Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:54]1([CH3:64])[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:64][C:54]1[CH:59]=[CH:58][C:57]([S:60]([O:43][CH2:42][C@H:14]2[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]2[CH2:12][C:11]2[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)(=[O:62])=[O:61])=[CH:56][CH:55]=1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyoxy)-3-((S,E)-3-(tert-butyl dimethylsilyoxy)oct-1-enyl)cyclopentyl)methanol (15 g, 0.023 mol) in dry CH2Cl2 (500 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (9.6 ml, 0.068 mol), then with p-Toluenesulfonic chloride (8.77 g, 0.046 mol). The mixture was poured to saturated sodium bicarbonate aqueous and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 85%.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=2)[CH:15]=1
Reactant: CCOC(=O)CC(=O)CCCl
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CCOC(=O)CCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 13903.8 %

Procedure:
4.28 mg of ethyl 5-chloro-3-oxopentanoate was dissolved in 40 ml of ethanol, 2.94 g of 2-amino-5-bromopyridine was added and the mixture was stirred all night by heating under reflux. The mixture was cooled down to room temperature, and the solvents were distilled outunder reduced pressure. Ethyl acetate followed by saturated sodium bicarbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer silicagel chromatography (hexane:ethyl acetate=50:50) to obtain 990 mg of the above compound as crude product.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[C:23](=O)[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[CH2:17][CH2:16]1)[CH3:14]>>[CH2:13]([CH:15]1[CH2:16][CH2:17][C:18]2[O:22][CH:21]=[CH:20][C:19]=2/[C:23]/1=[N:11]\[OH:12])[CH3:14]
Reactant: CCC1CCc2occc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCC1CCc2occc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: MS (EI) m/z (rel. intensity) 179 (M+, 21), 162 (50), 151 (43), 135 (99), 134 (99), 107 (86), 106, (83), 84 (34), 79 (35), 52 (47), 51 (48). HRMS (FAB) calcd for C10H13NO2+H 180.1024, found 180.1015.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11](Br)=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]([C:17]([CH3:18])=[CH:16][C:15]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c2c1CCC2
Reactant: C/C=C/C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)c2c1CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetylamino-7-bromoindane (2.8 g, prepared according to the method of A. Courtin, Helv. Chim. Acta 1980, 63(8), pages 2280-2286), ethyl crotonate (2.51 g), palladium diacetate (150 mg), tri-ortho-tolyl phosphine (450 mg) and tributylamine (10 mL) in dimethylformamide (30 mL) was stirred at 120° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, then allowed to stand for 48 hours, then partitioned between ethyl acetate (500 mL) and aqueous hydrochloric acid (300 mL, 1M). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL) and then filtered. The clear yellow filtrate was dried over sodium sulfate then evaporated. The residue was subjected to normal phase HPLC on silica under gradient elution conditions using ethyl acetate, heptane and methanol mixtures (from 20:80:1 to 90/10/1, v/v/v) to give the title compound (1.9 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[N:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[C:13]1[N:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=1[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)-3-neopentylpyridine in THF (25 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (10 mL), and the mixture was stirred at room temperature for 5 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.50 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=[O:20]>N1C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[CH3:18])=[CH:7][CH:6]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of 5 g (19.3 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 25 mL of pyridine was treated with 2.2 mL (23.3 mmol) of Ac2O. The mixture was stirred at 60° C. for 2 hours and the solvent partially evaporated. The residue was distributed between a diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 5.7 g of crude N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide that was dissolved in 100 mL of DMF, treated with 3.4 mL (22.7 mmol) of DBU and then dropwise at 0° C. with 3.8 mL (22.7 mmol) of TESCI. The mixture was stirred at RT for 10 hours and then poured into a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 8.3 g of crude N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide which was dissolved in 100 mL of THF and treated with 3.4 mL of a 1M BH3*THF-solution in THF. The mixture was kept at reflux for 4 hours and the solvent partially evaporated. After addition of a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 9:1 yielded 7.5 g (96%) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine, light yellow oil, MS: 402 (MH+).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[N:12]([C@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:20][CH:18]([OH:19])[C@H:17]([OH:31])[C@H:16]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+:13]=[N-:14].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N:12]([C@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:20][C@@H:18]([O:19][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[C@H:17]([OH:31])[C@H:16]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+:13]=[N-:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)[C@@H](O)C(O)O[C@@H]1COCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@@H]1O[C@H](COCc2ccccc2)[C@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1O)(C(C)C)C(C)C
Reaction time: 19 h
Yield: 59.4 %

Procedure:
Triisopropylsilyl chloride (0.63 mL, 3.0 mmol, 1.2 equiv) was added to a solution of hemiacetal 223 (0.959 g, 2.49 mmol, 1.00 equiv), imidazole (0.409 g, 6.01 mmol, 2.41 equiv), and 4-dimethylaminopyridine (29 mg, 0.24 mmol, 0.096 equiv) in dimethylformamide (2.5 mL). After 19 h, the yellow solution was concentrated and purified by silica gel chromatography (hexane/ethyl acetate 19:1 to 9:1) to afford 224 (0.800 g, 1.48 mmol, 59% yield) as a colorless oil. Rf=0.49 (hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3) δ 7.43-7.24 (m, 10H), 4.78 (d, J=11.8, 1H), 4.75 (d, J=11.8, 1H), 4.55 (d, J=11.6, 1H), 4.52 (d, J=12.0, 1H), 4.51 (d, J=7.3, 1H), 3.98 (d, J=3.6, 1H), 3.72 (ddd, J=9.5, 7.3, 2.1, 1H), 3.69-3.58 (m, 3H), 3.56 (dd, J=9.6, 3.7, 1H), 2.26 (d, J=2.2, 1H), 1.19-0.99 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 137.86, 137.84, 128.70, 128.63, 128.08, 128.05, 127.97, 127.93, 98.09, 80.69, 73.81, 73.78, 72.80, 72.01, 68.83, 59.83, 17.96, 17.90, 12.33; FTIR (neat film) 3463.8, 2943.4, 2866.2, 2108.6, 1455.3, 1366.1, 1280.0, 1185.4, 1099.0, 1028.7, 1014.6, 997.6, 883.5, 805.4, 736.3, 695.5, 669.0 cm−1; HRMS (ESI) m/z: Calcd for C29H43N3O5SiNa (M+Na+) 564.2870. found 564.2870.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH:14]=O)[CH:5]=1>>[CH2:1]([NH:3][CH2:14][C:6]1[CH:5]=[N:4][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2]
Reactant: CCN
Reactant: O=Cc1cnc2ccccc2c1
Product: CCNCc1cnc2ccccc2c1

Procedure:
prepared by reaction of ethylamine with quinoline-3-carbaldehyde
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16](F)[CH:15]=1>>[F:20][C:18]1[CH:17]=[C:16]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:15]=[C:14]([Br:13])[CH:19]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccc2ccccc2c1
Product: Fc1cc(Br)cc(OCc2ccc3ccccc3c2)c1
Yield: 92 %

Procedure:
Using the procedure described in the first paragraph of the portion of Example 3 which is concerned with the preparation of starting materials, 2-naphthalenemethanol was reacted with 1-bromo-3,5-difluorobenzene to give 5-fluoro-3-(naphth-2-ylmethoxy)bromobenzene (92%), m.p. 65°-67° C.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C@@H:14]([NH:23]C(=O)OC(C)(C)C)[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:23][C@@H:14]([CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:13][N:2]([CH3:1])[C:3](=[O:4])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C[C@H](CC1CCC(=O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@@H](N)CC1CCC(=O)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 1-(N-methyl-N-(benzyloxycarbonyl)amino)-3-(4-oxocyclohexyl)propan-2-ylcarbamate (300 mg, 0.72 mmol) was dissolved in 5 mL of 20% TFA/CH2Cl2 and stirred 1 hr at rt. The solvent was removed to give the crude (S)-benzyl 2-amino-3-(4-oxocyclohexyl)propyl(methyl)carbamate, which was used directly for the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH:37](I)[CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:37]([O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])[CH:38]([CH3:40])[CH3:39])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)C(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Product: CC(C)C(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 15.9 %

Procedure:
In the same manner as in Example 81, 84 mg of the title compound was prepared from 367 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 300 mg of 1-(cyclohexyloxycarbonyloxy)-2-methylpropan-1-yl iodide.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C(Cl)Cl.[CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])=[O:9].[Cl-].[NH4+]>CO>[OH:9][CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])[CH:1]=[CH2:2]
Reactant: COC(=O)N1C(C=O)CSC1c1ccccc1
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: C=CC(O)C1CSC(c2ccccc2)N1C(=O)OC
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of 310 ml. (0.440 mole) of vinylmagnesium chloride (from Ventron Corp., 1.42 molar in tetrahydrofuran) and 250 ml. of methylene chloride, which had been previously prepared and kept at -74°C., a solution of 14.2 g. (0.0565 mol) of 4-formyl-3-carbomethoxy-2-phenylthiazolidine dissolved in 50 ml. of methylene chloride was added over a period of 7-10 minutes, while the temperature of the reaction was kept at -60° to -70°C. After addition, the reaction mixture was stirred for 30 minutes at the same temperature while 30 ml. of methanol were slowly added, followed by addition of 150 ml. of saturated ammonium chloride. When the addition was finished, the mixture was allowed to reach room temperature and extracted with 3 × 300 ml. of methylene chloride. The combined organic phases were washed with 2 × 200 ml. of water, dried with sodium sulfate, and evaporated to give 13.7 g. (87% yield) of crude 4-(1-hydroxyprop-2-en-1-yl)-3-carbomethoxy-2-phenylthiazolidine which was obtained as thick oil. This contains a small amount of starting material which, for future separation purposes, is convenient to convert into its corresponding alcohol. To this end, the crude product, dissolved in 100 ml. of tetrahydrofuran was slowly added to a solution of 0.9 g. (0.0503 mol) of sodium borohydride in 75 ml. of water and 75 ml. of tetrahydrofuran. After addition, the resulting yellow emulsion was stirred for 2 hours at room temperature. 55 ml. of 1N hydrochloric acid were then slowly added, the tetrahydrofuran removed in vacuo and the residue extracted with 3 × 100 ml. of ethyl acetate. The combined organic phases were washed with 100 ml. of 5% sodium bicarbonate solution and finally with 2 × 100 ml. of water. Drying with magnesium sulfate and evaporating the solvent gave 13.0 g. of the desired product, which can be used as such for the further transformations or it can be further purified by chromatography on silica gel, using benzene/ethyl acetate (1:1) as eluent. 4.1 g. (corresponding to a yield of 26% from a starting material) of very pure product was obtained as pale yellow thick oil.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[N:28]=1>>[F:25][C:3]1[C:2]([C:35]#[C:34][C@@:32]([OH:36])([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)[CH3:33])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1cc(F)c(Br)cc1-2
Product: Cc1nc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2CN2CCCC2)no1
Yield: 10.4 %

Procedure:
10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similarly to as described in General Procedure F with non-critical modifications to afford 9.8 mg (10.4%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(pyrrolidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=481.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]([CH2:33][C:34]2[N:38]=[C:37]([C:39](OCC)=[O:40])[O:36][N:35]=2)[CH3:32])(=[O:30])=[O:29])=[C:23]([CH3:44])[CH:22]=1.ClCCCl>C(Cl)Cl>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][C:39]([C:37]2[O:36][N:35]=[C:34]([CH2:33][N:31]([S:28]([C:24]3[C:23]([CH3:44])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[CH3:27])(=[O:30])=[O:29])[CH3:32])[N:38]=2)=[O:40])=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)NCCc3ccc(C4=NCCN4)cc3)n2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (bis TFA salt, 108 mg, 0.26 mmol) in DCM (3 mL) at 0° C. was added trimethyl aluminium (2 M in toluene, 0.13 mL, 0.26 mmol) and the mixture was stirred at 0° C. for 15 min. Ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (50 mg, 0.13 mmol) was added dropwise as a solution in DCM (2 mL), followed by TEA (0.045 mL, 0.32 mmol). The reaction was stirred at ambient temperature for 18 h, after which time TEA (0.110 mL, 0.79 mmol) and DCE (4 mL) were added. The reaction was heated to 60° C. for 18 h, then partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (2×20 mL). The aqueous layer was extracted with DCM (2×10 mL) and these extracts were dried over MgSO4 and solvents were removed in vacuo. A portion of the product was purified using prep method A.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=12.S(OC)(O[CH3:23])(=O)=O.O>CS(C)=O>[CH3:23][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:6]2[CH2:5][C:4]3[C:15]([C:7]1=2)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c2c(c3ccccc31)Cc1ccccc1-2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (375 mq, 15.6 mmol) was added to dimethylsulfoxide (DMSO) (13 cm3) under an atmosphere of nitrogen. The solution was then heated to 70° C. until no more gas (H2) evolved. The solution was cooled to room temperature and 5,10-dihydroindeno[1,2-b]indole (2.69 g, 13.1 mmol) dissolved in a minimum amount of DMSO was added. After stirring at room temperature for 1 hour, dimethyl sulphate (1.5 cm3, 15 mmol) was introduced, and stirring continued for a further 1 hour. Water (3 cm3) was cautiously added, and the reaction then poured into ice/water. The solid thus formed was collected by suction filtration, washed firstly with water, dried on the water pump, and then washed with petrol (60°-80° C.). Crystallization from ethanol yielded colourless needles of the title compound. Yield: 1.52 g (53%). M.p. 152° C. 1H NMR (CDCl3) δ: 3.55 (2H, s,), 3.85 (3H, s,), 6.8-7.4 (8H, m, arom.).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:19])[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:19][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanol and DBU in dioxane. ES-MS m/e (%): 286 (M{81Br}+H+, 99), 284 (M{79Br}+H+, 100), 258 ([M{81Br}+H—CH2═CH2]+, 52), 256 ([M{81Br}+H—CH2═CH2]+, 50).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:19][CH2:18][NH:17][CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8][C:7]=4[C:6]=3[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(Cl)cc1)N1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Yield: 104.4 %

Procedure:
The 7-nitroquinoxalinedione from Example 31 (100 mg, 0.38 mmol) was treated with the CDI adduct of 4-chlorobenzoic acid (0.57 mmol) by a procedure similar to that in Example 32 to give a yellow solid (159 mg, 99% yield). mp=280-283° C. (dec.). MS(CI) M+1 401; CHN calc'd for C18H13ClN4O5 within ±0.4.