Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15](OC)[O:16]C)=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[O:16])=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1CC=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of 2-tert-butyl-3-(2,2-dimethoxy-ethyl)-6-nitro-1H-indole (0.80 g, 2.6 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL, 50%) at 0° C. and the resulting solution was stirred at room temperature for 6 h. Saturated sodium bicarbonate was added until pH>7. The aqueous layer was extracted with methylene chloride several times. The combined organic layers were dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.62 g, 91%). LCMS (m/z): 261.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:35][C:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2-amino-2-phenylpropane (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 67 mg of the title compound as a colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:37]7[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 55.6 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 211 (1 g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool down, the volatiles were removed under vacuum. The residue was triturated with H2O and finally with EtOH to yield 0.572 g of the title compound (yield: 55%). 1H NMR (300 MHz, d6-DMSO): δ 2.71 (s, broad, 4H), 2.86–3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93–6.95 (dd, 1H, J=8.2 Hz, 1.9 Hz), 7.00 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=1.9 Hz), 7.24–7.30 (m, 3H), 7.38–7.41 (dd, 1H, J=8.2 Hz, 1.74 Hz), 7.49 (s, 1H), 8.12 (s, 1H), 10.32 (s, 1H). M+1=573.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:8]([C:9](O)=[O:10])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:8]([C:9]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:10])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: CCCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 3 h

Procedure:
4-Butyloxyquinaldic acid (0.83 g) in dry dimethylformamide (25 ml) was treated with N,N'-carbonyldiimidazole (0.55 g) and the mixture stirred at 60° for 3 hours. 5-Aminotetrazole (0.35 g) was added and the solution kept 72 hours and evaporated to a volume of 5 ml. Dilute hydrochloric acid was added and the 4-butyloxy-N(1H-tetrazol-5-yl)quinaldamide formed was crystallised from aqueous dimethylformamide, m.p. 282° (d).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][OH:46].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[CH2:45][OH:46])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OC[C@@H]1CCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC[C@H]3CO)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 68.7 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (119 mg, 0.208 mmol) was dissolved in N,N-dimethylacetoamide (1.2 mL), and the solution was treated with (S)-(+)-2-pyrrolidinemethanol (0.205 mL, 2.08 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain (S)-4-chloro-5-[3-(2-hydroxymethylpyrrolidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (91.0 mg, yield 69%).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H].O1C2C(=CC=CC=2)C=CC1=O>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: O=c1ccc2ccccc2o1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mMol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 μl acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product. 1H NMR (dDMSO): δ1.02 ppm (t, 3H, J=7.4 Hz, butyric methyl), δ1.73 ppm (m, 2H, J1 ≈J2 =7.3 Hz, butyric methylene), δ2.70 ppm (t, 2H, J=7.2 Hz, butyric methylene), δ4.07 ppm (d, 2H, J=5.6 Hz, glycine methylene), δ7.67 ppm (s, 1H, coumarin), δ8.35 ppm (s, 1H, coumarin), δ8.90 ppm (s, 1H, coumarin), δ9.00 ppm (t, 1H, J=5.6 Hz, amide).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>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.CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12]([NH2:20])=[N:11][C:10]2([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)[CH:3]=1)[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1
Reactant: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1-c1cnccn1
Yield: 54.8 %

Procedure:
1-(3-Bromo-4-methoxyphenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (1.5 g, 3.12 mmol), 2-tributylstannylpyrazine (1.268 g, 3.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.361 g, 0.31 mmol) and DMF (10 mL) were heated in a microwave oven for 20 min at 150° C. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with DCM (40 ml) and silica powder was added and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% 0.1M NH3 in Methanol in DCM) to afford the title compound (0.82 g, 54.8%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH2:7](Br)[C:8]#[CH:9]>>[CH2:9]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])[C:8]#[CH:7]
Reactant: O=C1CCCN1
Reactant: C#CCBr
Product: C#CCN1CCCC1=O
Yield: 58 %

Procedure:
As in Example 6, 15 g (0.18 mol) of 2-pyrrolidinone and 18.65 mL (1 equivalent) of propargyl bromide were reacted, then distilled in vacuo (66˜71° C./0.1 mmHg) to obtain 11.94 g (58% yield) of 1-propargyl pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].C(=O)(O)[O-].[K+]>CCO.O>[Br:1][C:2]1[CH:8]=[C:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: C#CC(=O)OCC
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Br)no1
Yield: 78 %

Procedure:
Dibromoformaldoxime (407 mg, 2.07 mmol) (prepared via the procedure of J C Rohloff, et. al., Tetrahedron Lett 1992, 33:3113-6), and ethyl propiolate (311 mg, 3.17 mmol) were dissolved in 10 ml of 50% aqueous EtOH. While stirring, a solution of 243 mg (2.43 mmol) of potassium bicarbonate in 5 ml of water was added dropwise over 1 h. The resulting solution was stirred for an additional 4 h, diluted with 25 ml of water, and extracted with chloroform (3×25 ml). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to a colourless oil, 345 mg (78% yield) as a 7:1 mixture of the 5- and 4-carboxylates.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:24])([CH3:25])[C:22]#[C:23][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: C#CC(C)(C)OCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)COC(C)(C)C#Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-bromo-4′-chloro-4-methylbiphenyl (12.6 g, 44.7 mmol) and (1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester (prepared according to WO2001/066544) (8.4 g, 53.8 mmol) in triethylamine (70 ml) is added bis(triphenylphosphine)palladium(II) dichloride (0.63 g, 0.9 mmol) and copper(I) iodide (0.34 g, 1.8 mmol). The reaction mixture is degassed and flushed with nitrogen (×3), then stirred under nitrogen at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth to remove the catalyst, and the filtrate evaporated in vacuo. The residue is resubjected to the same reaction conditions (8.4 g 1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester, 0.63 g bis(triphenylphosphine)-palladium(II) dichloride, 0.34 g copper(I) iodide in 70 ml triethylamine under nitrogen) and stirred at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth, then concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate 3:1) to afford [3-(4′-chloro-4-methylbiphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid methyl ester (6.70 g,) as an oil.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH2:6]([O:5][C:3]([C:2]([F:9])([F:8])[C:11]1([OH:10])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Powdered zinc (2.82 g, 0.043 mol) was suspended in tetrahydrofuran (50.0 mL) under flow of argon gas, and the suspension was mixed with ethyl bromodifluoroacetate (7.31 g, 0.036 mol) at room temperature, followed by stirring under reflux for five minutes. The mixture was further mixed with a solution of tert-butyl 4-oxopiperidinecarboxylate in tetrahydrofuran (3.00 mol/L, 10.0 mL, 0.030 mol), followed by stirring under reflux for two hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with ethyl acetate and diluted hydrochloric acid (1.00 mol/L), followed by separation. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: chloroform=1:9) and thereby yielded tert-butyl 4-(ethoxycarbonyldifluoromethyl)-4-hydroxy-piperidinecarboxylate (7.39 g, 76%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1.[C-:27]#[N:28].[Na+]>>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1)#[N:28]
Reactant: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Yield: 74.4 %

Procedure:
1-(8-Bromooctyl)-4,5-diphenyltriazole (ex. example 60a) (1.8 g) was reacted with sodium cyanide in a method similar to Example 60b). Work-up and recrystallisation from dichloromethane and hexane gave 1-(8-cyanooctyl)-4,5-diphenyltriazole (1.16 g, 74.4%) as a white solid, m.p. 77°-8° C. Found: C, 77.03; H, 7.25; N, 15.35%; C23H26N4 requires: C, 77.06; H, 7.31; N, 15.63%.
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[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[O:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[O:39]1[CH2:40][CH:41]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)[CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5=CCOCC5)cc34)n2)C1
Temperature: 150 °C
Yield: 80.2 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (260 mg, 0.445 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (140 mg, 0.667 mmol), potassium phosphate (283 mg, 1.334 mmol), and PdCl2(Amphos) (31.5 mg, 0.044 mmol) in dioxane (4044 μL) and water (404 μL) was heated in the microwave for 10 min at 150° C. The crude was purified via automated flash chromatography (silica gel) with 100% hexanes to 40% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (210 mg, 0.357 mmol, 80% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 588.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(NC3CCC3)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(NC5CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and cyclobutyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 172.1.1) to give the title compound as a white solid. (HPLC: tR 2.29 min (Method A); M+H=440 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 2H), 7.93-7.84 (m, 3H), 7.58-7.55 (m, 1H), 6.80-6.76 (m, 1H), 6.34 (d, 1H), 3.94-3.85 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 2.44-2.34 (m, 2H), 1.96 (s, 3H), 1.93-1.73 (m, 4H))
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CN(C=O)C>O>[CH2:27]([O:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=1)[CH:26]=[CH2:25]
Reactant: Oc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A mixture of 4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (7.7 g), potassium carbonate (7.1 g), allyl bromide (6.0 g) and DMF (100 ml) was stirred at 50°-60° C. for 3 hours. After cooling the mixture, water was added and the mixture was extracted with ether. The ether layer was washed with water and dried, and the solvent was distilled off to obtain 8.8 g of 6-allyloxy-4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole. This compound (8.8 g) was refluxed in 100 ml of aniline for 3.5 hours. After cooling the mixture, concentrated hydrochloric acid and then water were added and the mixture was extracted with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was purified by column chromatography using 1% methanol/methylene chloride as an eluant, and 6.3 g of 7-allyl-4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (m.p. 211°-212° C.) was obtained. This compound (6.4 g) was dissolved in 300 ml of methylene chloride and 10.2 g of m-chloroperbenzoic acid was slowly added to the solution while it was stirred and cooled, and the stirring was continued for 3 hours. After cooling, water and then 50 ml of a 2N sodium hydroxide aqueous solution were added to the mixture, which was extracted with methylene chloride. The mehtylene chloride layer was washed with water and dried, then the solvent was distilled off to yield 5 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol. m.p. 109.5°-111° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]1.O[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C1COCC1>[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([O:38][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:34]1
Reactant: CN1CCC(O)C1
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccnc2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To 629 mg (2.4 mmol) of PPh3 in 13 mL of dry THF at −20° C. was added 378 μL (2.4 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 220 μL (2.0 mmol) of 1-methyl-3-hydroxypyrrolidine and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 190 mg (2.0 mmol) of 3-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (9:1, CHCl3:MeOH) to obtain 260 mg (72.9%) of a clear oil: 1H NMR (300 MHz, CDCl3) δ 8.26 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=4.2 Hz), 7.22-7.13 (2H, m), 4.85 (1H, m), 2.89-2.76 (3H, m), 2.48-1.95 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.6 (M+H+).