Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([F:13])[C:3]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].C([Li])CCC.Br[C:27]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:37])[C:30]([CH:38]2[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:40][CH2:39]2)=[CH:29][CH:28]=1.Cl>O1CCCC1.CCCCCC.[Br-].[Zn+2].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:37])[C:30]([CH:38]3[CH2:39][CH2:40][CH:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:42][CH2:43]3)=[CH:29][CH:28]=2)=[C:3]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[F:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ccc(Br)c(OCOCCOC)c1F
Reactant: CCCCCC1CCC(c2ccc(Br)c(C(=O)OC)c2F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2ccc(-c3ccc(OCCCC)c(F)c3OCOCCOC)c(C(=O)OC)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
16.4 g (0.046 mol) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxy-methoxy)benzene were dissolved in 20 ml of tetrahydrofuran, and 31.6 ml (0.052 mol) of a 15 percent solution of n-butyllithium in hexane were added at −70° C. After addition of a solution of 5.94 g (0.027 mol) of zinc bromide in 30 ml of tetrahydrofuran, the batch was allowed to thaw, and the resultant solution was added at the boiling point to a mixture of 18 g (0.046 mol) of methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate and 730 mg (1.00 mmol) of Pd(dppf)2Cl2 in 60 ml of tetrahydrofuran. The batch was refluxed for 4 hours, stirred overnight at room temperature, acidified using dilute hydrochloric acid and extracted with MTB ether. The combined organic phases were washed with water, dried over sodium sulfate and evaporated. The crude product was chromatographed over silica gel with n-pentane/MTB ether (3:1), giving 14.6 g (55%) of methyl 4′-butoxy-3,3′-difluoro-2′-(2-methoxyethoxymethoxy)-4-(4-pentylcyclohexyl)-biphenyl-2-carboxylate as a yellow oil. This was dissolved in 56 ml of tetrahydrofuran, 11 ml of conc. hydrochloric acid were added, and the mixture was stirred overnight at room temperature. The precipitated product was filtered off with suction, washed with ethyl acetate and dried, giving 7.6 g (68%) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)-benzo[c]chromen-6-one as colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])[CH:5]=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OCC(F)(F)F)cc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(OCC(F)(F)F)cc1Br

Procedure:
To a solution of 2-bromo-4-(2,2,2-trifluoroethoxy)phenol (Description 20, 0.6 g) in acetone was added added K2CO3 (1 g) and methyl iodide (1 ml). The solution was heated to reflux for 1 h. and then evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase washed further with water and saturated brine. After drying (MgSO4) the solvent was removed in vacuo to give the title compound as a yellow oil. 1H NMR (250 MHz, CDCl3) δ3.87 (3H, s) 4.30 (2H, q, J 8 Hz), 6.82-6.92 (2H, m), and 7.20 (1H, d, J 3 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:19][CH2:18][CH2:17][CH2:20][OH:21])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cccc(Cl)n2)cc1
Reactant: NCCCO
Product: COc1ccc(Nc2cccc(NCCCO)n2)cc1
Yield: 64 %

Procedure:
95 mg of 6-chloro-N-(4-methoxyphenyl)pyridin-2-amine were mixed with 244 mg of n-propanolamine and the mixture obtained was treated in a vial analogously to the method as set out in Example 16b. 3-(6-(4-Methoxyphenylamino)pyridin-2-ylamino)propan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]3)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Temperature: 60 °C
Yield: 58.4 %

Procedure:
Palladium(II)acetate (17.1 mg, 76.0 μmol) was added to ethyl 6-bromo-2-quinolinecarboxylate (426.0 mg, 1.52 mmol, from Example 32c), 4-hydroxy-phenyl-boronic acid (314.6 mg, 2.28 mmol), triphenylphosphine (39.9 mg, 152.1 μmol), and potassium phosphate (1.13 g, 5.32 mmol). Then, dioxane (7.6 mL) was added to the mixture, followed by water (152 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 16 hours, then allowed to cool to room temperature. Water was added followed by ethyl acetate and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 260.5 mg (58%) of ethyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.74 (s, 1H), 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.19-8.10 (m, 3H), 7.72 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 4.42 (q, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15]C(OC(C)(C)C)=O)[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39]C(OC(C)(C)C)=O)[CH2:36][C@@H:35]([NH:47]C(OC(C)(C)C)=O)[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:56]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65]([C:67]5[CH:76]=[CH:75][C:74]6[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=6)[C:68]=5[OH:77])=[O:66])=[CH:60][CH:59]=4)=[O:57])[CH:29]=3)[N:24]=2)[CH2:10]1)=O)(C)(C)C.Cl>C(O)(C(F)(F)F)=O.CO>[NH2:15][C@@H:13]1[CH2:14][C@H:9]([NH2:8])[CH2:10][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH2:47])[CH2:36][C@@H:37]([NH2:39])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:56]([C:58]4[CH:63]=[CH:62][C:61]([NH:64][C:65]([C:67]5[CH:76]=[CH:75][C:74]6[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=6)[C:68]=5[OH:77])=[O:66])=[CH:60][CH:59]=4)=[O:57])[CH:29]=3)[N:24]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1C[C@H](N)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](N)C[C@H](N)C2)C1
Reaction time: 0.01 h
Yield: 78.7 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid [4-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-ylcarbamoyl)-phenyl]-amide (253) (9 mg, 8.5 μmmol) was dissolved in TFA (1 mL) and the mixture was shaken in a Teflon septum capped vial at room temperature for 3 hours. LC-MS indicated complete de-protection at this point. The solution was concentrated to give an orange oil. The oil was dissolved in MeOH (1 mL) and HCl (1 mL, 4.0 M in dioxane) was added and the mixture was vortexed for 20 seconds. A fine suspension was observed. The mixture was concentrated to an orange powder. Ethyl ether (5 mL) was added to the powder and vortexed for 2 minutes. The solid was collected by filtration and dried under high vacuum for 16 hours to give the desired product (254) as a yellow/green powder (5.4 mg, 6.69 μmmol, 78.7% yield, assuming a 4 HCl salt). LC-MS (ESI): (exact mass: 660.33) m/e=661.6 [M+1]+. 1H NMR (400 MHz, D2O): δ 1.70–1.82 (m, 2H), 2.61–2.65 (m, 2H), 2.78–2.94 (m, 2H), 3.57–3.60 (m, 2H), 3.67–3.68 (m, 4H), 3.97 (d, 2H, J=9.6 Hz), 4.23 (d, 2H, J=9.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=8.4 Hz), 7.18–7.29 (m, 3H), 7.32–7.53 (m, 6H), 7.74 (d, 2H, J=7.6 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:42]1[CH2:45][CH:44]([O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH2:43]1>CN(C=O)C>[O:42]1[CH2:45][CH:44]([O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:54][CH:53]=2)[CH2:43]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OC1COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OC1COC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid oxetan-3-yl ester (89.5 mg, 242 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (17 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O5, 465.21. found 465.4.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37](O)=[O:38])=[C:35]([F:45])[CH:34]=1.COC[CH2:49][S:50]([NH2:53])(=[O:52])=[O:51].CS(N)(=O)=O>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:38])=[C:35]([F:45])[CH:34]=1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 72 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.090 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H), 4.42-4.35 (m, 1H), 3.30 (s, 3H), 2.38-2.34 (m, 1H), 2.30-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.86-1.77 (m, 1H), 1.59-1.32 (m, 4H), 1.25-1.04 (m, 3H), 0.88-0.79 (m, 2H), 0.66-0.59 (m, 2H); MS (ES−) m/z 368.1 (M+1).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl.Cl.[CH2:13]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][Cl:29])[CH2:23][CH2:22]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].[NH4+].[OH-]>O>[ClH:29].[CH2:13]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:23][CH2:22]1)[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccccc1N
Reactant: ClCCN1CCN(CCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: NC(=O)c1ccccc1NCCN1CCN(CCc2ccccc2)CC1
Yield: 23.7 %

Procedure:
A mixture of 13.6 g anthranilamide, 34.5 g 4-phenethylpiperazinoethyl chloride dihydrochloride, 17.5 g sodium acetate, and 50 ml water was refluxed for 24 hours, 50 ml water and 50 ml NH4OH was added and the mixture cooled. The liquid was decanted and the oily solid dissolved in 100 ml propanol, 200 ml water added and the solid filtered. The solid was dissolved in 2 liters of dry ether, acidified with dry HCl gas and filtered. The HCl salt was recrystallized from propanol to give 9.2 g product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:75][CH3:76])[CH2:66][CH2:67][CH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][CH2:67][CH2:66][N:65]([CH2:75][CH3:76])[CH2:63][CH3:64])[CH2:70]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CCCC1CCCNC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC1CCCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)C1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(3-diethylamino-propyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]1([NH:7][S:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:10])=[O:9])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)NC2CCCCC2)cc1
Solvent: CC(C)O
Product: Nc1ccc(CS(=O)(=O)NC2CCCCC2)cc1
Yield: 86.9 %

Procedure:
By a procedure similar to that described in example 9(b) the product of stage (a) (6.4 g) was hydrogenated to give the title compound (5.0 g), m.p. 141°-143° (from isopropanol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C@H:13]([NH:17][C:18](=[O:37])[CH2:19][CH:20]3[C:25](=[O:26])[NH:24][CH2:23][CH2:22][N:21]3[S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.B(O)(O)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([NH2:49])=[O:48])[CH:42]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.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].CCO>[O:26]=[C:25]1[NH:24][CH2:23][CH2:22][N:21]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:20]1[CH2:19][C:18]([NH:17][C@@H:13]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:41]3[CH:42]=[C:43]([CH:44]=[CH:45][CH:46]=3)[C:47]([NH2:49])=[O:48])[CH:16]=[CH:15][C:14]1=2)=[O:37]
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)N[C@@H]2CCCc3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)N[C@@H]2CCCc3cc(-c4cccc(C(N)=O)c4)ccc32)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 25 mL pressure tube was added (R)-5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (150 mg, 0.25 mmol), benzamide-3-boronic acid (Frontier, 63 mg, 0.38 mmol), tetrakis(triphenylphosphine)-palladium (O) (Aldrich, 30 mg, 0.025 mmol), Toluene (1.5 mL), EtOH (0.4 μL), and 1M NaHCO3 (0.4 mL) at room temperature under N2. The reaction mixture was sealed and stirred at 80° C. overnight, cooled to room temperature, and diluted with EtOAc (40 mL). The organic layer was separated, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to provide the title compound. MS (ES1): 561 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[OH:4].[C:13](OCC)(OCC)(OCC)[CH3:14]>C1(C)C=CC=CC=1.C1COCC1>[N+:10]([C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[N:1]=[C:13]([CH3:14])[O:9][C:8]=2[CH:7]=1)([O-:12])=[O:11]
Reactant: Nc1c(O)cc([N+](=O)[O-])cc1O
Reactant: CCOC(C)(OCC)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc2c(O)cc([N+](=O)[O-])cc2o1
Yield: 39.4 %

Procedure:
To a stirred solution of the 2-amino-5-nitroresorcinol (2.9 g, 0.017 mole) in toluene (50 ml) and THF (5 ml) was added triethyl orthoacetate (4.1 g, 0.0255 mole). This mixture was heated to reflux for one hour. Upon cooling, the product crystallized out of solution and was collected and dried to yield a tan solid (1.3 g, 39.4 percent). TLC showed the product to be pure.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:22]=[CH2:23].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:23][CH:22]([CH2:21][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CCOc1ccc(OC)cc1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCC2CC(Cn3ccnc3)(c3ccc4ccccc4c3)N(C)O2)cc1

Procedure:
A mixture of compound 2 (13.0 g, 0.049 mol) and p-methoxyphenyl allyl ether (12.07 g, 0.073 mol) in 400 ml of toluene is refluxed for 48 hours, cooled, and the solvent removed in vacuo leaving a dark oil. Chloroform is added to the oil and carbon is added to decolorize the solution which is filtered through a bed of celite. The chloroform is evaporated and the oil that remained is purified by flash chromatography on silica gel (eluent comprised of 98% CHCl3 and 2% MeOH). The resulting tan solid (5.56 g, 26%) is recrystallized from ethyl acetate, m.p. 143°-145° C. (Found: C, 72.58; H, 6.46; N, 9.66. C26H27N3O3 requires: C, 72.71; H, 6.34; N, 9.78).
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH:19]1([CH:24]2[CH2:35][CH:34]=[CH:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH:27]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:26]=[N:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:25][CH:24]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([NH2:26])[CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1=CCC(C2CCCC2)N=NC(C2CCCC2)CC=CCC1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: NC(CCCCCCCCC(N)C1CCCC1)C1CCCC1

Procedure:
The procedure described in (a) is repeated, starting from 200 g (0.666 mole) of crude 3,12-dicyclopentyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) and using correspondingly reduced amounts of catalyst and solvent, affording after purification by chromatography and distillation 39.2 g (19% of theory) of 1,10-diamino-1,10-dicyclopentyl-decane as a colourless oil [b.p. 174°-178° C./0.002 torr; nD20 =1,4885; IR spectrum (liquid) includes bands at 3355, 3278, 1613-1 ].
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1F

Procedure:
41.4 g of the crude diethyl (2,4-difluorobenzoyl)malonate in 130 ml of water and 170 mg of p-toluenesulphonic acid are refluxed for 8.5 hours. The mixture is extracted using methylene chloride, and the methylene chloride phase is washed with water, dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)CCN2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1cnc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (4.40 g, 36.6 mmol) in a mixture of pyridine (4.4 mL) and dichloromethane (20 mL) was gradually added dropwise to bromine (7.00 g, 43.8 mmol) in dichloromethane (20 mL) cooled to 0° C., and the resulting reaction mixture was stirred at 0° C. for 20 minutes, after addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1 (v/v)) to give the title compound as a brown solid (2.83 g, yield 39%).
Reaction SMILES: CC(C)([O-])C.[K+].C([O:9][C:10](=O)[CH2:11][N:12]([C:14](=[O:30])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:13])C.O>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]2[C:10](=[O:9])[CH2:11][N:12]([CH3:13])[C:14]2=[O:30])=[CH:24][CH:25]=1
Reactant: CCOC(=O)CN(C)C(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Temperature: 27.5 °C

Procedure:
To a suspension of potassium tert-butoxide (88 g) in toluene (1000 mL) is added a solution of ethyl-N-[2-[2-(4-chlorophenoxy)phenyl]acetyl]-N-methylglycinate (250 g) in toluene (1000 mL), under nitrogen at 15-25° C. and the mixture is maintained for 12-15 hours at 25-30° C. Water (3000 mL) is added and the mass is maintained for 1-2 hours at 0-5° C. Organic and aqueous layers are separated and the organic layer is washed with water (1000 mL). Aqueous layers are combined and washed with ethyl acetate (2000 mL). The pH of combined aqueous layers is adjusted to 2-2.5 by addition of aqueous HCl (100 mL) at 0-5° C. The solid is collected by filtration and washed with water (200 mL), then is dried to afford the crude title compound. The crude compound is further purified by heating at reflux a solution of crude 3-(2-(4-chlorophenoxy)phenyl)-1-methylpyrrolidine-2,4-dione in toluene (3600 mL) for 30-60 minutes, followed by cooling to room temperature. Solid that forms is collected by filtration, washed with hexane (500 mL), and dried to afford a purified title compound. Yield: 130 g. Purity by HPLC: 99.48%.