Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12](O)=[O:13])[CH2:6]2.B.O>C1COCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][OH:13])[CH2:6]2
Reactant: O=C(O)C1Cc2ccc(C(F)(F)F)cc2C1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
The above 5-trifluoromethyl-indan-2-carboxylic acid (1.03 g, 4.47 mmol) was dissolved in THF (25 mL) and cooled to 0° C. To this solution was added a solution of borane in THF (1M, 6.5 mL). The mixture was warmed to room temperature and stirred for 1 hr. The mixture was treated with water (5 mL) and solvents were evaporated. The residue was extracted with ether and hydrochloric acid (1M). The organic phase was washed with brine and sodium bicarbonate solution. The ether solution was dried and solvents were evaporated to give oily material as 5-trifluoromethyl-indan-2-yl-methanol (0.98 g).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.I[C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: COC(=O)c1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-n1c2ccccc2c2cnccc21
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A mixture of 16.8 g (100 mmol) of 5H-pyrido[4,3-b]indole [244-69-9], 28.8 g (110 mmol) of methyl 2-iodobenzoate [610-97-9], 34.6 g (250 mmol) of potassium carbonate, 6.4 g (100 mmol) of copper powder and 100 g of glass beads (diameter 3 mm) in 300 ml of DMF is stirred at 130° C. for 24 h. After cooling, the mixture is filtered through a short Celite bed, the bed is rinsed with DMF, and the latter is removed in vacuo. The residue is dissolved in 500 ml of dichloromethane, and the solution is washed three times with 200 ml of 0.5 N sodium hydroxide solution each time and dried over magnesium sulfate. After removal of the dichloromethane in vacuo, the residue is recrystallised once from ethyl acetate and dried in vacuo (p=0.1 mbar, T=60° C.). Yield: 19.3 g (64 mmol), 64%; purity: 97% (1H-NMR).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[N:7]([CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CN(C)C=O>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[N:7]([CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1
Reactant: CN(C)CCCl
Reactant: COCn1c(=O)c2cccnc2c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCn1c(=O)c2cccnc2c2ccc(OCCN(C)C)cc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
8-hydroxy-6-(methoxymethyl)benzo[h][1,6]naphthyridine-5(6H)-one (58 mg, 0.22 mmol) and potassium carbonate (94 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (5 ml) and added with 2-(dimethylamino)ethyl chloride (39 mg, 0.0.27 mmol). The resulting mixture was stirred for 2 hours at 90° C. and poured into ice water. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=6:1) to obtain the title compound (53 mg, yield: 73%, white solid).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:4]=1.C(=O)(O)[O-].[Na+].N#N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:2][N:3]1[CH:8]=[CH:7][CH2:6][C:5]([C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4]1
Reactant: C[n+]1cccc(C(=O)NCCc2ccc(O)cc2)c1
Agent: N#N
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: CN1C=CCC(C(=O)NCCc2ccc(O)cc2)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 1.15 g (3 mmol) of the product of Example 27 in 200 ml of deaerated water, 1.5 g (18 mmol) sodium bicarbonate were added. While the mixture was bubbled with N2 gas, 2.09 g (12 mmol) of sodium dithionite were gradually added to the mixture. The mixture was stirred under N2 for 1 hr and then extracted twice, each with 100 ml of ethyl acetate. The combined extract was washed with water, dried over anhydrous Na2SO4 and distilled on rotovap. Yield, 0.38 g (50%) of yellowish semisolid which reduced alcoholic AgNO3TS instantaneously. (PMR as expected.)
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[N:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:29][C:30]1[C:31](F)=[C:32]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][C:32]([N+:36]([O-:38])=[O:37])=[CH:31][C:30]=1[F:29]
Reactant: O=c1cc[nH]c(N=C(c2ccccc2)c2ccccc2)c1Cl
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a reactor was added 24 g of 3-chloro-2-(diphenylmethyleneamino) pyridin-4(1H)-one, DMF (100 mL), cesium carbonate (12.7 g; 0.5 eq) and difluoronitrobenzene (9.3 mL; 1.1 eq). The reaction mixture was heated to 95° C. and stirred for three hours. After the reaction was complete, the reaction mixture was poured onto crushed ice and the solids were filtered off and washed with water. The crude solids were charged back to the reactor and dissolved in THF (200 mL). Methanol was added and the mixture was distilled at a constant volume of 350 mL, until THF had been azeotropically removed. Additional methanol (100 mL) was added and the suspension was cooled to room temperature. The solids were filtered and dried under vacuum to yield 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy) pyridin-2-amine (23.3 g; 67% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[CH:14]([NH:16][CH2:17][C:18]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:19])=[O:15]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=CNCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)CNC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Diethyl 2-aminomalonate hydrochloride (4.2 g), formylglycine (2.3 g) and 1-hydroxybenzotriazole (2.7 g) are dissolved in dimethylformamide (50 ml). To the solution are added N,N'-dicyclohexylcarbodiimide (4.33 g) and triethylamine (2.12 g) at 0° to 5° C. The mixture is stirred at the same temperature for 2 hours and at room temperature for 15 hours. The reaction mixture is concentrated under reduced pressure. To the residue is added ethyl acetate, and the mixture is filtered to remove insoluble materials. The filtrate is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography [solvent; chloroform-ethyl acetate (1:5)]to give diethyl 2-[(N-formylglycyl)amino]malonate (4.1 g), m.p. 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:4][N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][CH2:13][C:12]2[CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=[CH:10][C:11]=2[F:16])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1cc(-c2ccnc(Cl)n2)ccc1F
Product: CC(C)(C)OC(=O)N1CCC(NCc2cc(-c3ccnc(Cl)n3)ccc2F)CC1

Procedure:
Intermediate 89 was coupled with 4-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product was >95% pure and had the expected M+H+ of 421.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[C:17]([C:40]2[N:44]=[CH:43][NH:42][N:41]=2)=[C:18]([NH:21][C:22](=[O:39])[CH2:23][N:24]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[S:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:64][N:65]([CH3:70])[CH2:66][CH2:67][CH2:68]O>O1CCCC1>[Cl:15][C:16]1[C:17]([C:40]2[N:44]=[CH:43][N:42]([CH2:68][CH2:67][CH2:66][N:65]([CH3:70])[CH3:64])[N:41]=2)=[C:18]([NH:21][C:22](=[O:39])[CH2:23][N:24]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[S:19][CH:20]=1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)n1
Reaction time: 2 h

Procedure:
Diisopropyl azodicarboxylate (0.30 ml, 1.52 mmol) was added dropwise to a heterogeneous mixture of N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (111 mg, 245 umol), polymer supported triphenylphosphine (500 mg, 1.50 mmol), and 3-(dimethylamino)propan-1-ol (300 mg, 2.91 mmol) in tetrahydrofuran (5 ml) at 0° C. After stirring for 2 h, the heterogeneous mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by HPLC to yield N-(4-chloro-3-(1-(3-(dimethylamino)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.33 min by HPLC (M+=539 and 541). 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7, 1H), 7.18 (s, 1H), 6.87 (d, J=9.6 Hz, 1H), 5.32 (s, 2H), 4.31 (t, J=6.6 Hz, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.75 (s, 6H), 2.17 (m, 2H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>C(OCC)(=O)C>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)c1ncccc1NC(=O)C(C)CSC(C)=O
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1NC(=O)C(C)CS

Procedure:
Following the procedure of Example 2, but substituting an equivalent amount of methyl 3-(2-acetylthiomethyl-propionamido)-picolinate, obtained as disclosed in Example 24, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate and using ethyl acetate as eluent for the chromatography column, methyl 3-(2-mercaptomethyl-propionamido)-picolinate is obtained; m.p. 55°-56° C., from petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15].N1C=CC=CC=1>CN(C=O)C>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:15]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
To a solution of 5-aminoindan (4.66 g, 35.0 mmol) in anhydrous DMF (26 ml) was slowly added methoxyacetyl chloride (5.70 g, 52.50 mmol) followed by pyridine (8.5 ml, 105.0 mmol). The red solution was stirred at room temperature for 3.5 hours under argon, then it was partitioned between ethyl acetate (200 ml) and 1N HCl (120 ml). The organic layer was washed with more 1N HCl (120 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with diethyl ether; the white precipitate was collected by filtration, washed with diethyl ether to afford the title compound (5.93 g, 83%), m.p. 104-105° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.06 (m, 2H, 2-CH2), 2.87 (m, 4H, 1-CH2 and 3-CH2), 3.50 (s, 3H, OCH3), 4.00 (s, 2H, 2-CH2OMe), 7.22 (m (overlap with CHCl3 peak), 2H, 6-H, 7-H), 7.52 (s, 1H, 4-H), 8.18 (s, 1H, CONH); MS (ESI, m/z): 432 [(2M+Na)+, 30%], 206[(M+H)+, 100%]. Found C, 70.10; H, 7.38; N, 6.81; C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:19]([S:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
K2CO3 (1.23 g, 8.92 mmol) was added to a mixture of methyl 4-sulfanylbenzoate (1.00 g, 5.95 mmol), 1-bromo-2-methyl-propane (970 μL, 8.92 mmol), and DMF (10 mL) at rt. The mixture was allowed to stir for 4 h at rt before the solids were filtered off. The solids were washed with ethyl acetate, and then were discarded. The combined filtrates were partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl 4-(isobutylthio)benzoate (82%) as a clear oil. ESI-MS m/z calc. 224.1, found 225.2 (M+1)+. Retention time: 1.59 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Na+].C(O)C.S(O[CH:46]([CH3:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48])(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:52])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C-:27]#[N:28].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][CH:21]=2)(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: [C-]#N
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(S(=O)(=O)c2ccc(CCc3ccc(F)cc3F)cc2)cc1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
2,4-Difluoro-1-(2-{4-[(4-fluorophenyl)sulfonyl]phenyl}ethyl)benzene (Example 122, 20 mg, 0.053 mmol) was dissolved in dimethylsulfoxide (0.1 mL) and sodium cyanide (5.2 mg, 0.106 mmol) was added. The reaction was heated to 100° C. overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield the title compound as a white solid (7 mg, 36%) δH (400 MHz, d6 DMSO): 8.10-8.07 (4H, m), 7.89 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz), 7.29 (1H, q, J=7.6 Hz), 7.14-7.10 (1H, m), 6.98-6.94 (1H, m), 2.94-2.86 (4H, m).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCCC2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])[CH:2]=[CH2:3].[Cl-].[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:13]
Reactant: ClCCCBr
Reactant: C=CCn1c(=O)[nH]c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCn1c(=O)n(CCCCl)c2ccccc21
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred and heated mixture of 17.5 parts of 1,3-dihydro-1-(2-propenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminimum chloride and 150 parts of a sodium hydroxide solution 60% are added dropwise 20.5 parts of 1-bromo-3-chloropropane at 60° C. Upon completion, stirring at 60° C is continued for 5 hours. The reaction mixture is cooled, water is added and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 21 parts (84%) of 1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+:20].Cl.ClCC([NH:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/[C:33](Cl)=[O:34])[N:31]=1)=O.Cl.CNC(=S)[S-].[Na+]>C(OCC)(=O)C.O.C1COCC1>[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/[C:33]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]23)=[O:34])[N:31]=1.[Na+:20]
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: CNC(=S)[S-]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Yield: 55.1 %

Procedure:
In 500 ml of a (1:1) mixture of water and THF was suspended 11.9 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid, and 19.4 g of sodium hydrogencarbonate was added under ice-cooling and stirring. To the suspension was added 20.6 g of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride, followed by stirring for 30 minutes. The reaction mixture was shaken with 100 ml of water and 150 ml of ethyl acetate. The aqueous layer was taken and adjusted to pH 7.0 with 1N-hydrochloric acid under ice-cooling and stirring. To the mixture was gradually added 12.0 g of sodium N-methyldithiocarbamate at room temperature under stirring to remove the amino group. After shaking with 200 ml of ethyl acetate, the aqueous layer was taken and concentrated to 50 ml under reduced pressure. The residue was subjected to a column chromatography on XAD-II (1.2l) eluting with water. The fractions containing the objective compound were collected, concentrated under reduced pressure, and then lyophilized to give 12.4 g of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate as pale yellow powders.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:20][CH:21]([CH3:24])[CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:20][CH:21]([CH3:24])[CH2:22][N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CN1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added 2-methylpropanal (17 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E16). MS (ES+) m/e 313 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.Cl>CCOCC>[ClH:1].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:15][CH2:14]1
Reactant: OCc1cnc2ccc(Cl)nn12
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: OCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 65 %

Procedure:
Prepared from (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (7) and and 3-morpholinopropylamine according to general procedure 4 (StepB). The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (174 mg, 65%) as a yellow solid; 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=9.7 Hz, 1H), 7.63 (s, 1H), 6.98 (d, J=9.7 Hz, 1H), 4.89 (s, 2H), 3.93-3.91 (m, 4H), 3.55-3.52 (t, J=6.6 Hz, 2H), 3.34-3.25 (m, 6H), 2.22-2.16 (m, 2H); 13C NMR 75 MHz, CD3OD) δ 156.3, 135.7, 130.7, 124.7, 123.5, 118.0, 65.1, 56.7, 53.5, 53.3, 39.6, 24.3; HPLC tR=7.4 min (Synergi), 98.9%; ES-MS: (M+H)=292 m/z.