Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC>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>[C:38]([C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12)(=[O:40])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 100 °C
Yield: 27 %

Procedure:
To a sealable flask containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was added tributyl(1-ethoxyvinyl)tin (0.079 g, 0.22 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). The mixture was flushed with N2, and the tube was sealed and heated to 100° C. After 16 h of heating, the mixture was cooled to rt, and the solvent was removed in vacuo. The residue was dissolved in DMF and was filtered through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC to give the title compound as an off-white solid (0.025 g). LCMS: m/e 463.38 (M+H)+, ret time 1.88 min (method 2). 1H NMR (500 MHz, CDCl3) δ ppm 11.02 (s, 1H) 8.35 (s, 1H) 8.31 (d, J=2.75 Hz, 1H) 7.52-7.62 (m, 5H) 3.81-3.85 (m, 2H) 3.61-3.65 (m, 2H) 3.39-3.43 (m, 2H) 3.31-3.35 (m, 2H) 2.80-2.83 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:41])[N:17]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:19]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:3][C:2]([NH:14][CH:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[N:17]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:40])[F:39])=[CH:34][CH:35]=2)[C:16]1=[O:41])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=CC(c2cccc(C(F)(F)F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(NC1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Dissolve (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (5.89 g, 10.0 mmol) in acetic acid (30 mL) and add sodium cyanoborohydride (1.26 g, 20.0 mmol). Stir for 30 min at ambient temperature. Pour reaction mixture into a mixture of saturated sodium bicarbonate solution and ethyl acetate. Extract the aqueous layer with additional ethyl acetate. Combine the organic extracts and wash with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify by silica gel chromatography (45% EtOAc-hexane) to yield (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one (2.55 g, 43%) as a racemic mixture. LC-MS ESI m/z: 592.0 (M+H)+, Tr=2.63 min., method 2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][O:27][CH2:26][N:23]1[C:19]2[N:20]=[CH:21][N:22]=[C:17]([C:15]3[CH:14]=[N:13][N:12]([CH:8]([C:4]4[CH:5]=[N:6][CH:7]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=4)[CH2:9][C:10]#[N:11])[CH:16]=3)[C:18]=2[CH:25]=[CH:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then copper(I) iodide (0.005 g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(II) chloride were added. The reaction mixture was sealed in a tube and stirred at room temperature overnight. The resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}propanenitrile as a yellow oil (60 mg, 72.6), LCMS (M+1)+: 542).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][NH:23][OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]=[C:28]=[O:29]>O1CCOCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][CH2:22][N:23]([C:28]([NH:27][CH3:26])=[O:29])[OH:24])[CH:16]=3)[C:11]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN=C=O
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Reaction time: 12 h

Procedure:
2-(3-Phenylpropyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (498 mg, 1.5 mmol) is dissolved in dioxane t 15 mL) and methyl isocyanate (0.22 mL, 3.7 mmol) is added. After 12 hours, the reaction mixture is diluted with EtOAc (150 mL) and the organic phase washed with 2N HCl (2×200 mL), H2O (4×200 mL), saturated NaHCO3 solution (2×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes and recrystallized from CH2C2 /hexanes to give 2-(3-phenylpropyl)-6-{2-[N-(methylaminocarbonyl)-N-hydroxyamino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-139°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(CS([O-])(=O)=O)C.Cl.[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:45]1.[C:53]1([C:59]2([C:65]([OH:67])=[O:66])[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[ClH:1].[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:45]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:62]3[CH2:61][CH2:60][C:59]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)([C:65]([OH:67])=[O:66])[CH2:64][CH2:63]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: CCCS(=O)(=O)[O-]
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide pyrrolidin-3-yl]-ethyl-methanesulfonate (2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride (2.8 g, 3.9 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane, 3% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[N:34][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:37]=2)[C:32]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[N:31]1.[Li+].[Cl-]>O1CCOCC1.[Cu]I.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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[N:34]=[C:33]4[C:32]([N:52]5[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]5)=[N:31][N:30]([CH3:29])[C:38]4=[CH:37][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(n1)c(N1CCN(C)CC1)nn2C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(N3CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (22 mg, 0.046 mmol) in dioxane (2 mL), was added 1-methyl-3-(4-methylpiperazin-1-yl)-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine (20 mg, 0.038 mmol), CuI (7 mg, 0.038 mmol), LiCl (8 mg, 0.19 mmol) and Pd(PPh3)4 (4.4 mg, 0.004 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, washed with sat. NaHCO3, extracted with EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, first eluting by 0-100% EtOAc in hexanes, then eluting by 0-20% MeOH in dichloromethane to give the product. LCMS-ESI+: calc'd for C33H37ClN6O3S: 633.2 (M+H+); Found: 633.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@@H:16]([CH2:18]I)[C@@H:14]([OH:15])[C@H:12]1[OH:13].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](CI)[C@@H](O)[C@H]1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](C)[C@@H](O)[C@H]1O

Procedure:
To a solution of 1e (80 mg, 0.21 mmol) in anhydrous tetrahydrofuran (12.5 ml) under argon is added 2,2′-azobisisobutyronitrile (AIBN) (38 mg, 0.23 mmol) followed by tributyltin hydride (215 μl, 0.78 mmol). The reaction solution is placed in an 80° C. bath, refluxed 3.5 h, and evaporated to a solid. This material is purified by preparative TLC (Analtech GF, 10×20 cm, 1,000μ) with 9:1 CHCl3/MeOH as solvent. Pure 1f crystallized in two crops from acetonitrile as a white solid.
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=2Cl)=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[CH3:29][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[C:18]2[C:13]=1[CH2:12][C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(-c2ccc(Cl)cc2Cl)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(-c2ccccc2)cc2c1C[C@@H]1CCNC[C@H]21
Temperature: 20 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of cis-3-benzyl-6-(2,4-dichloro-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (85 mg, 0.20 mmol) in MeOH (3.0 mL) was added Pd(OH)2 (17 mg, 20 wt %) and catalytic amount of acetic acid. The reaction mixture was stirred at 20° C. for 3 days under H2 atmosphere, filtered through celite and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 1/1) to give the title compound (22 mg, 0.084 mmol): MS (ES) 264.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1cccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 3-bromobenzene-1-sulfonamide (216 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (70 mg, 13%). MS (ISP) 510.4 [(M+H)+]; mp 240° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:16][C:5]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[O:8][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OCc1ccccn1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccn2)c(F)c(-c2ccco2)n1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To a stirred solution of 260 mg (0.80 mmol) trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester in 15 ml DME were added 0.27 ml (2.80 mmol) 2-(hydroxymethyl)pyridine and 0.12 ml (0.80 mmol) DBU and the mixture heated at 50° C. for 2 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in dichloromethane/ether/hexane afforded 22 mg (10%) 5-fluoro-4-furan-2-yl-6-(pyridin-2-ylmethoxy)-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 286 (M+, 100), 107 (52).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)=[CH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH2:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: C=C(c1ccccc1)c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=C(c1ccccc1)c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.360 g, 2.00 mmol), [3-(1-phenylvinyl)phenyl]methanol (0.421 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hrs. Hexane (15 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (0.641 g, yield 86%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[I-].[K+].[C:33]([O-:36])(=[O:35])[CH3:34].[Na+]>C1C=CC=CC=1.CN(C=O)C>[C:33]([O:36][CH2:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[S:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)[O-]
Reactant: Cc1csc2cncnc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [I-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc2cncnc12
Temperature: 75 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
7-methyl-thieno[3,2-d]pyrimidine (500 mg, 3.33 mmol) was dissolved in benzene (11 mL), added with NBS (539 mg, 3.33 mmol) and AIBN (27 mg, 0.17 mmol), and refluxed for 2 hours at 75° C. The reaction mixture was slowly cooled to room temperature, and added with potassium iodide (553 mg, 3.33 mmol) and DMF (5 mL), followed by stirring for 1 hour at 40° C. Sodium acetate (273 mg, 3.33 mmol) was added thereto, followed by further stirring for 3 hour at 40° C. Additionally, sodium acetate (273 mg, 3.33 mol) was added thereto, and the reaction mixture was stirred for 12 hours at 40° C. The reaction mixture was subjected to extraction with ethyl acetate, washed with water and NaS2O3 solution, dried and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (140 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:5]=[C:4]([F:20])[C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].[F:25][C:26]1[N:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:7]=[C:2]([F:1])[C:3]=1[S:21]([NH:24][C:28]1[CH:29]=[CH:30][N:31]=[C:26]([F:25])[N:27]=1)(=[O:23])=[O:22]
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(N)(=O)=O)c(F)c1
Reactant: Fc1ccnc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccnc(F)n2)c(F)c1
Yield: 50.9 %

Procedure:
A solution of the 2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.23 g, 0.65 mmol) prepared in Example 111c, 2,4-difluoropyrimidine (0.23 g, 1.96 mmol) and potassium carbonate (0.36 g, 2.61 mmol) in DMF (6.5 mL) was stirred at 120° C. for 3 hours. After allowing to cool, water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate/methanol=6:1) to yield the title compound (150 mg, 51%) as a colorless amorphous solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[ClH:1].[CH2:8]([NH:15][C:16]([C:18]1[O:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[N:20][C:19]=1[CH3:44])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(N2CCNCC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 3 %

Procedure:
4 M HCl in 1,4-dioxane (4 mL, 16 mmol) was added to a solution of tert-butyl 4-(5-(benzyl carbamoyl)-4-methyl oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. This was concentrated under reduced pressure, yielding 3.6 mg (3%) of the title compound as an off-white solid. LC-MS: RT=4.12 min, [M+H]+=408.7.
Reaction SMILES: Br[CH:2]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH:22]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O1CCOCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([CH2:2][C:3]([OH:5])=[O:4])=[CH:22][C:11]=3[N:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(Br)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reaction time: 3 h

Procedure:
A solution of methyl α-bromo-2-p-chlorophenyl-5-benzoxazolylacetate (3 g.) in dioxan (30 ml.) was treated with aqueous 2N sodium hydroxide solution. The mixture was acidified and crude α-bromo-2-p-chlorophenyl-5-benzoxazolylacetic acid was filtered off. This solid was dissolved in ethanol (30 ml.) and palladium on charcoal added. The solution was hydrogenated for 3 hours. The catalyst was removed and the solution was evaporated to dryness. The residue was crystallised to give 2-p-chlorophenyl-5-benzoxazolylacetic acid, m.p. 241°-242° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.S[C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncn2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Phosphorous oxychloride (4.60 g, 30 mmol) was added to dimethylformamide (32 ml) and stirred for 20 min at 0° C. 2-Mercapto-3-methyl-6-(4-pyrimidyl)-3H-pyrimidine-4-one (4.40 g, 20 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. The reaction mixture was poured into ice water, neutralized by solid potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (ethyl acetate) gave the title compound (1.20 g, 27%).