Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[F:11][C@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1N1C=C(C)C(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.N1C=C2C(N=CN2)=NC=1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[O:14][C@H:15]([CH2:18][OH:19])[C@@H:16]([OH:17])[C@@H:12]2[F:11])=[CH:4][N:3]=1
Reactant: Nc1ncc2[nH]cnc2n1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1ncc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3F)c2n1
Temperature: 37 °C
Yield: 40.2 %

Procedure:
2-Aminopurine (Pacific Chemical Laboratories, 0.3 g, 2.2 mmoles) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (C. H. Tann et al., J. Org. Chem., 50:3647, 1985; 0.3 g; 1.2 mmoles) were suspended in 25 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (12,000 I.U.) (T. A. Krenitsky, et. al, Biochemistry, 20:3615, 1981) was added and the suspension stirred at 37° C. On day 3, 5,500 I,U, of purine nucleoside phosphorylase (T. A. Krenitsky, et al., Biochemistry, 20:3615, 1981 and U.S. Pat. No. 4,381,444) was added. On day 18, the reaction was diluted to 200 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.4% (w/v) potassium azide. On day 26, 0.4 g of 2-aminopurine, 8.000 I.U. of thymidine phosphorylase, and 2,800 I.U. of purine phosphorylase were added. On day 41, 0.2 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymidine, 8,000 I.U. of thymidine phosphorylase and 2,800 I.U. of purine nucleoside phosphorylase were added. On day 48, the reaction was diluted to 1,000 ml with 5 mM potassium phosphate buffer, pH 7.0 which contained 0.04% (w/v) potassium azide and 2.0 g of 2-aminopurine, 16,000 I.U. of thymidine phosphorylase and 5,500 I.U. purine nucleoside phosphorylase were added. On day 54, 1 g of 2-aminopurine, 8,000 I.U. of thymidine phosporylase, and 2,800 I.U. of purine nucleoside phosphorylase were added. On day 68, the suspension was evaporated to near dryness. Three volumes of ethanol were added to precipitate the protein and the suspension filtered. The title compound which was contained in the filtrate was purified by chromatography on AG1X2-hydroxide (Bio-Rad) with methanol/water (9/1) as the solvent followed by chromatography on silica gel with acetonitrile/water (95/5) as the solvent. Lyophilisation yielded 0.13 g of the title compound that analysed as a 0.3 hydrate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:23]I>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[C:4]([I:23])[CH:3]=1
Reactant: II
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Dissolve tert-butyl 1-(6-chloropyridin-3-yl)ethylcarbamate (3.77 g, 14.7 mmol) in THF (60 mL). Add tert-butyllithium (1.7 M heptane solution, 25.9 mL, 44.0 mmol) at −78° C. under N2. Stir the reaction solution for 0.5 h at −78° C. Add a solution of iodine (5.59 g, 22.0 mmol) in THF (44 mL) dropwise over 30 min under N2 at −78° C. Stir the resulting solution at −78° C. for 1 h, then from −78° C. to RT for 1 h. Quench the reaction with water. Extract with ethyl acetate. Wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4. After filtration, concentrate and purify the crude by FCC (0.1% to 1% 2 M NH3 methanol solution/CH2Cl2) to afford the title compound (1.34 g, 24%) with 98% HPLC purity. MS (ES) m/z 383 [M+1]+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=1.N1CCCCC1>C(O)C>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)Cc1cccnc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cccnc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Here, 3,5-di-t-butyl-4-hydroxybenzaldehyde (223 g, 0.952 mol), Ethyl 3-pyridylacetate (157.2 g, 0.952 mol), piperidine (81 g, 0.952 mol) and p-tolunesulfonic acid (0.5 g) are combined in ethanol (2,400 ml) and heated at reflux for 48 hours. The reaction mixture is allowed to cool to room temperature and then stirred on an ice bath, whereupon the product begins to crystallize. The mixture is stored in the freezer overnight, filtered and rinsed with cold ethanol-water (1:1). The product is dried, giving ethyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2-(3-pyridyl)propenoate (169.1 g) Mp 119.5°-120.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH2:17][CH3:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O.[I-].[K+]>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]([CH2:17][CH3:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1

Procedure:
A mixture of 4-hydroxy-α-ethyldesoxybenzoin (44.5 g.), sodium carbonate (18.5 g.), potassium iodide (1.4 g.) and benzyl chloride (19 ml.) in ethanol (350 ml.) and water (50 ml.) was stirred and heated under reflux for 8 hours. The mixture was cooled, filtered and the residue washed with water to give 4-benzyloxy-α-ethyldesoxybenzoin (54.3 g.), m.p. 71° C.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][C@H:5]([CH2:7][OH:8])[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21].FC1(F)C[C@H](CO)N(CCCCCCC(OC)=O)C1=O>ClCCl.CO>[F:22][C:2]1([F:1])[CH2:6][C@H:5]([CH:7]=[O:8])[N:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:3]1=[O:21]
Reactant: COC(=O)c1ccc(CCN2C(=O)C(F)(F)C[C@@H]2CO)cc1
Agent: COC(=O)CCCCCCN1C(=O)C(F)(F)C[C@@H]1CO
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CCN2C(=O)C(F)(F)C[C@@H]2C=O)cc1

Procedure:
(R)-methyl 4-(2-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)ethyl)benzoate was prepared from 12b using the oxidation procedure (Step K) described for the preparation of intermediate 13a from intermediate 12a; TLC Rf 0.4 (solvent system: 95:5 v/v dichloromethane-methanol); 1H-NMR (CDCl3) δ 9.2 (s, 1H), 7.9 (dd, 2H), 7.24 (dd, 2H), 3.98-3.91 (m, 1H), 3.87 (s, 3H), 3.74-3.48 (m, 2H), 3.51-3.46 (m, 2H), 3.1-2.8 (m, 2H), 2.48-2.22 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(C(=O)OC)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc(C(=O)O)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Methyl 3-tert-butyl-5-(2-methoxyethoxy)benzoate (O5.043; 2.0 g) was dissolved in methanol (30 ml) and THF (60 ml), and lithium hydroxide solution (30 ml, 1 M in water) was added. The mixture was heated to 40° C. and stirred for 3 h. Then the organic solvents were drawn off and the aqueous phase was adjusted to pH 3 with 1 N hydrochloric acid. The mixture was extracted with EA, dried, filtered and concentrated. 1.9 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Yield: 100 %

Procedure:
238 g (0.885 mol) of 2-bromo-4-(trifluoromethyl)benzoic acid, 1000 ml of absolute ethanol and 100 ml of concentrated sulfuric acid are introduced successively into a 2-liter round-bottomed flask. The reaction mixture is brought to reflux for 6 hours and then poured, after cooling, onto 2.5 liters of ice-cold water; the oil formed is extracted with ethyl acetate. The organic phase is successively washed with water, with 1N sodium hydroxide solution and then again with water. After drying over magnesium sulfate, the solvent is evaporated to provide 263 g (yield: 100%) of ethyl 2-bromo-4-(trifluoromethyl)benzoate in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].O=[C:22]([CH2:28][CH3:29])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24]([C:23]1[C:22]([CH2:28][CH3:29])=[N:1][C:2]2[C:3]([C:19]=1[NH2:20])=[C:4]([O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])[CH:16]=[CH:17][CH:18]=2)=[O:25]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Product: CCCNC(=O)C(C)(C)COc1cccc2nc(CC)c(C(=O)OC)c(N)c12

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and methyl 3-oxopentanoate as a yellow solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 0.75 (t, J=8.0 Hz, 3H), 1.17 (t, J=8.0 Hz, 3H), 1.26 (s, 6H), 1.40 (m, 2H), 2.84 (q, J=8.0 Hz, 2H), 3.04 (q, J=8.0 Hz, 2H), 3.85 (s, 3H), 4.13 (s, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.27 (dd, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.81 (m, 3H). MS 388 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[NH:10][N:9]=1.[CH2:31]=[O:32]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1
Reactant: C=O
Reactant: C[C@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Solvent: CO
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO

Procedure:
(S)-1-[3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]propan-2-ol (2.4 g, 5.5 mmol) was suspended in 50 mL MeOH and stirred. Formaldehyde (3.3 mL, excess) was added and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 2.0 g of 1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol, MS (M+H)=462.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][N:13]1C(OC)=O.Br>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][NH:13]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1C
Agent: Br
Product: Cc1cc(C(F)(F)F)ccc1[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
(2R,4S)-Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (1.45 g, 3.77 mmol) was dissolved in hydrogen bromide (33% in HOAc, 19.82 mL, 113.18 mmol) and stirred overnight. The mixture was evaporated and purified on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. 5-((2R,4S)-2-(2-Methyl-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (810 mg, 65%) was isolated as a white powder. 1H NMR (400 MHz, cdcl3) δ 1.35 (q, 1H), 1.52 (dq, 1H), 1.88-2.01 (m, 2H), 2.42 (s, 3H), 2.75-2.85 (m, 1H), 2.89-3.00 (m, 1H), 3.12-3.18 (m, 1H), 3.93 (d, 1H), 5.76 (s, 1H), 7.49-7.54 (m, 2H), 7.73 (d, 1H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1312.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH2:23][N:24]([CH2:27]C)[CH2:25]C)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:27])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCN(CC)CCC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccccc1
Reactant: O=Cc1ccccc1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-diethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (30 g) and benzaldehyde (6.9 cc), 4-diethylamino-1,2-diphenyl-2-buten-1-ol (Z) hydrochloride (3.2 g) is obtained, after recrystallisation from acetone, in the form of white crystals melting at 140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[NH:30][C:29]2[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:28]=2[N:27]=1.Cl.[OH-].[Na+]>C(O)CCC.O1CCCC1>[F:36][C:32]1[C:33]([F:35])=[CH:34][C:28]2[NH:27][C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][C@H:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:30][C:29]=2[CH:31]=1
Reactant: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Methyl 2-[(4′-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate (264 mg, 0.02 mmol) was dissolved in n-butanol (8 mL), 2-chloro-5,6-difluoro-1H-benzimidazole (185 mg, 0.98 mmol) and 4 N HCl (0.2 mL) were then added, and the resulting mixture was heated at 90° C. for 5 h. The mixture was then cooled to rt, and solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and then treated with 1 N aqueous sodium hydroxide (2.45 mL, 2.45 mmol). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (9.1 mg, 3%). LC-MS m/z 462.3 (MH+), ret. time 3.23 min; 1H NMR (300 MHz, DMSO-d6) δ 1.69-1.81 (m, 4H), 1.98-2.18 (m, 2H), 3.14-3.22 (m, 1H), 4.04-4.09 (m, 1H), 7.38 (t, 2H), 7.77-7.84 (m, 6H), 8.05 (d, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:25][N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([NH:34][CH2:35][C:36]2[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=2)=[O:33])[C:27]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:40]3[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=3)[CH2:35][NH:34][C:32]([C:28]3[C:27](=[O:45])[N:26]([CH2:25][C:24]4[CH:46]=[CH:47][C:48]([F:49])=[C:22]([F:21])[CH:23]=4)[CH:31]=[CH:30][CH:29]=3)=[O:33])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 75 °C
Yield: 84.4 %

Procedure:
Into a vial was dissolved 1-benzenesulfonyl-5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (581 mg, 0.00125 mol) and 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid (453 mg, 0.00114 mol) and palladium acetate (13 mg, 0.000057 mol; Strem) and triphenylphosphine (32 mg, 0.00012 mol; Aldrich) in acetone (5.4 mL, Acros;). To this was added 2.0 M of sodium carbonate in water (1.8 mL). The vial was flushed under an atmosphere of argon and sealed and was heated at 75 Celsius for 1 hour. The reaction was evaporated then diluted with methylene chloride, washed with water, dried with magnesium sulfate, filtered, and concentrated. The residue was taken up in methylene chloride and purified by silica gel chromatography using hexanes/ethyl acetate as eluent (Rf=0.33 in 1:3 hexanes/ethyl acetate) to yield 663.8 mg (85%) of product. MS m/z=689.09 M+H.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40]2[N:44]3[CH:45]=[C:46]([O:49][C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[C@@H:53]([NH2:60])[CH2:52][CH2:51]4)[CH:47]=[CH:48][C:43]3=[N:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CO>CN(C=O)C.C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40]2[N:44]3[CH:45]=[C:46]([O:49][C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[C@@H:53]([NH:60][C:5]([NH:6][C:7]5[N:8]([C:16]6[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=6)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=5)=[O:4])[CH2:52][CH2:51]4)[CH:47]=[CH:48][C:43]3=[N:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CC5CCN(C(=O)OC(C)(C)C)CC5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
A dark brown solution of (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 162 mg, 0.401 mmol), Intermediate 22b (174 mg, 0.364 mmol) and DIPEA (0.079 mL, 0.455 mmol) in DMF (5 mL) was stirred at 100° C. for 3 h. The solution was cooled to RT, concentrated in vacuo, suspended in water (10 mL) and extracted with DCM (2×10 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a brown gum. FCC, using 2-6% MeOH in DCM, gave the title compound as an off-white solid (155 mg, 58%). LCMS (Method 3): Rt 4.16 min, m/z 733 [MH+].
Reaction SMILES: C=C[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2(C)[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.N1C=CC=CC=1.C1C=C[NH+]=CC=1.Br[Br-]Br.C1(O)C=CC=CC=1>C(OCC)(=O)C>[CH3:21][C@:20]12[CH2:19][CH2:18][C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C:15]=3[CH2:14][CH2:13][C:12](=[O:22])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CCC3=C1CC2
Reaction time: 0.02 h
Yield: 30.8 %

Procedure:
Estra-5(10,16-dien-3-one (3) (0.38 g, 1.5 mmole), in pyridine (5.0 ml, 62 mmol) was cooled in an ice-salt bath to -13 C. and pyridinium bromide perbromide (1.58 g, 4.94 mmole) was added in small portions so that T←4 C. After swirling 1 min. phenol (0.25 g, 2.7 mmole) was added and reaction continued 24 h at room temperature. Ethyl acetate (50 ml) was added and the reaction mixture was washed with 25 ml of 1N HCI, two 25 ml portions of saturated copper sulfate, 25 ml of 5% sodium hydroxide, and 25 ml of brine. After drying our magnesium sulfate, filtration, and concentration under reduced pressure the residue was taken up in 10 ml of abs. ethanol, granular zinc (0.33 g, 5.0 mg-atom) was added, and the mixture was refluxed 1/2 h. The supernatant was removed, the residue was washed with 10 ml of abs. ethanol, and the combined supernatants were concentrated under reduced pressure. The resulting resin was flash chromatographed on silica gel using 15% ethyl acetate/hexane as eluent. Appropriate fractions were pooled, concentrated, and then recrystallized from hexane to give solid product (117.5 mg, 0.4619 mmol, 31%), m.p. 87-92 C.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15]([O:19][C:20]([NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][C:3]=2[F:14])[CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: COc1ccc2ncc(F)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c2n1
Yield: 48 %

Procedure:
According to procedure F and starting from 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine and (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine the title intermediate was isolated as a yellow oil (304 mg, 48%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].S(=O)(=O)(O)O.[CH2:18](OCC)C.O>CO>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C=O)ccc1O
Reaction time: 0.25 h

Procedure:
5-Formyl-2-hydroxy-benzoic acid (11.3 g) was dissolved in methanol (35 ml) and conc. sulfuric acid (3 ml). The mixture was heated at reflux for 40 h. Diethyl ether was added, and the mixture was poured into water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in a mixture of dioxane (80 ml) and water (50 ml) and treated with 6N hydrochloric acid (2.5 ml). After 15 min., dioxane was removed in vacuo. The mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.