Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[S:5][C:4](=[C:8]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[S:3]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:21][N:22]([CH3:26])[C:23]([O:7][CH:6]1[CH:2]([O:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[S:3][C:4](=[C:8]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[S:5]1)=[O:24]
Reactant: CCCOC(=O)C(C(=O)OCCC)=C1SC(O)C(O)S1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCOC(=O)C(C(=O)OCCC)=C1SC(OC(=O)N(C)C)C(OC(=O)N(C)C)S1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.0 g (3.1 m mole) of di-n-propyl 4,5-dihydroxy-1,3-dithiolane-2-ylidenemalonate was dissolved in 5 ml of pyridine, 1.33 g of N,N-dimethylcarbamoyl chloride was dropped into the solution, which was stirred for 18 hours at room temperature.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[CH:15]1([NH:21][SiH:2]2[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]2[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: NC1CCCCC1
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In an argon atmosphere, 5.70 g (24.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 100 mL of hexane and after adding 4.86 g (49.0 mmol) of cyclohexylamine, the mixture was stirred at room temperature for 4 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was sublimated (heating temperature: 160° C./7.0×102 Pa) to obtain 2-cyclohexylamino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHCy) as a white solid (yielded amount: 6.95 g, yield: 96%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH:19]=[C:18]2[C@:13]([CH:21]=[O:22])([CH2:14][CH2:15][C:16](=[O:20])[CH2:17]2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[CH2:6][CH2:5]1>C(O)C.[Pd]>[CH3:1][C@@H:2]1[CH2:19][C@@H:18]2[C@:13]([CH:21]=[O:22])([CH2:14][CH2:15][C:16](=[O:20])[CH2:17]2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[CH2:6][CH2:5]1
Reactant: C[C@@H]1C=C2CC(=O)CC[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1C[C@H]2CC(=O)CC[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
A solution of 7α-methyl-5-androstene-3,17,19-trione in ethanol is hydrogenated with 5% palladium on charcoal. The catalyst is removed by filtration and the resulting solution evaporated to dryness. Crystallization of the residue from a pentane-ether solution results in the preparation of 7α-methyl-5α-androstane-3,17,19-trione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([C:15](=O)[NH:16][CH2:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[CH3:14][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:28])=[O:29])[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Hg+2]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)n23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl-carbamoyl)-piperidine-1-carboxylate (53 g, 100 mmol) and Lawesson's reagent (22.4 g, 55.2 mmol) in 1,4-dioxane (500 mL) was heated at about 80° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then was partitioned between EtOAc (1000 mL) and saturated aqueous NaHCO3 (700 mL). The organic layer was washed with additional saturated aqueous NaHCO3 (700 mL), dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was dissolved in 1,4-dioxane (500 mL) then mercury (II) trifluoroacetate (54.0 g, 127 mmol) was added. The reaction was stirred at about 25° C. for about 1 h. The reaction was partitioned with saturated aqueous Na2S2O3 (500 mL)/water (500 mL) with DCM (1000 mL). The layers were filtered through Celite® and the Celite® pad was washed with DCM (500 mL). The combined layers were separated then the organic layer was washed with saturated aqueous NaHCO3 (800 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and then coned in vacuo. The resulting residue was purified on silica gel (330 g) using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (40.5 g, 79%) as a yellow foam: LC/MS (Table 1, Method b) Rt=2.62 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]3[C@@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][NH:20][CH2:19]3)=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1.NC(N)=O.[C:34](O)(=[O:37])[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]3[C@@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][N:20]([C:35](=[O:36])[CH2:34][OH:37])[CH2:19]3)=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1
Reactant: O=C(Nc1cc2[nH]nc(OCC(F)F)c2cn1)N[C@H]1CNC[C@@H]1c1ccccc1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(N)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc2[nH]nc(OCC(F)F)c2cn1)N[C@H]1CN(C(=O)CO)C[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
In a 4 mL, 1 dram vial were added 1-(3-(2,2-difluoroethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((3R,4S)-4-phenylpyrrolidin-3-yl)urea: (20 mg, 0.050 mmol, Intermediate 34B), glycolic acid (8 mg, 0.099 mmol), HATU (37.8 mg, 0.099 mmol) and DIEA (0.025 ml, 0.149 mmol) all in DMA (0.5 ml). The solution was shaken at room temperature over night. The solution was analyzed by LC/MS and found to contain the desired compound. The filtered crude solution was directly injected to the Gilson semi-preparative HPLC (0.1% TFA in ACN and Water on a Waters Sunfire C18 ODB, 5 uM, 19 mm×100 mm, Part No. 186002567 column using a gradient of 10%-60% ACN over 12 minutes). The fractions were analyzed by LC/MS and the pure fractions were concentrated to provide 1-(3-(2,2-difluoroethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((3R,4S)-1-(2-hydroxyacetyl)-4-phenylpyrrolidin-3-yl)urea (101), was isolated as an off white powder. MS: [M+H]+ m/z 461.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH3:37][O:36][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:20]=1[NH:19][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[NH:6][C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: COCC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: COCC(C)N1CCC(=O)Nc2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 100 °C
Yield: 20.1 %

Procedure:
10-chloro-2-(1-methoxypropan-2-yl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 137; 35 mg, 0.13 mmol)), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 34 mg, 0.13 mmol) and p-toluenesulphonic acid monohydrate (61 mg, 0.32 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated at 100° C. for 18 hrs. The reaction mixture was cooled to room temperature dissolved in MeOH and added to a 2 g SCX-2 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the resultant material purified by base modified reverse phase HPLC to yield the title compound as a cream coloured solid (13 mg, 20%)
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Yield: 93 %

Procedure:
A solution of 3-(4(R),7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester ((Enantiomer 1, SFC (Table 1, Method 8), Rt=3.090 min, 0.250 g, 0.62 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at 25° C. for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R),7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #54-1, Enantiomer 1, SFC (Table 1, Method 9), Rt=4.110 min, 0.240 g, 93%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.048 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29][C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH:38]1(CO)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:29][CH2:27][CH:38]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: OCC1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Yield: 79.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (56 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (115 mg, yield 80%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:23][CH:22]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12.[CH2:37]([O:41][C:42](Cl)=[O:43])[CH2:38][CH2:39][CH3:40].CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH:36][C:42]([O:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:43])(=[O:35])=[O:34])=[CH:25][CH:26]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12
Reactant: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reactant: CCCCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCOC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(CCC)nc3c(C)c(NC(=O)CCC)cnc32)cc1
Reaction time: 14 h

Procedure:
To a mixture of 7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']biphenyl-4-yl]methyl-6-[(1-oxobutyl)amino]-3H-imidazo[4, 5-b]pyridine (60 mg, 0.112 mmol) and 4-dimethyaminopyridine (41 mg) in pyridine (1.5 mL) was added n-butylchloroformate (0.071 mL, 0.56 mmol). After 14 h at r.t., MeOH (1 mL) was added and the mixture was concentrated, dissolved in CH2Cl2 (40 mL), washed with 5% aqueous citric acid (2×20 mL), concentrated, and purified (SiO2, (89:9:1CH2Cl2 /MeOH/NH4OH) to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cccc(Cl)c2)c(-c2ccccc2)n1
Yield: 48.6 %

Procedure:
6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (110 mg, 49%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 3-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: C([N:8]1[CH:12]=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:20]1[C:32]2[C:31]([S:33][CH3:34])=[C:30]([CH2:35][C:36]([OH:38])=O)[CH:29]=[C:28]([CH3:39])[C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[S:41](N)(=[O:43])=[O:42].N12CCCN=C1CCCCC2>O1CCCC1.O>[CH2:13]([N:20]1[C:32]2[C:31]([S:33][CH3:34])=[C:30]([CH2:35][C:36]([CH2:12][NH:8][SH:41](=[O:43])=[O:42])=[O:38])[CH:29]=[C:28]([CH3:39])[C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSc1c(CC(=O)O)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CSc1c(CC(=O)CN[SH](=O)=O)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
74.6 mg (0.26 mmol) of carbonyldiimidazole was added to 1 ml of a solution of 50 mg (0.13 mmol) of (9-benzyl-4-methyl-1-methylthiocarbazol-2-yl)acetic acid, as obtained in Example 14, in tetrahydrofuran, and the reaction mixture was stirred for 1 hour at room temperature. After this time, 43.8 mg (0.26 mmol) of methanesulfonamide and 70.0 mg (0.26 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to the mixture which was first stirred overnight at room temperature and then refluxed for 2 hours. After this time, an excess of water was added to the mixture, and the resulting aqueous layer was extracted with ethyl acetate. The extracted organic layer was first washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and the solvent was then removed by evaporation under reduced pressure. The residue was subjected to column chromotography (eluent: a 50% v/v solution of ethyl acetate in hexane) to yield 48 mg (80%) of the title compound.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)=O.ClCCl.[NH2:11][C:12]([C:14]1[CH:15]=[C:16]([F:36])[C:17]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:18][C:19]=1[Cl:20])=O>C(N(CC)CC)C>[Cl:20][C:19]1[N:18]=[C:17]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])[C:16]([F:36])=[CH:15][C:14]=1[C:12]#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C(N)=O)cc1F
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Trichloroacetyl chloride (0.55 ml) was added dropwise to a dichloromethane (17 ml) suspension containing tert-butyl cis-2-(5-aminocarbonyl-6-chloro-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.74 g) and triethylamine (1.38 ml) under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 3:1), diisopropylether was added, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.26 g) was thus obtained.
Reaction SMILES: [C:1]1([NH2:9])[N:6]=[C:5]([NH2:7])[N:4]=[C:3]([NH2:8])[N:2]=1.O[P:11](O)(O)=O>O>[N:2]1[C:3]([NH2:8])=[N:4][C:5]([NH2:7])=[N:6][C:1]=1[NH2:9].[P:11]
Reactant: O=P(O)(O)O
Agent: Nc1nc(N)nc(N)n1
Solvent: O
Product: [P]

Procedure:
Melamine polyphosphate and a process for preparing melamine polyphosphate are described, inter alia, in WO 97/44377. According to this reference, melamine polyphosphate having a solubility of 0.01 to 0.10 g per 100 ml water at 25° C., a pH between 2.5 and 4.5, and a melamine/phosphorus molar ratio of between 1.0 and 1.1, may be obtained as a 10 wt % aqueous slurry at 25° C. WO 97/44377 also describes a two-step process for preparing the disclosed melamine polyphosphate slurry. In the first step melamine, urea, and an aqueous orthophosphoric acid solution (containing at least 40 wt % orthophosphoric acid), are mixed to produce a reaction mixture having a melamine/orthophophoric acid molar ratio between 1.0 and 1.5 moles and a urea/orthophophoric acid molar ratio between 0.1 and 1.5 at a temperature between 0 and 140° C. The resulting reaction mixture is then stirred at a temperature between 0 and 140° C. and dehydrated to produce a powdery product comprising a double salt of orthophosphoric acid with melamine and urea. This powdery product is then heated to between 240 and 340° C. and maintained in this temperature range for between 0.1 and 30 hours while preventing agglomeration to obtain melamine polyphosphate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[C:14]([CH3:17])=[CH:15][S:16][C@H:11]12)=[O:8].[Se](=O)=[O:31]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:24])([Cl:25])[Cl:23])=[O:19])[C:14]([CH2:17][OH:31])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=[Se]=O
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)=CS[C@@H]21
Solvent: CCO
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(CO)=CS[C@@H]21
Reaction time: 2 h

Procedure:
To a solution of β,β,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-2-cephem-4-carboxylate (0.94 mg., 2 mmole) in ethanol (10 ml.) is added selenium dioxide (0.111 g., 1 mmole) keeping the reaction temperature at about 25°C. The reaction mixture is stirred for two hours, filtered, diluted with water (30 ml.) and extracted with chloroform. The chloroform extracts are washed successively with water, sodium bicarbonate and water. The solvent is removed under vacuum to afford a residue which is chromatographed on silica gel using chloroform and ethyl acetate to afford substantially pure β,β ,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-hydroxymethyl-2-cephem-4-carboxylate.
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(O)(=O)C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:12][O:11][C:9]([CH:8]1[CH2:7][C:6]([C:19]#[N:20])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][C:3]1=[O:21])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
4-cyano-4-phenylheptanedioic acid dimethyl ester (14.45 g, 0.05 mole) was dissolved in dry tetrahydrofuran (350 ml). Sodium tert-butylate (9.6 g, 0.1 mole) was then added in portions. During this addition the reaction mixture turned an orange colour. The reaction mixture was then boiled under reflux for 5 hours. During the boiling a beige-coloured pasty suspension was formed. The reaction mixture was cooled to room temperature overnight. 2.5N acetic acid (170 ml) was slowly added dropwise to the reaction mixture while cooling with ice. Toluene (100 ml) was then added to the reaction mixture. The organic phase was separated and washed with saturated sodium hydrogen carbonate solution (3×70 ml), water (3×50 ml) and sodium chloride solution (1×70 ml). After drying over Na2SO4, the solvent was distilled off on a rotary evaporator and the residue was recrystallised from methanol. The desired product was obtained in a yield of 10.7 g (83%) as a yellow solid with a melting point of 75°-80° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH:32]([C:34](O)=[O:35])[CH2:31][NH:30]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:34]([CH:32]1[CH2:31][NH:30][C:29](=[O:28])[NH:33]1)=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C1NCC(C(=O)O)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)C3CNC(=O)N3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A solution of 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2, Compound 90) (100 mg, 0.273 mmol), in CH2Cl2:DMF (1:1, 3 mL), then treated with 2-oxo-imidazolidine-4-carboxylic acid (50 mg, 0.321 mmol), followed by the addition of diisopropylethylamine (100 μL, 0.819 mmol) and PyBOP (198 mg, 0.383 mmol). The reaction stirred at room temperature for 8 h. The solution was washed with a saturated aqueous solution of NaHCO3 (10 mL) followed by brine (10 mL). The organic portion was dried over MgSO4, filtered and evaporated to an oil which was purified by reversed phase HPLC to afford product as a colorless solid (39 mg, 30%). LC/MS (Method B) 3.60 min, [M+1]+ 479. Potency class A.