C:19]=2[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:17]1.C(=O)(O)[O-].[Na+]>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.C(OCC)(=O)C>[CH2:2]([C:25]1[N:24]=[CH:23][C:22]2[CH2:21][CH2:20][C:19]3[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:17][N:16]([CH3:15])[C:28]=3[C:27]=2[N:26]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(SC)nc1-2
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: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(Cc3ccccc3)nc1-2
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere, a 0.5 M solution of benzylzinc bromide in THF (3.11 mL, 1.556 mmol) was added to a mixture of ethyl 1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (237 mg, 0.778 mmol) and Pd(PPh3)4 (9 mg, 0.0078 mmol, 1%). After 20 hours of heating at 60° C. under nitrogen, the mixture was cooled to room temperature, shaken with aqueous sodium bicarbonate and ethyl acetate and then filtered. The organic phase was then separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4, evaporated and the crude was purified on silica gel (eluant dichloromethane/methanol 97/3). 20 mg of the title compound were isolated.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:15]1=[O:38])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:35])[F:36])[C:15]1=[O:38])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Reaction time: 2 h
Yield: 68.3 %

Procedure:
3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.21 g, 2.27 mmol) was added to 50 mL of a stirring solution of 15% TFA/methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 100 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1-5% methanol/methylene chloride) gave 670 mg (68%) of a light pink foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].BrBr>C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:16])=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1ccc(C#N)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
A 5.0 g. portion of 6-(p-cyanophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (prepared as described in Example 44 of U.S. Pat. No. 3,824,271) is slurried in 25 ml. of acetic acid. A solution of 1.4 ml. of bromine in 25 ml. of acetic acid is added and the reaction mixture is heated on a steam bath for 30 minutes. A 400 ml. portion of ice water is added and the resulting solid is collected by filtration. This product is heated in 200 ml. of a mixture of ethyl acetate and methanol at the boiling point and filtered free of insolubles. The filtrate is concentrated to about 75 ml., cooled in ice and the resulting white solid collected and dried, yielding 6-(p-cyanophenyl)-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14](=[O:17])([O-])[O-].[K+].[K+].[I-].[K+].[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:22]([C:7]1[CH:6]=[C:14]([CH:10]=[CH:9][CH:8]=1)[O:17][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:25])[CH2:11][CH2:12][CH2:13][CH2:4][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCCCC(=O)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
This ketone (1.2 g) was refluxed with 2-chloromethyl-quinoline hydrochloride (1.3 g), potassium carbonate (8.6 g), potassium iodide (0.05 g) and cesium carbonate (0.05 g) in acetone (300 ml) for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated, dissolved in chloroform, and then washed with sodium hydroxide solution (5%), water and brine. After drying, all volatiles were removed. The residue was purified by chromatography on silica gel (25% ethyl acetate in hexanes). The pure desired product was isolated as a tan solid, m.p. 52°-55° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1.O.[OH-].[Na+]>CS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:9][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1cccc(Br)c1)c1nc2cc(F)ccc2[nH]1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol (example 437E, 3.30 g) and 1-methylpiperidin-4-ol (2.37 g) in methanesulfonic acid (10 mL) is heated overnight in a sealed tube at a temperature close to 140° C. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/1) to afford 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole. 1H NMR: 9.92 (sl, 1H), 7.60 (s, 1H), 7.55-6.85 (m, 6H), 5.80 (s, 1H), 3.65-3.50 (m, 1H), 2.80-2.65 (m, 2H), 2.34 (s, 3H), 2.15-1.65 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1cc(F)ccc1F
Product: N#Cc1cccnc1-c1cc(F)ccc1F
Yield: 66 %

Procedure:
Prepared in 66% yield from 2-chloronicotinonitrile and 2,5-difluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (CDCl3) δ 7.19-7.23 (m, 2H), 7.29-7.34 (m, 1H), 7.48 (dd, J=8.0, 4.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.92 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH2:37][C:34]([F:38])([F:33])[CH2:35]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:31])([F:32])[CH2:30]2)=[O:26])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: FC1(F)CNC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 134 using (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 119) and 3,3-difluoroazetidine. Off-white solid. MS (EI): 563.1 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.Cl[CH2:6][C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1.C(=O)([O-])O.[Na+]>CCO>[NH:8]1[C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:7]1[CH2:6][C:1]#[N:2]
Reactant: ClCc1nc2c([nH]1)CCCC2
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: N#CCc1nc2c([nH]1)CCCC2
Reaction time: 1 h
Yield: 92.1 %

Procedure:
An aqueous solution (30 ml) of potassium cyanide (15 g) was ice-cooled, then, an EtOH (140 ml) solution of 2-(chloromethyl)-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (12.0 g) was added, and stirring was performed at room temperature for 1 hour and then at 50° C. for 1, hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, followed by concentration under reduced pressure and extraction with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (28% aqueous ammonia/methanol/chloroform) to obtain 4,5,6,7-tetrahydro-1H-benzimidazol-2-yl acetonitrile (8.6 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)O)C1C=CC=CC=1>C(O)(=O)C>[OH:35][C:23]1[CH:22]=[C:21]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: OC(CCCCCCCCCCOCc1ccccc1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: OCCCCCCCCCCCc1ccc(O)c(O)c1
Yield: 68.9 %

Procedure:
In 40 ml of acetic acid was dissolved 4.4 g of 11-benzyloxy-1-(3,4-dibenzyloxyphenyl)-1-undecanol and the compound was catalytically reduced in the presence of 1 g of 10% palladium-carbon at room temperature and under atomospheric pressure until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and after adding 300 ml of water to the filtrate, the product was extracted twice each time with 70 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to provide a solid product. The solid product was recrystallized from 10 ml of a mixture of ethyl acetate and toluene (1:1) to provide 1.5 g of 11-(3,4-dihydroxyphenyl)-1-undecanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH2:46]([O:48][C:49](=[O:53])[CH2:50][CH2:51][NH2:52])[CH3:47].C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:46]([O:48][C:49](=[O:53])[CH2:50][CH2:51][NH:52][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([F:1])[CH:3]=1)[CH3:47]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Combine 3-Fluoro-4-hydroxy-benzoic acid (1.0 g, 6.4 mmol), PyBOP (4.0 g, 7.69 mmol), 3-amino-propionic acid ethyl ester hydrochloride (1.47 g, 9.6 mmol) and ethyl-diisopropyl-amine (4.55 mL, 25.6 mmol) in N,N-dimethyl-formamide (20 mL). Stir for sixty-six hours at room temperature. Dilute reaction with ethyl acetate and water. Wash organic layer with saturated solution of ammonium chloride and water. Extract combined aqueous fraction with ethyl acetate. Wash combined organic fractions with saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure. Purify on silica gel chromatography (20-80% Ethyl acetate/hexanes gradient) to provide 1.24 g of title compound (76%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:27]([N:23]1[CH:22]=[C:21]2[C:25]([CH:26]=[C:18]([C:10]3[CH:9]=[C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:2][CH2:3]4)[N:16]4[C:11]=3[C:12]([NH2:17])=[N:13][CH:14]=[N:15]4)[CH:19]=[CH:20]2)=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 7-azepan-4-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (17 pt, 0.22 mmol) and N,N-diisopropylethylamine (136 μL, 0.78 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (21%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.90 (s, 1 H), 7.78 (dd, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.14 (dd, 1 H), 6.61 (s, 1 H), 5.64 (s, 2 H), 3.19-3.56 (m, 4 H), 2.90 (s, 3 H), 1.66-2.20 (m, 7 H); ES-MS m/z 516.30 [M+H]+, HPLC RT (min) 3.07.