Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:36][C:37]3[CH:45]=[CH:44][C:40]4[O:41][CH2:42][O:43][C:39]=4[CH:38]=3)[C:12](=O)[CH2:13][C:14]3[N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:17][C:18]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[O:41]1[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:12][CH2:13][C:14]3[N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:17][C:18]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:38][C:39]=2[O:43][CH2:42]1
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC(=O)N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CCN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N,N-bis-benzo[1,3]dioxol-5-ylmethyl-2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetamide (150 mg, 0.249 mmol) in tetrahydrofuran (25 mL) is cooled to 0° C. under a nitrogen atmosphere. Lithium aluminum hydride (95%, 30 mg, 0.747 mmol) is added in one portion and the reaction allowed to stir overnight warming to room temperature. Water (0.03 mL), sodium hydroxide (15% solution, 0.03 mL), and water (0.09 mL) are added and the reaction mixture is allowed to stir at 0° C. for 15 minutes. Magnesium sulfate is then added and the crude solution is filtered through a bed of Celite washing with 2% methanol in dichloromethane (100 mL). The crude sample is concentrated in vacuo and flash chromatographed on SiO2 using an eluent of dichloromethane:methanol 95:5 to afford bis-benzo[1,3]dioxol-5-ylmethyl-[2-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine as a colorless syrup.
Reaction SMILES: CC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[CH:31]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32]1>[Cu]I>[CH:31]1([O:36][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: OC1CCCC1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: Cc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Product: COc1ccc(OC2CCCC2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 5-methyl-1,10-phenanthroline (39 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 4-iodoanisole (234 mg, 1.0 mmol) and cyclopentanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 30:1) provided 128 mg (67% yield) of the title compound as a colorless oil.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O.[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:35]=[C:30]3[C:29]([C:42]3[CH:43]=[N:44][N:45](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:46]=3)=[CH:28]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC.CCOC(C)=O.O>[C:18]1([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:35]=[C:30]3[C:29]([C:42]3[CH:46]=[N:45][NH:44][CH:43]=3)=[CH:28]2)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(N3CCOCC3)cnc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(N3CCOCC3)cnc21
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
Triisopropylsilane (0.058 mL, 0.28 mmol), trifluoroacetic acid (TFA, 0.2 mL) and water (0.02 mL) were added to a solution of 56 (0.093 g, 0.14 mmol) in CH2Cl2 (2 mL). After string for 15 minutes, the pH of the mixture was adjusted to pH 7-8 with saturated aqueous NaHCO3 and product was extracted with CH2Cl2 twice. The combined organic solutions was dried (MgSO4) and concentrated to afford a tan syrup. Hexane:AcOEt (1:1) solution of was added to the syrup and the mixture was cooled with ice-water bath. The precipitate was filtered off, washed with hexane and dried to afford 57 (0.037 g, 63%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.06-3.10 (m, 4H), 3.80-3.84 (m, 4H), 7.34 (d, J=0.27 Hz, 1H), 7.39-7.44 (m, 2H), 7.48-7.53 (m, 1H), 7.68 (s, 1H), 7.79 (bs, 1H), 8.09-8.13 (m, 2H), 8.18 (d, J=0.27 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=O.[C:7]1(O)[CH:12]=[CH:11]C=[CH:9][CH:8]=1.[OH-].[K+].C(N)CN.[O-][Si]([O-])=O.[Mg+2]>>[O:1]([CH2:5][CH2:4][NH2:3])[C:2]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C1NCCO1
Agent: O=[Si]([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: NCCN
Product: NCCOc1ccccc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a 250 mL round bottom flask equipped with a thermocouple, heating mantle, nitrogen inlet/outlet, a condenser and a stir bar was added 2-oxazolidinone (14.8 g, 170 mmole), phenol (10.0 g, 106.3 mmole), potassium hydroxide (596 mg, 10.6 mmole) and ExxonMobil™ Aromatic 100 solvent (100 mL). The resulting mixture was heated to reflux temperature for 3 h. Reaction progress was monitored by TLC and 1H NMR. Once the phenol was consumed, ethylenediamine (3.6 mL, 53 mmole) was added and the reaction mixture was continued to stir at reflux temperature for 2 hrs. The reaction mixture was then cooled to room temperature. Florisil® (5 g) was added and the reaction mixture was filtered over Celite. The reactor and the filter cake were washed with ExxonMobil™ Aromatic 100 solvent (2×10 mL). The combined filtrates were concentrated under reduced pressure to give 12.3 g (84%) of the desired product as a yellow oil. Purity level was determined by NMR to be ˜95%. 1H NMR (CDCl3, 400 MHz) δ 7.22-7.14 (m, 2H), 6.89-6.77 (m, 3H), 3.80 (dd, 2H, J=5.3, 5.3 Hz)), 2.90 (dd, 2H, J=5.4, 5.4 Hz), 1.41 (bs, 2H), 13C NMR (CDCl3, 400 MHz) 158.9, 129.4, 120.7, 114.4, 70.0, 41.5, MS (ESI) for C8H11NO [M+H] calc. 137.08. found 137.56.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[C:13](=O)[O:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)(C)C(O)C)C=CC=CC=1.C(N(CC)CC)C.[BH4-].[Li+].[H-].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][O:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: CC(O)C(C)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
0.673 g (2 mmol) of cis-1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4,6-trione and 0.435 g (2 mmol) of (-)-3,3-diphenyl-2-butanol ([α]36520 =-338.9° (1% in ethanol)) in 5 ml of toluene are heated under reflux for 6 hours in an apparatus standing under argon. After cooling 0.28 ml (2 mmol) of triethylamine and 5 ml of tetrahydrofuran are added thereto. The solution obtained is added dropwise within 30 minutes at 40° C. under argon to a solution of 4.8 ml of a 1 molar lithium borohydride solution in tetrahydrofuran (4.8 mmol) and the mixture is left to react at 40° C. for 14 hours. The excess hydride is decomposed at 10° C. with 5 ml of 3N HCl and the mixture is stirred at 60° C. for 30 minutes. The product obtained is isolated and purified as described in Example 2 and there is obtained 0.333 g of (3aS,6aR)-1,3-dibenzyl-dihydro-1H-furo[3,4-d]imidazole-2,4(3H,3aH)-dione. [α]D20 =+38.7° (1% in CHCl3), which corresponds to an optical purity of 62.4% e.e.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:13][CH2:12]2)=[C:7]2[C:3]=1[C:4](=[O:37])[N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:6]2=[O:25].C([O-])(=O)C.[Na+].[CH3:43][S:44]([CH:47]=[CH2:48])(=[O:46])=[O:45]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC(N(C)C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:5]1[C:4](=[O:37])[C:3]2[C:7](=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:2]=2[CH:48]=[CH:47][S:44]([CH3:43])(=[O:46])=[O:45])[C:6]1=[O:25]
Reactant: COc1ccc(CN2C(=O)c3c(Cl)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Reactant: C=CS(C)(=O)=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)c3c(C=CS(C)(=O)=O)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 150 °C
Yield: 19.4 %

Procedure:
A 10 mL sealed tube was charged with Compound 10 (100.0 mg, 0.19 mmol), sodium acetate (22.0 mg, 0.27 mmol), bis(tri-t-butylphosphine)palladium (0) (13.0 mg, 0.03 mmol), methyl vinylsulfone (0.02 ml, 0.23 mmol), and dimethylacetamide (1.0 mL). The tube was charge with argon and sealed. The mixture was heated at 150° C. for 24 h. The mixture was cooled to room temperature and purified via flash chromatography (230-400 mesh silica gel 60, gradient 90:10-50:50 hexanes:ethyl acetate) to give 21.7 mg (19%) of Compound 62 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=15.6, 1 H), 7.48-7.53 (m, 5H), 7.01-7.08 (m, 3H), 6.70-6.90 (m, 3H), 4.64 (s, 2H), 4.42 (q, J=6.9 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.33-3.80 (m, 8H), 3.07 (s, 3H), and 1.86 (d, J=6.7 Hz, 3H); MS (ES+) 590 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[Cl-].[C:23]([O:27][C:28](=[O:31])[CH2:29][Zn+])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:23]([O:27][C:28](=[O:31])[CH2:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: COc1ccc(CN2CCc3cc(Br)ccc3C2=O)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3cc(CC(=O)OC(C)(C)C)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (1.9 g, 5.5 mmole), Q-phos (0.0632 g, 0.11 mmole) and Pd(dba)2 (0.0781 g, 0.11 mmole) in 10 ml THF were added to 2-tert-butoxy-2-oxoethylzinc chloride 15 ml (0.55 M) under argon. The reaction mixture was stirred at room temperature for 16 hours. Next a third of the initial amount of Q-phos, Pd(dba)2 and zinc enolate were added and the mixture heated for 1 hour at 70° C. to bring the reaction to completion. 2 g of [2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetic acid tert-butyl ester was isolated by flash chromatography using silica gel column chromatography with 10%-40% ethyl acetate in hexane as eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[N:5]=[C:4]([NH2:13])[N:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1>CCO>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][O:10][CH2:9]3)[N:5]=[C:4]([NH2:13])[N:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)cc(C2CCOC2)n1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C3CCOC3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A solution of 4-chloro-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine (500 mg, 2.51 mmol), N—BOC piperazine (960 mg, 5.15 mmol) and pyridine (500 uL, 6.1 mmol) in EtOH (10 mL) was heated at 90° C. for 4 h. Upon cooling to rt a thick precipitate formed which was collected by filtration. The material was rinsed with EtOAc to afford 125 mg of a white solid. The filtrate was concentrated and triturated with Et2O-EtOAc (1:1) to yield an additional 600 mg of material (82% combined). MS (ESI): mass calcd. for C17H27N5O3, 349.2; m/z found, 350.3 [M+H]+. 1H NMR (CDCl3): 5.86 (s, 1H), 4.70 (br s, 2H), 3.90-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.55-3.60 (m, 4H), 3.45-3.50 (m, 4H), 3.18-3.26 (m, 1H), 2.20-2.30 (m, 1H), 2.09-2.18 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)([O-])=O.[N+](C1C=CC=C2C=1CCCC2)([O-])=O.[H][H]>CO.[Pd]>[CH:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCC2
Agent: [Pd]
Agent: O=[N+]([O-])c1cccc2c1CCCC2
Solvent: CO
Product: Nc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 6-nitro-1,2,3,4-tetrahydronaphthalene and 5-nitro-1,2,3,4-tetrahydronaphthalene (5.5 g, 31.1 mmol) in MeOH (50 mL) was added 10% palladium on carbon (3.18 g, 3.0 mmol) under nitrogen, then replaced with hydrogen atmosphere (2 L). The resulting mixture was stirred at room temperature for 16 h, and filtered through Celite. The filtrate was concentrated, and the residue was purified by silica gel column (PE/EtOAc v/v 10:1) to give 5,6,7,8-tetrahydronaphthalen-2-amine as a white solid (2 g, 40% yield). ESI MS: m/z 148 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 6.88 (d, J=8.0 Hz, 1H), 6.49 (dd, J=2.0 Hz, J=8.0 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 3.49 (s, 2H), 2.69-2.67 (m, 4H), 1.78-1.75 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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]([C:5]1[S:6][C:7]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1

Procedure:
A degassed solution of 5-Bromo-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (70 mg, 0.15 mmol) and 3-fluorophenyl boronic acid (32 mg, 0.23 mmol) in a mixture of DME (2.0 mL) and 2M aqueous Na2CO3 (1.0 mL) was treated with Pd(PPh3)4 (17.6 mg, 0.015 mmol). The reaction was heated at reflux for 18 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried and concentrated to a residue that was purified by preparative chromatography using EtOAc:hexanes as eluent to provide 5-(3-Fluoro-phenyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as an oil contaminated with triphenylphosphine oxide that could not be removed (61.7 mg). 1H NMR (CDCl3, 400 MHz): 7.65 (dd, 3H), 7.53 (t, 2H), 7.43 (m, 5H), 7.32 (m, 1H), 7.1 (m, 1H), 7.02 (s, 1H), 4.56 (m, 1H), 3.82 (s, 3H), 3.40 (m, 1H), 2.14 (br s, 1H), 2.05-1.88 (m, 4H), 1.78 (m, 1H), 1.68-1.54 (m, 5H), 1.51-1.26 (m, 4H), 0.98 (m, 1H), 0.75 (d, 3H), 0.72-0.54 (m, 2H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].[NH4+].[Cl-]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:25]=1
Reactant: Nc1cncc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cncc(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
LiHMDS (1.0M in THF, 10.0 mL, 10.0 mmol) was added dropwise to a stirred solution of 3-amino-5-fluoropyridine (588 mg, 5.26 mmol) in anhydrous THF (10 mL) under a nitrogen atmosphere at −78° C. After 20 min 2,4-difluoro-1-nitrobenzene (0.55 mL, 5.0 mmol) was added and stirring at −78° C. was continued for 1 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (×2) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) to afford the title compound as an orange solid (428 mg, 34%). LCMS (Method C): RT 3.27 min [M+H]+ 252.16
Reaction SMILES: Cl.CN.[C:4]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5].[CH2:16]([N:18](CC)CC)[CH3:17]>O1CCCC1.O.C(OCC)(=O)C>[C:4]([C:6]1[CH:7]=[C:8]([S:12]([NH:18][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CCN(CC)CC
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Methylamine hydrochloride (736 mg, 10.9 mmol) was added to a solution of 3-cyano benzene sulfonyl chloride (2.0 g, 9.9 mmol) and triethylamine (3.45 ml, 24.7 mmol) in tetrahydrofuran (30 ml) and the resulting mixture left to stir at room temperature under a nitrogen atmosphere for 16 h hours. The reaction mixture was diluted with water (30 ml) and ethyl acetate (50 ml). The organic phase was separated and dried (sodium sulfate) and reduced in vacuo to give the title compound as a colourless solid (1.68 g, 86%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([O:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11].[N-]=C=O.Cl>O.CN(C)C(=O)C>[C:9]([O:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: Nc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: Cl
Agent: [N-]=C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(O)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Into a 1 liter fask 500 g of N,N-Dimethyl acetamide and 173.5 g (1.6 mole) of p-aminophenol were added. This mixture was placed in cold bath and 234.9 g (1.5 mole) of methacryloyl oxyethyl isocyanate was added over a period of 1 hour. After the addition was complete, stirring was continued for 5 hours at room temperature. The mixture was tested for isocyanate functionality using IR spectroscopy. 30 ml of concentrated HCl was added to the mixture and was stirred for 15 minutes. The mixture was poured into 4.5 liter of water. The deposit was filtered, washed and dried to produce 370 g of 2-(N′-(4-hydroxyphenyl)ureido)ethyl methacrylate.
Reaction SMILES: C1COCC1.C[Si](Cl)(C)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].I[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>[Zn].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].O.CN(P(N(C)C)(N(C)C)=O)C>[C:16]([O:15][C:13]([CH2:12][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
11.4 g (0,170 mol) of powdered zinc and 50 ml of THF are introduced into a three-necked flask, 2.2 ml of trimethylsilyl chloride are added and the mixture is stirred for 15 minutes, 28 ml (0.174 mol) of tert-butyl 2-bromoacetate are then introduced dropwise and the mixture is stirred for 30 minutes. It is cooled to 0° C., (icebath), 5 g (4.3 mmol) of tetrakis(triphenylphosphine)palladium(O), 10.8 g (43.5 mmol) of 4-iodobenzoic acid and 50 ml of HMPA are introduced and the mixture is heated to 40° C., for one hour. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (95:5). After evaporation of the solvents, 8.1 g (80%) of the expected product, melting point 132°-133° C., are collected.
Reaction SMILES: [OH:1][C:2]1[C:15]([O:16]S(C2C3C=CC(=[N+]=[N-])C(=O)C=3C=CC=2)(=O)=O)=[C:14]([O:33][S:34]([C:37]2[C:46]3[CH:45]=[CH:44][C:43](=[N+:47]=[N-:48])[C:42](=[O:49])[C:41]=3[CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+](=C1C=CC2C(S(OC3C=CC(C(C4C=CC(OS(C5C6C=CC(=[N+]=[N-])C(=O)C=6C=CC=5)(=O)=O)=CC=4)=O)=CC=3)(=O)=O)=CC=CC=2C1=O)=[N-].OC1C=C(OS(C2C3C=CC(=[N+]=[N-])C(=O)C=3C=CC=2)(=O)=O)C=CC=1C(C1C=CC=CC=1)=O.[N+](=C1C=CC2C(S(OC3C=C(OS(C4C5C=CC(=[N+]=[N-])C(=O)C=5C=CC=4)(=O)=O)C=CC=3C(C3C=CC=CC=3)=O)(=O)=O)=CC=CC=2C1=O)=[N-].BrC(CBr)COS(C1C2C=CC(=[N+]=[N-])C(=O)C=2C=CC=1)(=O)=O.[N+](=C1C=CC2C(S(OC3CCC(C(C4CCC(OS(C5C6C=CC(=[N+]=[N-])C(=O)C=6C=CC=5)(=O)=O)CC4)(C)C)CC3)(=O)=O)=CC=CC=2C1=O)=[N-]>>[OH:1][C:2]1[C:15]([OH:16])=[C:14]([O:33][S:34]([C:37]2[C:46]3[CH:45]=[CH:44][C:43](=[N+:47]=[N-:48])[C:42](=[O:49])[C:41]=3[CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccccc3)c(O)c2OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)C1=O
Agent: CC(C)(C1CCC(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)CC1)C1CCC(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)CC1
Agent: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)OCC(Br)CBr)C1=O
Agent: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccc(OS(=O)(=O)c4cccc5c4C=CC(=[N+]=[N-])C5=O)cc3)cc2)C1=O
Product: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccccc3)c(O)c2O)C1=O

Procedure:
2-hydroxy-3,4-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy) benzophenone (1); 2,3,4-tris(6-diazo-5,6-dihydro-5-oxy-1-naphthalenesulfonyloxy) benzophenone (11); 4,4'-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy) benzophenone (12); 2-hydroxy-4-(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy) benzophenone (2); 2,4-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy) benzophenone (15); or 2,3-dibromo-1-(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy) propane (17); or 4,4'-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalene sulfonyloxy)isopropylidenebiscyclohexane (18).