Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:25])([F:26])[F:24])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester (0.058 g, 0.14 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.04 mL, 0.28 mmol), followed by pivaloyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred at room temperature for 10 minutes. After work-up with CH2Cl2 and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]O.O>CC(O)=O>[CH3:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[N:10][C:9]([S:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:31])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: OO
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(SCc3ccccc3)nn2)cc1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(S(=O)Cc3ccccc3)nn2)cc1

Procedure:
3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazine (0.08 g, 0.19 mmol) was dissolved in CH3CO2H (3 mL) and a 50% solution of H2O2 in H2O (0.026 mL, 0.16 mmol) was introduced. The reaction mixture was stirred and monitored by LC-MS, and after 5 h was evaporated to a residue, which was treated with H2O (20 mL) and CH2Cl2 (30 mL). The organic layer was washed with saturated NaHCO3 solution (20 mL), saturated brine (10 mL) and dried (MgSO4) before being evaporated to a white solid (0.051 g, 64%), m.p. 145° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][CH2:34][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH:12]2[C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11]
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCCCN(C)C)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.24 g) as starting materials, 5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ethyl acetate, and oxalic acid (0.12 g) was added. The precipitated solid was collected by filtration to give 5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide 3/2 oxalate (0.36 g). melting point: 142.6° C.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][C:28]=1OC)C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[CH3:37]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][CH:2]([F:1])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (93%). MS (ESI): m/z=248.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (36 mg, 32%). MP=209-210, LCMS 514.09 (M+H), HPLC purity 91%, 1H-NMR (CDCl3, 400 MHz) δ 9.39 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.63-7.58 (m, 2H), 7.32-7.25 (m, 3H), 7.05-7.03 (m, 1H), 3.75-3.65 (m, 2H), 3.10 (s, 3H), 2.37-2.27 (m, 2H), 2.08-2.04 (m, 2H), 1.35 (s, 6H), 1.20 (t, J=9.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CCO.O.[Fe]>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:22])[C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a suspension of above 2-benzoxy-N-methyl-N-(4-nitrophenyl)acetamide in EtOH (8 mL) and H2O (4 mL) was added ammonium formate (1.3 g, 20 mmol) and Fe (0.47 g, 8.4 mmol). After heating at reflux for 2 h, the reaction was cooled to room temperature, iron was filtered off, and the filtrate was diluted with EtOAc and water, EtOAc layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated under vacuo to provide 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide (0.4 g, 53%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH3:8])[NH:5][C:4]1=[O:9])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]#[N:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:7]([CH:6]1[CH:3]([CH2:1][CH3:2])[C:4](=[O:9])[N:5]1[CH2:21][C:22]#[N:23])[CH3:8]
Reactant: N#CCBr
Reactant: CCC1NC(=O)C1CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)N(CC#N)C1CC
Temperature: 0 °C

Procedure:
(3RS,4RS)-3,4-diethylazetidin-2-one (step 2) (100 mg, 0.786 mmol) in dry THF (5 ml) was cooled to −78° C. and was treated with lithium bis(trimethylsilyl)amide (0.786 ml, 0.786 mmol) [1M in THF]. The solution was allowed to warm to 0° C. then re-cooled to 0° C. before adding bromoacetonitrile (0.060 ml, 0.865 mmol). The mixture was allowed to warm to RT overnight. 10% Aqueous citric acid (30 ml) was added and the mixture was extracted with ether (4×40 ml). The combined organic layers were dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-100% Et2O in iso-hexane afforded the title compound;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:23][C:24]1[CH:25]=[C:26]([CH3:49])[C:27]2[O:31][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[N:29][C:28]=2[CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]4[O:31][C:27]5[C:26]([CH3:49])=[CH:25][C:24]([CH3:23])=[CH:48][C:28]=5[N:29]=4)=[CH:38][CH:37]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
A mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.15 g, 0.00036 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.16 g, 0.00045 mol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) and sodium carbonate (0.095 g, 0.0009 mol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature. Additional tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) was added to the mixture. The reaction was stirred at 80° C. for 3 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-50% methanol t dichloromethane as a mobile phase to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.033 g, 0.00006 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1 M ammonium acetate over 10 min, 1 mL/min) Rt 11.6 min. MS: MH+ 527.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH2:50][CH2:49][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CN1CCN(CCO)CC1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 0 °C
Yield: 23.9 %

Procedure:
To a homogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]-triazin-6-ol (100 mg, 0.33 mmol) and triphenylphosphine (129 mg, 0.49 mmol) in 4 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran, cooled to 0° C. under a nitrogen atmosphere, was added dropwise a mixture of 2-(4-methylpiperazin-1-yl)ethanol (71 mg, 0.49 mmol) and diisopropylazodicarboxylate (0.10 μL, 0.49 mmol) in 2 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran. The mixture was stirred and allowed to warm to room temperature. The reaction was stirred for twelve hours before being concentrated in vacuo. The residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with chloroform (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (34 mg, 24%) as a yellow solid. 1H NMR (CDCl3) δ 8.20-8.10 (m, 2H), 7.82 (s, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 4.16 (t, 2H, J=5.7 Hz), 2.87 (t, 2H, J=5.7 Hz), 2.80-2.40 (m, 8H), 2.45 (s, 3H), 2.31 (s, 3H); MS(ESI+) m/z 431.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](F)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([C:12]2[CH:13]=[C:14]3[C:9]([C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6][N:5]3[C:2]([CH3:4])([CH3:1])[CH3:3])=[CH:10][C:11]=2[F:16])[CH2:28]1)=[O:25]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 600 mg (2.13 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid, 700 mg (3.2 mmoles) of 3-trifluoroacetylamino pyrrolidine hydrochloride and 1.3 mL (8.5 mmoles) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 3 mL pyridine was stirred 30 minutes at room temperature, evaporated to dryness and poured into water. The pH was adjusted to 7.5 with 1N hydrochloric acid. The precipitate was filtered to give 430 mg of 7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid. mp 200° C. dec. 409 mg (0.92 mmole) of that compound was suspended in 2 mL 1N NaOH and refluxed 2 hours. The solution was cooled and diluted with water, the pH was adjusted to 7.5 with 10% acetic acid. The precipitate was filtered, washed with water, dried and recrystallized as an hydrochloride in ethanol to give 180 mg of titled compound. MP>270° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:23]1([C:27]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (80 mg, 0.26 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (52 mg, 0.26 mmol) and caesium carbonate (172 mg, 0.53 mmol) in acetonitrile (3 mL) was stirred in a Smith Creator microwave at 160° C. for 1 hr. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue. The organic phase was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica eluting with a gradient of 0-10% methanol in DCM to give the title compound (36 mg, 31%) as a white foam. This compound was crystallised from ethyl acetate and isohexane using vapour diffusion techniques. 1H NMR δ (CDCl3): 2.12-2.19 (1H, m), 2.21-2.28 (1H, m), 2.34-2.42 (2H, m), 3.75 (3H, s), 3.88-3.93 (1H, m), 3.98-4.02 (3H, m), 4.23 (2H, t), 4.69 (2H, t), 4.95-4.97 (1H, m), 6.80 (1H, d), 6.87 (1H, t), 7.23 (1H, d), 7.27-7.30 (1H, m), 7.28-7.30 (1H, m), 8.34 (1H, d), 8.84 (1H, d), 8.98 (1H, s); m/z 465 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl.[F:4][C:5]([F:16])([F:15])[O:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1.[C:17]([C:19](=[C:23](SC)[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21])#[N:18]>C(O)C>[NH2:18][C:17]1[N:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]([F:15])([F:16])[F:4])[CH:8]=2)[N:14]=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nn(-c3cccc(OC(F)(F)F)c3)c(N)c2C(N)=O)cc1
Yield: 42.5 %

Procedure:
Powdered sodium hydroxide (88 mg, 2.2 mmol) was added to a solution of 3-trifluoromethoxyphenyl hydrazine hydrochloride (503 mg, 2.2 mmol) and 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol) in ethanol (20 ml) and the mixture heated at reflux for 18 h. On cooling, the solvent was removed under reduced pressure and the residue partitioned between water (80 ml) and ethyl acetate (100 ml). The aqueous layer was further extracted with ethyl acetate (2×80 ml) and the combined organic layers washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was recrystallised from isopropyl ether-heptane to give the title compound as white needles (320 mg) m.p. 177-179°. δH (CDCl3) 7.70 (1H, m), 7.51 (1H, d, J 8.0 Hz), 7.38 (1H, d, J 8.0 Hz), 7.40 (1H, m), 7.09 (1H, d, J 7.9 Hz), 5.74 (2H, br s), 5.35 (2H, br s) and 2.42 (9H, s).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([O:20]C(=O)C)[C@H:14]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[Cl:33])[O:13]1)=[O:11]>CO>[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([OH:20])[C@H:14]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[Cl:33])[O:13]1)=[O:11]
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reaction time: 15 h
Yield: 72467.5 %

Procedure:
Triethylamine (4.4 mL, 0.032 mL) was added to a solution of (2S,3S,4R,5R)3-azido-5-(6-chloro-purin-9-yl)-4-acetoxy-tetrahydro-furan-2-carboxylic acid methylamide (4 g, 0.011 mmol) in methanol (80 mL). After stirring for 15 hours, the mixture was concentrated and the residue purified by flash chromatography (5% methanol/dichloromethane) to afford 2.7 g (77%) of the title compound as a colorless solid. MS 339 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H); 8.2 (s, 1H); 7.62 (bs, 1H); 5.98 (d, 1H, J=6.7 Hz); 5.07 (t, 1H, J=6.2 Hz); 4.65 (dd, 1H, J=5.4, 2.7 Hz); 4.58 (m, 1H); 4.2 (bs, 1H); 2.88 (d, 1H, J=4.9 Hz); 1.67 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#[N:24].[Na+]>N.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:24])[CH3:11])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(C)cc1)c1ccccc1
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was salted and re-extracted. The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification. LC-MS: m/e 240 (M+H)+ (2.22 min).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13]2)[CH3:8].I[C:24]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:44])[CH:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:36][CH3:37])=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:24]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:44])[CH:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:36][CH3:37])=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27])[CH:14]=[CH:13]2)[CH3:8]
Reactant: CCOc1ccc2cc(B(O)O)ccc2c1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1ccc2cc(-c3ccc(NC(=O)C(CC)c4ccccc4)cc3C(N)=O)ccc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.5 ml of saturated aqueous sodium carbonate solution, 40 mg (0.18 mmol) of 6-ethoxy-2-naphthaleneboronic acid and 14 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 50 mg (0.12 mmol) of the compound of Example 5A in 3 ml of dioxane. The mixture is stirred at 80° C. overnight and, after addition of 50 ml of ethyl acetate, extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 10:90→95:5). 26 mg (44% of theory) of product are obtained.
Reaction SMILES: [I:1]I.[CH2:3]([S:10]/[C:11](/[Sn](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]\[CH:13]=[C:14](/[S:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([S:10]/[C:11](/[I:1])=[CH:12]\[CH:13]=[C:14](/[S:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[Sn:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: II
Solvent: ClCCl
Product: I/C(=C/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Iodine (56 mg, 0.22 mmol) in CH2Cl2 (10 mL) was added over a period of 2 h at 0° C. to 4 (200 mg, 0.20 mmol) in CH2Cl2 (20 mL) under argon. Analysis by TLC (1:2 CH2Cl2 :hexanes) indicated the disappearance of 4. The solution was slowly warmed to room temperature and then washed with NaHSO3 (2×25 mL) and KF solution (1×25 mL), dried (MgSO4), concentrated in vacuo and the residue purified by flash column chromatography (1:6 CH2Cl2 :hexanes) to afford 5 as a pale yellow oil (0.15 g, yield 97%): 1H NMR δ 6.6-7.8 (m, 27 H), 3.78 (s, 2 H), 3.75 (s, 2 H); 13C NMR δ 127-146 (several), 42.24, 40.46; Anal. Calcd for C36H31IS2Sn, C, 55.91; H, 4.04. Found, C, 56.12; H, 4.19.