Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][Mg]Br>>[CH2:14]([O:13][CH2:12][C@@H:11]([CH2:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C@@H:10]([OH:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Reactant: Cc1ccccc1C[Mg]Br
Product: Cc1ccccc1C[C@H](COCc1ccccc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
351 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53, was subjected to Grignard reaction in the same manner as in Example 53 by using 2-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsilyloxy-3-(2-tolylmethyl)-2-butanol as colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:36][C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[O:36][C:32]([CH3:31])=[CH:33][N:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.082 g, 0.6 mmol, 1.1 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 25 mg (25%) 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.28 (m, 2H), 1.40-1.44 (m, 2H), 2.21 (d, J=1.2 Hz, 3H), 2.29 (s, 3H), 2.82 (d, J=4.8, 3H), 6.66 (d, J=1.2 Hz, 1H), 7.38-7.44 (m, 4H), 7.57 (d, J=1.2, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.81-7.83 (s and m, 2H), 7.98-8.01 (m, 2H), 8.47 (q, J=4.8 Hz, 1H), 9.28 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+.
Reaction SMILES: O=C(C(=O)C)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(#N)C>[CH3:18][C:13]1[NH:14][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=1
Reactant: CCOC(=O)C(=O)C(C)=O
Reactant: NCc1ccccn1
Solvent: CC#N
Product: CCOC(=O)N1C=C(C)NC1c1ccccn1
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A mixture of 23.8 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime, 18 g of 2-aminomethyl pyridine and 250 ml of acetonitrile was refluxed for 7 hours and then stored at -10° C. overnight. The solid was collected, giving 20.68 g of 5-methyl-2-(2-pyridinyl)-1H-imidazole-3-carboxylic acid, ethyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[CH3:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Temperature: 70 °C
Yield: 51.7 %

Procedure:
Sodium hydroxide (43 mg) was added to a solution of ethyl 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D111) (310 mg) in iPrOH (10 mL) and water (10 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E85) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.24 (3H, s), 2.61 (2H, t), 2.96 (2H, t), 5.40 (1H, m), 7.34 (1H, d), 7.70 (2H, d), 8.11 (1H, t), 8.28 (1H, dd), 8.82 (1H, dd), 11.20 (1H, s), 12.11 (1H, br s). MS (ES): C22H22N4O4 requires 406; found 407.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:19]
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1F)C(=O)OCC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1c[nH]c2c(F)cc(I)cc2c1=O
Temperature: 90 °C
Reaction time: 108 h

Procedure:
Diethyl 2-((2-fluoro-4-iodophenylamino)methylene)malonate (Intermediate 10, 13.45 g, 33.05 mmol) was placed in a 250 mL round bottom flask with Eaton's Reagent (55 mL, 0.29 mol) and aged while stirring at 90° C. for 4-5 days. The reaction was then cooled to 5° C. and was slowly quenched with saturated sodium carbonate solution (500 ml) at 10° C. to form a clumpy brownish-yellow solid. The precipitate was vacuum filtered and washed with water (300 ml). The collected solid was dried under vacuum at 50° C. for 16 h, resulting in 10.7 g (90%) of light tan solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=C)[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=[O:29])[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(-n2ncc3c2CCc2cc(C=O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(4-propylphenyl)-7-vinyl-4,5-dihydro-3H-benzo[e]indazole (Preparation 136E, 85 mg, 0.270 mmol) in THF (5 mL) were sequentially added NMO in water (0.090 mL, 0.433 mmol) and osmium tetroxide in water (0.066 mL, 10.81 μmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (116 mg, 0.541 mmol) in water (2 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated out. Water (2 mL) was then added and the solid was filtered, washed with water (2×2 mL) and dried to give 65 mg crude product which was used directly for the next step. LC/MS M+1=317.1. The product had an HPLC retention time=3.92 min. (condition A);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[C:18]([F:21])([F:20])[F:19])=[CH:5][C:4]=1[Cl:22].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]([NH:32][C@@:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][O:35][CH2:34]2)=[O:31])[CH:27]=[N:28][CH:29]=1>>[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[C:26]([CH:25]=1)[C:30]([NH:32][C@@:33]1([C:38](=[O:39])[NH:1][CH2:2][C:3]2[C:4]([Cl:22])=[CH:5][C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=3[C:18]([F:21])([F:19])[F:20])=[CH:7][N:8]=2)[CH2:37][CH2:36][O:35][CH2:34]1)=[O:31]
Reactant: COc1ccc(Nc2cnc(CN)c(Cl)c2)c(C(F)(F)F)c1
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Product: COc1ccc(Nc2cnc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(Cl)c2)c(C(F)(F)F)c1

Procedure:
Analogously to Example 1e), (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (1.3 mmol) was reacted with (S)-3-[(5-amino-pyridin-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (product from Example 2b, 1.3 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30](=O)[CH3:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:30]([CH3:31])[CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:14])[CH3:2]
Reactant: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Reaction time: 6 h
Yield: 124.4 %

Procedure:
To a 25 ml volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (500 mg), toluene (1.75 ml), and 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4) (470 mg) were added. Water was removed by azeotropic distillation at 45-50° C. under 100 mmHg for 1.5 hours. To the mixture, toluene (1.75 ml) was added, and water was removed by azeotropic distillation at 60° c. under 120 mmHg for 6 hours. The reaction mixture was concentrated under reduced pressure to give 1.109 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)(C)(C)C.Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[N:37][CH:38]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:29][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:33]1[CH:38]=[N:37][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Reactant: CC1(c2ccc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(c2ccc(-c3ccc(N4CC(CO)OC4=O)cc3F)cn2)Cn2cc([N+](=O)[O-])nc2O1

Procedure:
The titled compound was prepared using the same procedure as described previously (see Example 2-1, Step 3), except that 5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-2-one, and 2-(5-Bromo-pyridin-2-yl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole were used as the starting materials, and TBAF deprotection required. The titled compound was obtained as slightly yellow solid (60 mg). ESI MS m/z 456 (M+H). 1H NMR (DMSO-d6) δ 8.79 (s, 1H), 8.14 (s, 1H), 8.05-8.12 (m, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.63 (dd, J=5.2, 2.8 Hz, 1H), 7.48 (dd, J=8.8, 2.0 Hz, 1H), 5.24 (t, J=5.6 Hz, 1H), 4.85 (d, J=10.8 Hz, 1H), 4.69-4.77 (m, 1H), 4.49 (d, J=10.8 Hz, 1H), 4.12 (t, J=8.8 Hz, 1H), 3.86 (dd, J=8.8, 5.6 Hz, 1H), 3.64-3.72 (m, 1H), 3.50-3.59 (m, 1H), 1.97 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[C:6]([CH:11]1[S:16][CH2:15][CH2:14][CH2:13][S:12]1)([O:8][CH2:9][CH3:10])=[O:7]>>[CH:5]1([CH2:4][C:11]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:12][CH2:13][CH2:14][CH2:15][S:16]2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C1SCCCS1
Product: CCOC(=O)C1(CC2CC2)SCCCS1

Procedure:
Preferably R3 is methyl, ethyl or isopropyl. Most preferably R3 is ethyl and the compound of Formula 5 is prepared by (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of a strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with bis(2-methoxyethyl)aminosulfur trifluoride.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1(C)C=CC=CC=1>[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C=Cc2ccc(C)cc2)cc1
Yield: 71 %

Procedure:
2.4 g(5.37 mmol) of (4-methylbenzyl)triphenylphosphonium bromide and 0.98 g(60%, 24.4 mmol) of NaH were refluxed in toluene for 6 hours. After cooled down, 0.586 g(4.88 mmol) of 4-methylbenzaldehyde was introduced gradually to the solution to be refluxed again for 6 hours. The resulted product was treated with water to be extracted with ethyl acetate. The solvent was distilled off and the residue was recrystallized in ethanol. Yield; 71%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[OH:15])[CH:10]=[C:11]([Br:13])[CH:12]=1.CN(C)[CH:26]=[O:27]>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:15])[CH3:16])[CH:10]=1)[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)c1cc(Br)cc(C=O)c1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (10.7 ml) was added dropwise to a stirred suspension of 3,5-dibromo-α-(4-fluorophenyl)-α-methylbenzenemethanol (5.90 g) in dry diethyl ether (160 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and then N,N-dimethylformamide (2.93 g) was added dropwise. Stirring at -78° C. was continued for 1 hour and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated, washed with water and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution was commenced with hexane/dichloromethane (1:1), and the ratio was gradually changed to hexane/dichloromethane (1:5). The later product fractions were combined and evaporated to give the title compound as an oil (2.10 g), Rf 0.15 (SS 1). Found: C,55.39; H,3.78. C15H12BrO2F requires C,55.75; H,3.74%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]([F:12])[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C([Br:17])(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([Br:17])([F:11])[F:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1C(F)F
Reactant: ClC(Cl)(Cl)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1cc(Br)ccc1C(F)(F)Br

Procedure:
A mixture of the title compound from Example 302 Step A (2.44 g, 10.5 mmol), CCl3Br (8 mL) and Na2CO3 (480 mg, 4.5 mmol) in a sealed vessel was illuminated by a sunlamp for 30 h. Purification by silica gel flash chromatography using 8:1 to 6:1 to 4:1 hexanes:DCM as mobile phase yielded the title compound: 1H NMR (500 MHz, CD2Cl2) δ 8.03 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][N:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=2)[CH:9]=1
Reactant: C1COCCN1
Reactant: Brc1ccc2nc(Br)nn2c1
Product: Brc1ccc2nc(N3CCOCC3)nn2c1
Yield: 65.7 %

Procedure:
A mixture of 2,6-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and morpholine (10 g, 10 ml, 115 mmol) was refluxed for 4 hours under argon atmosphere. The mixture was evaporated to dryness under reduced pressure. Flash chromatography (silica gel, 50 g, 30-100% heptane/ethyl acetate) afforded 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine (672 mg, 66%) as a light yellow solid. Mp.: 136° C. MS: m/z=283.0/285.0 (M+H+).
Reaction SMILES: [C:1]1([OH:12])([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B:13](OC)(OC)[O:14][CH3:15]>>[CH3:15][O:14][B:13]1[O:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5]2)[O:12]1
Reactant: OC1(C2(O)CCCC2)CCCC1
Reactant: COB(OC)OC
Product: COB1OC2(CCCC2)C2(CCCC2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12-methoxy-11,13-dioxa-12-bora-dispiro[4.0.4.3]tridecane was prepared as follows. 5 g of bicyclopentyl-1,1′-diol was dissolved in 50 ml of trimethyl borate. The reaction mixture was stirred at room temperature under nitrogen for 2 days. Excess solvent was removed in a rotary evaporator and the residue was purified by vacuum distillation. Yield of the 12-methoxy-11,13-dioxa-12-bora-dispiro[4.0.4.3]tridecane was 5.27 g (85%) as a liguid with b.p. 68-70° C. 1H NMR (500 MHz, C6D6, TMS): δ 1.20-1.90 (m, 16 H, CH2), 3.20 (s, 3 H, MeO).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=1)=[CH2:68]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[N:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[CH:67]=[CH:68][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), tri-ortho-tolylphosphine (10 mg, 0.031 mmol), palladium (II) acetate (2 mg, 0.0077 mmol) was added DMF (0.5 mL), triethylamine (32 uL, 0.232 mmol), and 2-vinylpyridine (42 uL, 0.388 mmol). The vial was flushed with nitrogen, and the reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 900 s. Water was added and the mixture was neutralized to pH 6 with 1N aqueous HCl, then extracted with EtOAc three times. The extracts were combined and concentrated in vacuo. The crude was treated with 1 mL of EtOH and 1 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 80° C. for 15 h. The mixture was neutralized to pH 7 with 1N aqueous HO, and the resulting precipitate was filtered, washed with water, dried in vacuo, and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol us a yellow solid (17 mg, 35% yield), 1H NMR (500 MHz, DMSO-d6) δ 6.78 (dd, J=2.0, 8.0 Hz, 1H), 7.13 (s, 1H), 7.15-7.20 (m, 2H), 7.26 (d, J=16.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.73 (dt, J=2.0, 8.0 Hz, 1H), 7.90 (d, J=16.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 9.56 (s, 1H), 12.1 (s, 1H). MS: m/z 314 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCI
Reactant: Nc1cccc(CC(=O)[O-])c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-6-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated under reduced pressure and crystallized to give ethyl 2-amino-6-biphenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:37]([NH2:36])=[O:38])[CH2:27][CH2:28]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)N1CCC(=C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Solvent: O
Solvent: ClCCl
Product: NC(=O)N1CCC(CC(=O)N2CCC(=C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by a similar procedure from 4-[2-[4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-piperidine (120 mg, 0.265 mmol) in CH2Cl2 (3 ml), to which TMSNCO (200 μl, 170 mmol) was added at 0° C. After 5 minutes at 0° C., the mixture was stirred 3.5 hours at room temperature. The reaction mixture was diluted with water and extracted with CH2Cl2 ; the organic phase was washed with NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was chromatographed on silica in 5%MeOH/CH2Cl2 and eluted with 10%MeOH/CH2Cl2 to afford a white solid (103 mg); HRMS: calc.: 497.1778; found: 497.1766.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH2:13].[Br:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:14][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]([NH2:13])=[C:6]([C:2]2[NH:3][CH2:4][CH2:5][N:1]=2)[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C2=NCCN2)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C2=NCCN2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of the title compound of Step B (0.38 g, 2.17 mmol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.38 g, 2.13 mmol) and the mixture was stirred at ambient temperature for 1 hour. Additional N-bromosuccinimide (0.06 g, 0.34 mmol) was added and the mixture stirred for an additional 0.5 hour before being diluted with ethyl acetate and washed three times with water. The combined aqueous fractions were extracted with ethyl acetate and the organic layer was washed with water. The combined organic fractions were dried (magnesium sulfate), concentrated and purified by flash column chromatography (silica gel, 2% then 5% methanol in dichloromethane) to give the title compound of Step C (94 mg) as a light brown oil.