Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH2:21])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].[C:27](Cl)(=[O:29])[CH3:28]>C(N(CC)CC)C.O.O1CCCC1>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][C:27](=[O:29])[CH3:28])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4]
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(C)=O)s3)CS[C@H]12
Yield: 63.8 %

Procedure:
7-Methylthioacetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g.) was dissolved in a mixture of triethylamine (0.9 g.), water (20 ml.) and tetrahydrofuran (30 ml.). To this solution was added dropwise a solution of acetyl chloride (0.53 g.) in tetrahydrofuran (10 ml.) at 0°-5° C. The mixture was stirred at the same temperature for an hour, and then the tetrahydrofuran was distilled off under reduced pressure. The remaining solution was washed with ethyl acetate (100 ml. ), adjusted to pH1 with 10% hydrochloric acid and then extracted with ethyl acetate (200 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, and the ethyl acetate was evaporated under reduced pressure. The residue was washed with acetone and then with ether to give 7-methylthioacetamido-3-(5-acetamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.4 g.). m.p. 145°-150° C (dec.).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][O-:14])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:29]1([CH3:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:10]=[CH:9]1
Reactant: [O-]Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(COCC2CCCCC2)c[nH]1

Procedure:
5 mmol of sodium (1-triphenylmethyl-1H-imidazol-4-yl)-methanolate and 5 mmol of cyclohexylmethane chloride are treated as described in Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=O)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:24])=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (1.1 eq) was suspended in an. THF and cooled to 0° C. under nitrogen. 1.6M nButyllithium in hexanes (1.1 eq) was added drop wise, and stirred for 30 minutes. 1-(2,4-Bis-benzyloxy-phenyl)-ethanone (1 eq) was dissolved in an. THF and added drop wise to the suspension. When addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature under nitrogen overnight. Methanol was added to the reaction mixture and the resulting solution was evaporated in vacuo. Hexane was added to the resulting oil and heated to reflux for 30 minutes, then filtered through Celite. The liquor was evaporated in vacuo to give an oil which was purified by column chromatography, eluting with 30% EtOAc in hexane, to give 2,4-Bis-benzyloxy-1-isopropenyl-benzene. Rf retention time 0.722, 3:1 Hexane: EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.Cl.[NH2:23][C:24]1[S:25][C:26]([F:29])=[CH:27][N:28]=1.Cl[C:31](OC)=[O:32]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:31](=[O:32])[NH:23][C:24]3[S:25][C:26]([F:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: Nc1ncc(F)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(CNc3ccc(Br)cc32)C1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CC[C@]2(C1)CN(C(=O)Nc1ncc(F)s1)c1ccc(Br)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that (R)-t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that 2-amino-5-fluorothiazole hydrochloride was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][C:3]=1[Cl:14])=[O:8].[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[Cl:14])=[O:8]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c(Br)cc2c(=O)o1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c([N+](=O)[O-])c(Cl)c(Br)cc2c(=O)o1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
5.4 g (20 mmol) of 5-bromo-4-chloroisatoic anhydride was suspended in 20 ml of conc. H2SO4 at −10° C. and cooled to −20° C. 2.1 g (21 mmol) of potassium nitrate was dissolved in 6 mL of sulfuric acid and cooled to 0° C., was then added dropwise to the reaction mixture. The reaction mixture was then stirred −10° C. for 15 min and warmed to room temperature overnight. The mixture was poured in to a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 3.2 g (50%) of 5-bromo-4-chloro-3-nitroisatoic anhydride. LCMS: 323 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:52]6[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]6)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (40.1 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial, with fitted magnetic stir bar, containing piperazine (0.18 mmol), and acetic acid (3.6 mg, 0.6 mmol). The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via Gilson HPLC (with 0.1% TFA in the solvents). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 29.8 mg (65.3%) of the title compound. LC-MS m/z 760 (M+H)+, 1.224 min (ret time).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([CH3:17])=[CH:5][CH2:6][CH2:7][C:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#N)[CH2:10][CH:9]=1.Cl.[OH2:19]>OO>[CH3:3][C:4]([CH3:17])=[CH:5][CH2:6][CH2:7][C:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:19])=[O:1])[CH2:10][CH:9]=1
Reactant: CC(C)=CCCC1=CCC(CC#N)CC1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CC(C)=CCCC1=CCC(CC(=O)O)CC1
Temperature: 25 °C

Procedure:
To a solution of sodium hydroxide (10.5 g) in water (150 mL) and 30% hydrogen peroxide (50 mL) is added the nitrile 2A (R=4-Methyl-3-pentenyl) (10 g). The reaction mixture is stirred at reflux overnight. The reaction is then cooled to room temperature, and poured into a mixture of ice (30 g) and hydrochloric acid (22 mL). The acid product is extracted with ethyl acetate, and the combined organic layers are washed with brine and dried over magnesium sulfate. The solution is concentrated in vacuo.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>O.ClCCl>[CH3:46][S:47]([O:29][C@H:26]1[CH2:25][CH2:24][C@@H:23]([C:10]2[CH:11]=[CH:12][C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])=[CH:14][C:9]=2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:28][CH2:27]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
To a round bottom flask containing cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (200 mg, 0.46 mmol) was added dichloromethane (10 ml) followed by triethylamine (96 μl, 0.69 mmol) and dimethylaminopyridine (catalytic amount). The flask was purged with argon and methane sulfonyl chloride (53 μl, 0.69 mmol) was added with stirring. Stirring was continued for a further 24 hr and the reaction mixture was poured into water and extracted with dichloromethane (4×20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/petrol, 1:9) afforded the title compound as an oil (194 mg, 82%). δH (CDCl3) 0.19 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 1.01 (9H, s), 1.20-1.35 (2H, m), 1.65-1.78 (4H, m), 2.15-2.22 (2H, m), 2.85-2.95 (1H, m), 3.02 (3H, s), 5.06 (1H, s), 6.30 (1H, d), 6.43 (1H, dd), 7.00 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:30]Br>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([Br:30])=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1nc(Br)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 127, STEP 2) (2.0 g, 0.0062 mol) in chloroform (160 mL) and under nitrogen was added pyridine (0.528 mL, 0.0064 mol), followed by a slow addition (˜1 h) of a solution of bromine (1.044 g, 0.0064 mol) in chloroform (16 mL). The reaction was diluted with water (100 mL) and the organic layer removed, dried over sodium sulfate, filtered and concentrated to an oil. The oil was chromatographed on silica using a gradient of 0 to 4% acetone/dichloromethane to give the title compound as a foam. M.S.(M+1): 401.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[CH:19][C:20](=[O:23])[NH:21][CH:22]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1.CN(C)C=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[CH:19][C:20](=[O:23])[NH:21][CH:22]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
5-[4-(4-Nitrobenzamido)phenyl]-2(1H)-pyrazinone (1.0 g) was added to a vigorously stirred suspension of palladium on charcoal (0.3 g, 5%) in ethanol (20 ml) followed by cyclohexene (20 ml). The reaction was heated under reflux for 24 hours, hot dimethylformamide was then added and the mixture was filtered. Evaporation of the filtrate gave a solid residue which was extracted with boiling glacial acetic acid, collected and dried to give the title compound (0.6 g, m.p. >300° C.; δ(DMSO-d6) 7.99 and 8.09 (2H, 2s, pyrazinone ring protons), 9.7 and 9.9 (2H, 2 broad s, =CH--NH--CO and --NH--CO).
Reaction SMILES: C([NH:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)(=O)CNC(C1C=CC=CC=1)=O.[Cl-].[Na+].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC(O)=O)=O)CCCNC(N)=N)=O)C(C)C)=O)CC2C=CC(O)=CC=2)=O)C(C)C)=O)CC2NC=NC=2)=O)CCC1)=O)C(O)=O>O>[NH2:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccccc1)C(=O)O
Agent: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Reaction time: 0.33 h

Procedure:
50 μl of a solution containing 0.01 mole/liter of hippuryl-histidyl-leucine (substrate) and 0-100 μl of a test compound solution were added to 300 μl of a 0.2M tris-hydrochloric acid buffer solution containing 0.2 mole/liter of sodium chloride. The total volume of said mixture was adjusted to 450 μl with water. Then, 50 μl of angiotensin-converting enzyme (ACE) isolated from pig's renal cortex were added to the mixture, and the mixture was allowed to stand at 37° C. for 20 minutes. The amount of histidyl-leucine produced from the substrate by the action of ACE was assayed microbiologically by the use of Leuconostoc mesenteroides P-60, and the ACE-inhibitory activity of the test compound was estimated therefrom. The results are shown in the following Table 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(CCc2ccc(CO)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a stirred solution of methyl 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate (2 g) in dry THF (40 ml) was added dropwise 1.0M diisobutylaluminium hydride solution in toluene (14.8 ml) at −78° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 4 hours, and then quenched with MeOH. AcOEt and 1N—HCl were added to the mixture, and extracted. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/MeOH (20:1) as an eluent to give N-{4-{2-[4-(hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (552.3 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl>CCO>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([F:17])([F:18])[F:16])[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Yield: 73.6 %

Procedure:
A mixture of 5-chloro-6-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (230 mg, 0.743 mmol), SnCl2 ·2 H2O (1.90 g, 7.43 mmol) and EtOH (300 mL) was refluxed for 24 h, then rota-evaporated to dryness. The residual solid was washed on a Bursch funnel with water (6×15 mL), and dried to give 153 mg (74%) of the title compound as a yellow powder. Mp>360° C. 1H NMR (DMSO-d6) 11.777 (s, 1H), 11.360 (s, 1H), 7.140 (s, 1H), 5.499 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[Cl:23][C:24]1[C:29]2[C:30](=[O:45])[N:31]3[CH2:44][CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38](=[N:40]O)[NH2:39])[C:28]=2[CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[Cl:23][C:24]1[C:29]2[C:30](=[O:45])[N:31]3[CH2:44][CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38]3[N:40]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:39]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)CC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Reaction time: 8 h
Yield: 37 %

Procedure:
1.4 g (13.5 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.6 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 elimination the solution was stirred at 70° for 30'. Then, 4.02 g (15 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. By evaporation of the solution and chromatography of the residue on 340 g of silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.99 g (40%) of (S)-8-chloro-1-(5-dimethylaminomethyl-1,2.4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 261°.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][Si](C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]=[CH2:21])=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]2[CH2:21][CH2:5][N:4]([CH2:10][CH2:11][CH3:12])[CH2:3]2)=[N:18][CH:19]=1
Reactant: C=Cc1ncc(Br)cn1
Reactant: CCCN(COC)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylmethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.CCN(CC)CC.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and 1.71 mL of Et3N in 15 mL of DCM, cooled to 0° C., are added 2.15 g (11.3 mmol) of tosyl chloride. The medium is allowed to warm to room temperature, and stirring is continued for 1 hour. The medium is taken up in 100 mL of DCM, washed successively with 0.11N HCl (2×20 mL) and brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 3 g of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate are obtained in the form of a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][CH2:10][C:11](=O)[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>O.ClCCCl>[CH2:7]([NH:8][CH:11]([CH3:12])[CH2:10][F:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CF
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of phenylmethanamine (5.63 g, 52.6 mmol) and 1-fluoropropan-2-one (4.0 g, 52.6 mmol) and DCE (50 mL) was added NaBH(OAc)3 (15.6 g, 73.6 mmol) and HOAc (3.01 mL, 52.6 mmol) and the reaction was capped and stirred at RT for 3 h. The reaction was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:5 to 500:10) to afford 6.2 g (70.5%) of N-benzyl-1-fluoropropan-2-amine (230).
Reaction SMILES: [CH2:1]=O.[C:3]([O:6][CH3:7])(=[O:5])[CH3:4]>>[C:3]([O:6][CH3:7])(=[O:5])[CH:4]=[CH2:1].[C:3]([OH:6])(=[O:5])[CH:4]=[CH2:1]
Reactant: C=O
Reactant: COC(C)=O
Product: C=CC(=O)O
Product: C=CC(=O)OC

Procedure:
A process according to claim 1 wherein formaldehyde and methyl acetate are reacted to produce methyl acrylate and/or acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[ClH:8].[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:12]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: Cl
Product: O=C(CCl)Nc1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
2-Amino-5-chloropyridine (3.85 g) was dissolved in ethyl acetate (60 mL), and, at room temperature, chloroacetyl chloride (2.39 mL) was added to the solution, followed by stirring for 1 hour. After the reaction mixture was heated and stirred at 60° C. for 30 minutes, chloroacetyl chloride (0.5 mL) was additionally added, and the mixture was stirred at 60° C. for additional 1 hour. Powder precipitated was collected by filtration, to thereby give the title compound (6.18 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:16][C:5]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[O:8][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCc2ccccn2)c(F)c(-c2ccco2)n1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To a stirred solution of 260 mg (0.80 mmol) trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester in 15 ml DME were added 0.27 ml (2.80 mmol) 2-(hydroxymethyl)pyridine and 0.12 ml (0.80 mmol) DBU and the mixture heated at 50° C. for 2 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in dichloromethane/ether/hexane afforded 22 mg (10%) 5-fluoro-4-furan-2-yl-6-(pyridin-2-ylmethoxy)-pyrimidin-2-ylamine as a white crystalline solid. EI-MS m/e (%): 286 (M+, 100), 107 (52).