Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].O.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:16][C:15](=[O:24])[NH:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC1(CO)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1(CO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-amino-1-cyclopentanemethanol (1.15 g, 10 mmol ) and NaHCO3 (0.84 g, 10 mmol) in acetone (14 mL)/water (14 mL) at room temperature was added benzyl succinimidyl carbonate (2.5 g, 10 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>CS(C)=O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ncccc2[N+](=O)[O-])c(Cl)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorophenol (0.64 g), powdered potassium hydroxide (0.24 g), and 2-chloro-3-nitropyridine (0.76 g) in dimethylsulfoxide (15 ml) was heated at 110° C. with stirring for 2 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 3:97, to yield 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) as a yellow semi-solid (0.45 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:13])[N:15]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH3:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Product: CCCCc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)OCC)cc3)c2)cc1
Temperature: 100 °C
Yield: 96.4 %

Procedure:
345 mg (1.5 mmol, 1.5 eq) of 1-butyl-4-isocyanatobenzene are added to 283 mg (1.0 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (prepared in Example 7c). The reaction mixture is heated at 100° C. by microwave for 30 minutes. The mixture is chromatographed on silica gel (15 g FlashSmart column) eluted with 80/20 heptane/ethyl acetate. 442 mg of ethyl 3-{3′-[3-(4-butylphenyl)-1-methylureido]biphenyl-4-yl}propanoate are obtained in the form of a yellow oil that crystallizes. Yield=96%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCl>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[Cl:21])=[O:28]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(C(=O)O)ccc1Cl

Procedure:
1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with 0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of 2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted at room temperature for 12 hours. The solvent was evaporated, the residue was mixed with 5% strength sodium bicarbonate solution and extracted twice with diethyl ether, and the aqueous phase was adjusted to pH 3 with HCl. The resulting precipitate was filtered off with suction.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:41]=2[CH:59](O)[CH3:60])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P([N:76]=[N+:77]=[N-:78])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[N:76]([CH:59]([C:41]1[N:42]([S:49]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)(=[O:50])=[O:51])[C:43]2[C:48]([C:40]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:60])=[N+:77]=[N-:78]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(C(C)N=[N+]=[N-])c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
A solution of DIAD (1.80 g, 8.89 mmol) in dioxane (5 mL) was added to a solution of triphenylphosphine (2.33 g, 8.89 mmol) in dioxane (20 mL) at 0° C. under a nitrogen atmosphere. After 10 min stirring, 1-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethanol (1.74 g, 4.44 mmol) in dioxane (15 mL) was added followed by diphenylphosphoryl azide (1.47 g, 5.53 mmol) in dioxane (5 mL). Stirring at 20° C. was continued for 16 h and then the crude reaction mixture was diluted with DCM and purified by column chromatography (Si—PCC, gradient 10-100% DCM in pentane) affording 2-(1-Azidoethyl)-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole as a gum (1.39 g, 75%). LCMS: RT 4.77 min [M-N3]+ 374.1.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[C:18]([CH3:35])=[CH:17][C:16]=2[F:36])=[O:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:48][NH2:49]>C1COCC1>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:49][CH3:48])[N:27]=[CH:28][C:23]=4[CH:22]=3)[C:18]([CH3:35])=[CH:17][C:16]=2[F:36])=[O:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C)c(F)cc3C)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C)c(F)cc3C)c(=O)n(C)c2n1
Yield: 50 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (31 mg, 0.061 mmol), MCPBA (19 mg, 0.079 mmol) and 2.0N methylamine in THF (0.4 mL) were converted to 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (15 mg, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.60 (s, 9H), 2.20 (s, 3H), 2.35 (s, 3H), 2.95 (s, 3H), 3.60-3.70 (m, 3H), 7.20-7.25 (m, 1H), 7.50 (s, 1H), 7.70 (s, 1H), 7.70-7.90 (m, 1H), 8.05 (m, 1H), 8.20 (s, 1H), 8.55 (m, 1H), 8.70-8.80 (m, 1H); MS (ESI) m/z: 493.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(F)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccc(F)cc3C1O)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
11.0 g of 8-[(7-fluoro-1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-1-phenyl-1,3,8-traizaspiro[4.5]decan-4-one (see example 187) is taken up in methanol (240 ml), cooled in an ice-bath and treated over a 20 minute period with 6.6 equivalents of sodium borohydride in water (58 ml). The mixture is then allowed to warm up to room temperature and stirred for 48 hours. The reaction mixture is diluted with ice-water (400 ml), stirred for 30 minutes and the precipitates that form are filtered off and dried in vacuo at 80° C to give the title compound (6.9 g), melting point 210°-212° C. The filtrate is extracted with 500 ml of methylene chloride to give another 4.3 g of crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1cccc(Cn2cncn2)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of 3-bromobenzylbromide (20.0 g, 80.0 mmol) in acetone (300 mL) was added 1,2,4-triazole (10.8 g, 120 mmol), potassium carbonate (11.0 g, 80.0 mmol) and potassium iodide (0.790 g, 4.72 mmol). The resulting white suspension was heated to 55° C. with vigorous stirring for 16 h. The yellow reaction mixture was cooled and ethyl acetate (100 mL) added. This was then washed with distilled water (100 mL×2), 1M NaOH(aq) (100 mL×2) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and solvent removed in vacuo to leave clear yellow oil. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as a yellow crystalline solid (12.4 g, 65%),
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:42])[CH2:5][CH2:6][CH2:7][C:8]([CH3:41])([CH3:40])[CH2:9][O:10][C:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:26]([O:28][CH2:29][C:30]([CH3:38])([CH3:37])[CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[O:27])=[CH:20][CH:21]=3)[C:16](=O)[C:15]=2[CH:14]=1)=[O:12]>O.[Pd]>[ClH:1].[ClH:1].[CH3:42][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][C:8]([CH3:41])([CH3:40])[CH2:9][O:10][C:11]([C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:26]([O:28][CH2:29][C:30]([CH3:37])([CH3:38])[CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[CH3:36])=[O:27])=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1)=[O:12]
Reactant: CN(C)CCCC(C)(C)COC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCC(C)(C)CCCN(C)C)ccc1-2
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN(C)CCCC(C)(C)COC(=O)c1ccc2c(c1)Cc1cc(C(=O)OCC(C)(C)CCCN(C)C)ccc1-2

Procedure:
A solution of 20.0 g (0.0321 mole) of bis(5-dimethylamino-2,2-dimethylpentyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride in water (total volume = 240 cc.) is hydrogenated over 8.0 g of 10% palladium on charcoal for 2 days at 53°C on a Parr hydrogenation apparatus. The reaction mixture is decanted from the catalyst, filtered through filtered acid, treated with charcoal and again filtered. This solution is made basic to phenolphthalein with 20% NaOH and extracted 3 times with CHCl3. The combined extracts were washed twice with water, dried over anhydrous Na2SO4, filtered and the filtrate made acid to Congo Red with ethereal HCl. Most of the solvent is removed on the steam bath under vacuum and the resulting solid recrystallized from methanol-ether and from absolute ethanol. Bis(5-dimethylamino-2,2-dimethylpentyl)fluorene-2,7-dicarboxylate dihydrochloride thus obtained is dried for 4 hours under high vacuum at 80°C. M.P. 294°-295°C (gas evolution).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]C)=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:40]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25](=[O:27])[NH2:40])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[C:8]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Reactant: N
Solvent: CO
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(N)=O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A solution of 3-butyl-4-[[4-[1-(carbomethoxy)-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 1, Step F) in methanol is saturated with gaseous ammonia at 0° and then stirred at that temperature in a stoppered vessel for about 6 hours or until TLC indicates complete reaction. The mixture is then concentrated to dryness to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(OP(SC1OCCOC1SP(O[CH2:43][CH3:44])(OCC)=S)(OCC)=S)C.C(=O)(O)[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Zn].O1CCCC1>[CH3:9][N:8]1[CH2:44][CH2:43][CH:5]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:6][CH2:7]1
Reactant: CCOP(=S)(OCC)SC1OCCOC1SP(=S)(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(Br)cc32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(C4CCN(C)CC4)cc32)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
6-Bromo-1-(toluene-4-sulfonyl)-1H-indole (340 mg, 0.97 mmol), Tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol), and (3-diethoxyphosphinothioylsulfanyl-1,4-dioxan-2-yl)sulfanyl-diethoxy-sulfanylidene-phosphorane (Ruphos) (47 mg, 0.1 mmol) were placed into a reaction container. After deaeration, the air was replaced with nitrogen. Anhydrous tetrahydrofuran (THF) (5.0 ml) and a prepared zinc reagent suspension were added thereto, and this was stirred at 70° C. for 17 hours. After cooling it to room temperature, the reaction mixture was alkalinized with an aqueous solution saturated with sodium bicarbonate. The precipitated solid was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentration was performed. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6-(1-methyl-piperidin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole was obtained as a wax-like solid (293.7 mg, 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[C:16]1[N:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[F-].[Cs+].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O>[N:17]1[CH:16]=[CH:21][CH:20]=[C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1cccnn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2cccnn2)CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
The reaction mixture of tert-butyl piperidin-4-ylcarbamate (250 mg, 1.25 mmol), 3-bromopyridazine (258 mg, 1.62 mmol), CsF (37.9 mg, 0.25 mmol), and K2CO3 (518 mg, 3.74 mmol) in DMSO (12.5 mL) was heated at 100° C. for 20 h. Water and DCM were poured into the mixture, and the separated aqueous layer was extracted with DCM, the combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by column chromatography (Hexane:EtOAc=1:1) to give tert-butyl 1-(pyridazine-3-yl)piperidin-4-ylcarbamate (123 mg, 35%) as a pale yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.45 (9H, s), 1.92-2.12 (2H, m), 3.03-3.17 (2H, m), 3.55-3.80 (2H, m), 4.25-4.38 (2H, m), 4.52 (1H, brs), 6.92 (1H, d, J=9.2 Hz), 7.20 (1H, dd, J=4.4, 9.2 Hz), 8.56 (1H, d, J=4.4 Hz). NH peak was not observed. m/z=279.06 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]([NH2:20])=[O:24])[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1ccc(-c2nccc(-c3cccc(C#N)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(-c2nccc(-c3cccc(C(N)=O)c3)n2)cc1
Temperature: 70 °C
Yield: 98 %

Procedure:
A mixture of 3-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzonitrile (50 mg, 0.167 mmol) and aq. H2SO4 (257 μL, 0.65 M) is heated to 70° C. for 12 h. The mixture is cooled and adjusted to pH 7 with aq. sodium hydroxide (1 M). The mixture is partitioned between water and ethyl acetate, and the organic layer is washed with satd. aq. sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white crystalline solid (52 mg, 98%), m.p. 167-169° C. 1H NMR (300 MHz, acetone-d6): δ 8.91 (1H, d, J=6 Hz), 8.87 (1H, t, J=2 Hz), 8.54 (2H, d, J=9 Hz), 8.52 (1H, ddd, J=8, 2, 1 Hz), 8.15 (1H, ddd, J=8, 2, 1 Hz), 7.93 (1H, d, J=6 Hz), 7.80 (1H, br s), 7.68 (1H, t, J=8 Hz), 7.41 (2H, d, J=9 Hz), 6.96 (1H, br s), 3.01 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). 13C NMR (acetone-d6): δ 205.9, 168.4, 164.8, 163.4, 159.0, 152.4, 137.8, 136.2, 135.9, 130.6 (2C), 129.7, 128.9, 127.2 (2C), 126.8, 115.4, 34.7, 24.1 (2C). MS (ES+): m/e 319 (25), 318 (100).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[Cl-].Br[C:13]1[CH2:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:13]2[CH2:21][C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:5][CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Fc1ccc(CC2=Cc3ccccc3C2)cc1

Procedure:
To a suspension of freshly ground magnesium (0.58 g, 23 mmol) in 100 mL of ether was added about 3 mL of a 15 mL ether solution containing 3.0 g (21 mmol) of 4-fluorophenylmethyl chloride. The system was carefully heated and after initiation of the reaction, the remaining chloride solution added over 30 minutes while maintain a gentle reflux. After refluxing for 1.5 hours, the Grignard solution was cooled and cannulated to a mixture of 3.65 g (19 mmol) of 2-bromo-indene, 150 mg (0.20 mmol) of NiCl2(dppp) and 100 mL of ether. The system was gently heated to reflux overnight and then cooled and quenched by adding 150 mL of 1.0 M aqueous hydrochloric acid. The product was isolated and purified (hexanes/silica) as for 2-benzyl-indene. Yield: 3.45 g, 74 percent
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Product: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O

Procedure:
Prepared in analogy to example 31f from 7-(benzo[1,3]dioxol-5-yloxy)-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and POCl3. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.89 (s, 1H), 8.35 (d, 1H, J=9.2 Hz), 7.57 (d, 1H, J=1.9 Hz), 7.50 (m, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.65-6.56 (m, 2H), 6.03 (s, 2H), 4.47 (t, 2H, J=7.1 Hz), 1.9-1.4 (m, 4H), 0.99 (t, 3H, J=7.3 Hz).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[Cl:29][C:30]1[C:31]([C:40]([F:43])([F:42])[F:41])=[N:32][N:33]([CH2:36]C(O)=O)[C:34]=1[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CCOC(C)=O.CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:36][N:33]4[C:34]([CH3:35])=[C:30]([Cl:29])[C:31]([C:40]([F:42])([F:43])[F:41])=[N:32]4)[CH2:27][CH2:26]3)[C:15]2=[O:16])=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(N2CCC3(CCN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3)C2=O)ccc1Cl
Temperature: 25 °C

Procedure:
2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester ( 39.5 mg, 0.1 mmol, 1 equiv) was treated with 4 mL of 4N HCl in dioxane at rt for 1 h. The volatile was removed and to the residue were added 1 mL of DMF, (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (24.3 mg, 1 equiv), HATU (42 mg, 1.1 equiv), TEA (50 μL, 3 equiv). After stirring at rt over night, the mixture was taken up in EtOAc, washed with saturated sodium NaHCO3. Purification by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) gave 2-(4-Chloro-3-methoxy-phenyl)-8-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-2,8-diaza-spiro[4.5]decan-1-one. LCMS observed for (M+H)+: 519. Retention time: 4.75 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutes gradient of 20% to 95% B with a 1.1 minutes wash at 95% B (A=0.1 % formic acid/5% acetonitrile/94.9% water, B=0.1 % formic acid/99.9% acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][O:15]C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC=C1CCC(c2ccc(Br)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: O=CC1CCC(c2ccc(Br)cc2)CC1
Yield: 95.1 %

Procedure:
A mixture of 10.4 g of 1-bromo-4-[4-(methoxymethyli-dene)cyclohexyl]benzene and 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes in a round flask. Subsequently, the reaction mixture was poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. There were obtained 9.4 g of 4-(4-bromophenyl)cyclohexanecarboxaldehyde as white crystals; trans/cis ratio about 5:3.