Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(OCC)(=O)C.CCCCCC>[N:21]([CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CN=[N+]=[N-])C2
Yield: 81.1 %

Procedure:
Using 2-bromomethyl-2,5,8,8-tetramethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.28 g, 3.78 mmol) and sodium azide (1.96 g, 30.1 mmol), the procedure of Example 300 was followed (reaction, post-treatment, and recrystallization from ethyl acetate-hexane) to obtain 921 mg of the title compound as colorless needles (81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(c4ccc(N)cn4)CC3)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(N2CCC(COc3ccc4c(c3)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC4)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-[1-(5-aminopyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.017 ml) and pyridine (0.017 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=2:1). The obtained residue was dissolved in methanol and treated with active charcoal, and dried under reduced pressure to give the title compound (75 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:38][CH:37]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)cc1
Yield: 53.9 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxybenzylamine (0.27 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 53%) as a white solid. MS (ISP) 590.2 [(M+H)+]; mp 126° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CS(C)=O>[N:1]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cn2ccccc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
2-aminopyridine (500 mg, 5.31 mmol) and ethyl chloroacetoacetate (870 mg, 5.31 mmol) were dissolved in DMSO and heated to 100° C. for 1 h under inert atmosphere. After 1 h, water added to reaction mixture followed by Work-up (H2O/AcOEt) and purification on 60-120 mesh silicagel using AcOEt and petroleum ether (30:70) gave the title compound (110 mg) as a brown liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.06 (d, J 6.7, 1H), 7.59 (s, 1H), 7.55 (d, J 9.4, 1H), 7.14 (t, J 7.9, 1H), 6.75 (t, J 6.7, 1H), 4.12 (q, J 7.1, 2H), 3.87 (s, 2H), 1.3 (t, J 7.1, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:49][Cl:50]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:49][Cl:50])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)O)cc1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid (2.0 g, 5.0 mmole) in 1,4-dioxane (20 ml) was added a 40% solution of tetrabutylammonium hydroxide (3.1 g, 4.75 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and coevaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (10 ml) and iodochloromethane (13.2 g, 75 mmole) was added The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 50 ml ethyl acetate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.5 g=23%
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)cc1C
Yield: 34.7 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (5.0 g, 0.019 mol) and 4-methoxy-2-methylaniline (3.0 g, 0.022 mol) were heated under reflux in 1,4-dioxan (50 ml) for 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium bicarbonate solution, water and brine. The solution was dried and evaporated to an oil, which crystallised on standing. The crystals were triturated with ether and recrytallised from ethyl acetate to give 3-butyryl-4-(4- methoxy-2-methylphenylamino)-8-methoxyquinoline (2.4 g, 34.8%), m.p. 161°-3°.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C(O)C>[O:30]=[S:29]1(=[O:31])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:4]([C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]3[CH:18]=[CH:19][CH:20]=[C:8]3[C:7]=2[OH:21])=[N:32]1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccn21
Temperature: 180 °C
Yield: 50 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-benzenesulfonamide (0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.3 mL) and heated to 110° C. for 20 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The solid was washed with methanol and dried in vacuo to afford the desired product, 3-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-4-hydroxy-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.07 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.97 (6H, d, J=6.4 Hz), 1.28 (2H, bs), 1.61 (2H, q, J1=15.2 Hz, J2=6.8 Hz), 1.74 (1H, m), 4.43 (2H, t, J=8.0 Hz), 6.71 (1H, dd, J1=4.4 Hz, J2=2.4 Hz), 7.04 (1H, d, J=4.4 Hz), 7.23 (1H, t, J=8.0 Hz), 7.50 (1H, t, J=7.6 Hz), 7.63 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.0 Hz), 7.90 (1H, m); LC-MS (ESI) calcd for C19H20N4O4S 400.45. found 401.28 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=1[N:46]=[C:47]=[O:48]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:47]([NH:46][C:40]2[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:39]=2[F:38])=[O:48])[CH:32]=1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cc(C)ccc3F)c2)c1
Yield: 93.8 %

Procedure:
The reaction solution of dimethyl 5,5′-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate (140 mg, 0.265 mmol, 1.0 equiv.) and 2-fluoro-5-methylphenyl isocyanate (38.8 μL, 0.292 mmol, 1.1 equiv.) in DMF (3 mL) was stirred at room temperature for 3 hours. It was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:5 to 5:1) yielding the title compound as clear oil (169 mg). 1H NMR (DMSO-d6) δ: 9.14-9.15 (m, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.54 (d, J=2.3 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.81 (t, J=−1.8 Hz, 1H), 7.40 (dt, J=7.7, 1.9 Hz, 1H), 7.30-7.35 (m, 2H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 7.00 (br. s., 2H), 6.79-6.83 (m, 1H), 3.52-3.64 (m, 10H), 2.39 (t, J=7.3 Hz, 4H), 2.27 (s, 3H), 1.72-1.85 (m, 4H), 1.65-1.71 (m, 4H)
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13]#[N:14])C.[CH3:16][O:17][CH2:18][C:19]([NH:21][NH2:22])=O>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:3])[N:22]3[N:21]=[C:19]([CH2:18][O:17][CH3:16])[N:14]=[C:13]3[C:7]=2[CH:8]=1
Reactant: COCC(=O)NN
Reactant: CCOC(=O)Nc1ccc(Br)cc1C#N
Product: COCc1nc2c3cc(Br)ccc3[nH]c(=O)n2n1
Yield: 92 %

Procedure:
As described for example 1a) (4-bromo-2-cyano-phenyl)-carbamic acid ethyl ester (19.9 g, 74.2 mmol) instead of (4-chloro-2-cyano-phenyl)-carbamic acid ethyl ester using methoxymethyl-carboxylic acid hydrazide instead of cyclopropane-carboxylic acid hydrazide, was converted to the title compound (21.1 g, 92%) which was obtained as a light yellow solid. MS: m/e=308.9/310.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29](=[S:31])[NH2:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.CCO.Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[S:31][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: CCOC(=O)C(=O)CBr
Reactant: C[C@@H]1CN2c3c(cc4c(C(N)=S)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-8-carbothioamide (Intermediate 575, 54 mg, 0.128 mmol) in mixture of EtOH:DMF (1 mL: 0.5 mL) were added ethyl bromopyruvate (47 mg, 0.24 mmol) and molecular sieves, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give product as solid. Yield: 13 mg (20%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[O:35]1[CH:39]=[CH:38][CH2:37][CH2:36]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[C:36]3[CH2:37][CH2:38][CH2:39][O:35]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: C1=COCC1
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=C3CCCO3)CS[C@H]12

Procedure:
A mixture of 852 mg. of p-nitrobenzyl 7β-(2-thienylacetylamino)-3-azido-3-cephem-4-carboxylate and 20 ml. of 2,3-dihydrofuran was heated at the reflux temperature (54°-55° C.) for 15 minutes. The mixture was evaporated to dryness and the residue chromatographed over 8 g. of silica gel (toluene) using 400 ml. of 5% ethyl acetate in toluene vs. 400 ml. of ethyl acetate. Multiple fractions were collected and fractions containing the product were pooled and evaporated to dryness to give 559 mg. of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C.C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OCCc1ccccn1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(CCc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A mixture of 6-(2-furyl)-1H-purine-2-amine (50 mg, 0.25 mmol) and triphenylphosphine polystyrene (0.21 g, 0.62 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with 2-(2-hydroxyethyl)pyridine (61 mg, 0.50 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.115 g, 0.50 mmol), shaken for 16 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2-MeOH (100:5)] to give the title compound (36 mg, 47%) as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH3:71])[CH2:64][C:63]2[CH:65]=[CH:66][CH:67]=[C:68]([CH2:69]O)[C:62]=2[O:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:69][C:68]2[C:62]3[O:61][C:60]([CH3:71])([CH3:59])[CH2:64][C:63]=3[CH:65]=[CH:66][CH:67]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cccc3c2OC(C)(C)C3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 46%).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:2](=[O:5])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=S(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Chlorosulfonic acid (3.0 ml, 0.0454 mol, 150 M %) was added slowly to a solution of dry pyridine (9.84 ml, 0.121 mol) in dry dimethylformamide (60 ml) which had been cooled to -10°. The resulting clear solution was stirred for 10 minutes at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)c2OC
Yield: 34.2 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (163 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (156 mgs) were combined to give the title compound as off-white solid (101 mgs) 1H-NMR (CDCl3, 400 MHz): 9.67 (s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.69 (t, J=8.1 Hz, 1H), 7.60-7.58 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 4.49-4.43 (m, 1H), 4.40-4.31 (m, 1H), 3.87 (s, 3H), 3.59-3.52 (m, 1H), 3.31-3.28 (m, 1H), 3.18-3.13 (m, 1H), 2.80-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.06-1.99 (m, 1H), 1.37-1.33 (m, 6H), 1.22 (t, J=6.1 Hz, 3H), LC/MS: found (M+H)+=655.57; MP: 245-247° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].O.[NH2:28][NH2:29]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:29][NH:28][C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(CN2C(=O)c3[nH]nc(C)c3C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) and hydrazine hydrate at 100° C. for 16 hr. tR: 4.75 min (HPLC 1); tR: 1.05 min (LC-MS 2); ESI-MS: 368 [M+H]+ (LC-MS 2); ESI-MS: 366 [M−H]− (LC-MS 2).