Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[Cl:16].[OH-].[K+].CCCCCCC>CS(C)=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([O:17][C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: Clc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Yield: 21.1 %

Procedure:
A solution of 3,6-dichloropyridazine (4.47 g, 30.0 mmol), 3,4-dichlorophenol (4.89 g, 30.0 mmol) and potassium hydroxide (1.68 g, 30.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 60° C. overnight. The solvent was removed by evaporation in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Small amounts of starting material were removed by kugelrohr distillation. Crystallisation from ethyl acetate:heptane yielded the title compound (1.74 g, 21% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[H-].[Na+].Cl[C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1)[CH3:2]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]=2[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][C:6]1[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[N:8][C:7]=1[CH2:30][CH:31]1[C:43](=[O:44])[C:42]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:3][C:2]#[CH:1])[C:34]=2[CH2:33][CH2:32]1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCn1c2c(c3ccccc31)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 60 h

Procedure:
Propargyl bromide (0.086 ml) was added to a suspension of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl ]-4H-carbazol-4-one (500 mg) and potassium carbonate (265 mg) in acetone (10 ml) and the mixture was stirred under nitrogen for 60 h. More propargyl bromide (0.086 ml) was added and the mixture was stirred at room temperature for 24 h and then at reflux for 6 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a gum (650 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 80:19:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (95 mg) as a foam, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:hexane 4:1) Rf 0.30.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:21]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]>C1COCC1.CO>[F:3][C:4]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A 1M solution of NaOH (809 μL, 0.809 mmol) was added to a solution of 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (135 mg, 0.270 mmol) in 4:1 THF/MeOH (1.4 mL, 0.2M). The reaction mixture was stirred at room temperature for 30 minutes. The majority of the organic solvents were removed in vacuo. The resulting residue was acidified with 1N HCl (0.8 mL) and then partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with minimal CH2Cl2, and the precipitate was filtered and rinsed with Et2O to afford 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a solid (48 mg, 45% yield for 2 steps).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH:15]=[CH2:16]>C1(NC2C=CC3C(=CC=CC=3)C=2)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:16][CH2:15][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(Nc2ccc3ccccc3c2)cc1
Product: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Yield: 45.2 %

Procedure:
A solution of 25 g (0.167 mole) p-tert-butylphenol, 0.2 g sodium hydride (as 50% dispersion in oil), 0.2 g N-phenyl-2-naphthylamine (as basic polymerization inhibitor) in 75.0 g (0.586 mole) butyl acrylate was heated at 125° C. for four hours. The temperature was then reduced to 100° C. and the excess acrylate distilled under gentle vacuum. The resulting oil was filtered through 900 g silica gel (90 to 200 mesh) using chloroform as eluant to yield 21.0 g pure butyl 3-(p-tert-butylphenoxy)-propionate (45%).
Reaction SMILES: C[Mg]Br.[CH3:4]I.[CH3:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14]>CCOCC>[CH3:14][C:13]([OH:15])([CH2:12][CH2:11][O:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([CH3:6])[CH:8]=1)[CH3:4]
Reactant: CC(=O)CCOc1cccc(C)c1
Reactant: CI
Agent: C[Mg]Br
Solvent: CCOCC
Product: Cc1cccc(OCCC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl magnesium bromide in ether (50 mL), prepared from Mg (572 mg, 23.56 mmol) and MeI (3.34 g, 23.56 mmol), was added 4-(3-methylphenoxy)-2-butanone (2.1 g, 11.78 mmol) in 10 mL ether. The solution was stirred at room temperature for 30 minutes, after which quenched with water and dil. Hydrochloric acid. The organic layer was separated, dried over sodium sulfate, filtered through a silica plug. Colorless syrup 1.91 g (83%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(OC([N-:32][S:33](N1C=CC(=[N+](C)C)C=C1)(=[O:35])=[O:34])=O)(C)(C)C>C(#N)C>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH:3]2[CH2:2][NH:1][S:33](=[O:35])(=[O:34])[NH2:32])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(N)(=O)=O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 117.6 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in acetonitrile (2 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (190 mg) prepared by the method described in Organic Letters, 2001, 3 (14), 2241-2243, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (205 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4].[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([CH3:18])[C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4]
Reactant: COC(=O)C1=CC=C2N=NN=C2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1=CC=C2N=NN=C2C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 g of Benzotriazole-5-carboxylic acid methyl ester (5.64 mmol) was dissolved in 20 ml DMF at 0° C. To this solution was added 1 eq. of NaH (60%) at 0° C. The mixture was stirred for 30 min at 0° C., 801 mg (1 eq.) of Methyliodide were slowly added, and the resulting reaction mixture was stirred for 2 h at rt. EtOAc was added and the organic layer was washed extensively with brine and water, dried over MgSO4 and filtered to afford 1 g of crude Methyl-benzotriazole-5-carboxylic acid methyl ester as three different regioisomers. The separation was performed on silica gel using EtOAc/CH 3:7 as eluents.
Reaction SMILES: [NH2:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:17][C@H:16]3[N:13]([C:14](=[O:28])[C@@H:15]3[C@H:18]([O:20][Si](CC)(CC)CC)[CH3:19])[C:12]=2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[CH:7][CH:6]=1)=[O:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[NH2:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:17][C@H:16]3[N:13]([C:14](=[O:28])[C@@H:15]3[C@H:18]([OH:20])[CH3:19])[C:12]=2[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[CH:9][CH:10]=1)=[O:3]
Reactant: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(OC(N)=O)cc3)C[C@H]12
Reaction time: 0.75 h
Yield: 12.4 %

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (110 mg) prepared in the above step in THF (1.9 ml) was added under ice cooling acetic acid (11 mg). Then 1M tetrabutylammonium fluoride/THF solution (0.19 ml) was dropped thereto and the mixture was stirred at the same temperature for 45 minutes. The residue prepared by the same manner as step a) of example 11 was purified by silica gel thin-layer chromatography (chloroform/acetone=2/1) to give 4-nitrobenzyl (5R,6S)-3-{4-[(aminocarbonyl)oxy]phenyl}-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (11 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[CH:6]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:35]([O:37][CH3:38])=[O:36])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(=O)OC)C2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(indan-2-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][NH:19][C@H:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[CH3:21])[CH:5]=1)([O-:3])=[O:2].[CH2:28](I)[CH3:29].CCN(C(C)C)C(C)C>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[C@H:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCI
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN[C@@H](C)P(=O)(OC)OC)c2nc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)[C@@H](C)P(=O)(OC)OC
Temperature: 55 °C
Reaction time: 18 h

Procedure:
3.4 g (8.5 mmol) of dimethyl (R)-N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-aminoethylphosphonate, 8.9 ml (7.5 eq.) of ethyl iodide and 20.9 ml (14.5 eq.) of Hunig's base are mixed in 18 ml of acetonitrile and stirred at 55° C. for 18 hours. The reaction mixture is evaporated and slurried with ethyl acetate. The deposited solid is filtered off and washed with ethyl acetate. The title compound is obtained in the form of a yellow resin after evaporation of the filtrate and column chromatography using ethyl acetate/methanol (95:5) as eluent.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(CCN4CCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CCN5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 17 %

Procedure:
Intermediate 1c (270 mg, 0.74 mmol) was dissolved in 1,4-dioxane (6 mL) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 329 mg, 0.81 mmol) and DIPEA (257 μL, 1.48 mmol) were added. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% formic acid) to give the title compound (78.0 mg, 0.12 mmol, 17%). LCMS (Method 5): Rt 3.67 mins, m/z 633 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-2.06 (6H, m), 2.07-2.18 (1H, m), 2.22-2.30 (1H, m), 2.39 (3H, s), 3.08-3.16 (4H, m), 3.42-3.50 (4H, m), 4.87-4.92 (1H, dd, J 9.0, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (10H, m), 7.62-7.66 (1H, d, J 9.7), 8.07-8.09 (1H, d, J 1.6), 8.45 (0.6H, s).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([O:52][CH3:53])([C:13](=[O:51])[NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:19]=[C:18]3[C:43]2[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=2)[CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:50][O:49][C:45]1[CH:44]=[C:43]([C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([NH:14][C:13]([C:10]4([O:52][CH3:53])[CH2:11][CH2:12][NH:8][CH2:9]4)=[O:51])[CH:16]=3)[NH:20][N:19]=2)[CH:48]=[CH:47][N:46]=1
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(NC(=O)C4(OC)CCN(C(=O)OC(C)(C)C)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCNC4)cc23)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To the stirred solution 3-Methoxy-3-[3-(2-methoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester 7BV (2.95 g, 4.16 mmole) in DCM (50 mL) at r.t. was added triethylsilane (1.00 ml, 6.24 mmole) followed by TFA (10 mL). The mixture was stirred at r.t. under dry N2 gas for 4-5 hours. The mixture was evaporated to dryness and co-evaporated with dry toluene (2×75 mL). The resulting crude solid was purified on RediSep 120 g cartridge eluting with 2.5%-6% 2M NH3-MeOH/CH2Cl2 to yield an off-white solid 8BV (1.23 g, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(C)(C)C)(=O)C.Cl(O)(=O)(=O)=O>[C:2]([O:19][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:7])([CH3:3])[CH3:1]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Nα -(Benzyl-oxycarbonyl)-L-lysine (5.0 gm, 17.84 mmol) was dissolved in 268 ml of tert-butyl acetate containing 2.80 ml of perchloric acid (69-72% aqueous solution). The solution was stirred for 2 days at room temperature and then was extracted with water (3×200 ml). The combined aqueous layers were adjusted to pH 10 with 50% sodium hydroxide. The aqueous solution was then extracted with ethyl acetate (3×200 ml) and the organic layers dried over MgSO4. After filtration to remove MgSO4, the solvent was removed by evaporation at reduced pressure to provide Nα -(benzyloxycarbonyl)-L-lysine tert-butyl ester as a clear oil (2.16 gm, 36%). 1H NMR (CDCl3) 1.35 (s,9H), 1.40-2.0 (m,6H), 2.60 (t,2H), 4.10 (m, 1H), 4.98 (s,2H), 5.29 (bs,1H), 7.35 (s,5H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][N:36]1[CH2:41]COC[CH2:37]1.C=O.CN>CCO>[Br:1][C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:37][N:36]([CH3:41])[CH2:35][N:13]([CH2:14][CH3:15])[C:12]3=[O:16])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: CN1CCOCC1
Agent: C=O
Agent: CN
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (Jubilant) (3.0 g, 5.48 mmol) was suspended in EtOH (120 mL). N-methylmorpholine (3.0 mL, 27.4 mmol), aqueous formaldehyde (4.45 mL, 54.8 mmol) and methylamine solution (2 M) (13.7 mL, 27.4 mmol) were added and the reaction mixture stirred at rt for 16 h, followed by a further 4 hrs at 80° C. The reaction mixture was cooled to rt and the resulting precipitate filtered. The precipitate was washed with EtOH, Et2O and dried using a vacuum oven to afford the desired product (2.5 g, off white solid).
Reaction SMILES: [N+:1]([O-])([O:3]C(=O)C)=[O:2].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27].C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([N+:1]([O-:3])=[O:2])=[CH:19][C:14]=2[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: CN1C(=O)C(F)N=C(c2ccccc2)c2ccccc21
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1.2 g. of acetyl nitrate are added dropwise, at 10° to a stirred solution of 2.67 g. of 1-methyl-3-fluoro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one in 70 ml. of CCl4 and 20 ml. of acetonitrile. The mixture is stirred for 1 hour more at 10° and for 3 hours at 20° and is poured into ice cold sodium carbonate solution and worked up in the customary manner to give 1-methyl-3-fluoro-5-phenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazapin-2-one.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[NH:18][CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2].[H-].[Na+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[N:18]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 126.8 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.123 g, 0.314 mmol) in DMF (3.0 mL) at about 0° C. was added NaH (60% in mineral oil, 0.015 g, 0.37 mmol). The reaction mixture was stirred for about 5 min. 4-Methylbenzene-1-sulfonyl chloride (0.060 g, 0.314 mmol) was added and the reaction mixture was stirred for about 30 min. Additional NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added and the reaction mixture was stirred for about 10 min. Additional NaH (60% in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction mixture was stirred for about 15 min. Additional 4-methylbenzene-1-sulfonyl chloride (0.012 g, 0.063 mmol) was added and the reaction mixture was stirred for about 40 min. The reaction mixture was concd under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with water (15 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)-cyclopropanesulfonamide (0.218 g) as a red-orange oil containing 40 mol % DMF and 1 equivalent EtOAc: LC/MS (Table 1, Method n) Rt=0.88 min; MS m/z 548 (M+H)+.