Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:18](Cl)=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:12](Cl)=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:6]=1Cl)([CH3:3])[CH3:2].[Na].Cl>C(O)(C)C.O.C(OCC)C>[CH:9]([O:8][C:7]1[CH:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[CH:18]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=1)([CH3:10])[CH3:11]
Reactant: CC(C)Oc1c(Cl)c(OC(C)C)c(Cl)c(OC(C)C)c1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1cc(OC(C)C)cc(OC(C)C)c1
Yield: 97.9 %

Procedure:
3.55 g (0.01 mol) trichlorophloroglucinol triisopropylether in 100 ml isopropanol were mixed with 5 g sodium. Heating with reflux was continued until all sodium had been dissolved. This was followed by diluting with 100 ml water, neutralizing with hydrochloric acid of 15% by weight, taking up of the organic phase in ethyl ether, drawing off of the ethyl ether and distilling of the residue on a bulb tube (2-3 mbar, airbath temperature 130° to 150° C.). 2.47 g phloroglucinol triisopropylether were obtained, which corresponds to a yield of 98% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:10]=[CH:11]/[C:12]([O:14]CC)=O)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C[O-].[Na+].CO>C(O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]2[NH:1][C:12](=[O:14])[CH:11]=[CH:10][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ncc(OC)nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1cnc2ccc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of 0.85 g of ethyl (2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate in 40 mL of ethanol, 2.20 g of a 28% sodium methoxide/methanol solution was added, and the mixture was heated under reflux while stirring for 7 hours 30 minutes. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and to the resultant residue, water, a saturated aqueous ammonium chloride solution and chloroform were added, the organic layer was separated, and the aqueous layer was added with sodium chloride and extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off and washed with diethyl ether to obtain 0.64 g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[N:62]1([CH2:68][CH2:69][CH2:70][O:71][C:72]2[CH:80]=[CH:79][CH:78]=[C:77]3[C:73]=2[CH2:74][NH:75][CH2:76]3)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([C:26]([CH3:28])=[CH2:27])=[CH:14][C:10]=1[C:11]([N:75]1[CH2:74][C:73]2[C:77](=[CH:78][CH:79]=[CH:80][C:72]=2[O:71][CH2:70][CH2:69][CH2:68][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH2:76]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cc2c(c(OCCCN3CCOCC3)c1)CNC2
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (210 mg, 0.56 mmol) and diisopropylethylamine (0.25 mL, 1.4 mmol) in DCM (5 mL) was treated with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (287 mg, 0.62 mmol). After 1 hour a solution of 4-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindole (0.56 mmol, assuming a quantitative yield from the preceding step (C18)) in DCM (5 mL) was added. After 4 hours the mixture was diluted with ethyl acetate and washed with water, 1N sodium hydroxide solution and brine. The organic phase was dried (MgSO4) and concentrated to give a residue which was absorbed onto an SCX column. This was washed with 10% methanol/DCM then the product was eluted with 25% 2M methanolic ammonia/DCM) to afford an impure sample of the intermediate (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.[CH2:39]([N:41]([CH2:45][CH3:46])[CH2:42][CH2:43]S)[CH3:40]>>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH2:40][CH2:39][N:41]([CH2:45][CH3:46])[CH2:42][CH3:43])=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CCS
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN(CC)CC)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([CH:11]([CH2:15][C:16](Cl)=[O:17])[C:12](Cl)=[O:13])C.[CH3:19][CH2:20][O:21]CC>>[CH2:20]([O:21][C:16]([CH2:15][CH2:11][C:12]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])=[O:13])=[O:17])[CH3:19]
Reactant: CCOCC
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Reactant: ONc1ccccc1
Product: CCOC(=O)CCC(=O)N(O)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of N-phenylhydroxylamine (8 g) in ether (80 ml) at 0° C. was added dropwise over 10 minutes ethyl succinyl chloride (5.76 g). The reaction mixture was allowed to attain room temperature overnight, filtered and the filtrate evaporated to give N-(3-ethoxycarbonylpropionyl)-N-phenylhydroxylamine as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 77.5 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (214 mg, 0.7 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (250 mg, 1.1 mmol) according to the general procedure K. Obtained as a light yellow solid (260 mg).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[I-:18].[Na+].O1CCCC1>CC(C)=O.CCOCC>[I:18][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)CCC/C=C\CI
Reaction time: 0.03 h

Procedure:
To a solution of 31.4 g of cis-7-bromo-5-heptenoic acid, methyl ester in 260 ml of acetone, containing a trace of sodium carbonate was added a solution of 24.7 g of sodium iodide in 260 ml of acetone. A precipitate formed immediately. After 2 minutes, the solution was diluted with 850 ml of ether and filtered. A trace of sodium carbonate was added to the filtrate which was then stripped, redissolved in ether, refiltered, sodium carbonate added and the filtrate stripped, giving 37.9 g of light sensitive product. This product was stored in the cold as a 1M solution in either ether or tetrahydrofuran containing a trace of sodium carbonate and protected from the light. NMR: 5.95-5.2 ppm (2H, m, olefins), 3.85 ppm (2H, d, 7 Hz, ICH2), 3.65 ppm (3H, s, OMe), 2.45-2.0 ppm (4H, m, CH2 --CH2), 1.8 ppm (2H, q, 7 Hz, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH3:10][NH:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][S:12](=[O:14])(=[O:13])[NH:11][CH3:10]
Reactant: COc1ccccc1O
Reactant: CNS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)Oc1ccccc1OC
Yield: 65.8 %

Procedure:
A solution of 12.4 g (0.1 mole) of 2-methoxyphenol (guaiacol; Aldrich) and 13.1 g (0.1 mole) of methylsulfamoyl chloride (Preparation 22) in 150 ml of toluene was stirred and treated at reflux for 2 hr. The solvent was evaporated under reduced pressure and the only residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A, PrepPAK® 500A silica, ethyl acetate-hexanes, 1:2; flow rate 150 ml/min). Fractions containing the product were combined and the solvents evaporated under reduced pressure to yield an oil that solidified upon standing. The solid was recrystallized from benzene-petroleum-ether (30°-60° C.) to give 14.3 g (66%) of the title compound as a white solid, mp 68°-71° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1ncnc2ccsc12
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2ccsc12
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Sodium thiomethoxide (9.1 g) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (WO9849899, example 3A; WO9924440, example 1C) (17.0 g) in DMF (100 mL). After stirring for 90 minutes the mixture was poured into water (400 mL), extracted into EtOAc, washed with water, dried (MgSO4), and the solvent removed. Purification by flash chromatography on silica eluting with DCM:EtOAc (4:1) gave the title compound as a pale yellow solid (16.5 g, 69%);
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1>>[ClH:1].[ClH:1].[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][S:13][CH2:12]3)=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: NC1CCC(Nc2nc(Nc3ccc(OC(F)(F)F)cc3)c3ncn(C4CCSC4)c3n2)CC1
Yield: 92.3 %

Procedure:
The operation is carried out as in Stage 3 of Example 5 starting from 186 mg of the product obtained in Stage 1 above and 513 mg of trans-1,4-diaminocyclohexane, the reaction medium is taken to a temperature of approximately 140 to 145° C. for 4 hours 30 minutes then left to return to ambient temperature. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 and salification with 1.4 N hydrochloric acid in ethanol, separation is carried out, followed by washing with 10 ml of ethanol and drying at a temperature of approximately 50° C. In this way 117 mg of expected product is obtained in the form of pink beige crystals.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](NCC=C)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=O)C.[C:22](OCC)(=S)[C:23](N)=O.CC[OH:32]>>[NH2:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([O:17][CH2:22][CH3:23])=[O:32])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1
Reactant: CCOC(=S)C(N)=O
Reactant: CCO
Reactant: C=CCNC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Product: CCOC(=O)c1nc(-c2sc(N)nc2C)cs1
Temperature: 120 °C

Procedure:
In a microwave tube, 1-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-bromo ethanone, hydrobromide salt (Intermediate 2)(400 mg; 1.27 mmol; 1 eq.) is suspended in EtOH (7 ml). Ethyl thiooxamate (168.6 mg; 1.27 mmol; 1 eq.) is added and the mixture is heated at 120° C. for 15 min under microwave irradiation. The reaction is complete and a precipitate is formed. It is filtered and washed with EtOH, affording ethyl 2′-amino-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylate as its hydrobromide salt (201 mg; 45.3%). It is suspended in DCM/EtOH 2:1 mixture (9 ml) and Amberlyst A-21 (200 mg; 4.54 mmol; 3.58 eq.) is added. The mixture is shaken for 2 h30, filtrated and the solvents are evaporated, affording ethyl 2′-amino-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylate as yellow powder (146.2 mg; 43%). 1H NMR (DMSO-d6, 300 MHz) δ 1.33 (t, J=6 Hz, 3H), 2.32 (s, 3H), 4.38 (q, J=6 Hz, 2H), 7.17 (br s, 2H), 7.82 (s, 1H). M− (ESI): 268.17; M+ (ESI): 270.16. HPLC (method A), Rt: 1.54 min (purity: 99.6%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCNCC2)nc1
Reaction time: 15 h
Yield: 58.3 %

Procedure:
A mixture of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.2 g) in MeOH (50 ml) was hydrogenated over 10% palladium-carbon (1.5 g) under an atmospheric pressure of hydrogen at ambient temperature under stirring for 15 hours. After removal of the catalyst and solvent was evaporated in vacuo and the residue was triturated with AcOEt and IPE. The precipitate was collected by filtration to give methyl 6-(4-piperidylamino)nicotinate (1.77 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:13][CH:14]=[CH:15][C:16]#[N:17])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH:14][O:13][CH2:11][CH3:12])#[N:17]
Reactant: CCOC=CC#N
Reactant: N#Cc1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC=C(C#N)c1cc(F)ccc1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Cn1cc(N)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Temperature: 100 °C
Yield: 98 %

Procedure:
2,6-Dichloro-9-isopropyl-9H-purine (1.16 g, 5 mmol), as prepared in step 1 of Example 1, was mixed with 4-amino-1-methylpyrazole (1.02 g, 10 mmol) and DIPEA (1.74 mL, 10 mmol) in nBuOH (33 mL) and was stirred and heated at 100° C. (block temperature) for 1 hr. The reaction was cooled, and the volatiles were removed under vacuum to give a dark residue. Ethyl acetate (120 mL) was added and the mixture was washed with sat. aq. NaHCO3 (3×30 mL), dried over Na2SO4 and evaporated to give a dark residue. This residue was dissolved in ethyl acetate, passed through a thin pad of silica gel, and eluted with 90% ethyl acetate-10% ammonia (7 N in methanol). The eluent was evaporated to afford the title compound as a dark solid (1.43 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (br. s., 1 H) 8.38 (s, 1 H) 8.00 (s, 1 H) 7.68 (s, 1 H) 4.71 (quin, J=6.72 Hz, 1 H) 3.84 (s, 3 H) 1.52 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C12H14ClN7 292.1 with Cl isotope pattern (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][N:28]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=2)O1.C([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)#N>>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:52]4[CH:57]=[CH:56][C:55]([C:25]5[CH:26]=[N:27][N:28]([C:30]([C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=6)([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)[C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH:29]=5)=[CH:54][CH:53]=4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc4)cc3)[C@H]2C1

Procedure:
The title compound was prepared according to the procedure described in Example 7D, substituting the product of Example 41A for the product of Example 7C and substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole for 4-cyanophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.96 (s, 1H) 7.63 (s, 1H) 7.42-7.54 (m, 6H) 7.29-7.37 (m, 9H) 7.17-7.24 (m, 6H) 6.64 (d, J=8.82 Hz, 2H) 4.11-4.23 (m, 1H) 3.49-3.61 (m, 1H) 3.23-3.35 (m, 1H) 2.91-3.03 (m, 1H) 2.66-2.78 (m, 1H) 2.51-2.66 (m, 3H) 2.33 (s, 3H) 2.12-2.24 (m, 1H) 1.92-2.01 (m, 1H). MS: (M+H)+=586.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C:17](=O)[C:16](=[O:19])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].Cl.[NH2:21][OH:22].N1C=CC=CC=1.C(Cl)Cl>CN(C)C=O>[OH:22][N:21]=[C:17]1[C:16](=[O:19])[N:6]2[C:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])=[C:2]([CH3:1])[CH2:3][S:4][C@H:5]12
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=NO)[C@H]2SC1
Yield: 79.2 %

Procedure:
In dimethylformamide (5 ml) are dissolved 2,2,2-trichloroethyl 3-methyl-7-oxo-3-cephem-4-carboxylate (691 mg) and hydroxylamine hydrochloride (139 mg), followed by addition of pyridine (162 μl) and methylene chloride (10 ml). The mixture is refluxed in a Dean-Stark trap packed with Molecular Sieve 3A for 45 minutes. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The resultant solution is washed with water and aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is subjected to silica gel (20 g) column chromatography and elution is carried out with 5-13% ethyl acetatehexane to give 2,2,2-trichloroethyl 7-hydroxyimino-3-methyl-3-cephem-4-carboxylate as an oil (570 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: COc1cccc(N)c1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: COc1cccc(N)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 78 %

Procedure:
Starting from 2-amino-6-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (170 mg; 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14]Br)[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1.[C-:18]#[N:19].[K+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14][C:18]#[N:19])[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)OCC2(CBr)CC2)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)OCC2(CC#N)CC2)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 17.8 %

Procedure:
261 mg of compound 10a was dissolved in 5 ml ethanol. A solution of 98 mg potassium cyanide in 5 ml water was added and the mixture was stirred at 35° C. for two days. 10 ml of a saturated aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The combined extracts were dried with sodium sulfate and evaporated to give a yellow liquid. Purification with column chromatography (heptane/ethyl acetate 3/1) gave the title compound (38 mg) confirmed by NMR and LC/MS.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[CH3:11][NH:12][CH3:13].N1CCC[CH2:15]1>>[CH3:11][N:12]([CH3:15])[CH2:13][C:9]#[C:8][CH2:7][N:4]1[CH:5]=[CH:6][N:2]([CH3:1])[C:3]1=[O:10]
Reactant: C1CCNC1
Reactant: CNC
Reactant: C#CCN1CCN(C)C1=O
Product: CN(C)CC#CCn1ccn(C)c1=O

Procedure:
This product, a liquid, was prepared according to Example 1, Part B by substituting 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-imidazol-2-one for 1-methyl-3-(2-propynyl)-2-imidazolidinone and dimethylamine for pyrrolidine.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:16]([NH:17][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CO
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-octene oxide (42 g.) and hexamethylenediamine (19.05 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (I: R = CH3 (CH2)5, R' = H, X = (CH2)6Z = H) (17.2 g., m.p. 124.0°-127.4° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19]([NH:6][CH:4]1[CH2:5][N:2]([CH3:1])[CH2:3]1)=[O:20]
Reactant: CN1CC(N)C1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 1-methylazetidin-3-amine (1 equiv) in dry DCM (0.13 M) was added triethylamine (1.8 equiv). A solution of 3-methoxy-4-nitrobenzoyl chloride (0.91 equiv) in dry DCM was added and the reaction was stirred at room temperature for 5 min. The mixture was then concentrated and purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound (46.4% yield) as a yellow solid. MS (ESI) m/z 266.1 [M+H]+.