Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]1)=[CH:10][C:9]2=[O:21])[CH3:3].[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([F:35])[CH:34]=1)[NH2:31]>CC(N(C)C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]([NH:31][CH:2]([C:4]2[CH:5]=[C:6]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][C@@H:16]([CH3:20])[CH2:15]2)=[CH:10][C:9]3=[O:21])[CH3:3])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@@H](C)C3)oc12
Yield: 59.7 %

Procedure:
A solution of 8-(1-bromoethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (670 mg, 1.42 mmol) and 3,5-difluoroaniline (736 mg, 5.70 mmol) in DMA (4 mL) were stirred at 50° C. for 4 hrs then at rt over the weekend. The reaction mixture was diluted with ethyl acetate, washed with a sat. aq. sol. of sodium hydrogenocarbonate, water brine, dried over magnesium sulfate and concentrated to afford the crude product, which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness and the obtained foam was triturated with diethyl ether to give a white solid which was collected by filtration and dried under vacuum to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (400 mg, 60%). Mass Spectrum: M+H+ 472. NMR Spectrum (CDCl3): 1.25 (d, 3H), 1.61 (d partially hidden by H2O, 3H), 2.83 (ddd, 1H), 2.90 (bs, 3H), 3.08 (bs, 3H), 3.18 (dddd, 1H), 3.63-3.82 (m, 4H), 4.02 (ddd, 1H), 4.37 (bs, 1H), 4.88-4.97 (m, 1H), 5.55 (s, 1H), 5.97 (d, 2H), 6.13 (t, 1H), 7.72 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[CH:30]=[C:31](I)[S:32][C:25]=34)=[CH:19][CH:18]=2)[C:9]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][C:38]#[CH:39])[CH3:35]>>[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][C:38]#[C:39][C:31]1[S:32][C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:24]=2[O:23][C:20]2[CH:21]=[CH:22][C:17]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([C:11]3([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]3)=[O:10])=[CH:18][CH:19]=2)[CH:30]=1)[CH3:35]
Reactant: C#CCN(CC)CC
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)cc2)CC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3)c2s1
Yield: 27.4 %

Procedure:
Prepared from N-(4-fluorophenyl)-N-(4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)cyclopropane-1,1-dicarboxamide (155 mg, 0.24 mmol) and N,N-diethylprop-2-yn-1-amine (24 mg, 0.21 mmol) according to the procedure for Example 6, Step B. The crude product was purified on a Horizon reverse phase using Biotage 12M C18 column. The crude was loaded to the samplet with EtOAc and dried under vacuum. Product eluted at 55-75% acetonitrile and was obtained as a white powder (32 mg, 24%). 1H NMR (CDCl3, 400 MHz) δ 9.58 (s, 1H), 8.94 (s, 1H), 8.46 (d, J=5 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.54 (s, 1H), 7.47 (m, 2H), 7.14 (d, J=9.0 Hz, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.55 (d, J=5 Hz, 1H), 3.70 (s, 2H), 2.65 (q, J=7, 14 Hz, 4H), 1.71 (m, 4H), 1.13 (t, J=7.4 Hz, 6H) (350 mg, 31%). LRMS (ESI pos) m/e 557 (M+1).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:12]1([C:15](=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[O:19])[CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([C:15](=[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:16]=[CH:17][CH:18]([OH:19])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14]1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 66 %

Procedure:
The dianion of 1,1-dimethylethyl acetoacetate (22 mL of 0.5M solution, 11 mmol) was added to a solution of 4-cyclopropyl-5,5-bis(4-fluorophenyl)-2,4-pentadienal (2.0 g, 9.7 mmol) in 30 mL tetrahydrofuran at -70° C. The mixture was stirred for 2.5 hours at -70° C. and quenched with saturated ammonium chloride solution. The mixture was extracted with diethyl ether; the extracts were dried over magnesium sulfate and concentrated in vacuo to give 3,0 g of the title compound as an oil. MS(CI): m/e =468 for M+ of C28H30F2O4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:21])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:24](OC)[CH2:25][Br:26].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:11][C:12]2[C:13]([O:19][CH3:20])=[CH:14][CH:15]=[C:16]([CH3:18])[C:17]=2[C@H:24]([CH2:25][Br:26])[O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C)cc1CC(O)COCc1ccccc1
Reactant: COC(CBr)OC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Reaction time: 1.5 h

Procedure:
A solution of 1-benzyloxy-3-(2'-methoxy-5'-methylphenyl)-2-propanol (3.4 g, 12 mmol), from Step 1, and bromoacetaldehyde dimethyl acetal (1.7 mL, 14 mmol) in 25 mL of methylene chloride is cooled to 0° C. Boron trifluoride etherate (3.6 mL, 29 mmol) is added dropwise and the reaction mixture is stirred for 1.5 h. The resultant dark brown solution is poured into 50 mL of 10% aqueous sodium carbonate solution and the aqueous solution is extracted with 3×50 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-iodo-benzo[1,3]dioxol-5-ylmethyl)adenine (6 mg, 0.0145 mmol), Cs2CO3 (5 mg, 0.0145 mmol) and pent-4-ynyl tosylate (4.5 mg, 0.189 mmol) in anhydrous DMF (200 L) was stirred at 60° C. for 1.5 h. Following solvent removal, product (5.9 mg, 84.9%) was collected through silica gel column purification (EtOAc:hexanes:CHCl3:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDCl3) 7.29 (s, 1H), 6.59 (s, 1H), 5.94 (s, 2H), 5.83 (bs, 2H), 4.26 (s, 2H), 4.11 (t, J=7.4 Hz, 2H), 2.26-2.19 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.98-1.94 (m, 2H); 13C NMR (100 MHz, CDCl3) 150.9, 148.9, 147.8, 131.5, 118.8, 109.4, 101.9, 88.1, 82.3, 69.9, 42.3, 39.2, 28.2, 15.9; MS m/z 480.0 (M+H)+. HPLC: (a) 95.5% (60% water-40% acetonitrile); (b) 95.0% (35% to 55% acetonitrile).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].[OH-].[NH4+:17]>>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([NH2:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: [NH4+]
Agent: [OH-]
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O

Procedure:
The title compound was prepared by stirring 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran in ethanolic ammonium hydroxide solution at room temperature until thin layer chromatography showed consumption of the starting epoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23]OS(C)(=O)=O)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35].[N-:42]=[N+:43]=[N-:44].[Na+]>CS(C)=O.O>[N:42]([CH2:23][CH2:22][C:16]1[N:17]([CH3:21])[C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:11]1[N:6]([CH2:5][C:4]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:3]=3[O:2][CH3:1])[C:7](=[O:35])[C:8]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][C:10]=1[CH2:29][CH3:30])=[CH:20][CH:19]=2)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCN=[N+]=[N-])n2C
Temperature: 80 °C
Yield: 72.7 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (309.6 mg, 0.53 mmol), prepared according to procedure described in Example 159 Step 10, in DMSO (2 mL) was added NaN3 (100 mg, 1.54 mmol). The reaction mixture was heated at 80° C. for 1.5 h until complete consumption of starting material was observed. The reaction mixture was then diluted with H2O and the product was extracted with DCM (3×10 mL). The combined organics were washed with NaCl (aqueous saturated, 5 mL) and dried over Na2SO4. Upon solvent removal, the residue was purified by column chromatography using EtOAc/hexanes (gradient 0-80%) to afford methyl 6-(2-(2-azidoethyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (204.0 mg) in 73% yield. The product could not be completely separated from mesylate elimination by-product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[C:18]([Zn]C#N)#[N:19]>CN(C)C(=O)C.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>[F:17][C:10]1[CH:11]=[C:12]([CH:13]=[O:14])[CH:15]=[CH:16][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:18]#[N:19])[CH:7]=1
Reactant: N#C[Zn]C#N
Reactant: O=Cc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Oc2ccc(C=O)cc2F)ccn1
Yield: 30.4 %

Procedure:
To a solution of 4-((2-chloropyridin-4-yl)oxy)-3-fluorobenzaldehyde (580 mg, 2.31 mmol) and dicyanozinc (271 mg, 2.31 mmol) in N,N-dimethylacetamide (DMA) (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.230 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h, and then filtered. Direct purification via reversed phase chromatography (acetonitrile/water: 5%-95%, 0.25% NH4OH) afforded the title product (170 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]3[CH:36]=[N:35][C:34]([CH3:37])=[N:33]3)=[CH:26][C:25]=2[F:38])[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:38][C:25]1[CH:26]=[C:27]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:20]1[N:19]=[C:18]2[CH:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]2[N:21]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)c(F)cc1-n1cnc(C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OC(F)(F)F)cc2)c(F)cc1-n1cnc(C)n1
Yield: 54.8 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (820 mg, 1.480 mmol), sodium iodide (1.11 g, 7.40 mmol), and diisoproplylethylamine (0.256 mL, 1.48 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 420 mg (52% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 518.3. 1H NMR (500 MHz, CHLOROFORM-4) δ ppm 8.55 (s, 1 H), 8.09 (d, J=7.6 Hz, 1 H), 7.48 (d, J=11.6 Hz, 1 H), 7.19-7.26 (m, 4 H), 6.83 (d, J=3.4 Hz, 1 H), 4.18-4.35 (m, 3 H), 3.81 (s, 3 H), 2.47 (s, 3 H), 2.16-2.24 (m, 1 H), 1.96-2.15 (m, 3 H), 1.80-1.95 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[CH:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(N(CC)CC)C.[Pd]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=COC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CCOC(COCc2ccccc2)C1
Yield: 56.8 %

Procedure:
A mixture of (RS)-2-benzyloxymethyl-2,3-dihydro-4H-pyran-4-one (0.82 g, J. Org. Chem., 44, 811 (1979)) in ethanol (15 ml) containing 10% Pd—C (0.089 g) and triethylamine (10 drops) was hydrogenated until NMR spectroscopy indicated almost complete reaction. The solution was evaporated and the residue purified by silica-gel MPLC [25% EtOAc/hexanes] and then bulb-to-bulb distillation [220° C./2 mmHg] to give the title ketone (0.47 g, 56%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:30](=[CH:31][C:32]=2Br)[O:29][CH2:28][C:27]2[N:22]3[CH:23]([CH3:35])[C:24](=[O:34])[NH:25][N:26]=2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CC1(C)CC(C)OB([C:44]([C:46]([F:49])([F:48])[F:47])=[CH2:45])O1.CCOC(C)=O>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>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:30](=[CH:31][C:32]=2[C:44]([C:46]([F:49])([F:48])[F:47])=[CH2:45])[O:29][CH2:28][C:27]2[N:22]3[CH:23]([CH3:35])[C:24](=[O:34])[NH:25][N:26]=2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of K2CO3 (0.12 g, 0.86 mmol), Pd(PPh3)4 (0.099 g, 0.086 mmol), 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester ((Example 1, Step B, 0.20 g, 0.43 mmol) and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (0.38 g, 1.7 mmol) in DME (15 mL) and water (2.5 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to ambient temperature. EtOAc (50 mL) and water (30 mL) were added and the organic portion was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-(1-trifluoromethyl-vinyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.14 g, 68%). 1H NMR (CDCl3, 400 MHz): δ 8.14 (brs, 1H), 6.83 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 5.73 (s, 1H), 4.66 (q, J=6.8 Hz, 1H), 4.56 (d, J=12.8 Hz, 2H), 4.26 (m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 3.70 (m, 2H), 1.53 (t, J=6.8 Hz, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([C:16](=[O:28])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(C=CC(=O)C(C)C(=O)C=Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)C(C)C(=O)CCc2ccc(O)c(OC)c2)ccc1O
Yield: 41.4 %

Procedure:
4-Methyl-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (6a, 0.20 g, 0.5 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (100 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford an oil. The crude oil was twice chromatographed on silica gel with ethyl acetate/hexane to give a semi-solid. The crude semi-solid was distilled bulb to bulb to give 80 mg (38%) of a pale yellow oil; 1H NMR: δ enol form: 1.69 (s, 3H), 2.72 (m, 8H), 3.83 (s, 6H), 5.48 (s, 2H), 6.69 (m, 4H), 6.79 (d, 2H, J=7.5 Hz); keto for: 1.23 (d, 3H, J=7.2 Hz), 2.72 (m, 8H), 3.57 (q, 1H, J=7.0 Hz), 3.83 (s, 6H), 5.48 (s, 2H), 6.69 (m, 4H), 6.79 (d, 2H, J=7.5 Hz); 13C NMR: δ 12.5, 29.2, 43.3, 55.9, 61.4, 111.0, 114.2, 120.7, 132.4, 143.9, 146.3, 206.1; Exact mass calcd for C22H26O6: 386.1729, observed (M+H) 387.1783.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([SnH](CCCC)CCCC)CCC.O>O1CCCC1.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>[Cl:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 34.4 %

Procedure:
To a solution of 2,5-Dichloro-nicotinoyl chloride (15 g, 0.071 mol) in tetrahydrofuran was added tributyl-stannane (24.9 g, 0.086 mol) portionwise over 45 minutes. The resulting mixture was stirred at ambient temperature for 50 minutes, and then treated with tetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.00071 mol). The reaction mixture was stirred at ambient temperature for 4 hours, poured into water; the product was extracted with ethylacetate, the combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10% ethyl acetate/hexanes) followed by recrystallization from hexanes/ethylacetate gave the title compound (4.3 g).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([O:19][C:20]([NH:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]([C:39]2[N:40]=[CH:41][N:42](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:43]=2)([C:35]([O:37][CH3:38])=[O:36])[C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C(Cl)Cl.O>[C:15]([O:19][C:20]([NH:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]([C:39]2[N:40]=[CH:41][NH:42][CH:43]=2)([C:35]([O:37][CH3:38])=[O:36])[C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1c[nH]cn1
Reaction time: 5 h
Yield: 87.7 %

Procedure:
0.20 g (1.70 mmol, 272 μl) of triethylsilane and 1.76 g (15.46 mmol, 1.19 ml) of trifluoroacetic acid were added to a solution of 1.00 g (1.55 mmol) of the compound from example 12c in 15 ml of CH2Cl2 while cooling in ice and stirring, and stirring was continued at 0° C. After 5 h, while cooling in ice, 10 ml of water were added and the pH was adjusted to 9 with 2N NaOH. The resulting precipitate was filtered off with suction, triturated in about 20 ml of CH2Cl2, filtered off with suction and dried. 0.55 g of the desired compound was obtained.
Reaction SMILES: C1([NH:7][S:8](=[O:11])(=[O:10])[OH:9])CCCCC1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:48]=[CH:47][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:47][CH:48]=2)[CH2:15][CH2:14]1.[S:8](=[O:10])(=[O:9])([O-:11])[NH2:7]
Reactant: O=S(=O)(O)NC1CCCCC1
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCO
Product: NS(=O)(=O)[O-]

Procedure:
A solution of N-cyclohexylsulphamic acid (Fluka, Buchs, Switzerland; 732 mg, 4 mmol) in ethanol (100 mL) is added to a solution of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol (150 mL at 90° C.). The solution is evaporated to dryness under reduced pressure and the resulting residue is re-crystallized from ethanol-isopropanol. The product is filtered-off and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, sulphamate as a crystalline solid, having the following analytical properties: Analysis found: C, 61.13; H, 6.75; N, 15.87; O, 11.80; S, 4.57%. H2O, 1.69%. Calculated for C35H44N8O4S-0.40 i-PrOH-0.70 H2O: C, 61.28; H, 6.90; N, 15.79; O, 11.50; S, 4.52%. H2O, 1.78%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[N:26]=[CH:25][N:24]=[C:23]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:22]=1)[CH2:16][CH2:15]2)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:50]([S:54](Cl)(=[O:56])=[O:55])[CH2:51][CH2:52][CH3:53]>ClCCl>[CH2:50]([S:54]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:17]3[C:18]4[C:14](=[CH:13][C:12]([S:9]([CH3:8])(=[O:10])=[O:11])=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[CH:22]=2)[CH2:29][CH2:30]1)(=[O:56])=[O:55])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCS(=O)(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Trifluoroacetic acid (727 μL) was added at 0° C. to a dichloromethane (2.90 mL) solution of the tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (145 mg, 0.306 mmol) produced in Example 1, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. To a dichloromethane (3.70 mL) solution of the obtained residue and diisopropylethylamine (1.07 mL, 6.14 mmol), a dichloromethane (1.85 mL) solution of 1-butanesulfonyl chloride (72.0 mg, 0.461 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 1 hour and then at 80° C. for 3 hours. The solvent was distilled off under reduced pressure. To the residue, methanol was added, and the deposit was collected by filtration. The obtained crude product was washed with methanol to obtain the title compound as white powder (125 mg, yield: 82%).