Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](Cl)=[O:27]>CC(C)=O>[CH3:1][O:15][C:7](=[O:16])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH:10][C:26](=[O:27])[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17]
Reactant: COc1ccccc1CC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1NC(=O)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a mixed solution of acetone (300 ml) and a 6% aqueous potassium carbonate solution (200 ml) there were added 10.2 g (67 mmol) of methyl ester of anthranilic acid. 12.5 g (67 mmol) of 2-Methoxyphenylacetic acid chloride were added dropwise under cooling thereto and the resulting reaction mixture was stirred at room temperature for 4 hours. The resulting precipitates were collected by filtration to obtain 15.7 g (yield 78%) of N-(2-methoxyphenylacetyl)-anthranilic acid methyl ester.
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16](=[O:20])[CH2:17][CH2:18][Cl:19])[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)(=O)=O.[H][H]>C(O)C.[Pd]>[Cl:19][CH2:18][CH2:17][C:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(C(=O)CCCl)cc2N1

Procedure:
3.0 Grams of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 0.5 g of palladium black were suspended in 200 ml of ethanol and the suspension was subjected to catalytic reduction under 3 atmospheric pressure of hydrogen gas at a room temperature for 5 hours under stirring condition. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was recrystallized from ethanol to obtain 1.2 g of 7-(3-chloropropionyl)-3,4-dihydrocarbostyril in colorless powdery-like crystals. Melting point: 159°-161° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:20]1([C:19](=[O:26])[CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Lithium diisopropyl amide (16.9 mL, 1.5 M in cyclohexane, 25.4 mmol) was added to THF (40 mL) at −78° C. A solution of 4-picoline (2.50 mL, 25.4 mmol) in THF (30.0 mL) was added dropwise to the LDA solution. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled down to −78° C. A solution of N-methoxy-N-methylbenzamide (1) (5.00 g, 29.6 mmol) in THF (20.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered, and the solvent was removed under vacuum to give the crude product. The crude material was triturated with hot hexane, and filtered to give 1-phenyl-2-(pyridin-4-yl)ethanone (2) as a yellow solid (3.53 g, 17.9 mmol, 70% yield).
Reaction SMILES: [ClH:1].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2([C:22]([NH:24][OH:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].BrC[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.[CH2:38](N(CC)CC)C.Cl>CO.C(OCC)C>[ClH:1].[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([C:16]2([C:22]([NH:24][OH:25])=[O:23])[CH2:21][CH2:20][N:19]([CH2:38][C:30]3[CH:29]=[CH:28][CH:37]=[CH:36][C:31]=3[C:32]([O:34][CH3:35])=[O:33])[CH2:18][CH2:17]2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:3]#[C:4][CH3:5]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCNCC2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(Cc3ccccc3C(=O)OC)CC2)cc1
Yield: 69.5 %

Procedure:
To 4-{[4-(2-butynyloxy)phenyl]sulfonyl-3-N-hydroxy-4-piperidinecarboxamide hydrochloride (prepared from Example 76) (2.5 g, 6.43 mmol) and methyl 4-(bromomethyl)benzoate (1.62 g, 7.07 mmol) in methanol (100 mL) at 50° C. was added triethylamine (2.25 mL, 16.1 mmol). After 30 min additional methanol (50 mL) was added. After 18 h the reaction mixture was concentrated in vacuo and 1N aqueous hydrochloric acid (10 mL) and water was added. The resulting solid was isolated and to it was added methanol (20 mL) and 1N hydrochloric acid in diethylether (15 mL). To the resulting solution was added diethyl ether. Trituration of the precipitate gave methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinyl}methyl)benzoate hydrochloride as a white powder (2.4 g). 1H NMR (dmso d6, 300 MHz) δ1.85 (t, 3H, CH3, J=2.2 Hz), 2.1-3.5 (m, 8H, CH2), 3.87 (S, 3H, OCH3), 4.40 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J=2.2 Hz), 7.1-8.1 (m, 8H, ArH), 9.3-11.2 (m, 31 NH, NHOH). Electrospray MS m/z 501.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>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>[F:11][C:12]1[CH:17]=[C:16]([CH:27]=[CH:28][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[NH:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccc(F)cc1
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: [Na+]
Solvent: CCOC(C)=O
Product: Fc1cccc(C=Cc2c[nH]c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of 4-bromoindole (1.0 g), which had been synthesized according to the method of J. Org. Chem. (1986, Vol. 5, No. 26, p. 5106.), 4-fluorophenylboronic acid (1.1 g), tetrakis(triphenylphosphine)palladium (0.24 g), a 10% aqueous solution (10 ml) of sodium carbonate and toluene (20 ml) was heated under reflux for 4 hr. Then ethyl acetate was added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system). To the resulting residue was added trifluoroacetic acid (10 ml) and a 1 M solution (6.8 ml) of a borane/tetrahydrofuran complex in tetrahydrofuran followed by stirring the mixture at 0° C. for 1 hr. After adding water, the resultant mixture was concentrated under reduced pressure. Then ethanol and an aqueous solution of sodium hydroxide were added thereto and the reaction mixture was stirred for 30 min. After adding ethyl acetate to the reaction solution, the layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.5 g) as a colorless oil (yield: 46%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24]>>[NH2:20][C:21]1[C:22]([C:23]#[N:24])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:7]
Reactant: N#Cc1c(N)cccc1F
Reactant: COc1ccc(CNC(=O)NCC(C)(C)CO)cc1
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Yield: 60 %

Procedure:
Prepared as in Example 197b (Method B) from 1-(3-hydroxy-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 218c) and 2-amino-6-fluorobenzonitrile in 60% yield. MS 383 (MH+).
Reaction SMILES: C[Si](C)(C)CCOC(=O)NC[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:23]=1.[F-].[CH2:28]([N+:32](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:28][NH:32][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][C:13]=2[CH:23]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOC(=O)NCc1ccc2oc(-c3ccccc3)nc2c1
Agent: [F-]
Solvent: C1CCOC1
Product: CNc1ccc2oc(-c3ccccc3)nc2c1
Yield: 27 %

Procedure:
Dissolve (2-phenyl-benzoxazol-5-yl-methyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (0.4, 0.99 mmol) in anhydrous THF (5 mL) and treat with 1M tetrabutylammonium fluoride in THF (1.5 mL, 1.54 mmol). Heat the mixture at reflux for 30 min, evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.1 g, 27%).
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CS(C)=O>[CH:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)=[CH:16][CH:17]=1)([CH3:25])[CH3:24]
Reactant: CC(C)OCc1ccc(Cc2ccc(NC(=O)OCC[Si](C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)OCc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid 2-trimethylsilanylethyl ester (734 mg, 1.84 mmol) in dry dimethyl sulfoxide at 20° C. under argon atmosphere was added tetra-n-butylammonium fluoride in tetrahydrofuran (5.52 mL, 5.52 mmol). After the mixture was stirred for 1 hour, the solution was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous phase was extracted with diethyl ether (2×20 mL), and the combined organic layers were washed with water and brine, dried (Mg2SO4), and evaporated in vacuo. The crude product was purified by flash chromatography to give pure 4-(4-isopropoxymethyl-benzyl)-phenylamine (405 mg, 86%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:12]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Reaction time: 72 h
Yield: 82.8 %

Procedure:
A suspension of 3-hydroxy-4-methoxybenzaldehyde (30 g, 0.2 mol), cyclopentyl bromide (35.77 g, 0.24 mol) and potassium carbonate (38.6 g, 0.28 mol) in N,N-dimethylformamide (200 ml) was stirred vigorously for three days. Water (300 ml) was added and the mixture was extracted four times with ethyl acetate. The combined organic extract was washed three times with 10% aqueous sodium hydroxide solution, once with water, once with brine, dried (sodium sulfate) and evaporated to provide the title compound as a clear orange oil (36.47 g, 83%). 1H-NMR (400 MHz, CDCl3): δ 9.84 (s, 1H), 7.43 (dd, 1H, J=8.3 Hz, 1.8 Hz), 7.39 (d, 1H, J=1.8 Hz), 6.96 (d, 1H, J=8.3 Hz), 4.86 (m, 1H), 3.93 (s, 3H), 2.0 (m, 2H), 1.8-1.95 (m, 4H), 1.63 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[C:18]([O:22][C:23](=[O:33])[N:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([N:24]([CH3:25])[C:23](=[O:33])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:27][CH2:28]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (335 mg, 1.07 mmol) was reacted with tert-butyl-(trans)-4-aminocyclohexyl(methyl)carbamate (366 mg, 1.61 mmol) to afford the desired product (470 mg, 87%) as an orange foam: ESI MS m/z 502 [C25H32BrN3O3+H]+.
Reaction SMILES: [CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([O:18]C)=[O:17])[CH:2]=1.[OH-].[K+].C(O)C.O1CCOCC1>O>[CH:1]1[C:6]2[CH:7]=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=[O:17])[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1N=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 269 mg. (1 mmole) of the ester of Example 9 to a solution of 132 mg. (2 mmole) of 85% aqueous potassium hydroxide in a mixture of 6.5 ml. of ethanol, 0.65 ml. of dioxane and 1.3 ml. of water. Stir at room temperature for 2 hours. Filter and evaporate the solution to a small volume. Dilute with 9 ml. of water and acidify with acetic acid. Filter wash the solids with water and dry. Dissolve the product in 9 ml. of hot tetrahydrofuran, filter and dilute with 9 ml. of methanol. Evaporate to a thick slurry, dilute with 2 ml. of methanol, filter and wash with methanol. Dry to obtain the title product, (m.p. sinters 289° C., m.p. 290°-291° C. dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9][CH2:8]1.C(=O)([O-])O.[Na+].FC(F)(F)S(O[CH2:36][CH:37]([F:39])[F:38])(=O)=O>C(O)C.C(Cl)Cl>[F:38][CH:37]([F:39])[CH2:36][N:9]1[CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccn1)O2
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(c1ccccn1)O2
Temperature: 80 °C

Procedure:
To tert-butyl 10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (63 mg, 0.19 mmol) in ethanol was added sodium hydrogen carbonate (64 mg, 0.76 mmol) followed by the addition of 2,2-difluoroethyl trifluoromethanesulfonate (49 mg, 0.23 mmol) and reaction mixture was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature and diluted with DCM and the organic layer was washed with 1:1 NaOH:NaHCO3 solution. The organics were separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate as an oil. To the oil was added HCl (237.5 μL of 4 M in dioxane, 0.95 mmol) at room temperature under an atmosphere of nitrogen and the reaction mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was triturated with ether to give 8-(2,2-difluoroethyl)-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (45 mg, 79%). ESI-MS m/z calc. 297.3. Found 298.4 (M+1)+; Retention time: 0.35 minutes (3 min run).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:32]([C:34]1[CH:39]=[C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:37]=[CH:36][CH:35]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(C#N)c3)c2c1
Yield: 3.4 %

Procedure:
N-[3-(3-Cyanophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.75 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 380 mg of 3-cyanophenylboronic acid, 30 ml of dimethylformamide, 2.85 ml of a saturated aqueous sodium hydrogencarbonate solution and 37 mg of tetrakis(triphenylphosphine)palladium[0]. 20 mg of N-[3-(3-cyanophenyl)-1 H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 240° C. (analysis C21H16N4O4S2.H2O % calculated C, 53.61; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.95; H, 3.85; N, 11.68; S, 13.18).
Reaction SMILES: N[C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N([O-])=O.[Na+].[S:36](=[O:38])=[O:37].[ClH:39]>C(O)(=O)C.O.[Cu]Cl>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([S:36]([Cl:39])(=[O:38])=[O:37])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: O=S=O
Reactant: Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 1 °C
Reaction time: 1 h

Procedure:
(7R)-2-Amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (400 mg, 1.0 mmol; Example 7, free base) was dissolved in a mixture of acetic acid, conc. hydrochloric acid and water (2:1:1, 10 ml) at RT. At −10° C., a solution of sodium nitrite (72 mg, 1.0 mmol, 1.1 eq.) in water (1.1 ml) was slowly added dropwise to the reaction mixture. The mixture was allowed to warm to 0-2° C. and then cooled once more to −10° C. This solution was added to a solution of glacial acetic acid (11 ml) whose temperature had been adjusted to −10° C. beforehand and which had been saturated with sulfur dioxide gas and to which copper(I) chloride (18.8 mg, 0.019 mmol, 0.2 eq.) had been added. For a short while, there was a vigorous reaction. The mixture was stirred at −10° C. for 1 h, then warmed to 15° C. and stirred for another 1 h. The reaction solution was then once more cooled to 0° C. The product was precipitated by dropwise addition of this reaction solution to stirred ice-water (60 ml). The beige precipitate was filtered off, taken up in ethyl acetate, washed with saturated sodium chloride solution and then dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was dried under high vacuum. The product was obtained as a solid (415 mg, 63% pure, 55% of theory).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:13]=[C:12](Br)[S:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.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>[N:1]1([C:7]([C:9]2[CH:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[S:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(c1csc(-c2ccccn2)c1)N1CCCCC1
Yield: 12 %

Procedure:
A mixture of piperidin-1-yl-(5-bromo-thiophen-3-yl)-methanone (76 mg, 1 eq.), tributyl(2-pyridyl)tin (0.102 mL, 1 eq.) and PdCl2(PPh3)2 (0.011 g, 0.1 eq) were heated at 100° C. in toluene (1 mL) for 6 hours. The solvent was evaporated and the residue purified by column chromatography (EtOAc/iso-hexane) to give the desired product (9.2 mg, 12%). LCMS m/z 273 [M+H]+ R.T.=2.73 min (Analytical Method 3).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][NH:16][C:17](=O)[C:18]1[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]([Cl:28])=[N:20][CH:19]=1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[O:14][C:17]([C:18]2[CH:19]=[N:20][C:21]([Cl:28])=[CH:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])=[N:16][N:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)NCCCO[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(NCCCO[Si](C)(C)C(C)(C)C)o1
Temperature: 50 °C

Procedure:
N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinecarboxamide (50) (1 g, 2.2 mmol) in DCM (40 mL) was stirred at room temperature. Added triphenyl phosphine (6 mmol, 3 equiv.), Et3N (18 mol, 8 equiv.) and CCl4 (6 mmol, 3 equiv.). The reaction mixture was heated at 50° C. for 3 h. Reaction mixture was diluted using DCM. The DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and EtOAc: Pet. Ether as eluent to provide the desired compound, N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-amine. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 1.2 min; LCMS (ES-API), m/z 426.9 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
A mixture of 10 g (0.0825 mol) p-fluorobenzonitrile, 47 g (0.3282 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 17 g (0.123 mol) of K2CO3, and 100 ml of acetonitrile is stirred at 90°-100° C. for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pasty solid. Trituration with ether furnishes 13.4 g (67%) of title compound: IR (KBr) 2210 and 1600 cm-1 ; NMR (CDCl3) δ 7.48 (d, 2H), 6.88 (d, 2H), 4.0 (s, 4H), 3.58-3.40 (m, 4H), and 1.90-1.70 (m, 4H).