Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([C@H:13]1[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-(methylsulfonyloxy)piperidine-1-carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90° C. overnight under N2. The solution mixture was cooled to ˜30° C., diluted with ethyl acetate (˜300 mL), and washed with water (700 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M+H−100]+, 373 [M+Na]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=S.CI.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CO.C(O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[NH:9]
Reactant: COc1ccccc1CN
Reactant: NC(=S)Nc1nccs1
Solvent: CO
Solvent: CI
Solvent: CCO
Product: COc1ccccc1CNC(=N)Nc1nccs1
Reaction time: 4 h

Procedure:
400 mg (2.51 mmol) N-1,3-thiazole-2-yl-thiourea were suspended in 20 ml of methanol and 392 mg (2.76 mmol) methyl iodide were added. The reaction mixture was stirred for 4 hours at reflux. Following removal of the solvent by vacuum distillation, the residue obtained was dissolved in 20 ml ethanol, 1.72 g (12.6 mmol) 2-methoxybenzylamine were added and the mixture was stirred for 20 hours at reflux. The solvent was removed on the rotovap. The residue was separated by preparative HPLC(RP-18 column, eluent water/acetonitrile/0.1% acetic acid) and 380 mg N-(2-methoxybenzyl)-N′-1,3-thiazole-2-ylguanidine were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (5.72 g, 18.5 mmol) and phosphoryl chloride (60 mL) according to the general procedure I. Obtained as a white solid (6.04 g, 99%). MS (EI) 326.0 [(M)+]; mp 82° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.N>[Cu].C(OCC)(=O)C>[N:1]1([C:12]2[CH:13]=[C:14]([O:15][CH3:16])[CH:7]=[CH:8][C:9]=2[CH:10]=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C=O)cc1Br
Agent: [Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)c(-n2ccnc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To an aqueous solution (15 mL) of imidazole (5.69 g), 3-bromo-4-methoxybenzaldehyde (3.00 g) and copper powder (86 mg) were added, and the reaction solution was agitated for three days at 100° C. under nitrogen atmosphere. A concentrated ammonia water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:ethyl acetate), and 321 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](F)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][CH2:23][SH:24].C(Cl)Cl.N1C=CC=CC=1>O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:16](=[O:17])[NH:21][CH2:22][CH2:23][SH:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with 25m (136.0 mg, 0.51 mmol) and 2-aminoethanethiol hydrochloride (57.8 mg, 0.51 mmol) were added 2 mL freshly distilled CH2Cl2 and anhydrous pyridine (82 μL, 1.02 mmol). The reaction immediately clouded then cleared after 30 minutes. The reaction was stirred for 3 hours at room temperature, then poured into water and extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, once with saturated brine, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 123.0 mg (38% from 24m) of 26m as a colorless oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH2:19]N)([F:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O.[BH3-][C:24]#[N:25].[Na+]>CO>[CH:1]([N:14]1[CH2:17][C:16]([CH2:19][N:25]([CH3:24])[CH3:21])([F:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: NCC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.2 %

Procedure:
(1-Benzhydryl-3-fluoroazetidin-3-yl)methanamine (0.5 g, 1.0 eq.) was dissolved in methanol and HCHO (0.138 g, 2.5 eq.) and NaCNBH3 (0.47 g, 4.0 eq.) were added at 0° C. The reaction mixture was stirred for 14 h at room temperature, then quenched with aqueous ammonium chloride solution and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 150 mg of 1-(1-benzhydryl-3-fluoroazetidin-3-yl)-N,N-dimethylmethanamine (100%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
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: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 4d (10 g, 35.85 mmol), 5-bromofuran-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 2.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 M hydrochloric acid. Then the mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V/V=1:1). The residue was dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl) furan-2-carboxylic acid 4e (4.23 g, yield 56.1%) as a grey solid.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
Triethylamine (0.64 g, 6.3 mmol) was added dropwise to a mixture of the amine hydrochloride salt (compound 4, 0.70 g, 3.1 mmol) and methane sulfonyl chloride (0.36 g, 6.3 mmol) in tetrahydrofuran (35 mL). After stirring at room temperature for 2 hours, the mixture was filtered, diluted with ethyl acetate, and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/heptane to give colorless crystals (0.39 g, 47%); mp 86–88° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40].Cl>C1COCC1.CCCCCC>[CH2:13]([CH:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:36])[CH:27]([CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCCC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reactant: O=C(CBr)N1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CC(CCC1CCCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.92 mL, 13.68 mmol) in dry THF (50 mL) was cooled to −20° C. A 2.5M solution of n-butyl lithium in hexane (4.4 mL) was added with a syringe. The mixture was stirred for 30 min and then cooled to −78° C. A solution of 4-benzyl-3-(4-cyclohexyl-butyryl)-oxazolidin-2-one (3 g, 9.12 mmol) in THF (10 mL) was added slowly over 3 min. Stirring was continued for 30 min, then a solution of 2-Bromo-1-morpholin-4-yl-ethanone (2.28 g, 10.94 mmol) in THF (4 mL) was added over 3 min. The mixture was allowed to come to room temperature over 5 h. 1N HCl (50 mL) was added and the product was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried with MgSO4 and evaporated under vacuum. The product (1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-(2-cyclohexyl-ethyl)-4-morpholin-4-yl-butane-1,4-dione) was obtained after purification by flash chromatography as a single diastereomer (2.5 g). 1H NMR: (CDCl3) 7.35–7.22(m, 5H), 4.69–4.62 (m, 1H), 4.28–4.10 (m, 3H), 3.76–3.46 (m, 8H), 3.37 (d, J=13.6 Hz, 1H), 2.91 (ddd, J=16.4 Hz, J=13 Hz, J=3 Hz, 1H), 2.76 (ddd, J=13.5 Hz, J=11 Hz, J=3 Hz, 1H), 2.51 (dt, J=13.6 Hz, J=3 Hz, 1H), 1.76–0.80 (m, 15H). MS: (M+H)+ 457.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2]>C(O)C.[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Yield: 82.8 %

Procedure:
A solution of 0.30 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 16 mL of ethanol and 8 mL of 10% aqueous sodium hydroxide was refluxed for 5 hours. After cooling, the reaction mixture was filtered, and the solvent was removed in vacuo. The residue was dissolved in water, and the solution was acidified to pH 3.5 using hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from aqueous ethanol to furnish 0.24 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (m.p. 180°-181°); NMR (200 MHz, DMSO-d6):δ8.26 (s, 1H); 8.04 (d, 1H); 7.77 (d, 1H); 7.52 (t, 1H); 7.36 (A2M2, 4H); 5.30 (s, 2H); 4.48 (s, 2H); 2.57 (t, 2H); 1.64 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([CH2:31][C:30]3[N:26]([CH2:25][C:24]4[CH:33]=[CH:34][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:27]=[N:28][CH:29]=3)[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CN2CCC3(CC2)C(=O)NCN3c2ccccc2)cc1

Procedure:
A solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (230 mg, 1 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (265 mg, 1 mmol), and diisopropylethylamine (0.52 mL, 3 mmol) in anhydrous acetonitrile (5 mL) was stirred at room temp. for 2 days. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH:17]1[CH:16]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:19]=[N:18]1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: c1csc(-c2cn[nH]c2)n1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
To a solution of 2-bromothiazole (1 g, 6 mmol) in toluene (20 mL) and ethanol (10 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.41 g, 7.3 mmol), 2 M sodium carbonate solution (17.3 mL) and Pd(PPh3)4 (7 mg, 0.06 mmol). The reaction mixture was purged with argon for 15 min. The resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), the organic solvent was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford racemic 2-(1H-pyrazol-4-yl)thiazole as brown liquid (520 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.22 (br s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H); LC-MS m/z calculated for [M+H]+152.02. found 152.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:9]=1)[C:5]#[N:6].ClC1C=C(C=C(Cl)N=1)C(N)=[O:22].OC1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:9]=1)[C:5]([NH2:6])=[O:22]
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Reactant: NC(=O)c1cc(Cl)nc(Cl)c1
Agent: OC1CCNCC1
Product: NC(=O)c1cc(Cl)nc(N2CCC(O)CC2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 26 starting from 2,6-dichloroisonicotinamide and 4-hydroxypiperidine (both commercially available).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=[O:19])CCC1=O.BrC1C2C=CC=C([N+]([O-])=O)C=2OC=1.C(N(CC)CC)C>CS(C)=O.F[B-](F)(F)F.[Ag+]>[N+:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1OCC2
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])c1cccc2c(Br)coc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1COc2c1cccc2[N+](=O)[O-]

Procedure:
Schema 3 illustrates an alternative method of producing the above benzofuranyl-3-on-7-yl uracils by the oxidation of a 2,3-dihydro-4,6-optionally disubstituted-7-nitrobenzofuran (Compound III in Schema 1). The 2,3-dihydro-7-nitrobenzofuran is treated with N-bromosuccinimide while being irradiated with light. The product of this reaction, a 3-bromo-7-nitrobenzofuran (VIII), is then reacted with silver tetrafluoroborate in dimethyl sulfoxide in the presence of triethylamine, yielding the corresponding 2,3-dihydro-7-nitrobenzofuran- 3-one (IX). This compound may be used in place of compound III in Schema I to produce the corresponding 3-(2,3-dihydrobenzofuran-3-on-7-yl)-1-alkyl-6-haloalkyluracil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C1(C)C=CC=CC=1.I[C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([O:51][CH3:52])[CH:45]=1>COCCOCCOC>[CH3:52][O:51][C:46]1[CH:45]=[C:44]([CH:49]=[C:48]([CH3:50])[CH:47]=1)[O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: COc1cc(C)cc(I)c1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (prepared according to Kuchkova et al., Synthesis, 1045-1048, 1997) (0.24 g, 1.0 mmol), Cu(I)I (0.019 g, 0.10 mmol)) and 3,4,7,8-tetramethyl-[1,10]phenanthroline (0.047 g, 0.20 mmol)) were added to an oven dried sealed tube, sealed with a rubber septum, and flushed with a stream of nitrogen for 15 min. Anhydrous toluene (5 mL), anhydrous diglyme (1 mL) and 1-iodo-3-methoxy-5-methylbenzene (2) (0.273 g, 1.10 mmol) were added via a syringe with vigorous stirring under a stream of nitrogen at room temperature. The rubber septum was replaced with the Teflon cap and the sealed tube was heated at 120° C. in an oil bath for 18 h. The reaction was allowed to cool to room temperature, and then quenched with ethyl acetate. The resulting suspension was filtered through a celite pad. The filtrate and the washings were concentrated to dryness. The crude product was purified by flash chromatography (Hexanes/EtOAc, 9:1) to yield (1S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (4) (0.33 g, 92% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)[CH:12]=2)[CH:4]=[N:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C=C[C:40]2N(O)N=[N:43][C:41]=2[CH:42]=1.C1(N)CC1>CN(C=O)C>[CH:41]1([NH:43][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:16]([C:15]3[CH:14]=[N:13][N:11]4[CH:12]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:8]=[N:9][C:10]=34)=[CH:17][CH:18]=2)[CH2:42][CH2:40]1
Reactant: Cn1cc(-c2cnc3c(-c4ccc(C(=O)O)cc4)cnn3c2)cn1
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(-c4ccc(C(=O)NC5CC5)cc4)cnn3c2)cn1
Temperature: 120 °C

Procedure:
4-[6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoic acid (50 mg, 0.16 mmol) was dissolved in DMF (2 mL). Resin bound CDI (288 mg, 0.4 mmol), HOBT (26 mg, 0.17 mmol), and cyclopropylamine (20 mg, 0.32 mmol) was added. The reaction was sealed and heated in the microwave at 120° C. for 20 minutes. The reaction was cooled to ambient temperature, filtered and purified by reverse phase chromatography to give N-cyclopropyl-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzamide as a yellow solid: LC/MS [M+H]=359.0.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]S(C4C5C=CN=CC=5C=CC=4)(=O)=O)=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:45]([O:52][C:53](Cl)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Cl-].[Na+].[OH-].[Na+]>C(Cl)Cl.CO.C(N(CC)CC)C>[CH2:45]([O:52][C:53]([N:42]1[CH2:41][CH2:40][N:39]([C:37](=[O:38])[C@H:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[NH:14][S:11]([C:6]2[C:5]3[CH:4]=[CH:3][N:2]=[CH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:13])[CH2:44][CH2:43]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1

Procedure:
620 mg of the crude product obtained in Example 28 was dissolved in 10 ml of methylene chloride, and to the solution were sequentially added 0.29 ml of benzyloxycarbonyl chloride and 3.04 ml of triethylamine with ice cooling. After stirring for two hours with ice cooling, 40 ml of saturated sodium chloride aqueous solution was added to the reaction mixture, which was then extracted twice with 20 ml of chloroform, and the extract was dried over magnesium sulfate and concentrated under a reduced pressure to obtain a residue. The residue was dissolved in 6 ml of methanol, and after the addition of 2 ml of 1N sodium hydroxide aqueous solution, the mixture was refluxed for two hours, dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (80:1 to 50:1) to obtain 336 mg of the title compound as colorless crystals.
Reaction SMILES: C([Li])CCC.[C:6]1([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>CCCCCC.CCOCC>[N:16]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[C:14]([CH:23]=[O:24])=[CH:13][CH:12]=[CH:11]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc2c(N3CCCC3)cccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cccc2cccc(N3CCCC3)c12
Temperature: -20 °C

Procedure:
n-Butyllithium (14.7 ml of a 1.7 M solution in hexane) was added dropwise to a stirred solution of 1-(1-naphthyl)pyrrolidine (25.00 mmol, 5.00 g) in dry ether (50 ml) at −20° C. under argon. After 48 hours a solution of dry N,N-dimethylformamide (6.2 ml, 75.00 mmol) in ether (10 ml) was added dropwise at −78° C. to the reaction mixture. The mixture was allowed to warm to −20° C. over 4 hours, then quenched with a solution of methanol (15 ml) and allowed to warm to room temperature. The reaction mixture was diluted with ether (100 ml), washed with water (3×150 ml) and with brine (150 ml), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluent to afford the aldehyde which was crystallized from hexane.