Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](OC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccccc1OC
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3OC)nc(=O)c1-2
Yield: 52.7 %

Procedure:
Sodium (590 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.65 g, 12 mmol), followed by methyl 2-methoxyphenylacetate (4.7 g, 26 mmol) were added. The reaction mixture was refluxed overnight, the solvent was stripped and the residue was treated with water and then 2N HCl. The product was collected by filtration and recrystallized from ethyl acetate to afford 2.23 g of 1-cyclopentyl-3-ethyl-6-(2-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 145°-146° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>CN(C=O)C>[O:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To NaH (60 wt % in mineral oil; 0.047 g, 1.176 mmol) in 1 mL DMF was added phenol (0.111 g, 1.176 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1, 0.050 g, 0.168 mmol) was added and the reaction became dark red. After 30 min at RT, the reaction was heated to 70° C. The reaction was judged complete after 5 h at 70° C., and was cooled to RT and quenched with saturated aq. NH4Cl and EtOAc. The organic layer was sequentially washed with water, and saturated aq. NaCl, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50%-90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.048 g, 0.135 mmol, 80% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (1H, br. s), 8.49 (1H, d, J=8.8 Hz), 8.12 (1H, dd, J=7.6, 1.6 Hz), 7.74-7.87 (1H, m), 7.56-7.66 (2H, m), 7.33-7.52 (5H, m), 6.84-7.01 (2H, m), 3.31-3.38 (2H, m), 2.39 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 356.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:20](=[O:22])[CH3:21])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1ccc(O)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
3-Tert-butyl-4-methoxyphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (658 mg) and acetyl chloride (599 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was dried under the reduced pressure. Scandium trifluoromethane sulfonate (327 mg) was added to the compound thus obtained, the mixture was suspended in toluene (5 ml), and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, and the reaction solution was then filtered. The solvent was removed from the filtrate by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give 1-(4-tert-butyl-2-hydroxy-5-methoxy-phenyl)-ethanone (30 mg, yield 5%).
Reaction SMILES: C(N1[C:9]2=[N:10][CH:11]=[C:12]([N+]([O-])=O)[CH:13]=[C:8]2[C:7]([C:17](O)=O)=C1)(C)(C)C.CC(C)[N:22]=C=NC(C)C.CCN(C(C)C)C(C)C.N1C2C(=CC=CN=2)C=C1>C(Cl)Cl.CN(C=O)C>[NH:22]1[C:7]2[C:8](=[CH:13][CH:12]=[CH:11][CH:17]=2)[CH:9]=[N:10]1
Reactant: CC(C)(C)n1cc(C(=O)O)c2cc([N+](=O)[O-])cnc21
Reactant: CC(C)N=C=NC(C)C
Agent: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the AMEBA II resin (0.1 g, 1 mmol/g, 0.1 mmol) in DCM/DMF (1:1, 2 ml), 1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3 eq), DIC (1.5 eq) DMAP (0.5 eq) and DIPEA (1 eq) were added. The reaction mixture was shaken at room temperature for 20 hours and then the resin was isolated by filtration. The resin was washed sequentially with DMF (2 ml), DCM (2 ml), DMF (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml) and dried in vacuo to give the resin bound 7-azaindole.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH:7]2[O:11]CCO2)=[CH:4][CH:3]=1.[CH3:14][CH:15]1[CH2:20][CH2:19][C:18]2[C:21](OC(=O)[C:17]=2[CH2:16]1)=[O:22].O.[C:27](O)(=[O:29])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[C:7](=[O:11])[C:17]3[CH2:16][CH:15]([CH3:14])[CH2:20][CH2:19][C:18]=3[C:21]2=[O:22])=[CH:12][C:13]=1[CH:27]=[O:29]
Reactant: CC1CCC2=C(C1)C(=O)OC2=O
Reactant: Clc1ccc(NC2OCCO2)cc1
Reactant: CC(=O)O
Solvent: O
Product: CC1CCC2=C(C1)C(=O)N(c1ccc(Cl)c(C=O)c1)C2=O
Yield: 83 %

Procedure:
29.2 g (0.15 mol) of 4-chloro-(1,3-dioxolan-2-yl)-aniline and 24.9 g (0.15 mol) of 4(R,S)-methylcyclohexene-1,2-dicarboxylic anhydride were stirred in 250 ml of glacial acetic acid for 3 days at 230° C. and for 10 hours at 70° C.; water was added to induce precipitation, followed by recrystallization and drying. There was obtained 38 g (83%) of N-(4-chloro-3-formylphenyl)-4(R,S)-methyl-3,4,5,6-tetrahydrophthalimide (m.p. 132°-1330° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:8]2[N:9]=[CH:10][N:11]([CH3:24])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 20 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 10dd (0.141 g, 0.34 mmol), potassium carbonate (0.141 g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved in dimethylformamide (3 mL). After 20 hours, the reaction mixture is diluted with EtOAc and washed with water (3×), potassium carbonate, and brine. The organic layer is dried (Na2SO4) and concentrated to a brown oil. The N3 and N1 alkylated regioisomers are separated by flash chromatography (EtOAc). The recovery of the N3 alkylated regioisomer is 20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
A mixture of 250 mg of 4-isopropanesulfonamidobenzoylchloride 1, 181 mg of 4-bromoaniline 2, 106 mg of triethylamine, and 5 ml of methylene chloride is stirred at room temperature for 5 minutes. The reaction mixture is neutralized with a sodium bicarbonate solution, and extracted with methylene chloride. The organic layer is concentrated under reduced pressure, and the residue is chromatographed on a column of silica-gel. The eluate with 3% methanolmethylene chloride is concentrated, and the residue is crystallized from ethyl acetate-isopropyl ether. The crude resulting crystals are recrystallized from ethyl acetateisopropyl ether to give 200 mg of 4'-bromo-4-isopropanesulfonamidobenzanilide 3 as pure specimen, m.p. 213°-214° C.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[C:5]1([O:12][CH3:13])[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7].[OH-].[Na+]>O.O1CCOCC1>[F:3][CH:2]([F:4])[O:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[O:12][CH3:13]
Reactant: FC(F)Cl
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1OC(F)F
Yield: 71.9 %

Procedure:
58 g of chlorodifluoromethane are passed into a solution of 55.5 g of guaiacol and 130 g of sodium hydroxide in 300 ml of water and 300 ml of dioxane at 60° C. The mixture is filtered at 10° C. and the organic phase is separated off, dried with anhydrous potassium carbonate and distilled. 56 g (73%) of 1-difluoromethoxy-2-methoxybenzene of boiling point 75°-79° C./0.9 kPa are obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1.CN(C)C=O.[BH4-].[Na+]>O>[CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15][CH:14]=2)=[N:8]1
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(C(=O)O)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CO)n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 28 mg of 6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carboxylic acid and 1 ml of N,N-dimethylformamide was added 84 mg of N,N′-carbonyldiimidazole, followed by stirring at room temperature for 15 hours. Then, 200 μl of an aqueous solution of 20 mg of sodium borohydride was added thereto and the resulting mixture was stirred. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:20]1([O:26][C:27](=[O:28])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(N2CCCCC2)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(N2CCCCC2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine (1.01 g, 5.7 mmol) and pyridine (12 ml) are stirred in dry CH2Cl2. Phenylchloroformate (1.3 g, 8.5 mmol) is added to this mixture and stirred for 24 h at room temperature. Water and a solution of 1:1 EtOAc/hexanes is added and the organic layer is separated. The organic layer is washed with 1N HCl three times and with brine once. The organic layer is dried over Na2SO4, filter, and evaporated in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-carbamic acid phenyl ester. Mass spec.: M−1=280 (AP−).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([O:10]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:9].[Br:26]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:26][CH2:9][C:8]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)=[O:10]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A mixture of 5-bromopyrimidine (2.20 g, 13.85 mmol), (1-ethoxyvinyl)tributyltin (5.00 g, 13.85 mmol), and tetrakis(triphenylphosphine)palladium (1.60 g, 1.38 mmol) in toluene (20 ml) was refluxed for 29 h, and then cooled to room temperature. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give an oily residue. The residue was diluted with THF (30 ml) and water (8 ml). N-Bromosuccinimide (2.96 g, 16.61 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h and concentrated to ca. 10 ml. The residue was diluted with ethyl acetate (200 ml) and washed with water (100 ml×2), then dried (MgSO4). Removal of solvent gave an oily residue, which was purified by flash column chromatography eluting with ethyl acetate-hexane (1:3) to afford 2.60 g (94%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][CH3:14])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:17][NH2:18]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:18][N:17]=1)[CH3:14]
Reactant: NN
Reactant: CCC(=O)c1ccc(OC)cc1C(=O)O
Solvent: O
Product: CCc1n[nH]c(=O)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-propionylbenzoic acid with hydrazine hydrate.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:12][Si](C=[N+]=[N-])(C)C.C1(C)C=CC=CC=1>CO.C1C=CC=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1([NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NC1(CC(=O)O)CCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CC1(N)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of (1-amino-cyclopentyl)-acetic acid hydrochloride (363 mg, 2.02 mmol) in a 1:1 mixture of anhydrous methanol/benzene (20 mL) cooled to 0° C. under a nitrogen environment was treated dropwise via syringe with a 2.0 M solution of trimethylsilyldiazomethane in toluene (2.0 mL, 4.0 mmol). The reaction mixture was allowed to warm to 25° C., stirred for 1 h, and concentrated in vacuo to give (1-amino-cyclopentyl)-acetic acid methyl ester (311 mg, 98%) as a colorless oil. LC-MS (ESI) calculated for C8H15FNO2: 157.2, found 158.2 [M+H+].
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:39])[C:17]([C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[O:28])=[CH:18][N:19]3[CH:24]3[CH2:26][CH2:25]3)=[CH:14][C:13]=2[F:40])[CH2:7][C@H:6]1[CH3:41])=[O:4].[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C)C=O>[ClH:1].[N:42]([CH2:2][C:3]([N:5]1[CH:6]([CH3:41])[CH2:7][N:8]([C:12]2[C:21]([O:22][CH3:23])=[C:20]3[C:15]([C:16](=[O:39])[C:17]([C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])=[O:28])=[CH:18][N:19]3[CH:24]3[CH2:26][CH2:25]3)=[CH:14][C:13]=2[F:40])[CH2:9][CH:10]1[CH3:11])=[O:4])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(N2C[C@@H](C)N(C(=O)CCl)[C@@H](C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N2CC(C)N(C(=O)CN=[N+]=[N-])C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Product: Cl

Procedure:
50.0 mg of the compound of Example 80A and 15.6 mg (0.24 mmol) of sodium azide are stirred in 3 ml of N,N-dimethylformamide in a closed reaction vessel at 90° C. over night. After fine purification by preparative RP-HPLC (Method 6) 46 mg of the target compound are obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([C:37]([F:40])([F:39])[F:38])=[O:36])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C=O)C>[F:40][C:37]([F:38])([F:39])[S:35]([C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[O:11])=[CH:18][CH:17]=3)[N:23]=2)=[CH:30][CH:31]=1)=[O:36]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 6 ml water the resulting precipitate was collected and combined with additional material obtained by extraction of the aqueous phase at pH=3 with ethyl acetate, drying (sodium sulfate) and evaporation. Purification by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) gave 130 mg (77%) powder.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]1[CH2:25][C:26]#[CH:27].I[C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[O:1]=[C:2]1[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:3]1[CH2:25][C:26]#[C:27][C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(I)cc1C2
Reactant: C#CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)CC12CCCCCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CCCCCC2)N(CC#Cc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12CCCC2
Temperature: 50 °C

Procedure:
A stirred suspension of tert-butyl 16-oxo-15-prop-2-yn-1-yl-6,15-diazadispiro[4.2.6.2]hexadecane-6-carboxylate (110 mg, 0.294 mmol, described in Intermediate 23), (2R)-5-iodo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (106 mg, 0.294 mmol, described in Intermediate 27), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol), copper(I)iodide (23 mg, 0.121 mmol), and triethylamine (0.082 mL, 0.588 mmol) in degassed DMF (1.5 mL) was heated at 50° C. for 30 min. The reaction was quenched with water (30 mL), partitioned with saturated NaHCO3 solution (30 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to yield the title compound. MS: m/z=609 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C.Cl>C1(C)C=CC=CC=1>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]3[N:22]=[N:21][NH:20][N:2]=3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 moles) in toluene (2.3L) was added trimethyltin azide (525 g, 2.55 moles) at r.t. The mixture was refluxed for 24 h, cooled to r.t., filtered, washed with toluene and sucked dry in a funnel. The precipitate was resuspended in toluene (3.5 L) and THF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). Addition of HCl gas was continued for another 20 min. with stirring whereupon a white precipitate formed. The reaction mixture was stirred over night. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrarole. m.p. 152°-154° C.; 1H-NMR (CDCl3):2.40 (s, 3H), 7.19 (dd, 1H), 7.55 (m, 2H), 8.25 (dd, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[C:16]([C:18]1([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33]#[N:34])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)#N.C[OH:36].Cl>CN(C=O)C.O>[C:33]([CH2:32][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]2[C:18]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16](=[O:36])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:2]2=[S:3])=[CH:25][CH:26]=1)#[N:34]
Reactant: N#CCCCc1ccc(NC2(C#N)CCCC2)cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCC3)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-Isothiocyanato-2-trifluoromethylbenzonitrile (96) (36 mg, 0.16 mmol) and 4-[4-(1-Cyanocyclopentyl amino)phenyl]butanenitrile (93) (20 mg, 0.08 mmol) in DMF (1 mL) was heated under microwave irradiation at 80° C. for 6 h. To this mixture was added methanol (10 mL) and aq. 1 N HCl (3 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to give 4-(1-(4-(3-Cyanopropyl)phenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]non-3-yl)-2-trifluoromethylbenzonitrile (92) [ND-2]