Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][CH2:14][C@@:15]1([CH2:30][NH:31]C(=O)C(F)(F)F)[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>N>[P:1]([O:13][CH2:14][C@@:15]1([CH2:30][NH2:31])[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:29])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CNC(=O)C(F)(F)F)(COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: N
Product: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 18 h

Procedure:
4′-C-(N-trifluoroacetylaminomethyl)thymidine triphosphate (8) was dissolved in concentrated aqueous ammonia solution and allowed to stand for 18 hours at ambient temperature. The solution was then lyophilised to give the title compound (9) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:20]C)[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH2:7])[CH3:2].[CH3:22][O:23]CCNC>>[CH3:22][O:23][CH2:2][CH2:1][N:3]([CH3:20])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH2:7]
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Reactant: CNCCOC
Product: COCCN(C)CC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using 2-methoxy-N-methylethanamine LC/MS (M+H)+: 299. HPLC ret. time (Condition B): 1.480 min.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.[F:14][C:15]1([F:22])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1.C([Li])CCC>[F:14][C:15]1([F:22])[CH2:20][CH2:19][C:18]([O:21][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH2:16]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCC(F)(F)CC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(C)OC1=CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of N,N-diisopropylamine (3.30 g, 32.6 mmol) in THF (50 mL), n-butyl lithium (1.65 M solution in hexane (18.0 mL, 29.7 mmol) was added dropwise with cooling on ice. The reaction solution was stirred at 0° C. for 30 minutes. Then, 4,4-difluorocyclohexanone (3.60 g, 26.8 mmol) was added thereto at −78° C., and the reaction solution was stirred at −78° C. for 1 hour. To the reaction solution, chlorotrimethylsilane (4.4 mL, 34.8 mmol) and triethylamine (8.0 mL, 57.4 mmol) were added, and the mixture was stirred at −78° C. for 2 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added, followed by extraction with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=98:2) to yield the title compound (2.10 g, 56%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH2:44]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: NCC1OCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3OCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and C-[1,3]dioxolan-2-yl-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.61 (m, 6 H), 3.27-3.30 (m, 4 H), 3.60-3.89 (m, 6 H), 4.70-4.89 (bd, 1 H), 6.20-6.34 (bd, 1 H), 6.94-6.99 (m, 1 H), 7.14-7.21 (m, 2 H), 7.40 (d, J=8.0 Hz, 1 H), 7.44 (s, 1 H), 7.52-7.61 (m, 3 H), 7.81 (d, J=7.3 Hz, 1 H), 7.96-7.98 (m, 1H), 8.21(s, 1 H), 10.42 (s, 1 H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9].[F:22][C:23]([F:45])([F:44])C1C=C(S(N2C3C(=C(C=C)C=CC=3)C=C2)(=O)=O)C=CC=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O>[F:22][C:23]([F:45])([F:44])[C:5]1[CH:4]=[C:3]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=3[CH:13]=[CH:12]2)(=[O:9])=[O:10])[CH:2]=[CH:7][CH:6]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
The experimental for Intermediate 16 was followed using 1-{[3-(trifluoromethyl)phenyl]sulfonyl}-4-vinyl-1H-indole (348 mg, 0.99 mmol; Intermediate 18), OsO4 (13 mg, 0.05 mmol), 2,6-lutidine (230 μL, 2.0 mmol) and sodium periodate (0.848 g, 3.96 mmol). The title compound was obtained (368 mg, 105%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C16H10F3NO3S m/z 354 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH2:6][C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]1([CH2:4][C:5]2[N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[N:14]=[N:15][C:6]=2[C:7]([OH:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)CC1CC1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CC2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 101.7 %

Procedure:
Ethyl 4-cyclopropyl-3-oxobutyrate (1.20 g, 7.05 mmol, 1.2 eq.) obtained in Example 96a) and 4-azido-N-ethylbenzamide (1.20 g, 5.88 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (556 mg, 7.35 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 2.5 hr. 2% Aqueous sodium carbonate solution (40 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed twice with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 5° C. The precipitate was collected by filtration, washed with cold water and dried to give the title compound as a pale-brown powder (1.88 g, 5.98 mmol, 101.7%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Li+].I[CH3:18]>CN(C=O)C>[CH3:18][N:13]1[C:12](=[O:14])[CH:11]=[CH:10][N:9]=[C:8]1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccnc(Nc2ccccc2)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccccc2)nccc1=O
Reaction time: 0.42 h
Yield: 61.6 %

Procedure:
To a solution of 2-(phenylamino)pyrimidin-4(3H)-one (0.250 g, 1.34 mmol) in DMF (10 mL) was added LiH (0.012 g, 1.47 mmol). The reaction mixture was stirred for 25 minutes and then iodomethane (0.166 mL, 2.67 mmol) was added. The reaction was stirred at room temperature for 18 hours, the quenched with H2O and partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow oil. The crude product was purified by flash column chromatography, eluting with 30:1 dichloromethane/methanol. The desired product (0.166 g, 62%) was obtained as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=6.2 Hz, 1H), 7.46 (m, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 6.48 (s, 1H), 6.01 (d, J=6.6 Hz, 1H), 3.58 (s, 3H). LRMS (ESI pos) m/e 202 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH3:4].[Si:20]([O:27][CH2:28][CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33](Cl)[C:32]=3[C:31]1=2)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1>[Si:20]([O:27][CH2:28][CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:11][CH:8]4[CH2:9][CH2:10][C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:3][CH3:4])[CH2:6][CH2:7]4)[C:32]=3[C:31]1=2)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 18 °C
Reaction time: 14 h
Yield: 47.1 %

Procedure:
Sodium hydride (605 dispersion in mineral oil, 283 mg, 7.08 mmol, 3.65 equiv) was treated with tert-butyl N-(1-ethyl-4-hydroxycyclohexyl)carbamate (430 mg, 1.77 mmol, 0.91 equiv) in 50 mL of distilled THF at room temperature for 30 mins. Then a solution of (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (25.1, 716 mg, 1.94 mmol, 1.00 equiv) in THF (5 mL) was added dropwise and the resulting solution was stirred for 14 hr at 18° C. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to afford the corresponding tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (480 mg, 43%) as a colorless oil. MS: 576 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[C:8]([C:7]1[CH:11]=[C:3]([C:1]#[C:2][C:18]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[N:17]=2)[CH:4]=[CH:5][C:6]=1[CH3:12])(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccc(C)c(C(N)=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 120 °C
Yield: 68.9 %

Procedure:
To a mixture of 5-ethynyl-2-methylbenzamide (I71) (0.041 g, 0.25 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.105 g, 0.230 mmol), PdCl2(PPh3)2 (0.011 g, 0.016 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and copper(I) iodide (0.010 g, 0.53 mmol) in DMF (2 mL) was added triethylamine (0.091 mL, 0.65 mmol). The mixture was then heated under microwave irradiation at 120° C. for 30 minutes. The resulting mixture was concentrated under reduced pressure then purified using silica gel column chromatography (0-100% EtOAc/petroleum benzine 40-60° C.) to give title compound (I72) (0.092 g, 69%); 1H NMR (400 MHz, d5-DMSO) δ 10.24 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.58 (m, 4H), 7.39 (m, 1H), 6.96 (d, J=9.0 Hz, 2H), 3.46 (dd, J=6.3, 3.3 Hz, 4H), 3.06 (m, 4H), 2.42 (s, 3H), 1.42 (s, 9H). LCMS Method C: rt 6.22 min; m/z 581.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=[O:48])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:40][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:22]2[CH:23]=[N:24][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N+:19]([O-:48])=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)cc1OC(F)F
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: [O-][n+]1ccc(CC(c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 162 %

Procedure:
To a solution of 4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-{6-[4-(trifluoromethoxy)phenoxy]-3-pyridyl}ethyl}pyridine (340 mg, 0.598 mmol) from Step 5 above in a mixture of 6 mL of CH2Cl2 and 0.6 mL of MeOH, was added MMPP (222 mg, 0.359 mmol) in one portion. The mixture was stirred 24 h at room temperature and the reaction was completed with an other 50 mg of MMPP. The reaction was quenched with a saturated aqueous NaHCO3 solution and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to afford the title compound as an amorphous solid (340 mg, 97%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:23]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3.02 g (20 mmol) of methyl anthranilate in 30 ml of methylene chloride was added 2.22 g (22 mmol) of triethylamine. Into the mixture, a solution of 2.39 g (22 mmol) of methoxyacetyl chloride in 15 ml of methylene chloride was dropwise added under chilling with ice. The resulting mixture was then stirred for 1 hour. After adding ice, the stirred mixture was made alkaline by addition of 1 N aqueous sodium hydroxide and then extracted with chloroform. The organic portion was collected and washed sequentially with 3 N HCl, 6 N HCl, water and saturated aqueous sodium chloride. The washed chloroform portion was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.6 g of the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([Br:14])[O:13][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Br:14][C:12]1[O:13][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2oc(Br)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2oc(Br)cc2[nH]1

Procedure:
2-Bromo-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (Krutosikova, A.; Kovac, J.; Dandarova, M.; Lesko, J.; Ferik, S., Collect. Czech. Chem. Commun., 46: 2564-2573 (1981)) was hydrolyzed according to Procedure E (4 equiv 2 N NaOH, ethanol; reflux 5h, room temperature overnight; after concentration to remove ethanol, residue partitioned between ethyl acetate and 2 N HCl; combined organic phases dried over Na2SO4; no purification).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a cold (−78° C.) solution of 2-methylthiazole (2.80 g, 28.2 mmol) in anhydrous THF (100 mL) was added butyllithium (19.41 mL, 31.1 mmol) dropwise. After stirring for 60 min at −78° C., a solution of tributylchlorostannane (9.14 mL, 33.9 mmol) in anhydrous THF was added to the reaction mixture. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm to RT over a 2 to 3 h period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with ether (3×200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The crude product was purified on a silica gel column eluting with 10-50% EtOAc in Hexane over a 60 min period. The fractions were collected and solvent was removed in vacuo to give the title compound as a yellow oil (72%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.71-0.92 (m, 9H), 0.96-1.18 (m, 6H), 1.23-1.38 (m, 6H), 1.40-1.64 (m, 6H), 2.69 (s, 3H), 7.56 (d, J=12.69 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[CH:9][CH2:10][NH:11][CH2:12][CH:13]([NH:17]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)[C:14]([OH:16])=[O:15])[C:4](=[O:35])[CH2:3]1.N1CCCCC1>CN(C=O)C>[NH2:17][CH:13]([CH2:12][NH:11][CH2:10][CH:9]=[C:5]1[C:4](=[O:35])[CH2:3][C:2]([CH3:1])([CH3:36])[CH2:7][C:6]1=[O:8])[C:14]([OH:16])=[O:15]
Reactant: CC1(C)CC(=O)C(=CCNCC(NC(=O)OCc2cccc3c2Cc2ccccc2-3)C(=O)O)C(=O)C1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(=CCNCC(N)C(=O)O)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The resin prepared according to example 1 (7.085 g) in DMF was treated with 20% piperidine in DMF (40 mL) for 10 min and filtered. Another 40 mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3×40 mL), MeOH (3×40 mL) and DCM (3×40 mL). The resin was dried in vacuo.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1.O>CC(N(C)C)=O>[Br:10][C:11]1[C:12]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Oc2ccccc2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Sodium hydride dispersion in oil (˜70%, 0.68 g) was added in portions to a well stirred solution of phenol (1.33 g, 14 mmol) in DMA (100 mL). After stirring the mixture for 1 h at 50° C. 3-bromo-2-chloro-5-methyl-pyridine (2.68 g, 13 mmol) was added and stirring continued for 28 h at 100° C. The cooled mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 1.4 g of the title compound as a colorless oil, 1H NMR(CDCl3): =2.27 (s, 3H), 7.12 (d, 2H), 7.19 (t, 1H), 7.39 (t, 2H), 7.76 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN1C(=O)CCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=3)[N:3]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3cc(Cl)ccc3n2)CC1
Yield: 66 %

Procedure:
A mixture of 2,6-dichloro-4-(2-fluoro-phenyl)-quinazoline (0.92 g, 3.14 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 4.08 mmol, 1.3 equiv; commercially available) in anhydrous NMP (8 mL) was heated by microwave irradiation to 180° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of heptane/ethyl acetate (6:1 h 1:1) providing 0.66 g (66%) of the title compound. MS (ISP): 457.4 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.CO.O>[CH2:17]([CH:5]([C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a solution of the 2-benzyl-N-benzyloxy-malonamic acid ethyl ester (19 g, 58.1 mmol) dissolved in a mixture of THF (70 mL) and MeOH (200 mL) was added a solution of NaOH (5.4 g, 135 mmol) in water (100 mL). The mixture was stirred at room temperature for 24 hours, and evaporated to remove volatile organic solvents. The aqueous residue was diluted with water (200 mL), and washed with DCM (200 mL). The aqueous layer was saved and acidified to pH-4 by adding concentrated HCl. The desired product was precipitated, washed with water, dissolved in acetone (200 mL), and evaporated to dryness, affording intermediate (12a) as a white solid (14.2 g). 1H-NMR (CD3OD, 300 MHz) δ (ppm) 7.20-7.06 (m, 5H), 4.60-4.56 (d, 1H), 4.42-4.38 (d, 1H), 3.10-2.98 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:23]#[N:24].CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([C:9](=[O:10])[C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:30][CH2:29]1)[C:23]#[N:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 40.6 mg (0.15 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 39.9 mg (0.18 mmol) 3-Chloro-4-piperazin-1-yl-benzonitrile (WO9625414) and 62.5 ul (0.45 mmol) NEt3 in 1 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 1 ml CH3CN/DMF/HCOOH 3/5/2 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 4.9 mg (8%) of the title compound.