Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23].Cl>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:24])[CH3:23]
Reactant: N#CC1(c2ccc(Br)cc2)CCC1
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C2(C#N)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.9 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)cyclobutanecarbonitrile (2.8 g, 11.9 mmol) in anhydrous THF (70 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (7.44 mL, 14.9 mmol). The reaction mixture is stirred at that temperature 10 min., then N-methoxy-N-methyl-acetamide (2.50 mL, 23.8 mmol) is added and the solution is then left to warm-up to room temperature over 1 h. A mixture of brine (30 mL) and 1 N HCl (15 mL) is then slowly added and the solution is extracted with EtOAc (3×100 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography using a 0 to 20% EtOAc in hexane gradient to yield 1-(4-acetylphenyl)cyclobutanecarbonitrile (1.35 g, 57%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D) δ 8.03-(2H, m), 7.56-7.50 (2H, m), 2.94-2.81 (2H, m), 2.71-2.57 (2H, m), 2.62 (3H, s), 2.57-2.40 (1H, m), 2.18-2.05 (1H, m).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[C:35]3([C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:34]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN>C(#N)C.[Cu]I>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C@H:33]2[C@@:35]3([C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]([C:2]4[N:3]=[CH:4][N:5]([C:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:6]=4)[C:36]3=[O:44])[CH2:34]2)=[CH:31][CH:32]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1Nc2ccccc2C12CC2c1ccc(Cl)cc1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C1N(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 21 h

Procedure:
4-Iodo-1-trityl-1 H-imidazole (210 mg, 0.48 mmol) was added to a suspension of racemic (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (107 mg, 0.4 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere. A steady stream of nitrogen was bubbled through the suspension as it was heated to 40° C. over 15 minutes. Potassium carbonate (110 mg, 0.8 mmol), copper (I) iodide (12 mg, 15 mol %), and N,N-dimethylethylenediamine (0.12 mmol, 30 mol %) were added and the reaction mixture was heated to 80° C. and kept for 21 hours under nitrogen atmosphere. The mixture was cooled to room temperature, filtered and concentrated to give the title product. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give racemic trans-2-(4-chlorophenyl)-1′-(1 H-imidazol-4-trityl)spiro[cyclopropane-1,3′-indolin]-2′-one (157 mg, 68%). LC/MS m/e calcd. for C38H28ClN3O: 577, observed (M+H)+: 578.2 MS calcd. for C38H28ClN3O 578, obsd. (ESI+) [(M+H)+] 579.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.[CH2:15]1[C:18]2([CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH:24]=[CH2:25])[CH2:19]2)[CH2:17][NH:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:16]2[CH2:17][C:18]3([CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH:24]=[CH2:25])[CH2:19]3)[CH2:15]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: C=CC(=O)N1CCC2(CNC2)C1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N1CCC2(C1)CN(C(=O)CNc1cc(Cl)c(Cl)cc1O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
The mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (47 mg, 0.2 mmol), 1-(2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one (40 mg, 0.2 mmol), EDCI.HCl (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol) and Et3N (0.61 mg, 0.6 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (13 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H), 6.78 (s, 1H), 6.60-6.50 (m, 2H), 6.13 (dt, J=2.4, 16.4 Hz, 1H), 5.67 (dd, J=2.4, 10.4 Hz, 1H), 5.19 (dd, J=5.2, 10.0 Hz, 1H), 4.16-4.07 (m, 2H), 3.90-3.83 (m, 2H), 3.75-3.72 (m, 3H), 3.61-3.52 (m, 2H), 3.42-3.39 (m, 1H), 2.16-2.13 (m, 1H), 2.06-2.03 (m, 1H). ESI-MS m/z: 382.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:9][C:8]([Br:21])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:10]([CH2:11][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][C:8]([Br:21])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: COc1ccc(C(=O)c2cc(Br)c3c(c2Br)CCC3)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(Cc2cc(Br)c3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.3 %

Procedure:
To a solution of ketone 5-1 (3.9 g, 9.5 mmol) in CH2Cl2/CH3CN (31 mL/31 mL) were added triethylsilane (4.8 mL, 28.5 mmol) and boron trifluoride diethyl etherate (3.7 mL, 28.5 mmol) at 0° C. under nitrogen atmosphere. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 h. To the mixture was added saturated K2CO3 solution (50 mL) slowly and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired product 6 (3.2 g, 8.1 mmol, 85%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28]O)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Oc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Diethyl azodicarboxylate (630 μL, 4.00 mmol) was added to a mixture of 2-hydroxypyridine (0.380 g, 4.0 mmol), tert-butyl(2-hydroxyethyl)carbamate (0.322 g, 2.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in THF (6.0 mL). The mixture was stirred overnight at RT, and concentrated. The residue was chromatographed on silica gel with EtOAc in hexanes to give the product (0.353 g, 74.1%). LCMS: (M+H)=239.2.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH2:20][CH3:21])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([CH2:20][CH3:21])[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: O
Reactant: CCc1nc(Cl)c(C=O)[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCc1nc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
A solution of sodium chlorite (4.41 g, 48.8 mmol) and sodium dihydrogen phosphate monohydrate (3.9 g, 28.3 mmol) in water (11 mL) was added to a stirred solution of 4-chloro-2-ethyl-1H-imidazole-5-carbaldehyde (0.763 g, 4.81 mmol), 2-methyl-2-butene (30 mL of a 2M solution in THF, 60 mmol), and tert-butanol (3.7 mL) in THF (15 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×40 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.715 g, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.86 (br. s., 2H), 2.59 (q, 2H), 1.17 (t, 3H). ES-LCMS: m/z 174.9, 176.9 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([C:9](Cl)=[C:10]([CH3:13])[CH:11]=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])=[CH:15][CH:16]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C=O)=C(Cl)c1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Yield: 88 %

Procedure:
4-tert-Butyl-β-chloro-α-methylcinnamaldehyde (71 g), 1.0 g of 5% Pd/C, 40 g of 30% sodium hydroxide solution, 40 g of water and 32 g of methanol were placed in a Parr apparatus and hydrogenated at 20-50 psi until the theoretical amount of hydrogen had been absorbed (about 31/2 hrs.). The solution was filtered and the aqueous phase extracted with 100 g of ethylene dichloride. The solution was distilled to yield 53.9 g (76%) of the desired product, bp 100° (1.0 mm).
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[CH:12]=[C:11]([CH3:13])[S:10][C:7]=2[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][C:11]([CH3:13])=[CH:12][C:6]=12
Reactant: Cc1cc2c(=O)c([N+](=O)[O-])c[nH]c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(Cl)c([N+](=O)[O-])cnc2s1
Yield: 68 %

Procedure:
A mixture of 2.26 g of 5-nitro-2-methylthieno[2,3-b]pyridine-4(7H)-one 2 and 10 ml of phosphorus oxychloride is refluxed for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is taken up on ethyl acetate. The organic phase is dried over magnesium sulfate and treated with activated charcoal. The mixture is filtered and the solvent is evaporated in vacuo. The crude product is recrystallized from ethyl acetate-n-hexane to give 1.90 g (68%) of Compound 3 as colorless crystals melting at 96°-98° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.O=S(Cl)[Cl:35]>>[Cl:35][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:32])[CH:21]=2)=[N:25][CH:26]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CO)cn4)sc23)c(F)c1)NC1CC1
Reactant: O=S(Cl)Cl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500 mL round-bottom flask containing 64 (5.34 g, 11.85 mmol) was added slowly SOCl2 (30 mL, 411 mmol). The yellow solution was stirred at RT for 2 h and cooled to 0° C. The reaction mixture was quenched by addition of ice (150 g) and water (100 mL), and the yellow suspension was shaken at RT for 1 h. The solid was collected by filtration, rinsed with water and dried under high vacuum. The crude product was triturated with AcOEt to afford the title compound 65 (5.55 g, purity ˜40% by HPLC, contaminated with the des-cyclopropyl side-product) as a yellow solid. MS (m/z): 469.1 (M+H). The material was used in the next step with no additional purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][C@H:8](O)[CH2:9][C@H:3]1[CH2:4][CH2:5]2.S(Cl)([Cl:13])=O.[OH-].[Na+].C(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][CH:8]1[CH2:9][CH:3]2[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]2)[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN1C2CCC1CC(Cl)C2
Reaction time: 8 h

Procedure:
To a solution of 95 g pseudotropine in 420 ml abs. CHCl3 are added dropwise at 0° 195 ml thionyl chloride within 20 minutes. The reaction mixture is refluxed for 4 hours, then left overnight at room temperature and then heated to 60°-65° for 3 hours. The mixture is then diluted with CH2Cl2 to a volume of ca. 100 to 150 ml and poured on ice-water. A 35% aqueous NaOH solution is added to a pH 11 and then dry ice to a pH 10. After extraction with CH2Cl2 and distillation of the extracts (second fraction~97°-98°) the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([C:19]#[C:20][S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][C:16]2=[O:28])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=[O:34].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:34])[NH:17][C:16]2=[O:28])[CH3:14])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 448 mg of (3S, 4S)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)ethynyl]-2-azetidinone in 5 ml of anhydrous methylene chloride was added, under an atmosphere of nitrogen gas, 0.4 ml of trifluoroacetic acid, with stirring and ice-cooling. Stirring was continued for 30 minutes under ice-cooling and for a further 1.5 hours at room temperature. The reaction mixture was then poured into a mixture of 1.0 g of sodium bicarbonate, 10 ml of water and 20 ml of ethyl acetate. The mixture was saturated with sodium chloride and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer and the ethyl acetate extracts were combined, and the combined solution was washed successively with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of cyclohexane and ethyl acetate, to afford 95.0 mg (yield 63.0%) of the title thioester compound, as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:21])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (120 mg, 0.48 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (23 mg, 0.57 mmol, 60% dispersion in oil) and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was then cooled to 0° C. and methyl iodide 0.04 ml, 0.64 mmol) was added dropwise. After stirring for 16 hours at room temperature, the mixture was quenched by addition of water (10 ml) and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulphate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colorless oil (52 mg, 41%); MS (ISP): 264.0 ([M+H]+), 208.1 ([M+H-Me2C═CH2]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][N:13](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:12]#[N:13]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
A suspension of bromoarene 2 (801 mg; 3.7 mmol) and zinc cyanide (570 mg; 4.85 mmol; 1.3 eq.) in degassed dimethylformamide (15 mL) was stirred at room temperature under nitrogen in the dark for 45 min and then treated with tetrakis(triphenylphosphine) palladium(O) (310 mg, 1.6 mmol). The mixture was stirred at 90° C. for 18 h; filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography on silica gel, eluent EtOAc-hexane (1:1) to afford the title compound 274 (380 mg, 63% yield). 1H NMR: (400.2 MHz, CDCl3) δ (ppm): 8.22 (d, J=8.6 Hz; 1H); 7.19 (d, J=1.8 Hz; 1H); 6.95 (dd, J=1.8, 8.6 Hz; 1H); 6.27 (bs; 2H). MS: calc: 163.1; found: 164.1 (M+H)
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N([O-])=O.[Na+].O.[C:15]([O:18]CC)(=[O:17])[CH3:16]>C(O)(=O)C>[C:15]([O:18][C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])(=[O:17])[CH3:16]
Reactant: CCOC(C)=O
Reactant: CSCC[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSCC[C@@H](OC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
D-Methionine (14.9 g, 0.10 mol) was stirred in 300 ml of acetic acid. Sodium nitrite (13.8 g, 0.2 mol) was added portionwise over 45 minutes while maintaining the temperature in the range 20°-30° C. After stirring for an additional 90 minutes at room temperature, the resulting yellow solution was stripped in vacuo to solids which were distributed between 300 ml each of water and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and stripped to yield 7.0 g of title product as a yellow oil, used directly in the next step; tlc Rf 0.08 (3:1 hexane:ethyl acetate).
Reaction SMILES: N#N.[CH3:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:5](O)=[O:6].CC[N:17](CC)CC.ClC(OCC)=O.[NH4+].[OH-]>C1COCC1>[CH3:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:5]([NH2:17])=[O:6]
Reactant: CCN(CC)CC
Reactant: C/C(=C\c1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: N#N
Agent: [NH4+]
Solvent: C1CCOC1
Product: C/C(=C\c1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-2-methyl-3-phenylacrylic acid (19.0 g, 116 mmol) and Et3N (17.1 mL, 122 mmol) in THF (500 mL) at 0° C. was treated with ethyl chloroformate (11.4 mL, 117 mmol) and the reaction mixture was stirred at 0° C. for 15 min. A solution of NH4OH (250 mL of a 25% aq. solution) in THF (150 mL) was then added and the reaction mixture was stirred at rt for 90 min. The aq. layer was extracted twice with CH2Cl2 and the combined org. extracts were washed with water, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. TLC:rf (1000:50:4 CH2Cl2—MeOH—NH4OH)=0.25
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=O)=O.O>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][O:24][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]=2[CH2:25][OH:26])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C)cc1
Reactant: COc1cc2cc(CO)c(CO)c(-c3cccnc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc2cc(COCC(C)(C)C)c(CO)c(-c3cccnc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride in hexamethylphosphoric triamide (40 ml) is added a solution of 1-(3-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene in hexamethylphosphoramide (10 ml) under ice-cooling. The mixture is warmed to room temperature, and then stirred for 30 minutes. To the reaction solution is added neo-pentyl tosylate (3.67 g), and the mixture is reacted at 100° C. for 30 minutes. The mixture is allowed to cool, and thereto is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The resulting residue is subjected to silica gel column chromatography (eluent; chloroform:acetone=5:1), and the desired fractions are concentrated to give 1-(3-pyridyl)-2-hydroxymethyl-3-neo-pentyloxymethyl-6,7-dimethoxynaphthalene (1.5 g) as an oily product.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc(N[C@@H]2CCC[C@H](O)C2)ncc1C(N)=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 4-(tert-butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (250 mg, 0.918 mmol; synthesis described herein) and (1S,3R)-3-aminocyclohexanol (138 mg, 1.2 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (374 mg, 2.9 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (212.2 mg, 0.69 mmol, yield 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (brs, 1H), 8.12 (s, 1H), 5.53 (brs, 3H), 3.93-3.91 (m, 1H), 3.88-3.82 (m, 1H), 2.27-2.25 (m, 1H), 1.92-1.85 (m, 3H), 1.47 (s, 9H), 1.42-1.25 (m, 4H); MS (ESI) m/z=308.2 [M+1]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN1CCCC1=O.O>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: [Cl-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reaction time: 10 h

Procedure:
4-Nitro-2,6-dimethylphenyl trifluoromethanesulfonate (4.06 kg, 13.6 mol) is dissolved in anhydrous N-methylpyrrolidinone (42 L) and to this solution is added anhydrous lithium chloride (900 g) all at once. The internal temperature is raised to 120° at which time the color changes to a dark golden brown. After 10 hours at this temperature the color of the solution is dark brown. The reaction is then cooled to 5° and diluted with cold water (5°, 21 L) at such a rate as to keep the temperature below 15°. After the addition is complete the mixture is stirred for 1 hour at 5°. The product is collected by filtration and washed with water (4×1 L). This dark brown solid is dissolved in t-butyl methyl ether (42 L) and stirred first with charcoal and then anhydrous magnesium sulfate (10 pounds). After filtration the solvents are removed in vacuo (40°, 3 Torr) to obtain a tan solid which is dried in vacuo (25°, 3 Torr) for 2 days to obtain 4-chloro-3,5-dimethylnitrobenzene, m.p. 101°-105°.