Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=5)[C:27]#[N:28])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][CH2:51][CH2:52][N:53]1[CH:57]=[C:56](B2OC(C)(C)C(C)(C)O2)[CH:55]=[N:54]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][CH2:51][CH2:52][N:53]1[CH:57]=[C:56]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]4[C:19]5=[N:20][C:21]([C:24]6[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=6)[C:27]#[N:28])=[CH:22][N:23]=[C:18]5[N:17]=[N:16]4)[CH2:9]3)=[N:6][CH:7]=2)[CH:55]=[N:54]1
Reactant: N#Cc1cccc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)c1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(CCOC7CCCCO7)c6)cn5)CCO4)c3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
In a pressure tube reactor, (S)-3-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]-triazolo[4,5-b]pyrazin-6-yl)benzonitrile 50 mg (0.10 mmol) was added, and then potassium carbonate 43 mg (0.31 mmol) was added. Pd(dppf)2Cl2 4 mg (0.005 mmol) was further added, 1,4-dioxane 2 ml and 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole 40 mg (0.13 mmol) were added, and then H2O 0.5 ml was added. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 80° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 50% ethyl acetate/hexane gave 3-(1-(((2S)-4-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile 48 mg (0.08 mmol) with a yield of 70%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:11][NH:12][C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][O:36][C:37]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=[O:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)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.C(OCC)(=O)C>[C:16]([NH:15][C:13]([NH:12][CH2:11][C:10]1[CH:9]=[C:8]([C:44]2[CH:43]=[CH:42][CH:41]=[C:38]([CH:39]=[O:40])[C:37]=2[O:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[C:22]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][CH:20]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCCOCOc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC
Yield: 56.4 %

Procedure:
A 2 M solution of potassium carbonate (2.1 mL) was added to a magnetically stirred mixture of 1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea (1.4 g, 4.1 mmol), prepared as in Reference 11, and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (42 mL, 0.1 mM in toluene, 4.2 mmol), prepared as in Reference 15. The mixture was flushed with nitrogen and then tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1025 mmol) was added. The mixture was refluxed for 7 hours, cooled and then poured into a mixture of ethyl acetate and 5% citric acid. The organic phase was separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phase was dried and concentrated by evaporation. Product was purified from the residue by chromatography on silica gel utilizing 100% ethyl acetate to give 1-tert-butyl-3-[3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[I:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([I:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Ic1cn[nH]c1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(I)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-iodopyrazole and cesium carbonate in NMP. EI-MS m/e (%): 359 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([O:33]CC=C)[C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][C:16]=1[O:39][CH3:40].O1CCCC1CCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][C:16]=1[O:39][CH3:40]
Reactant: C=CCOc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OCCC1CCCO1
Solvent: O=CO
Product: COc1cc(Cn2c3ccccc3c3c(O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
10 g of 9-{4-[(5-methyl-2-phenyloxazole-4-yl)methoxy]-3-methoxybenzyl}-4-(allyloxy)-9H-carbazole was suspended in mixed solution (70 mL) of tetrahydrofuran-ethanol=4:1, 986 mg of triphenylphosphine, 84 mg of palladium acetate, and 2.1 mL of formic acid were added, and refluxed for 5 hours. The reaction mixture was allowed to cool, and then concentrated in vacuo, and the residue was crystallized from 10 mL of ethanol. The crystalline precipitate was isolated by filtration, washed with ethanol, dried under reduced pressure, and 8.96 g of the subject compound was prepared as pale yellow crystal.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].B1C2CCCC1CCC2.[OH:35]O.[OH-].[Na+]>>[F:1][C:2]([F:25])([C:21]([F:22])([F:23])[F:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:35]
Reactant: OO
Reactant: C=CCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Product: OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Into a clean flame dried 1 L RBF under current of N2, was put 12.86 g (34.48 mmol) of 54. To this was added 172 mL (86.2 mmol) of 9-BBN (0.5 M in THF). The reaction was stirred for 3 h. 23 mL of 30% H2O2 was then added dropwise to the reaction mixture followed by 49 mL of 15% aq. NaOH and the reaction mixture was stirred at 85° C. for 3 h. The mixture was then cooled to room temperature and THF was evaporated and the residue was diluted with H2O and extracted with EtOAc (3×). The combined organic layer was then washed with brine (1×), dried over MgSO4, filtered and the solvent was evaporated under vacuum. The residue was then purified using combiflash (120 g silica column) with hexane/ethyl acetate as eluent to furnish 10.15 g (76%) of compound 55 as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[C:10]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[C:26]([OH:28])[CH:27]=2)[N:9]=1.Br[CH2:32][C:33]#[N:34]>CN(C)C=O>[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=[C:10]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[C:26]([CH:27]=2)[O:28][CH2:32][C:33]#[N:34])[N:9]=1
Reactant: N#CCBr
Reactant: Nc1nc(SCc2ccccc2)nc(-c2cc(O)c(Cl)cc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2nc(N)nc(SCc3ccccc3)n2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Cesium carbonate (12 mg) was added to a dimethylformamide solution (1 mL) of 5-(4-amino-6-benzylsulfanyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenol (11 mg) obtained in Step 4 described above. A solution of α-bromoacetonitrile (3.6 mg) in dimethylformamide (0.2 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. After dilution with ethyl acetate (7 mL), the mixture was washed in succession twice with water (6 mL) and once with brine (3 mL). The mixture was then pre-dried over anhydrous sodium sulfate and filtered. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=8:2) to give [5-(4-amino-6-benzylsulfanyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenoxy]-acetonitrile (11 mg) as white solid.
Reaction SMILES: [C:1]1([N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[Si](C)(C)C)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([CH:47]=O)[CH:41]=[CH:40]2>O1CCCC1>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](/[CH:47]=[C:14](/[C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:13][CH:12]=1)\[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:41]=[CH:40]2
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Reactant: C[Si](C)(C)C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc2cc(/C=C(\c3ccccc3)c3ccc(N(c4ccccc4)c4ccccc4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
N,N-diphenyl-4-(phenyl(trimethylsilyl)methyl) aniline (5.0 g, 12.3 mmol) was dissolved in purified tetrahydrofuran (30 mL) under a nitrogen atmosphere, and n-butyllithium (8.4 mL, 13.5 mmol) was slowly added thereto at −78° C. The reaction mixture solution was stirred at room temperature for 8 hours. 6-bromo-2-naphthaldehyde (2.9 g, 12.3 mmol) dissolved in tetrahydrofuran (10 mL) was added thereto at room temperature. The reaction mixture solution was stirred at room temperature for 24 hours. The reaction mixture solution was subjected to extraction with dichloromethane and distilled water, and the extracted material is subjected to column chromatography (hexane:dichloromethane=9:1). The reaction solvent was removed, and then the residue material was dried in vacuum to thereby obtain a pale yellow solid (4.5 g, yield: 66%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3Cl)[CH:11]=2)=[O:9])[CH2:4]1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[NH:30][C:26]3[CH:27]=[C:28]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:20])=[CH:29]4)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COC1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3-methoxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 407 (MH+); HPLC Rf: 4.22 min.; HPLC purity 96%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])[NH:7][C:6]=2[CH:18]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>CC(C)=O>[CH3:17][O:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[NH:10][C:8]1[NH:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:18][C:6]=2[N:7]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Reactant: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OC(=O)c4ccccc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea (31 mg, example 82) and benzoic acid 4-chlorosulfonyl-phenyl ester (37 mg) in acetone (0.6 ml) was treated with triethylamine (33 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give benzoic acid 4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester (7.2 mg) as a off-white solid Mass spectrum: 511 [M+H]+; retention time=9.90 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[NH:9][N:8]=2)[CH:2]=1.CC([O-])(C)C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CS(C)=O>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:9]2[C:10]([CH2:12][CH3:13])=[CH:11][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8]2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1cc(-c2cccnc2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 3-(3-pyridinyl)-5-ethylpyrazole (13.2 g, 75.6 mmol) in DMSO (70 mL) was added t-BuOK (9.3 g, 83.2 mmol), and then 4-fluoronitrobenzene (8.8 mL, 83.2 mmol). The mixture was heated to 80° C. for 1 hr. After being cooled to room temperature, the mixture was quenched with water (300 mL). The resulting slurry was stirred for 30 min and filtered. The cake was washed with water and dried in oven under house vacuum at 40° C. overnight. The solid was then treated with a 1:2 mixture of ethyl acetate and hexane (150 mL) and the slurry was filtered. The solid was washed with the same solvent system and dried in an oven under house vacuum to give 1-(4-nitrophenyl)-3-(3-pyridinyl)-5-ethylpyrazole (18.5 g, 82%). 1H NMR (CDCl3, 400 MHz) 9.09 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.38, 7.76 (ABq, J=9.04 Hz, 4H), 8.17(m, 1H), 7.36 (m, 1H), 6.67 (s, 1H), 2.84 (q, J=7.5Hz, 2H), 1.36 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]([OH:12])=[O:11])[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C(=O)O
Reaction time: 18 h
Yield: 61 %

Procedure:
Combine diethyl t-butoxycarbonylaminomalonate (4.55 g, 16.5 mmol), a 6 M aqueous sodium hydroxide solution (6.65 mL, 40 mmol), and ethanol (30 mL). After 18 hours, evaporate in vacuo to remove most of the ethanol, dilute with water (50 mL) and extract with diethyl ether. Acidify to a pH of about 3 with aqueous 12M hydrochloric acid and extract twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to give the title compound (61%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:22][C:23]([CH3:24])=[O:25])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Cc1cc2c(C)cc(=O)oc2cc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc2oc(=O)cc(C)c2cc1C

Procedure:
A mixture of 4,6-dimethyl-7-hydroxycoumarin (III) (5.0 g), anhydrous K2CO3 (10 g), chloroacetone (2.5 ml) and acetone (150 ml) was refluxed for 12 h under stirring. From the refluxed mixture the solid was filtered and washed several times with acetone. The acetonic solution and the pooled washings were concentrated to dryness and the residue crystallized from MeOH, yielding 4,6-dimethyl-7-acetonyloxycoumarin (XXXVII) (5.1 g; m.p. 190° C.) ##STR42##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: CCI
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(F)cc(F)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2,4,6-trifluorophenylacetic acid (570 mg, 3.0 mmol), iodoethane (1.56 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) in 5 mL of dimethylsulfoxide is stirred at 50° C. for 3 h, and cooled to room temperature. The mixture is partitioned between diethyl ether and water. The organic layer is washed with water, and saturated sodium chloride, dried over magnesium sulfate, and filtered through magnesol. The filtrate is concentrated to give ethyl 2,4,6-trifluorophenylacetate as a light yellow oil (581 mg, 2.66 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[C:26]3[C:18](=[CH:19][N:20]=[C:21]4[C:25]=3[CH:24]=[CH:23][N:22]4S(C3C=CC=CC=3)(=O)=O)[NH:17][N:16]2C)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([N:15]2[C:26]3[C:18](=[CH:19][N:20]=[C:21]4[C:25]=3[CH:24]=[CH:23][NH:22]4)[N:17]=[N:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1Nc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2N1C1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(n2nnc3cnc4[nH]ccc4c32)CC1
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 4-(6-benzenesulfonyl-2-methyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.37 g, 0.75 mmol) in THF/methanol containing aqueous sodium hydroxide (3.75 mmol) was stirred for 16 hours. The solvent was evaporated under vacuum to a small volume, the residue dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 240 mg (90%) of 4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidine-1-carboxylic acid tert butyl ester. LCMS (Method I, ESI): RT=3.20 min, m+H=357.3; 1H NMR (400 MHz, DMSO) δ: 12.46 (s, 1H), 9.06 (s, 1H), 7.63 (t, 1H), 6.86 (m, 1H), 3.62 (m, 2H), 3.33 (m, 2H), 2.71 (m, 2H), 2.12 (m, 2H), 1.85 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:12])[CH:3]=1.[N:13]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:6]([N:31]2[CH2:32][CH2:33][CH:28]([N:13]3[CH2:14][CH2:15][CH:16]([O:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:18]3)[CH2:29][CH2:30]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Product: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(OC(=O)c3ccccc3)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])[CH3:2].ClC(Cl)(Cl)C(O)=O.[N-:20]=[N+]=[N-].[Na+]>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:20][C:7]2=[O:12])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cccc2c1CCC2=O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Product: CCc1cccc2c1CCNC2=O
Temperature: 0 °C
Yield: 21.3 %

Procedure:
A mixture of 0.9 g (5.63 mmol) of 2,3-dihydro-4-ethyl-1H-inden-1-one and 20 g of trichloroacetic acid was heated at 60°-65° for 30 minutes. To this was added 2.5 g (38.3 mmol) of sodium azide and the mixture was heated at 60°-65°, under nitrogen, for 18 hours. It was poured into 200 ml of ice water and extracted with methylene chloride. The organic layer was washed with saturated sodium hydrogen carbonate, saturated sodium chloride, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2) using a gradient from pure methylene chloride to 19:1 methylene chloride-methanol to give a solid which was rechromatographed using 98:1 methylene chloride-methanol. Recrystallization from toluene/hexane gave 0.21 g (21%) of product; mp 123°-126°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC1C=C([N+]([O-])=O)C=CC=1C(O)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 36 %

Procedure:
The procedure of Example 21 is repeated in every detail except that a chlorobenzene solution of 4-nitrobenzoic acid is employed in lieu of a benzene solution of 2-chloro-4-nitrobenzoic acid to obtain a 36% yield of 4'-chloro-4-nitrobenzophenone having a melting point equal to 100° C. to 101° C.