Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([CH2:12][P+](CCCC)(CCCC)CCCC)[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[CH:28]([C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=O>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10](/[CH:12]=[CH:28]/[C:30]3[N:35]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[C:32]([CH3:40])[CH:31]=3)[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(=O)Nc1cc(C)cc(C=O)n1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1nc2cc(Br)cnc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)cc(/C=C/c2nc3cc(Br)cnc3[nH]2)n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 6-brom-3H-midazo[4,5-b]pyridin-2-yl-methyl-tributyl-phosphonium-chloride (compound A5) are suspended in 50 ml of tetrahydrofuran and added to a suspension of sodium hydride (60% strength) in 50 ml tetrahydrofuran at room temperature. After vigorously stirring for 10 min, 1.43 g of N-(6-formyl-4-methyl-pyridin-2-yl)-acetamide (compound B11) is added in portions (10 min). Subsequently, the suspension is heated at 90° C. for 22 h. Thereafter, the mixture is filtered with suction and the remaining residue is rinsed with tetrahydrofuran. The pure title compound is obtained by evaporating the filtrate to dryness to afford 1.88 g of an amorphous solid. M.p. >350° C. ESI-MS: 372.1/374.1 (MH+; 99%/100%). TLC: Rf=0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:47]1([CH:53]2[CH2:57][CH2:56][NH:55][CH2:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:55]1[CH2:56][CH2:57][CH:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:54]1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1Cc1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1Cc1ccccc1)N1CCC(c2ccccc2)C1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
A solution of 5-benzylisoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidine (7 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1524.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1ncccn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ncccn2)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a solution of 0.214 g (2.25 mmol) of 2-aminopyrimidine in THF (4 mL) at 0° C. was added 1.25 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 20 min. A solution of 0.275 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (4:1), then with CH2Cl2/EtOAc (1:3) gave an orange powder. Recrystallization from ethanol gave 0.098 g (31% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyrimidinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (CDCl3) δ8.69-8.67 (m, 3H), 8.34 (t, JHF=53.3 Hz, 1H), 8.07 (br s, 1H), 7.91 (dd, J=7.9, 0.9 Hz, 1H), 7.49-7.40 (m, 2H), 7.05 (t, J=4.8 Hz, 1H), 3.96 (m, 4H), 3.83 (m, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.0; N, 29.6. Found: C, 53.6; H, 4.1; N, 29.4%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][NH:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1.CCN(CC)CC>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:10]2[CH:29]=[CH:30][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)=[CH:8][CH:9]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(Oc3ccc(F)cc3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 3-((4-(4-fluorophenoxy)benzylamino)methyl)benzylcarbamate (0.72 g, 1.64 mmol) in CH2Cl2 (15 mL) added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (0.45 g, 1.72 mmol) and Et3N (0.68 ml, 4.91 mmol). The reaction mixture was stirred at 0° C. under nitrogen for 1.5 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and saturated NaHCO3 solution. The organic layer was washed successively with brine, 1 N HCl, brine, and concentrated after drying over MgSO4 to give viscous solid (0.99 g, 82%). 1H NMR (CDCl3): δ 9.10 (bs, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H), 7.28-7.17 (m, 1H), 7.14-6.90 (m, 9H), 6.85 (d, J=8.3 Hz, 2H), 4.36 (m, 4H), 4.23 (m, 2H), 1.46 (s, 9H); MS (ESI): (M+H)+=605.2.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[Br:33])=O)(C)(C)C.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:26]([O:25][C:23]1[CH:22]=[CH:21][C:20]([Br:33])=[C:19]([CH:24]=1)[O:18][CH2:17][C@H:16]([NH2:15])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N[C@@H](COc1cc(OCc2ccccc2)ccc1Br)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (200 mg, 0.331 mmol) in methylene chloride (1 ml), followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, made basic with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=2/1, v/v) to give (R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (127 mg, Yield 76%).
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([O:16][CH3:17])[CH:3]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>CN(C)C=O.C(OCC)(=O)C>[Cl:15][C:14]1[C:2]([NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:4]([O:16][CH3:17])=[C:5]([CH:13]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COc1cc(N)c(Cl)cc1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCNc1cc(OC)c(C(=O)OC(C)(C)C)cc1Cl
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
The compound (480 mg, 1.86 mmol) obtained in Example 99a was dissolved in N,N-dimethylformamide (6 mL), 55% sodium hydride (89 mg, 2.79 mmol) was added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 20 minutes. Subsequently, ethyl 6-bromohexanoate (623 mg, 2.79 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:3, v/v) to give the title compound (338 mg; yield, 45%) as a pale orange color oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([CH2:15][C:16](O)=[O:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>O1CCCC1.O.C(OCC)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([CH2:15][C:16]([N:34]=[N+:35]=[N-:36])=[O:17])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1c2ccccc2CCc2cc(Cl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC(=O)CC1c2ccccc2CCc2cc(Cl)ccc21
Temperature: -10 °C

Procedure:
To a magnetically stirred, ice cold solution of 2-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylacetic acid (20.0 g, described in Example 2) in dry tetrahydrofuran (400 ml) is added, under an atmosphere of dry nitrogen, triethylamine (13 ml) and ethyl chloroformate (11.6 g). After stirring for 1 hr at 0° C., the suspension is cooled to -10° C. and a solution of sodium azide (6.4 g) in distilled water (40 ml) is added. After stirring for a further 1 hr at -10° C., the reaction mixture is diluted with diethyl ether (200 ml). The organic phase is dried over magnesium sulfate and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([OH:15])[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH2:11]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)[C:12]#[C:13][CH3:14]
Reactant: CC#CCO
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cnc(C(=O)O)cn1
Temperature: 65 °C
Yield: 11.4 %

Procedure:
To a slurry of 5-chloro-pyrazine-2-carboxylic acid (0.79 g, 5.00 mmol) in DMF (35 mL) were added 2-butyn-1-ol (3.74 mL, 50.0 mmol) and potassium tert-butoxide (2.24 g, 20.0 mmol). The resulting mixture was heated at 65° C. overnight. The reaction mixture was neutralized with 2 M HCl and then concentrated in vacuo. A part (400 mg) of the crude material was partitioned between 0.5 M NaOH and a 1:1 mixture of heptane and EtOAc. The aqueous phase was made slightly acidic (pH-3-4) by addition of 1 M HCl. To the obtained suspension was added NaCl (s) and the mixture was extracted twice with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to give 0.11 g of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (t, 3 H), 5.06 (q, 2 H), 8.42 (d, 1 H), 8.82 (d, 1 H), 13.38 (br. s., 1 H); MS (ES+) m/z 193 [M+H]+.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([F:20])=[CH:14][N:13]=1.[NH4+].[Cl-]>C1COCC1.O>[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]([OH:19])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:15]([F:20])=[CH:14][N:13]=1
Reactant: O=Cc1cc(Cl)ncc1F
Reactant: COC(CCBr)OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(O)c1cc(Cl)ncc1F)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
To a solution of Mg (0.71 g, 30 mmol) in THF (10 mL) are added cat. iodine and a solution of 3-bromo-1,1-dimethoxy-propane (3.99 g, 21.57 mmol) in THF (10 mL). The mixture is stirred at room temperature for 2 hours. At −30° C., to a solution of 2-chloro-5-fluoro-pyridine-4-carbaldehyde (2.0 g, 12.54 mmol) in THF (5 mL) is added to the above prepared Grignard reagent. The mixture is stirred at this temperature for 2 hours. Then the reaction mixture is cooled in an ice bath, saturated NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/hexane: 10%˜40%) to give 1-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethoxy-butan-1-ol (0.81 g, 25%). M/Z=264.13[M+1]
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1([C:39]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:40])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1

Procedure:
To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (9.46 g, 45 mmole) in dry THF (60 mL) was added 0.5M solution of KHMDS in toluene (100 Ml, 50 mmole) at −78° C. under argon with stirring. After addition of KHMDS, the reaction mixture was stirred for 1 h at −78° C. After this time, morpholine-4-carbonyl chloride (7.48 g, 50 mmole) was added. The resultant reaction mixture was stirred for 1 h at −78° C. and then 1 h at room temperature. The reaction mixture was then treated with cooled 1N NaOH (80 mL) and extracted with EtOAc (2×350 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated to afford the title compound (I-2) as a white solid. This product was used in next step without further purification. Analytical LCMS: single peak (214 nm), 2.799 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].[B-](F)(F)(F)[O+](C)C>O1CCCC1.C1CCCCC1.C(OCC)(=O)C>[C:15]([O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: C[O+](C)[B-](F)(F)F
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (10.00 g, 63.07 mmol) in tetrahydrofuran (126 mL) was treated with a solution of tert-butyl 2,2,2-trichloroacetimidate (23 mL, 126.14 mmol) in cyclohexane (126 mL). The reaction was stirred at 25° C. for 5 min and then was treated with boron trifluoride dimethyl etherate (3.2 mL, 25.23 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h and then was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded 5-chloro-pyrazine-2-carboxylic acid tert-butyl ester (12.73 g, 94%) as a colorless oil: EI-HRMS m/e calcd for C9H11ClN2O2 (M+) 214.0502, found 214.0510.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][O:10]C)[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]1)[N:15]=2.Cl>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]1)[N:15]=2
Reactant: COC=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-(2-Fluoro-4-(2-methoxyvinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (570 mg, 1.42 mmol) was dissolved in 1,4-dioxane (14 mL) before concentrated hydrochloric acid (1.18 mL, 14.16 mmol) was added and stirred at 65° C. for 1 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 1 N NaOH (aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetaldehyde after flash chromatography. MS (ESI) m/z: Calculated: 388.1; Observed: 389.0 (M++H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C[C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1.Cl[C:15]1[S:16][C:17]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:18]([CH3:20])[N:19]=1.C(OCC)(=O)C.CO>CC(N(C)C)=O>[CH3:20][C:18]1[N:19]=[C:15]([NH:13][C:11]2[S:12][CH:8]=[N:9][N:10]=2)[S:16][C:17]=1[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Cc1nc(Cl)sc1-c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nnc(N)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(Nc2nncs2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Caesium carbonate (0.08 g, 0.24 mmol) and 5-methyl-[1,3,4]thiadiazol-2-ylamine (0.031 g, 0.27 mmol) are added to a solution of 4-(2-chloro-4-methyl-thiazol-5-yl)-benzenesulfonamide (25d) (0.07 g, 0.24 mmol) in dimethylacetamide (2 ml). The mixture is heated with stirring at 110° C. for 18 hours. After adding more 5-methyl-[1,3,4]thiadiazol-2-ylamine (0.056 g, 0.49 mmol) heating is continued at 130° C. for an additional 8 hours. The solvent is removed and the product is purified by chromatography on silica eluting with ethyl acetate to give an orange solid. Trituration with ethyl acetate-methanol affords the title compound as a yellow solid (0.0081 g)
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]2[CH:38]=[N:39][CH:40]=[C:36]2[C:35](=[O:41])[N:34]([CH3:42])[CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:32]1[N:37]2[CH:38]=[N:39][CH:40]=[C:36]2[C:35](=[O:41])[N:34]([CH3:42])[CH:33]=1
Reactant: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)n2cncc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Cc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3cncn23)c1
Yield: 44.8 %

Procedure:
A mixture of the title compound from Step 1 (150 mg, 0.34 mmol), the title compound from Example 129 Step 1 (87 mg, 0.38 mmol), K3PO4 (217 mg, 1.02 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 70° C. for 18 hrs under N2. The resulting mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (70.0 mg, 45%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1H), 8.33 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.57 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.53-7.41 (m, 2H), 7.37 (s, 1H), 7.20-7.12 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.45 (s, 3H), 3.09 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). LCMS: 460.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:6]=2[CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with p-anisoyl chloride was accomplished as described in the procedure of Example 1 to give 5-chloro-2-phenyl-3-(4-methoxybenzoyl)benzofuran which was then demethylated as described above to give 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].CCN(CC)CC.CN1C(=O)CCC1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][C:16]([OH:17])=[C:11]([C:1]34[CH2:2][CH:3]5[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]5)[CH2:10]3)[CH2:8]4)[CH:12]=2)=[CH:23][CH:22]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Pd(OAc)2 (6.7 mg, 0.03 mmol) was added into a flask containing a mixture of 3-adamantan-1-yl-4′-bromo-biphenyl-4-ol (1.15 g, 2.99 mmol), tert-butyl acrylate (1.75 g, 11.96 mmol), NEt3 (1.25 ml, 8.97 mmol), tetrabutylammonium chloride (1.329 g, 4.78 mmol) and NMP (3 ml). The flask, equipped with a glycol-cooled condenser, was immerged in a pre-heated oil bath (110° C.) and the reaction mixture was stirred at this temperature overnight. The mixture was allowed to return to RT and was diluted with DCM and washed with H2O. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude reaction mixture was taken-up in dioxane (10 ml) and the resulting solution added dropwise to 40 ml of H2O. The suspension was then sonicated for 20 min and stirred overnight. After filtration of the latter, 1.2 g (93% yield) of the desired compound as a grey solid was obtained.