Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH3:14][CH2:15][N:16](CC)[CH2:17][CH3:18].[OH-].[Na+].C([O-])=O.[NH4+]>C(O)CCC.CCO.[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCN(CC)CC
Reactant: COc1cc2cccnc2c(N)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCCCO
Solvent: O
Product: COc1cc2cccnc2c(N2CCNCC2)n1
Temperature: 80 °C
Yield: 8.6 %

Procedure:
A solution of 6-methoxy-[1,7]naphthyridin-8-ylamine (2.25 g, 12.8 mmol), bis(2-chloroethyl)-benzlyamine (10.25 g, 38.6 mmol) and Et3N (5.34 mL, 38.6 mmol) in BuOH (100 mL) was heated at 100° C. for 72 hours. The cooled reaction mixture was poured into H2O (100 mL) and 2.5 N NaOH (100 mL), and extracted into EtOAc (2×200 mL). The organic phases were combined, dried over NASO4, filtered and concentrated. The resulting oil was purified twice by column chromatography (10% MeOH/CH2Cl2) affording a dark gold oil with BuOH impurity. This oil was dissolved in EtOH (50 mL) and 10% Pd/C (390 mg) and ammonium formate (730 mg) was added. The reaction mixture was heated at 80° C. for 2.5 hours. The cooled reaction mixture was filtered through a pad of celite and washed with EtOAc (50 mL). The organic phase was concentrated and purified by column chromatography (10% MeOH/CH2Cl2+NH4OH) affording 270 mg of the title compound as a dark orange oil. An analytical sample was prepared as the HCl salt from EtOAc.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:2].CN([CH:20]=[O:21])C.O>C1COCC1.C([Li])CCC>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCN(CCOCOC)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CCOCOC)c1ccc(C=O)cc1
Reaction time: 0.75 h
Yield: 91 %

Procedure:
68.0 g (0.23 mol) of N-ethyl-N-[2-(methoxymethyl)oxyethyl]-4-bromoaniline was dissolved in 500 ml of anhydrous THF in an atmosphere of nitrogen, and 280 ml (2.2-fold equivalent weight) of a 1.7M n-butyllithium solution (solvent: n-pentane) was dropwise added thereto at -78° C., followed by stirring for 45 minutes. To the reaction solution obtained, 25 ml of anhydrous DMF was added, and the solution was stirred for 8 hours while allowing the temperature to naturally rise to room temperature. Thereafter, 100 ml of water was added to the resulting reaction solution, which was then extracted with dichloromethane (100 ml×2). The organic layer was dried with anhydrous sodium sulfate, and thereafter concentrated under reduced pressure. The residue thus obtained was distilled under reduced pressure to obtain 51.0 g of N-ethyl-N-[2-(methoxymethyl)oxyethyl]-4-formylaniline (yield: 91%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C([Li])CCC.[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH:20]=O.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH:20]1[O:6][C:4](=[O:5])[CH2:3][CH2:2]1
Reactant: O=CCC1CC2C=CC1C2
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: O=C1CCC(CC2CC3C=CC2C3)O1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
In 80 g of dry tetrahydrofuran was dissolved 10.0 g of 3-bromopropionic acid. In a nitrogen atmosphere, 85.0 g of a hexane solution of 1.6M n-butyllithium was added to the solution at −78° C., followed by 30 minutes of stirring. Then a solution of 8.92 g 2-(5-norbornen-2-yl)acetaldehyde in 20 g hexamethylphosphoric triamide was added dropwise to the solution at the same temperature. With stirring, the temperature of the solution was gradually raised to 20° C. over 2 hours. Next, 80 g of 5% hydrochloric acid was added to the solution, which was stirred for one hour for lactonization. The organic layer was separated, washed with aqueous saturated sodium bicarbonate solution, washed with water, and concentrated in vacuum. Purification by silica gel column chromatography yielded 8.17 g (yield 65%) of γ-(5-norbornen-2-yl)methyl-γ-butyrolactone. The analytical properties of this compound were substantially identical with the data of Synthesis Example 1.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:20])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30]
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)c(C(=O)O)n2C)c1
Yield: 29 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (14-04) (60.0 mg, 28.41%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (260.0 mg, 0.588 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=O)[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:22][NH2:23]>C(O)C>[CH3:17][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:19]([CH3:20])=[N:22][N:23]=[C:1]3[CH3:2])=[C:6]2[CH3:18])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2)c1C
Reactant: NN
Solvent: CCO
Product: Cc1cc(-n2c(C)c3c(C)nnc(C)c3c2C)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(4-hydroxy-3-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.32 mmol) in ethanol (5 mL) was added hydrazine (20 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-methyl-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.09 (d, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 3.00 (s, 6H), 2.59 (s, 6H), 2.34 (s, 3H); MS (ESI) 282 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: CC(C)I
Reactant: O=C1C(Cc2ccc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Yield: 48.9 %

Procedure:
Treat a solution of 3-(2-chloro-4-hydroxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (0.2 g, 0.58 mmol) and 2-Iodopropane (0.06 mL, 0.64 mmol) in DMF (4 mL) with potassium carbonate (0.1 g, 0.7 mmol) and stir reaction overnight at room temp. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography and remove the solvent to afford 0.11 g (48%) of product. MS (m/e): 388 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1.Cl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.6 %

Procedure:
To a mixture of cyclopentylmethanol (8.7 g, 87 mmol) and 4-(dimethylamino)pyridine (0.5 g, 4.3 mmol) in dichloromethane (30 mL) and pyridine (30 mL) was added 4-methylbenzene-1-sulfonyl chloride (16.6 g, 87 mmol). The mixture was stirred at ambient temperature for 20 hours then diluted with 2 N aqueous HCl and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried with NaSO4, concentrated and the filtered thru a silica plug using hexanes:EtOAc (3:1) to afford the title compound (16.5 g, 64.9 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.12-1.27 (m, 2H), 1.47-1.61 (m, 4H), 1.64-1.78 (m, 2H), 2.12-2.30 (m, 1H), 2.45 (s, 3H), 3.90 (d, J=7.1 Hz, 2H), 7.32-7.36 (m, 2H), 7.76-7.81 (m, 2H); MS (DCI/NH3) m/z 272.1 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.[CH2:33]([N:35](CC)CC)[CH3:34].Cl.C(=N)(OCC)C.Cl>O.C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH:30][C:33](=[NH:35])[CH3:34])=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Agent: CCOC(C)=N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=N)NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a stirred suspension of (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (0.062 g, 0.14 mmol) in 2:1 THF-DMF (1.5 mL) was added triethylamine (0.026 mL, 0.19 mmol), followed by ethyl acetimidate hydrochloride (0.021 g, 0.17 mmol) at 0° C. The mixture was allowed to warm up to ambient temperature and stirring continued at 60° C. for 5 hours. The mixture was poured into water, neutralized with 1N HCl, extracted with EtOAc, dried (phase separator silicone treated filter paper) and concentrated to give (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N′-(1-iminoethyl)benzohydrazide (0.049 g, 72% yield) as a yellow oil.
Reaction SMILES: B.[Na].[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])=[C:19]([OH:22])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]>O1CCCC1.C(O)(=O)C.O>[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[CH:18]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=4)=[O:24])[CH:19]([OH:22])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Agent: B
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.92 h
Yield: 76.7 %

Procedure:
Sodium boron hydride (160 mg.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1 g.) in tetrahydrofuran (10 ml.), acetic acid (3 ml.) and water (1 ml.) at 0° C. over 10 minutes, and stirred at 0° to 3° C. for 55 minutes. After water was added to the resultant solution, the solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was pulverized with diethyl ether to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 0.77 g.), mp 172° to 175° C. (dec.).
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[N:4][N:5]([CH3:16])[C:6]=1[CH2:7][NH:8]C(=O)OC(C)(C)C.[ClH:19].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COC(C)(C)C>C(OCC)C>[ClH:19].[NH2:8][CH2:7][C:6]1[N:5]([CH3:16])[N:4]=[C:3]2[C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]=[C:17]2[NH2:18]
Reactant: Nc1ccccc1B(O)O
Reactant: Cn1nc(C#N)c(Br)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cn1nc2c(N)nc3ccccc3c2c1CN
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 94.6 %

Procedure:
A modification of the method described in Example 1283 was used to couple tert-butyl (4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)methylcarbamate (1.43 g, 4.53 mmol) with 2-aminophenylboronic acid hydrochloride (1.57 g, 9.06 mmol). The reaction was completed in 70 minutes. tert-Butyl methyl ether was used instead of chloroform in the work-up procedure. The coupling product was purified by IFC (silica cartridge, eluting with 40% to 60% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for 24 hours. Diethyl ether (50 mL) was added after the reaction cooled to room temperature. A precipitate was present and was isolated by filtration and dried on the vacuum filter funnel for three hours to provide 1.13 g of 1-(aminomethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride as a white solid, mp>250° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].C(OCC)C>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCNCC3)nc2)c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C4COC4)CC3)nc2)c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
A mixture of 197d (0.75 g, 2.1 mmol), oxetan-3-one (0.24 mL, 4.2 mmol), NaBH3CN (0.32 g, 5.1 mmol), and zinc chloride/diethyl ether (5.1 mL, 5.1 mmol) in methanol (30 mL) was stirred at 50° C. for 5 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 197e (550 mg, 64%). MS-ESI: [M+H]+ 421.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]#[C:17][CH2:18][CH:19]([C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)O>C(Cl)Cl>[F:7][CH:19]([C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH2:18][C:17]#[C:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1
Reactant: OC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
DAST (19 μL, 0.15 mmol) was added dropwise to a solution of 4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol (30 mg, 0.11 mmol) in DCM (1.5 mL) at −78° C. The reaction mixture was stirred for 15 min. at −78° C., quenched by the addition of water at 0° C. and extracted twice with DCM. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 10 mg (36 μmol, 33%) of 2-(1-fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline as an orange semi-solid with a purity of 70%.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[C:12]=1[C:19]([OH:21])=[O:20]
Reactant: CCCCCc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 2.70 ml, 0.028 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 13 (5.10 g, 0.028 mol) in dry THF (30 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The acidic mixture was washed with ether (twice), and the combined ethereal layers were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a colourless solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:15]=2[CH:22]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:15]([CH2:22][NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH:16]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(OCCCCCCc2ccccc2)c(C=O)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Product: CC(C)(C)OC(=O)NCCCNCc1ccc(OCCCCCCc2ccccc2)c(CNCCCNC(=O)OC(C)(C)C)c1

Procedure:
N,N'-bis(N-tert.butoxycarbonyl-3-amino propyl)-4-(6-phenylhexyloxy)-1,3-benzenedimethanamine (MS: M+H+ =627) was prepared from 4-(6-phenylhexyloxy)-1,3-benzenedicarboxaldehyde and N-tert.butoxycarbonyl-3-aminopropanamine using the method in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]1[C:35]([O:37][CH3:38])=[O:36]>CO.[OH-].[Pd+2].[OH-]>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][C:13]1[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]([C:35]([O:37][CH3:38])=[O:36])[CH:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2[N+](=O)[O-])N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2N)N1
Reaction time: 4 h

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (3.0 g) and palladium hydroxide, 20 wt % on carbon (300 mg) in MeOH (50 ml) was stirred under hydrogen atmosphere by balloon for 4 hours. Catalyst was removed by filtration and filter cake was washed with CH2Cl2. The combined organic solvent was evaporated to afford a dark green solid (2.61 g192%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13](Br)[C:14](=[C:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])O)[CH3:2].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13]=[C:14]=[C:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH3:2]
Reactant: CCN1C(=C(Br)C(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=C=C=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Reaction time: 0.08 h

Procedure:
The product of Example 14 (1.33 g, 0.002 mol) and triethylamine (1.0 g, 0.01 mol) in dry acetonitrile (25 ml) is stirred as triphenylphosphine (1.15 g, 0.0044 mol) is added in one lot. After stirring for a further 5 minutes, the dye separates, is collected and washed with acetonitrile, to yield 0.34 g (53 %) of crude dye, which is purified by recrystallization from acetonitrile, mp. indistinct.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:12]=[CH:11][C:10]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:25][C:24]([C:10]2[CH:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[C:9]=2[S:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: SC1CCCCC1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCC2)cc1

Procedure:
Methyl 4-[4-(cyclohexylcarbamoyl)-5-cyclohexylsulfanylpyrazol-1-yl]benzoate was prepared from cyclohexylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) by the same process used for Intermdiate#96.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:19][CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:21][CH2:22]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:36]1[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)hex-5-enamide (240 mg, 0.52 mmol) in dichloromethane (4 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (10.4 mg, 3 mol %) and 1,2-bis(diphenylphosphino) ethane (12.2 mg, 6 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.152 mL, 1.04 mmol) was added dropwise, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, 30-100% ethyl acetate in heptane) gave 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (212 mg, 69%). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d, J=2 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.12 (dd, J1=8.5 Hz, J2=2 Hz, 1H), 6.97 (s, NH, 1H), 5.48 (s, NH, 1H), 4.32 (m, 2H), 3.02 (m, 2H), 2.84 (m, 1H), 2.47 (tt, J1=12.5 Hz, J2=3 Hz, 1H), 2.01 (s, 3H), 1.86 (m, 2H), 1.30-1.55 (m, 6H), 1.34 (s, 9H), 1.24 (s, 12H), 1.02-1.22 (m, 1H), 0.75 (t, J=7.5 Hz, 2H).