Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12].N(OCCC(C)C)=O>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1N
Reactant: O=[N+]([O-])c1ccccc1
Agent: CC(C)CCON=O
Product: COc1cc(F)ccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 7.7 grams of 4-fluoro-2-methoxyaniline, 200 ml. of nitrobenzene, and 9.0 grams of isoamyl nitrite, is warmed on the steam bath until a vigorous reaction with evolution of gas sets in. This evolution is allowed to proceed without heating until it has subsided, and the mixture is then heated on the steam bath for an additional 3 hours. The excess of nitrobenzene is removed in vacuo. The residue is purified for the desired isomer by elution from a silica gel column using petroleum-benzin to yield 4'-fluoro-2'-methoxy-4-nitrobiphenyl.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(Cl)Cl.C(O[C@@H:17]1[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@@H:28]([CH3:30])[O:29][C@H:17]1[N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:9])=[N:4][C:5]1=[O:8])(=[O:22])[CH3:21]
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
5-Fluorocytosine (2.42 g, 18.8 mmol) was suspended in toluene (10 ml) and hexyamethyl-disilazane (3.03 g, 18.8 mmol). The mixture was heated at 100° C. overnight. After concentrating the reaction mixture under reduced pressure, methylene chloride (30 ml) and 5-deoxy-1,2,3-tri-O-Acetyl-β-D-ribofuranoside (4) (5.16 g, 18.8 mmol) were added to the residue. Then, anhydrous stannic chloride (4.90 g, 18.8 mmol) was added dropwise to the ice-cooled reaction mixture over a period of 20 min. After stirring the mixture at room temperature for an additional 2 h, sodium bicarbonate (10 g) was added, followed by the dropwise addition of water (20 ml). After stirring the resulting mixture at room temperature overnight, 4% sodium bicarbonate solution was poured into the reaction mixture and stirred for additional 1 h. The mixture was then extracted with water-methylene chloride. The organic layer was collected, dried with Na2SO4, the solvent was removed under reduced pressure to give brown syrup. The residue was then partially purified by silica gel chromatography using CH2Cl2:MeOH (5:1) as an eluent to yield crude target compound (5) (4.455 g, 13.5 mmol, 72%). 1H NMR in DMSO-d6: δ1.34 (d, 3H, J=6.4 Hz, H-5), 2.05, 2.06 (2s, each 3H, OMe), 4.14 (q, 1H, J=5.0 Hz, H-4), 5.10 (t, 1H, J=6.4 Hz, H-2), 5.43 (dd, 1H, J=6.31 Hz, H-3), 5.77 (dd, 1H, J=1.0 Hz, H-1), 7.71 (br s, 1H, N—CH═C—F), 7.97 (br s, 1H, NH), 8.02 (d, 1H, J=7.0 Hz, NH).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[C:35]([NH:42][CH2:43][CH2:44]Br)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:18]3[S:23][C:22]([CH2:44][CH2:43][NH:42][C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc2nc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-(2-(3-(tert-butyldimethylsilyloxy)phenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (166 mg, 388 μmol, 1.0 eq.) was solved with dry THF (3 ml) under room temperature and added to a round-two-neck flask that was heated under vacuum and flushed with nitrogen. The solution was then cooled to −78° C. and n-BuLi (315 μl, 1.6 M solution in hexanes, 1.3 eq.) was added dropwise. After stirring for 20 min., 2-(boc-amino)ethyl bromide (130 mg, 582 μmol, 1.5 eq.) was added to the reaction mixture and the reaction mixture was stirred at −78° C. for 20 min. and then warmed to room temperature. The reaction mixture was further stirred at room temperature overnight.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:13][C:14](Cl)=[O:15])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1.[CH3:21][NH:22][CH2:23][C:24]([OH:26])=[O:25]>>[CH3:21][N:22]([C:14](=[O:15])[CH2:13][C:6]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3][C:2]1=[O:1])[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CNCC(=O)O
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccccc21
Product: CN(CC(=O)O)C(=O)CC1(c2ccccc2)C(=O)Oc2ccccc21

Procedure:
This compound was prepared according to the process described in Example 11, starting with 2-(2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride and N-methyl glycine.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[C:7]=1[Cl:17])C.[OH-].[K+]>C(O)C>[Cl:17][C:7]1[C:8]2[C:13](=[CH:12][C:11]([F:16])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1ccc2cc(F)ccc2c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2cc(F)ccc2c1Cl

Procedure:
A mixture of N-(1-chloro-6-fluoro-2-naphthyl)carbamic acid ethyl ester (600 mg, 2.24 mmol) and KOH (1.51 g, 26.9 mmol) in ethanol (20 mL) is heated to reflux temperature under N2 atmosphere for 12 hours. After cooling, the reaction mixture is concentrated by rotary evaporator. The residual oil is purified by flash chromatography on silica gel (3:1 hexanes/EtOAc) to give 1-chloro-6-fluoro-2-aminonaphthalene as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccoc2cc(Br)ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1CCOc2cc(Br)ccc21
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 7-bromo-4H-chromen-4-one (26 g, 116 mmol) in dry THF (500 mL) under nitrogen for 1 hr, cooled to −80° C., and 173 mL of diisobutylaluminium hydride (2M in Toluene) was added over 30 minutes. The reaction was stirred at the same temperature for 30 min, quenched with a SiO2 (52 g)/water (52 mL) suspension, and allowed to warm to 0° C. The solution was filtered, the SiO2 washed with EtOAc, and the combined filtrate was concentrated to dryness. The residue was dissolved in CHCl3 (400 mL), washed with 1N NaOH (300 mL), dried over Na2SO4 and concentrated. Purification by chromatography on SiO2 (60-120 mesh) EtOAc/Pet ether (gradient elution 0-15%) afforded 7-bromochroman-4-one 18.1 g (69%) a pale yellow solid. LCMS 229.0 (M+2H); 1H NMR (DMSO-d6) 7.64-7.67 (d, 1H), 7.32 (s, 1H), 7.22-7.25 (d, 1H), 4.53-4.57 (t, 2H), 2.76-2.80 (t, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: Cl
Product: O=C(Cc1cccc(Br)c1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-bromophenyl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 244, (S)-3-(benzyloxy)-2-(2-(3-bromophenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 43.3%). MS (EI) for C30H26BrFN2O4. found 578.4 (MH+).
Reaction SMILES: [F-].[Cs+].[CH2:3]([NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5].S(Cl)([Cl:17])=O.C([O-])(O)=O.[Na+]>O.ClCCl>[CH2:3]([N:6]=[C:7]([Cl:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CCCN=C(Cl)c1ccccc1

Procedure:
(5RS,6SR,7SR)-6-Tert-butoxycarbonyl-7-(2-benzyloxy-4-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine N-oxide(224 mg, 0.395 mmol) and CsF(1.82 g) were dried under reduced pressure. To the mixture were added dichloromethane(4.0 ml) under nitrogen atmosphere and N-propylbenzimidoyl chloride(210 mg) which was prepared from benzoic acid N-propylamide and thionyl chloride. The solution was stirred vigorously under heating at reflux, treated with an aqueous saturated solution of NaHCO3 and water, stirred at room temperature to make the solution homogeneous and extracted with dichloromethane. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent the residue was purified by MPL(E. Merck Kieselgel 60 lobar column/dichloromethane:acetone=100:1 to 50:1 to 30:1) to give (5RS,6SR,7SR)-6-tert-butoxycarbonyl-7-(2-benzyloxy-4-methoxyphenyl)-2-[(N-benzoyl)propylamino]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine(138 mg).
Reaction SMILES: [F:1][C:2]([F:33])([CH:30]([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[F:33][C:2]([F:1])([CH:30]([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Yield: 52.9 %

Procedure:
Methyl 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (177 mg, 0.38 mmol) was stirred with 1.9 mL aqueous sodium hydroxide solution (2 M) in 3.9 mL methanol overnight at room temperature, and then concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Flash chromatography gave 91 mg of 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid; 1H NMR (300 MHz, CD3OD) δ 7.92 (d, 2H), 7.41 (d, 2H), 7.40 (d, 2H), 7.02 (d, 2H), 6.32 (tt, 1H), 4.45 (tt, 2H), 3.98 (d, 2H), 3.88 (d, 2H), 3.69 (br s, 1H), 3.64 (br s, 1H), 3.17 (d, 1H), 3.12 (d, 1H), 2.90 (dd, 1H), 2.85 (dd, 1H), 2.02 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CO.[C:28]1([CH2:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(C3CCC(NCc4ccccc4)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To methyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (300 mg, 0.874 mmol) was added MeOH (4 mL), phenylmethanamine (112 mg, 1.048 mmol) and last dry 4 Å molecular sieves. The reaction was stirred at room temperature for 16 h. Then NaBH4 (165 mg, 4.37 mmol) was added and stirred at room temperature for 2 h followed by LCMS. To the reaction was added 150 mL of ethyl acetate, washed with saturated sodium bicarbonate, water (2×), saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue to give 352 mg of the desired product in 2:1 trans to cis ratio, used as is (93%). LCMS (m/z): 435.3 (MH+), 0.68 min and 0.72 min.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[ClH:39].CCOCC>O1CCOCC1>[ClH:39].[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][C:19]=3[F:37])=[O:16])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cccc(OC(F)F)c4)c3)c(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
(S)-tert-butyl 2-(4-(1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylate (102 mg, 0.2 mmol) was dissolved in dioxane (0.75 ml) and a solution of HCl in dioxane (4M, 0.75 ml, 3 mmol) was added. The reaction mixture was stirred for 90 min at 60° C. After cooling ether was added, the solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford (S)-1-(3-(difluoromethoxy)phenyl)-N-(2-fluoro-4-(morpholin-2-yl)phenyl)-1H-pyrazole-4-carboxamide hydrochloride (84 mg, 91%) as a white solid. MS (ISP): 433.2 ([M+H]+).
Reaction SMILES: C([C:4]1[C:5]([O:16][CH2:17][C:18]([Cl:20])=[CH2:19])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH3:15])(=O)C.ClC(=C)[CH2:23][O:24]C1C(O)=C2C(C(C)=CC(=O)O2)=CC=1>>[Cl:20][C:18](=[CH2:19])[CH2:17][O:16][C:5]1[C:4]([O:24][CH3:23])=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][C:11](=[O:14])[O:12]2)=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1O
Product: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1OC

Procedure:
As shown in FIG. 24, the synthesis pathway for the compounds of the present invention involves starting with the following compound, Compound 1: ##STR5## This starting compound in the synthesis of Compound 2 is 4,5'-dimethyl-8-methoxypsoralen. The synthesis of this precursor compound has been described previously in the literature. See Bender, et al., J. Org. Chem. 44:2176 (1979). Alternatively, the starting compound may be synthesized by the following method: 8-acetyl-7-(2-chloroallyl)oxy-4-methylcoumarin, described in Bender, et al., J. Org. Chem. 48:2709 (1983), is initially oxidized to a phenolic compound, 7-(2-chloro-2-propenyl)oxy-8-hydroxy-4-methylcoumarin, and then methylated, providing 7-(2-chloro-2-propenyl)oxy-8-methoxy-4-methylcoumarin. Claisen rearrangement provides 6-(2-chloro-2-propenyl)-7-hydroxy-8-methoxy-4-methylcoumarin, which is then converted to 4,5'-dimethyl-8-methoxypsoralen.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:27]#[N:28])=[C:15]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][C:21]3O[CH:23]=[CH:24][CH:25]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[C:29](O)([C:31](F)(F)F)=O>ClCCl>[C:27]([C:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[S:16][C:15]=1[NH:17][C:18](=[O:26])[CH2:19][CH2:20][C:21]1[CH:25]=[CH:24][CH:23]=[CH:31][CH:29]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)CCc3ccco3)c2C#N)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(NC(=O)CCc2ccccc2)sc2c1CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg of 3-cyano-2-(3-furan-2-yl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester are dissolved in 7 ml of a mixture of dichloromethane and TFA and stirred at room temperature for 3 h. Evaporation of the solvent gives 250 mg of the desired product as TFA salt in sufficient purity for the next steps.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[N:33]1([CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]6[S:38][CH:42]=[CH:41][CH:40]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Yield: 44 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F, and purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH to generate the product in 44% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.6 (s, 4H) 2.7 (s, 3H) 3.8 (s, 2H) 4.0 (t, J=6.0 Hz, 2H) 6.5 (m, 2H) 6.9 (m, 2H) 7.1 (m, 3H) 7.2 (m, 2H) 7.4 (m, 2H) 7.4 (m, 1H) 7.5 (t, J=2.3 Hz, 1H) 7.7 (m, 1H) 7.9 (d, J=1.8 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 616 [M+H]+.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[I-].[K+].[Si:17]([N:24]1[C@H:27]([CH2:28][C:29]([S:34][CH3:35])([S:32][CH3:33])[S:30][CH3:31])[C@@H:26]([C:36](=[O:38])[CH3:37])[C:25]1=[O:39])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(O)(=O)C>C(OCC)(=O)C.C(OCC)C>[Si:17]([N:24]1[C@H:27]([CH2:28][C:29]([S:34][CH3:35])([S:32][CH3:33])[S:30][CH3:31])[C@@H:26]([C@H:36]([OH:38])[CH3:37])[C:25]1=[O:39])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CSC(C[C@@H]1[C@@H](C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CSC(C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
K-Selectride® (3.64 ml of 0.5 M, 1.82 mmol) is added by syringe to a mixture of potassium iodide (126 mg., 0.758 mmol) and (3S,4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one (298 mg, 0758 mmol) in freshly distilled ethyl ether (8 ml) at room temperature. The resulting mixture is stirred at room temperature for 2.5 hours, then quenched by the addition of acetic acid (218 mg., 3.64 mmol). The resulting mixture is diluted with ethyl acetate (25 ml) and filtered through celite. Removal of solvents in vacuo gives an oil which is chromatographed on silica gel (ether:petroleum ether) to yield 252 mg of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one. N.M.R. (R isomer, CDCl3 +D2O) δ4.15(dq,l), δ3.95(ddd,l,J=9.5,2.3), δ3.26(dd,l,J=8,2.3), δ2.37(m,2), δ2.16 (s,9), δ1.37(d,3,J=6,6), δ1.0(s,9), δ0.26(s,6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl[C:15]1[N:20]=[C:19]2[N:21]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:22]=[C:23]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:18]2=[CH:17][CH:16]=1.ClCCl.P([O-])([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]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:20]=[C:19]3[N:21]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:22]=[C:23]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[C:18]3=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Cn1cc(-c2nn(C3CCCCO3)c3nc(Cl)ccc23)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2ccc3c(-c4cnn(C)c4)nn(C4CCCCO4)c3n2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of (3,5-dimethoxyphenyl)boronic acid (0.13 g, 0.71 mmol), 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (0.15 g, 0.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (30 mg, 0.04 mmol) and potassium phosphate (200 mg, 0.94 mmol) in 1,4-dioxane (1.0 mL) and water (0.13 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 90° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (180 mg). LCMS (M+H)+=420.1.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li][CH2:17][CH2:18][CH2:19][CH3:20].C(C(C)=O)C.OS(O)(=O)=O>C1COCC1>[CH2:18]([C:19]1([CH3:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]2[C:2]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:17]
Reactant: CN(c1ccccc1)c1ccccc1Br
Reactant: [Li]CCCC
Agent: O=S(=O)(O)O
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CCC1(C)c2ccccc2N(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Methyl ethyl ketone (0.302 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.57 g (57%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.66 (dd, J=6.8 Hz, J=0.8 Hz, 3H), 1.78 (t, J=1.2 Hz, 3H), 3.10 (s, 3H), 5.49 (m, 1H), 6.66 (m, 3H), 7.18 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 14.2, 15.2, 16.5, 24.2, 39.2, 39.6, 113.8, 114.1, 117.1, 117.4, 122.4, 124.4, 125.7025.9, 128.0, 128.2, 128.5, 128.8, 128.9, 130.6, 131.5, 136.4, 140.4, 144.3, 145.8, 146.9, 149.2, 149.4. HRMS (ESI) calc for C17H19N [M+H]+ 238.1590, found 238.1587. IR (KBr plate) 692 (m), 747 (m), 1345 (m), 1444 (m), 1499 (s), 1592 (s), 1602 (s), 2918 (m), 3024 (m) cm−1.