Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:41]2[CH2:42][CH2:43][C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3ccccc3C2)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
A 2 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (60.0 μmol) was added to 1,2,3,4-tetrahydroisoquinoline (9.59 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (150 μL, 5 eq) and the reaction was stirred at room temperature for 60 hr. Some of the deprotections were incomplete so 2-3 drops of concentrated hydrochloric acid was added to these and they were stirred for another 24 hr. The ether and hydrochloric acid were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 42.9% yield. LCMS m/z (%)=392 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (t, J=5-81 Hz, 2 H), 3.09-3.17 (m, 2 H), 3.69 (t, J=5.6 Hz, 2 H), 3.69 (s, 3 H), 4.12 (t, J=5.56 Hz, 2 H), 4.63 (s, 2 H), 6.32 (d, J=2.02 Hz, 1 H), 7.13 (d, J=9.09 Hz, 1 H), 7.19 (s, 3H), 7.43 (d, J=2.53 Hz, 1 H), 7.47 (d, J=1.52 Hz, 1 H), 7.57 (dd, J=9.09, 3.03 Hz, 1 H), 7.87 (s, 2 H), 8.60 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([I:28])[CH:30]=4)[C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN[C@@H](C)C2
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(Cc1cccc(I)c1)[C@@H](C)C2
Reaction time: 8 h

Procedure:
(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (250 mg, 0.86 mmol) from step 2 above was dissolved in DMSO (8.0 mL). The flask was charged with K2CO3 (594 mg, 4.30 mmol) and 3-iodo-benzylbromide (255 mg, 0.86 mmol). The mixture was then sealed with a septum and placed in 50° C. oil bath and allowed to stir overnight. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic layers were washed with aqueous LiCl (three times), followed by brine and then dried over Na2SO4. Solvent removal under reduced pressure gave crude product. Purification over silica via automated flash chromatography (0 to 20% MeOH/CH2Cl2 over 20 min.) gave after solvent removal the product as a white solid: LCMS [M+H]=507.3
Reaction SMILES: [CH3:1][C:2]([NH2:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7][N:6]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(O)(=O)C.C(Cl)Cl.C(Cl)Cl>[CH3:18][S:17]([C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH2:20])([CH3:1])[CH3:19])=[N:6][CH:7]=2)[CH:16]=[CH:15][N:14]=1)=[O:29]
Reactant: CSc1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)c1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1

Procedure:
1,1-Dimethyl-3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-2-yl]-prop-2-ynylamine (500 mg, 1.76 mmol) in acetic acid/DCM (2.6 ml/8.8 ml) was treated at 0° C. with mCPBA (content 70%, 455 mg, 2.64 mmol) for 10 minutes. The reaction mixture was diluted with DCM and washed with 2N-solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered, evaporated to give the title compound as brownish crystals. Yield: 500 mg (98%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[F:20][C:21]([F:29])([F:28])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([C:21]([F:29])([F:28])[F:20])[CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: FC(F)(F)C1CCCNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCCC(C(F)(F)F)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (±)-3-trifluoromethylpiperidine hydrochloride by the method described in Example 41. Colorless solid (123 mg, 82%). 1H NMR (CDCl3) 1.53-1.76 (m, br, 2H), 1.84-1.95 (m, br, 1H), 2.10-2.22 (m, br, 1H), 2.31-2.43 (m, br, 4H), 2.92-3.16 (m, br, 2H), 4.28-4.45 (m, br, 1H), 4.54-4.72 (m, br, 1H), 7.34 (d, J=4.0, 1H), 7.47 (d, J=4.0, 1H). 13C NMR 7.7, 23.5, 24.2, 40.5 (q, J=27), 44.0 (br), 46.3 (br) 114.5 (q, J=2), 118.5 (q, J=271), 126.1 (q, J=283), 127.8, 129.1, 131.4, 139.3, 155.0 (q, J=41), 157.6, 162.8. 19F NMR −72.8, −63.2. LC/MS 6.99 min, [M+1]+ 413.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:15][C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]#[N:17])[CH2:12][CH2:13]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(CCN2CCNCC2)cn1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(CCn2ccnc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-Imidazol-1-yl-ethyl)-piperazine (commercially available from CHESS GmbH) (1.0 g, 5.44 mmol), bromoacetonitrile (740 mg, 6.0 mmol) and K2CO3 (1.65 g, 12.0 mmol) in CH3CN (15 mL) is stirred at RT. After completion the product is isolated by filtration with Celite and washed with CH3CN and dried under reduced pressure to give the title compound as oil; ES-MS: M+H=220.2: CtRet=1.70.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:42])([F:41])[C:25]1[C:29]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:42][C:24]([F:23])([F:41])[C:25]1[C:29]2[CH2:30][NH:31][CH2:32][CH2:33][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(F)(F)F)c2C1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCNC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added tert-butyl 3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was treated with 1:1 TFA/DCM (2 mL) for 2 h before being concentrated to dryness. Purification by preparative basic HPLC gave (R)—N-(5-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.3 mg, 5.2 μmol, 6.1%). MS (ESI): m/z [M+H]+ 443.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].[H-].[Na+].[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[N:17]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:16](=[O:20])[NH:15]2)[C:7]1=[O:21]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12

Procedure:
A solution of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (3.76 g.) in dry N,N-dimethylformamide (50 ml.) was stirred during the addition of sodium hydride (0.50 g.) [50% w/w dispersion in oil]. When the addition was complete, the solution was stirred until effervescence had ceased (about 1 hour). Chloromethyl pivalate (1.55 g.) was then added. The mixture was stirred for 18 hours and then poured into water (200 ml.). The aqueous mixture was carefully acidified by addition of concentrated hydrochloric acid and the precipitated material has extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×100 ml.) and then with brine (1×150 ml.), dried (MgSO4) and evaporated. The oil obtained was dissolved in ethyl acetate (100 ml.) and silica gel (10 g., type 7734 available from E. Merck Darmstadt, West Germany) was added. The mixture was evaporated and the residue was added to the top of a column of silica gel (150 g. Merck type 7734) made up in toluene. Elution with an increasing gradient of ethyl acetate in toluene with analysis by thin layer chromatography (SiO2 :50% ethyl acetate/toluene) of the fractions of eluate and combination and evaporation of those containing the major component (relative flow value: 0.6) gave 1'-(3,4-dichlorobenzyl)-1-pivaloyloxymethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione as a white solid (1.3 g.), m.p. 209°-211° C., after recrystallisation from a mixture of ethyl acetate and 60-80 petrol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=2[N:17]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH:16]=1.[C:31]([C:33](=[CH:37][CH:38]1[CH2:40][CH2:39]1)[C:34](O)=[O:35])#[N:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:24][C:22]1[C:23]2[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])=[CH:16][N:17]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34]([C:33](=[CH:37][CH:38]3[CH2:40][CH2:39]3)[C:31]#[N:32])=[O:35])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: N#CC(=CC1CC1)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)cn2CC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC(=CC1CC1)C(=O)N1CCCC1Cn1cc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
To a mixture of 5-(2-fluoro-4-phenoxy-phenyl)-7-pyrrolidin-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (100 mg, 0.25 mmol, 1.0 eq), 2-cyano-3-cyclopropyl-acrylic acid (42 mg, 0.3 mmol, 1.2 eq) and DIEA (97 mg, 0.75 mmol, 3.0 eq) in 10 ml of DCM was added HATU (145 mg, 0.38 mmol, 1.5 eq). The mixture was stirred for 4 h at RT under N2. LCMS showed the reaction was completed. The reaction mixture was concentrated and purified by Pre-TLC to provide 71 mg (54%) of the title compound. LCMS: m/z 523.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6): δ 0.866˜0.920 (m, 2H), 1.177˜1.194 (m, 2H), 1.569 (m, 1H), 1.721 (m, 2H), 1.883 (m, 2H), 3.200 (m, 2H), 3.511 (m, 1H), 4.360˜4.475 (m, 2H), 6.125 (m, 2H), 6.642˜6.664 (m, 1H), 6.898˜6.920 (m, 1H), 6.977˜7.010 (m, 1H), 7.150˜7.232 (m, 4H), 7.371˜7.471 (m, 3H) and 8.131 (m, 1H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)C1
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)C1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl 3-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate (3.70 g, 12.0 mmol) and dimethylaniline (4.0 mL, 30 mml) was added phosphoryl trichloride (40 mL). The mixture was heated at 50° C. for 5 h and concentrated in vacuo. The residue was diluted with methylene chloride (100 mL) and quenched with saturated NaHCO3 (100 mL). The mixture was separated and the aqueous layer was extracted with chloride (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1). LC/MS RT=2.09 min (5 min method). Mass calculated for, M+H 322.12, observed 337.14.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.CNCCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O[N:37]=[C:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O>[N:1]1([C:6]2[CH:14]=[C:10]([C:11]3[O:13][N:45]=[C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[N:37]=3)[CH:9]=[N:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=C(O)c1cncc(-n2cccc2)c1
Reactant: NC(=NO)c1cccnc1
Agent: CCN=C=NCCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: c1cncc(-c2noc(-c3cncc(-n4cccc4)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-(1H-pyrrol-1-yl)nicotinic acid (Maybridge, 188 mg, 1.00 mmol) in dimethylformamide (anhydrous, 5 mL) was added N-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (Aldrich, 192 mg, 1.00 mmol) and 1-hydroxybenzotriazole (HOBT) hydrate (Fluka, 153 mg, 1.00 mmol). The mixture was stirred at ambient temperature for 20 minutes. N′-Hydroxynicotinimidamide (137 mg, 1.0 mmol) was added and the mixture was stirred for 6-10 hours, and then warmed to 140° C. for 2-4 hours. The reaction was cooled to ambient temperature and triturated with water (10 mL). The precipitate was filtered and dried under vacuum to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 6.34-6.44 (m, 2H), 7.60-7.82 (m, 3H), 8.50 (dt, J=8.1, 1.9 Hz, 1H), 8.71 (dd, J=2.5, 1.9 Hz, 1H), 8.84 (dd, J=4.6, 1.5 Hz, 1H), 9.21 (d, J=1.7 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 290 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[NH:3]1.[OH-].[NH4+:18]>>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([NH2:18])(=[O:15])=[O:14])[CH:8]=2)[NH:3]1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A suspension of 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 40 ml of 25% ammonium hydroxide is stirred at room temperature for 6 hours. Then it is filtered, the separated material is washed with water and acetone, filtered, dried, dissolved in a slight amount of hot dimethyl sulfoxide, and the product is precipitated from the solution by adding a slight amount of 2-propanol to it. Thus 0.70 g (15%) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide is obtained, m.p.: >360° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](Cl)=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[N:15][N:14]2[CH:23]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH3:34])([C:30]([O:32][CH3:33])=[O:31])[C:26]1([CH3:36])[CH3:35]>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([NH:24][C@@H:25]3[CH2:29][CH2:28][C@:27]([CH3:34])([C:30]([O:32][CH3:33])=[O:31])[C:26]3([CH3:36])[CH3:35])=[C:17]([C:20](=[O:21])[NH2:22])[CH:16]=[N:15][N:14]2[CH:23]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](N)C1(C)C
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Hunig's base (1.27 mL, 7.29 mmol) was added to a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 625 mg, 2.277 mmol) and (1S,3R)-methyl 3-amino-1,2,2-trimethylcyclopentanecarboxylate (464 mg, 2.505 mmol) in NMP (5692 n1). The reaction was heated at 90° C. for 14 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water (3×10 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure to give a light yellow oil. The crude product was chromatographed on the silica gel column eluted with 0-50% ethyl acetate in hexane to afford the title compound (583 mg, 1.308 mmol, 57.5% yield) as a white solid. LC/MS found [M+H]+=425.1. 1H NMR (400 MHz, MeOD) δ ppm 8.13 (1 H, s), 7.60-7.66 (1 H, m), 6.88-6.95 (1 H, m), 4.43-4.52 (1 H, m), 3.71 (3 H, s), 2.62-2.71 (1 H, m), 2.31-2.39 (1 H, m), 1.65-1.76 (1 H, m), 1.55-1.64 (1 H, m), 1.32 (3 H, s), 1.09 (3 H, s), 0.98 (3 H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21]C(C(C)(C)C)=O)[CH:17]=[CH:16][C:15]=3[Cl:28])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[ClH:31]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:30]([Cl:31])=[CH:29][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH2:21])[CH:17]=[CH:16][C:15]=3[Cl:28])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1ccc2nc(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2c1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Reaction time: 8 h

Procedure:
A mixture of 1.15 g (2.4 mmol) Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-benzimidazole-5-carboxylate and 10 ml 4M HCl in Dioxane was stirred overnight. The reaction mixture was concentrated under reduced pressure to give the sub-title compound. Yield: 1.0 g (100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([O:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:32]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[C@H:15]([OH:40])[CH2:14][N:13]([O:41][CH:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12]
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)ON(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To an ice cold solution of tert-Butyl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-[4-(benzyloxy)benzyl]-2-hydroxypropylcarbamate (1.5 g, 2.3 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (10 mL). After stirring at 5° C. for 3 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (80 mL), washed with saturated sodium bicarbonate (2×50 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (1.27 g, quant.) as an off-white foam. 1H NMR (DMSO-d6): δ 0.77 (6H, dt), 1.07-1.72 (4H, m), 1.82 (2H, br), 2.28 (1H, t), 2.58-3.05 (4H, m), 3.43-3.53 (1H, m), 3.95-4.03 (1H, m), 4.86 (1H, br s), 5.01 (2H, s), 6.16 (2H, s), 6,86 (2H, d), 7.03 (2H, d), 7.12-7.40 (8H, m);
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29].[OH-].[Na+]>C(Cl)Cl>[CH3:3][C:4]1[N:9]=[C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][N:13]([S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1.[CH2:27]([S:30]([N:13]1[CH2:12][CH2:11][CH:10]([C:16]#[N:17])[CH2:15][CH2:14]1)(=[O:32])=[O:31])[CH2:28][CH3:29]
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1cccc(C2(C#N)CCNCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(C#N)(c2cccc(C)n2)CC1
Product: CCCS(=O)(=O)N1CCC(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(6-methylpyridin-2-yl)piperidine-4-carbonitrile dihydrochloride (II-3) (2.74 g, 10 mmole) in DCM (60 mL) containing DIEA (5.16 g, 40 mmole) was added n-C3H7SO2Cl (1.57 g, 11 mmole) at 0° C. The resultant reaction mixture was stirred for 2 h at 0° C. After this time, LCMS indicated that the reaction was completion. 2N NaOH (30 mL) was added to the reaction. The resultant reaction mixture was stirred for 2 h at rt. After this time, the DCM layer was separated. The aqueous solution was extracted with DCM (3×80 mL). The combined DCM solution was washed with brine, dried over MgSO4, filtered and concentrated to afford the desired product 4-6-methylpyridin-2-yl)-1-(propylsulfonyl)piperidine-4-carbonitrile (II-4A). Analytical LCMS: single peak (214 nm), 2.967 min. This product was used in next step reaction without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([C:22](=[N:30][O:31][CH3:32])[CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:22]([C:19]([OH:21])=[O:20])=[N:30][O:31][CH3:32])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CON=C(Cn1nnnc1S)C(=O)O
Agent: FB(F)F
Agent: N
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (0.99 g) and 1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazole-5-thiol (0.95 g) in dry acetonitrile (10 ml) was added boron trifluoride etherate (1.55 g) and the resulting solution was stirred at 50° C. for 2 hours. Water (10 ml) was added to the reaction mixture and the solution was adjusted to pH 3.5 with conc. aqueous ammonia under ice-cooling to give precipitates which were filtered, washed with water and dried to give 7-amino-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.0 g), mp 170° to 180° C. (dec.).