Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[C:3]1=[O:16].[Cl:18][C:19]([Cl:24])([Cl:23])C(O)=O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:10])([F:11])[C:5]([F:12])([F:13])[C:4]([F:14])([F:15])[C:3]1([C:19]([Cl:24])([Cl:23])[Cl:18])[OH:16]
Reactant: O=C1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Reactant: O=C(O)C(Cl)(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OC1(C(Cl)(Cl)Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Temperature: -10 °C
Reaction time: 17 h

Procedure:
A solution of 30 g of perfluorocyclohexanone and 31.7 g of trichloroacetic acid was stirred in a pre-dried reaction vessel containing 113 mL of hexamethylphosphoramide. This mixture was cooled to -10° C. in a dry ice/acetone bath. Slight gas evolution was noted before and during the ketone addition. The stirred milky white reaction mixture was maintained at about 0° C. for an hour and then allowed to warm to 23° C. and stirring was continued 17 hours. The clear yellow solution was quenched with 150 mL of 10% HCl and then transferred to a separatory funnel with 400 mL of ethyl ether. This organic phase was washed with 4×500 mL of dilute HCl and then 300 mL of saturated NaCl solution. The solvent was removed by evaporation. The residue (33.7 g) contained 40.8% product by GC, confirmed by fluorine NMR. This carbinol can be converted to the corresponding acrylate by methods previously described (cf. Example 24).
Reaction SMILES: C(OC(N[C@H](C)CS(C1SC2C=CC=CC=2N=1)(=O)=O)=O)(C)(C)C.Cl.Cl.NC(C)C[C@H](S(C1SC2C=CC=CC=2N=1)(=O)=O)CC.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:77][C@@H:78]1[C@H:82]([O:83]C(=O)C)[C@@H:81]([CH2:87][O:88]C(=O)C)[O:80][C@H:79]1[N:92]1[C:116]2[N:115]=[C:114]([Cl:117])[N:113]=[C:96]([NH:97][C@H:98]([CH3:112])[CH2:99][S:100]([C:103]3[S:104][C:105]4[CH:111]=[CH:110][CH:109]=[CH:108][C:106]=4[N:107]=3)(=[O:102])=[O:101])[C:95]=2[N:94]=[CH:93]1)(=O)C.C[O-].[Na+]>C(OCC)(=O)C.CO>[S:104]1[C:105]2[CH:111]=[CH:110][CH:109]=[CH:108][C:106]=2[N:107]=[C:103]1[S:100]([CH2:99][C@H:98]([NH:97][C:96]1[C:95]2[N:94]=[CH:93][N:92]([C:116]=2[N:115]=[C:114]([Cl:117])[N:113]=1)[C@@H:79]1[O:80][C@H:81]([CH2:87][OH:88])[C@@H:82]([OH:83])[C@H:78]1[OH:77])[CH3:112])(=[O:101])=[O:102]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CS(=O)(=O)c4nc5ccccc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[C@H](CC(C)N)S(=O)(=O)c1nc2ccccc2s1
Agent: C[C@H](CS(=O)(=O)c1nc2ccccc2s1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](CS(=O)(=O)c1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
2-[(R)-2-(N-tert-Butyloxycarbonylamino)-1-propylsulphonyl]benzothiazole was prepared by oxidation of 2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylthio]benzothiazole (see Example 5) (0.55 g, 1.7 mmol) with "Oxone" on a Montmorillionite support. A mixture of the sulphonyl and sulphinyl derivatives was obtained, and the 2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylsulphonyl]benzothiazole was isolated following column chromatography. Deprotection was performed under standard conditions with hydrogen chloride in ethyl acetate. The resultant 2-[(R)-2-aminopropyl-1-propylsulphonyl]benzothiazole hydrochloride (0.088 g, 0.4 mmol) was reacted with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.18 g, 0.4 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)sulphonyl-2-propyl]-2-chloroadenosine using sodium methoxide in methanol provided the title N-[(R)-1-(2-benzothiazolyl)sulphonyl-2-propyl]-2-chloroadenosine as a foam (following column chromatography); 1H NMR (DMSO-d6) δ1.83 (3H, d, --CHCH3), 3.55, 3.66 (2H, ABX, H-5'a and H-5'b), 3.96 (1H, q, H-4'), 4.17 (1H, q, H-3'), 4.59 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.24, 5.68 (2H, 2d, 2'- and 3'-OH), 5.95 (1H, d, H-1'), 7.34, 7.47 (2H, 2t, Ar--H), 7.84, 8.01 (2H, 2d, Ar--H), 8.14 (1H, t, N--H), 8.71 (1H, s, H-8). HPLC retention time 13.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.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:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 39.3 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-acetamidobenzene (0.158 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.101 g, 40%) as an amorphous solid. FDMS m/e=348 (M+). EA calculated for C22H25N3O.¼ H2O: C, 75.07; H, 7.16; N, 11.94. Found: C, 74.94; H, 7.00; N, 11.61.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:71][C:72]([F:80])([F:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:76]3[CH2:77][CH2:78][CH:73]([C:72]([F:80])([F:79])[F:71])[CH2:74][CH2:75]3)=[O:40])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-Dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (Preparation 21) (0.94 g, 1.52 mmol), EDCI (0.358 g, 1.83 mmol), N-methylmorpholine (0.50 mL, 4.57 mmol), HOBT (0.511 g, 1.52 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.466 g, 3.05 mmol) in CH2Cl2 (15 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with NaHCO3, brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.586 g (51%) of the title compound: Mass spectrum (apci) m/z=753 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.FC(F)(F)[CH2:17][O-:18].[Na+]>FC(F)(F)CO>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[O:18][CH3:17]
Reactant: [O-]CC(F)(F)F
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: COc1nc(-n2cccn2)nc(N)c1Br

Procedure:
The following example was synthesized using the procedure described for Example 43 from Intermediate 5 using a solution of sodium 2,2,2-trifluoroethanolate in 2,2,2-trifluoroethanol:
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].C1C(=O)N([Cl:18])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Cl:18][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]c2ncccc2o1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 85 °C

Procedure:
A mixture of 3H-oxazolo[4,5-b]pyridin-2-one (36) (300 mg, 2.2 mmol, 1 equiv) and NCS (352 mg, 2.65 mmol, 1.2 equiv) in 5 mL of acetonitrile was heated at 85° C. overnight. The reaction solution was diluted with ethyl acetate (EtOAc), and washed with water. The organic solution was concentrated and purified by flash chromatography, to provide 6-Chloro-3H-oxazolo[4,5-b]pyridin-2-one (37): LCMS Retention time, 0.69 min; LCMS observed (M+H)+: 171.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([OH:13])=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:10][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([CH3:14])[C:7]=1[OH:13]
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)cc(N)c1O

Procedure:
11.0 g (50.0 mmol) 4,6-dinitro-o-cresol were hydrogenated with 2.0 g Raney nickel in 100 mL MeOH under a 5 bar hydrogen atmosphere for 4 h at RT. Then the catalyst was suction filtered and the filtrate was concentrated by rotary evaporation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.Cl.CN.[CH2:30]([N:32](CC)CC)C>C(O)C>[CH3:30][NH:32][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCCC3)n2)cc1
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)nc(N2CCCC2)n1
Temperature: 140 °C
Reaction time: 17 h
Yield: 43.9 %

Procedure:
0.62 g (0.00175 mol) of N-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide was dissolved in 20 ml of ethanol, treated with 1.36 g (0.0201 mol) of methylamine hydrochloride and 5.3 ml (0.038 mol) of triethylamine and stirred in an autoclave at 140° C. for 17 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and filtered off under suction. There was obtained 0.30 g (44%) of N-[4-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals; m.p. 271-274° C.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:4]2[N:5]([CH:10]=[N:11][CH:12]=2)[C:6](=[O:9])[NH:7][N:8]=1.O>C(O)(=O)C>[Br:1][C:12]1[N:11]=[CH:10][N:5]2[C:4]=1[CH:3]=[N:8][NH:7][C:6]2=[O:9]
Reactant: O=c1[nH]ncc2cncn12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]ncc2c(Br)ncn12
Reaction time: 1 h

Procedure:
A solution of bromine (8.0 gm., 0.05 mole) in acetic acid (10 ml.) is added to a mixture of imidazo[1,5-d]-as-triazin-4(3H)-one (6.8 gm., 0.05 mole) and acetic acid (500 ml.). The reaction mixture is stirred for 1 hour, poured into water and extracted with chloroform. The aqueous layer is separated, made slightly alkaline and extracted with ether. Evaporation of the chloroform and the ether layers yields 5.0 gm. of a solid (46.3%). This solid is recrystallized to afford the title product, a cream colored solid, m.p. 244°-245° C.(d).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15].[OH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:25][C:26]2[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=2)=[CH:22][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15]
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (400 mg), methyl 3-hydroxyphenylacetate (195 mg), potassium carbonate (320 mg) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals of methyl 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (470 mg, 85%). melting point: 88-89° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11]2)=[N:6]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1
Reactant: CN(C)CCn1cc2cc([N+](=O)[O-])ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCn1cc2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethyl-[2-(5-nitro-indazol-2-yl)-ethyl]-amine (0.300 g, 1.28 mmol), iron powder (0.715 g, 12.8 mmol) and ammonium chloride (0.0343 g, 0.641 mmol) was suspended in a 4:1 ethanol/H2O solution. The mixture was heated to reflux for 3 hours, cooled to room temperature and the solvents were removed under vacuo. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel followed by rinsing with triethylamine/ethyl acetate (1/4). The filtrate was concentrated to provide the titled product. 1H NMR (300 MHz, DMSO-d6) ppm 2.16 (s, 6H) 2.72 (t, 2H, J=6.44), 4.35 (t, 2H, J=6.44), 4.74 (s, 2H), 6.55 (dm, 1H), 6.72 (m, 1H), 7.30 (m, 1H), 7.89 (s, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[C:15]([O:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Oc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (63.6 g) was added to a solution of pyrocatechol (55 g) in water (230 mL), and to the resulting mixture was added dropwise benzoyl chloride (58 mL) over a period of 2 hours with vigorous stirring. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified carefully by dropwise addition of 2N hydrochloric acid (350 mL) and then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate (100 mL) and n-hexane (400 mL) to give the title compound (64.6 g) having the following physical data.
Reaction SMILES: C(O[CH2:9][C:10]([NH:12][N:13]1[CH2:21][C:20]2[C:15](=[C:16]([N+:22]([O-])=O)[CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:25])=[O:11])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14](=[O:25])[N:13]([NH:12][C:10](=[O:11])[CH3:9])[CH2:21]2
Reactant: O=C(COCc1ccccc1)NN1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NN1Cc2cccc(N)c2C1=O
Reaction time: 48 h

Procedure:
790 mg (2.3 mmol) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide are dissolved in 100 ml of methanol and combined with 80 mg palladium hydroxide. The reaction mixture is hydrogenated for 48 h at 4 bar H2 pressure and 25° C. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (90:10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH:30]C(=O)OC(C)(C)C)[CH2:28][C:27]([CH3:39])([CH3:38])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH2:30])[CH2:28][C:27]([CH3:39])([CH3:38])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-c4cn[nH]c4)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (364 mg, 0.64 mmol) in 10 mL of 20% TFA in CH2Cl2 was stirred at rt for 2 h. The reaction mixture was concentrated to give the product, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([NH2:16])=[O:15].C[Si]([N:21]=[C:22]=[O:23])(C)C>>[NH2:21][C:22]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[S:4][C:3]=1[C:14]([NH2:16])=[O:15])=[O:23]
Reactant: NC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Reactant: C[Si](C)(C)N=C=O
Product: NC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(3-chlorophenyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:31])[CH:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the title F compound, 3-(3-benzyloxy-4-nitro-phenyl)-2-t-butyloxycarbonylamino-propionic acid methyl ester (733 mg, 1.7 mmol) in a mixture of CH2Cl2-trifluoroacetic acid (1:1, 7 mL) is stirred at RT for 30 min, then evaporated. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted once more with EtOAc. The combined organic extracts are washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give 3-(3-benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester as a viscous yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[C:29]2[O:28][C:27]([CH2:30]Cl)=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O.CN(C=O)C>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][CH2:30][C:27]2[O:28][C:29]3[C:21]([O:20][CH3:19])=[CH:22][CH:23]=[CH:24][C:25]=3[CH:26]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: COc1cccc2cc(CCl)oc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2cc(COCCC(c3ccccc3)c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
3,3-diphenylpropanol (324 mg) and sodium hydride (60% dispersion in mineral oil, 54 mg) were added to DMF (5 ml) and the obtained mixture was stirred at room temperature for 15 minutes. 7-methoxy-2-chloromethylbenzofuran (250 mg) was then added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was added to saturated aqueous ammonium chloride solution (15 ml) to neutralize the mixture. Distilled water (20 ml) was added to the mixture and the resultant was extracted with 20 ml of ethyl acetate containing 15% of n-hexane three times. The organic layers were combined and washed with distilled water (10 ml) and with saturated brine (10 ml), followed by drying over anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure to dry the residue and the residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1) using silica gel to obtain the desired compound (394 mg, yield: 83%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([F:9])[F:8])=[N+]=[N-].[ClH:18].CCOCC>CCO.[OH-].[Pd+2].[OH-]>[ClH:18].[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([F:8])[F:9]
Reactant: CCOP(=O)(OCC)C(F)(F)CCCN=[N+]=[N-]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(F)(F)CCCN
Reaction time: 8 h

Procedure:
To a solution of diethyl 4-azido-1,1-difluorobutylphosphonate (1 eq) in EtOH (2 M) was added palladium hydroxide (0.05 eq) and 2 M HCl in ether (1.1 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was used for the next reaction without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][O:5][CH2:4][C@@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.CC(C)=[O:26]>>[C:6]([OH:26])(=[O:5])[CH3:2].[OH:1][C@H:2]1[CH2:6][O:5][CH2:4][C@@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CC(C)=O
Agent: O[C@H]1COC[C@@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[(3S,4S)-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 16) (2.37 g) is dissolved in acetone (100 ml) with heating, and the mixture is filtered. The filtrate is concentrated to about 60 ml volume, and thereto is added acetic acid (495 mg), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(3S,4S)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl) quinazoline monoacetate (2.37 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:41](=[O:42])[C:40]4[CH:39]=[CH:38][C:37]([N:36]([CH3:35])[CH3:46])=[CH:45][CH:44]=4)=[CH:32][CH:33]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(C(=O)Nc2ccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)cc2)cc1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidin-4-yl)-benzene-1,4-diamine trifluoroacetate (compound A1) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 4-dimethylaminobenzoyl chloride (288 mg, 1.21 mmol) portion wise. After 14 h at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.