Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[F:6][C:7]([F:37])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:30]([O:32]C)=[O:31])=[CH:29][C:24]=4[N:23]=[CH:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[F:37][C:7]([F:6])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:30]([OH:32])=[O:31])=[CH:29][C:24]=4[N:23]=[CH:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 70 °C

Procedure:
A 0.5M THF solution of methyl 1-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylate (3.7 g, 8.4 mmol) was treated with 10M NaOH (8.4 mL, 84 mmol) and enough methanol to make the mixture homogeneous. The reaction mixture was then heated at 70° C. for 24 h, after which it was concentrated in vacuo, taken up in water and acidified to pH 4 with 2M HCl(aq). The resulting precipitate was filtered and washed with water to afford 1-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylic acid. 1H NMR (DMSO-d6, 400 MHz) δ 5.26 (s, 2H), 7.26-7.29 (m, 2H), 7.43 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.63-7.66 (m, 4H), 7.94 (dd, 1H, J=8.8 Hz, 1.6 Hz), 8.33 (d, 1H, J=0.8 Hz), 8.62 (s, 1H); MS (ES+): m/z 429 (MH+).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20](C(OCC3C=CC=CC=3)=O)[CH3:21])[CH:16]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OCC)(=O)C>CO.[Pd]>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1

Procedure:
A solution of 475 mg of the above 1-(SR)-(3,5-bis(trifluoromethyl)-phenyl)methoxy-2-(SR)-phenyl-3-(RS)-(N-(benzyloxycarbonyl)-N-methylamino) cyclopentane in 5 mL of 1:1 methanol: ethyl acetate was hydrogenated over 100 mg of 10% Pd/C for 2 hours. The reaction was filtered and concentrated to afford the title compound as an oil. Mass spec (NH3/CI): 418 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([NH:32][CH3:33])[CH2:19]1)=[O:17].C(N(C(C)C)C(C)C)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([N:32]([S:43]([CH3:46])(=[O:45])=[O:44])[CH3:33])[CH2:19]1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentyl}-amide (36 mg) in acetonitrile (2 ml) were added N-ethyldiisopropylamine (0.03 ml) and mesyl chloride (0.01 ml). The reaction mixture was stirred at r.t. for 3 hrs, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 92:8) to give 5-chloro-thiophene-2-carboxylic acid [(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-(methanesulfonyl-methyl-amino)-cyclopentyl]-amide (32 mg) as off-white solid. MS 567.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([O:26][CH2:30][CH3:31])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Example 68 (60 mg, 0.14 mmol) in DMF (1 mL) was added bromoethane (152 mg, 1.4 mmol) and NaH (6 mg, 0.14 mmol) and the suspension was stirred for 1 h at rt. The reaction was quenched by adding 1N HCl and water. The reaction was diluted with EtOAc, washed with a saturated aq NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 85% CH2Cl2 in hexane to afford the title compound. (LC-2) HPLC/MS: 462.2 (M+1), 464.2 (M+3); Rt=4.51 min
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: CCO
Solvent: C1CCNCC1
Product: Nc1cc(NC2CC2)n2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 44 %

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (75 mg, 0.34 mmol) in 1.0 mL ethanol was added hydantoin (34 mg, 0.34 mmol) and piperidine (33 ul). The reaction was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and yellow precipitate was filtered, washed with ethanol to yield 45 mg (44% yield) Z)-5-((5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=300)
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23]OS(C)(=O)=O)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[H-].[Na+]>CN(C)C=O>[N:29]1([CH2:23][C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][N:2]([CH3:1])[S:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[CH2:18][CH2:19]2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CN(C[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-methanesulfonic acid 4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexylmethyl ester (example 5.2) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-(4-imidazol-1-ylmethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 416 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:35][CH2:36][CH2:37]O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:40].C([O-])(O)=O.[Na+]>ClCCl>[Br:40][CH2:37][CH2:36][CH2:35][S:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:29][CH:30]=1
Reactant: OCCCSc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (7.90 g, 30.0 mmol) was added to a solution of 3-(4-benzyloxy-phenylsulfanyl)-propan-1-ol (CAB02032, 4.12 g, 15.0 mmol) and carbon tetrabromide (4.98 g, 18.0 mmol) in dichloromethane (120 mL) at 0° C. (ice/water bath). The reaction mixture was allowed to warm up to room temperature and was stirred for another hour. The solution was transferred into a separation funnel and conc. NaHCO3-solution (50 mL) was added. The organic layer was separated, dried over sodium sulphate ad concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and hexane (100 mL) was added with stirring. The precipitated triphenylphosphine oxide was filtered off and washed with more EtOAc/hexane-mixture (1:4, 100 mL). The organic solutions were concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:10, Rf: 0.48). Yield: 4.96 g (98%) colourless oil, which becomes a solid after a couple of days. 1H-NMR (400 MHz, CDCl3) δ=2.07 (tt, i=7.0, 7.0 Hz, 2H, 2.95 (t, J=7.0 Hz, 2H), 3.50 (t, J=7.0 Hz, 2H), 5.04 (s, 2H, —OCH2Ph), 6.92 (d, J=9.0 Hz, 2H), 7.27-7.44 (m, 7H). 13C-NMR (100.5 MHz, CDCl3) 6=32.30, 32.50, 34.41, 70.44, 115.84, 126.15, 127.72, 128.31, 128.86, 133.65, 136.89, 158.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccc(Cl)cc2)n1
Product: O=C(NCCc1coc(-c2ccc(Cl)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 10 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (14 mgs, 10% yield). 1H NMR (CDCl3) δ 9.45 (s, 1H), 9.29 (s, 1H), 8.84 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 3.85 (d, J=5.1 Hz, 2H), 2.93 (t, J=5.4 Hz, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O3: 463.07. found: 464.1 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][CH:6]([N:23]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]3)[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Yield: 92.6 %

Procedure:
1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 310 mg, 0.98 mmol) was dissolved in acetonitrile (3.5 mL). Pyrrolidin-3-ol (104 mg, 1.2 mmol) and triethylamine (124 mg, 1.2 mmol) were added and the mixture was subjected to microwave single node heating for 10 minutes. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The solution was washed with water, dried over MgSO4 and then the solvent was evaporated. There was obtained 280 mg (93%) of 1-[1-(diphenylmethyl)azetidin-3-yl]pyrrolidin-3-ol as an oil. 1H NMR (300 MHz, CDCl3): 1.6-1.8 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.6 (m, 2H), 2.6-2.8 (m, 1H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 1H), 3.3-3.4 (m, 2H), 4.3 (m, 1H), 4.4 (s, 1H), 7.1-7.5 (m, 10H); LCMS: m/z 309 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][C@@H:17]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:16]3)[N:12]([CH3:28])[C:11](=[O:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O-:31].[Na+]>O1CCCC1>[Cl:8][C:7]1[C:2]([O:31][CH3:30])=[N:3][CH:4]=[CH:5][C:6]=1[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][C@@H:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16]2)[N:12]([CH3:28])[C:11](=[O:29])[CH:10]=1
Reactant: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ccnc(Cl)c2Cl)cc1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc(-c2cc(=O)n(C)c(N3CCO[C@@H](c4ccc(F)cc4)C3)n2)c1Cl
Temperature: 60 °C
Yield: 50.4 %

Procedure:
A suspension of 6-(2,3-dichloropyridin-4-yl)-2-((2S)-2-(4-fluorophenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.50 g, 1.15 mmol), and sodium methoxide (1.1 g, 20.4 mmol) in tetrahydrofuran (10 ml) was heated at 60° C. for 5 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-chloro-2-methoxypyridin-4-yl)-2-((2S)-2-(4-fluorophenyl) morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.27 g, 0.58 mmol, 50%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH2:5].Cl.O1CCOCC1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:35])[N:28]=[CH:27][N:26]=1>C(#N)C>[F:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[C:25]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:2]([CH3:1])[CH:3]=1)=[N:26][CH:27]=[N:28]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5-fluoroquinazoline (5 g, 27.5 mmol; obtained as described in PCT Int. Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80° C. for 2 hours. After cooling, the precipitate washed with acetonitrile. This precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer washed with brine and dried over MgSO4. Evaporation of the solvents gave 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum (CDCl3); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=2)[NH:5][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][C:49]1[C:57]([CH3:58])=[CH:56][C:52]2[NH:53][CH:54]=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[CH3:48][C:49]1[C:57]([CH3:58])=[CH:56][C:52]2[N:53]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=[O:13])[CH:10]=4)[N:5]=[C:4]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[N:3]=3)[CH:54]=[N:55][C:51]=2[CH:50]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3cccnc3)nc(=O)c2c1
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2ncn(-c3nc(-c4cccnc4)nc4ccc(C(N)=O)cc34)c2cc1C
Yield: 17.7 %

Procedure:
To a suspension of 4-oxo-2-(pyridin-3-yl)-1,4-dihydroquinazoline-6-carboxamide (prepared as described in scheme 4) (100 mg, 0.376 mmol, 1.0 eq.) in dry DMF (20 mL) was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (216 mg, 0.488 mmol, 1.3 eq.) and diaza(1,3)bicyclo[5.4.0]undecene (114.5 mg, 0.752 mmol, 2.0 eq.) following a procedure outlined in J. Org. Chem., 2007, 72, 1019440210. To the clear solution was then added 5,6-dimethyl-1H-benzo[d]imidazole (165.2 mg, 1.13 mmol, 3.0 eq.) and the mixture was stirred overnight at room temperature. The resultant precipitate was then collected by filtration and washed with dichloromethane, water, and ether. The product was dried in vacuo to give 26.3 mg of the desired product: (xlviii-a) as an off-white solid (6.7%). LCMS m/z=395.1 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 9.69 (s, 1H), 8.90 (s, 1H), 8.82 (d, J=15.2 Hz, 2H), 8.66 (s, 1H), 8.54 (d, j=8.6 Hz, 1H), 8.42 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=O.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:10]([CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])[O:6][N:5]=1
Reactant: N=C(CCl)NO
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 8.1 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 2.6 g of 3,3-dimethylbutyryl chloride were dissolved in 30 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 3-(chloromethyl)-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:25]1([S:31][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=3[CH:18]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(CSc3ccccc3)ccc2oc1=O

Procedure:
A mixture of 1 g of ethyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (3.75 mmol), 0.57 g of potassium carbonate (4.13 mmol), 2.07 g of thiophenol (18.75 mmol) and 10 ml of absolute ethanol is reflux for 3 h. After removal of the solvent by distillation under reduced pressure, the residue is taken up in chloroform. The organic phase is washed with water and then dried over MgSO4. The solvent is removed by distillation under reduced pressure and the residue is washed with hexane to remove the excess thiophenol. The title product is recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([OH:34])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17]>N1C=CC=CC=1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([O:34][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:11]=[C:10]([O:9][CH3:8])[C:15]=1[O:16][CH3:17]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)CCC(=O)O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
Succinic anhydride (0.9 g) was added to a solution of podophyllotoxin (207.2 mg, 0.5 mmol) in pyridine (12 mL). The resultant reaction mixture was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue. The crude residue was purified using a silica gel gravity column chromatography (35:7:1 CHCl3:MeOH:NH4OH) to give succinylpodophyllotoxin as white solid (198.5 mg, 80%) 1H NMR (500 MHz, DMSO-d6) δ 2.10 (d, J=5.4 Hz, 1H, H-4), 2.32 (dd, J=12.6, 4.8 Hz, 1H, H-2), 2.53 (m, 1H, H-3), 3.52 (s, 3H, OMe H-4′), 3.65 (dd, J=10.5, 7.5 Hz, 2H, H-11), 3.82 (s, 6H, two OMe groups, H-3′ and H-5′), 4.15 (t, J=7.9 Hz, 2H, CH2), 4.26 (t, J=7.9 Hz, 2H, CH2), 4.51 (d, J=5.4 Hz, 1H, H-1), 5.89 (s, 2H, OCH2O), 6.00 (s, 2H, H-2′, H-6′), 6.67 (s, 1H, H-8), 6.94 (s, 1H, H-5), 12.15 (s, 1H, CO2H). Mass (ESI) (M−1) calcd for C26H26N2O11 513.15. found 512.93.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:4]>[OH-].[K+]>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N2C(C(=O)O)CCC2c2ccc(F)cc2)cc1
Yield: 96.9 %

Procedure:
A solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (4.35 g, 11.5 mmol) in 1N potassium hydroxide solution (100 ml) was stirred at room temperature for 17 h. Aqueous work-up yielded (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid (4.05 g, yield 97%) as a white solid, m.p. 166° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:10][NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(CN)CCCC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CNC2CCCC2)CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.3 %

Procedure:
Methyl1-(aminomethyl)cyclopentane-1-carboxylate (Intermediate 259; 1.5 g, 9.54 mmol) and cyclopentanone (1.0 mL, 11.45 mmol) were stirred in DCM (40 mL). Sodium acetate (940 mg, 11.45 mmol) and sodium triacetoxyborohydride (3.04 g, 14.31 mmol) were added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in methanol and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a colourless oil (1.64 g, 81%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH2:4][S:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7].[OH:23]O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[CH2:4][S:5]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7])=[O:23]
Reactant: OO
Reactant: CC(SCC(=O)N(C)C)c1ccc(-c2ccccc2F)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)N(C)C
Yield: 57 %

Procedure:
The difficultly soluble isomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid dimethylamide was prepared analogous to Example 51 from [1-(2'-fluoro-4 -biphenylyl)-ethylthio]-acetic acid dimethylamide by oxidation with hydrogen peroxide in glacial acetic acid. Yield: 57% of theory; m.p. 131°-133° C (from toluene)