Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:26][NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:13]=[C:14]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:15]=1)[CH:2]([CH3:4])[CH3:3].[ClH:36]>>[Cl-:36].[CH2:1]([NH2+:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH2:16][NH2+:17][CH2:18][CH2:19][CH2:20][NH2+:21][CH2:22][CH2:23][CH2:24][NH3+:25])[CH:13]=[C:12]([CH2:26][NH2+:27][CH2:28][CH2:29][CH2:30][NH2+:31][CH2:32][CH2:33][CH2:34][NH3+:35])[CH:11]=1)[CH:2]([CH3:3])[CH3:4].[Cl-:36].[Cl-:36].[Cl-:36].[Cl-:36].[Cl-:36].[Cl-:36]
Reactant: Cl
Reactant: CC(C)CNCCCOc1cc(CNCCCNCCCN)cc(CNCCCNCCCN)c1
Product: CC(C)C[NH2+]CCCOc1cc(C[NH2+]CCC[NH2+]CCC[NH3+])cc(C[NH2+]CCC[NH2+]CCC[NH3+])c1
Product: [Cl-]
Reaction time: 1 h
Yield: 43 %

Procedure:
To N1,N1′-((5-(3-(iso-butylamino)propoxy)-1,3-phenylene)bis(methylene))bis(N3-(3-aminopropyl)propane-1,3-diamine) from step 6 was added methanolic HCl (50 mL, 1.0M). The reaction mixture was stirred for 1 h, the reaction mixture was concentrated under reduced pressure and the solid collected by vacuum filtration. The solid was washed with Et2O (10 mL) and hot MeOH (10 mL) to afford the desired product (0.14 g, 43%) as a white solid. 1H NMR (500 MHz, D2O) 6 ppm 7.21 (s, 1H), 7.19 (s, 2H), 4.30 (s, 4H), 4.23 (t, J=5.5 Hz, 2H), 3.29 (t, J=7 Hz, 2H), 3.25-3.19 (m, 12H), 3.12 (t, J=7.5 Hz, 4H), 2.95 (d, J=7 Hz, 2H), 2.25-2.03 (m, 11H), 1.01 (d, J=7.5 Hz, 6H). 13C NMR (125 MHz, D2O) 158.9, 133.0, 123.7, 117.1, 65.8, 54.8, 50.7, 45.7, 44.7, 44.6, 44.2, 36.7, 25.5, 25.2, 23.7, 22.6, 19.1. LRMS [M+H]+494.4.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](S(C3C=CC=CC=3)(=O)=O)[N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][Na]>C1COCC1>[CH3:25][O:26][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[N:11]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(S(=O)(=O)c2ccccc2)n1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a N2 purged reactor is charged 5.0 g (13.9 mmol) of 4d and 50 mL of anhydrous THF. The resulting slurry is treated drop-wise with MeONa (25 wt % in MeOH) (1.1 equiv). The resulting slurry is stirred for 1 h at room temperature, and a complete conversion is observed by LC-MS. The slurry is filtered, washed with IPA; and dried in oven overnight at 50° C. to give 1.94 g 3d as a white solid. The mother liquor is concentrated, 15 mL of IPA is added, and the mixture warmed until complete dissolution. The mixture is cooled down to 10° C. and held for 1 h. A second crop of solid is collected by filtration, and dried to yield another 1.17 g of white solid 3d, total 90% yield; mp 74.6-75.8° C. 1H NMR (400 MHz, CDCl3) δ 8.12-8.09 (m, 2H), 7.78-7.73 (m, 2H), 7.64 (tt, J=7.4, 1.3 Hz, 1H), 7.58-7.53 (m, 2H), 6.88 (dd, J=7.7, 1.4 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0, 155.7, 139.7, 138.9, 133.6, 129.1, 128.9, 115.5, 114.9, 54.0; HRMS (ESI) m/z 250.0528 (M+H+), calc. for C12H12NO3S 250.0532.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]>[Pd]>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: [Pd]
Product: CC(C)CCCC(C)CCCC(C)CCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Farnesol (572 g, 2.58 mole, 650 mL) was added to a 1000 mL Parr high pressure vessel containing 10% Pd/C (23 g, 4% by weight of farnesol). The reaction vessel was sealed and evacuated under house vacuum for 5 minutes after which time the reaction mixture was pressurized with H2 to 1000 psi. The reaction mixture was stirred at 25° C. and judged to be complete by thin layer chromatography (“TLC”, Rf=0.32, 90:10 hexane:ethyl acetate) after approximately 12 hours. The reaction vessel was depressurized under vacuum followed by venting to a N2 atmosphere. The reaction contents were vacuum filtered over a silica gel (60 Å from Aldrich) pad followed by washing of the silica gel with ethyl acetate (“EtOAc”, 3 L). The filtrate was concentrated on a rotary evaporator. The isolated product was further dried under high vacuum to remove any residual EtOAc to afford 3,7,11-trimethyldodecan-1-ol as a lightly tinted yellow viscous liquid. 1H-NMR (CDCl3, 500 MHz): δ 3.71 (m, 2H), 1.65-1.05 (m, 17H), 0.89-0.83 (overlapping t&d, 12H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([OH:16])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.2 %

Procedure:
Following the procedure as described in Example 11, except using the material from Example 24 (1.15 g, 2.66 mmol), CH2Cl2 (50 mL), TFA (5 mL, 64.9 mmol) and stirring at room temp for 18 h, 1.38 g of the title compound (quantitative yield) is obtained as a white solid as a mono TFA salt. LC/MS (Condition A): ret. T=2.86 min, (M+H)+ 376.13, and ret. T=3.03 min, (M+H)+ 376.13.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:58](=[O:59])[N:33]2[C:34]([C:55]([OH:57])=[O:56])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:58](=[O:59])[N:33]3[C:34]([C:55]([OH:57])=[O:56])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Yield: 83.1 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.03 g.), 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H- tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (2.6 g.), trimethylsilylacetamide (5.9 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CCC.[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=[O:30])[CH2:28]Cl)[CH3:23]>C(#N)C>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=[O:30])[CH2:28][S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(=O)O
Solvent: CC#N
Product: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a 0° C. solution of 3-methoxy-benzenethiol (5.75 g, 41.0 mmol) and potassium carbonate (11.45 g, 82.02 mmol) in acetonitrile (150 mL) is added butanoic acid, 4-chloro-3-oxo-butanoic acid ethyl ester 6.12 mL, 45.11 mmol). The mixture is stirred at room temperature for 2 hours and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25-30% EtOAc/Hexanes to provide the title compound (10.9 g, 99%). MS: 267.0 (M−1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[N:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[N:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)n1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C)n1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyrazin-2-yl)piperazin-1-yl]methanone (611 mg) described in Preparation Example 105 and (R)-4-methyloxazolidin-2-one (212 mg) described in Preparation Example 25, the title compound (528 mg) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Na].[Br:17][CH2:18][CH2:19][CH2:20][Cl:21]>CN(C=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2.[Br:17][CH2:18][CH2:19][CH2:20][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: BrCCCn1c2ccccc2c2ccccc21
Product: ClCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Carbazole (50.0 g, 0.3 mol) was dissolved in dry DMF (1.5 L). NaH (60% in oil, 18.8 g, 0.45 mol) was added under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 h. To the resulting sodium salt was carefully added under vigorous stirring a solution of 1-bromo-3-chloropropane in dry DMF (0.5 L). The mixture was stirred at room temperature for 10 h. The solvent was removed in vacuo. The residual oil was dissolved in CH2Cl2 (350 mL), washed with water (3×100 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil. The oil was triturated with cold n-heptane (3×50 mL), and the precipitate collected. This afforded the title compound (48.3 g, 66%) as a yellow solid. M.p. 39-40° C. 1H-NMR (δ CDCl3): 2.3-2.5 (m, 2H); 3.4 (t, 1H); 3.55 (t, 1H); 4.55 (d, t, 2H); 7.35 (m, 2H); 7.5 (d, 2H); 8.1 (d, 2H). The product was isolated as an 1:1 mixture of the 3-bromo- and 3-chloro-derivatives.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](O)([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[Cl:30][CH2:31][C:32]#[N:33].C(O)(=[O:36])C.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:30][CH2:31][C:32]([NH:33][C:26]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)([CH3:28])[CH3:27])=[O:36]
Reactant: CC(C)(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(=O)O
Reactant: N#CCCl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(NC(=O)CCl)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ol (0.715 g, 1.77 mmol) at 0° C. under argon was added 2-chloroacetonitrile (0.67 mL, 10.6 mmol), followed by acetic acid (1.4 mL) and sulfuric acid (0.90 mL). The resulting yellow reaction mixture was warmed to room temperature and stirred for 4 hours, during which LC-MS indicated completion of reaction. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine; dried (MgSO4). The organic layer was filtered and concentrated in vacuo. ISCO purification with 10% to 40% EtOAc/Hexanes afforded 2-chloro-N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-yl)acetamide as a white amorphous solid. MS (ESI) m/z: Calculated: 480.0; Observed: 481.1 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[N:21]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=[C:19]([O:32][CH2:33][CH2:34][OH:35])[C:18]=2[C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:43][C:44]1[CH:45]=[N:46][C:47](S(C)(=O)=O)=[N:48][CH:49]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOCC.CN(C=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[N:21]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=[C:19]([O:32][CH2:33][CH2:34][O:35][C:47]3[N:48]=[CH:49][C:44]([Cl:43])=[CH:45][N:46]=3)[C:18]=2[C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
Sodium hydride (16 mg, 60% suspension in mineral oil) was added to a stirred solution of 4-(tert-butyl)-N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2-hydroxyethoxy)-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (105 mg) (Preparation 28) in anhydrous THF (5 ml) at room temperature under a nitrogen atmosphere and the resulting mixture was stirred for 10 minutes at room temperature. DMF (2 ml) was added to the reaction mixture, followed by 5-chloro-2-(methylsulphonyl)pyrimidine (39 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into an aqueous solution of 1.0M citric acid (50 ml) and ether (50 ml) and the aqueous phase was separated. The organic phase was washed with water (30 ml) and then dried over magnesium sulfate, filtered and concentrated under pressure. The orange/brown residue was purified by chromatography on a Biotage Flash 12i cartridge at 10 psi using 20% ethyl acetate/hexane as eluant to give the title compound as a pale yellow oil (90 mg).
Reaction SMILES: OO.[H][H].[CH:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[CH:14]1[CH:15]=[C:16]2[C:17]([OH:19])=[C:18]3[C:9](=[C:10]([OH:20])[C:11]2=[CH:12][CH:13]=1)[CH:8]=[CH:7][CH:6]=[CH:5]3
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: [H][H]
Agent: OO
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
An anthraquinone process is known as an industrial hydrogen peroxide production process. In this process, an anthraquinone compound is dissolved in an organic solvent to obtain a working solution, and in a hydrogenation step the anthraquinone compound is reduced with hydrogen in the presence of a hydrogenation catalyst so as to produce an anthrahydroquinone compound. Next, in an oxidation step the anthrahydroquinone compound is converted back into the anthraquinone compound, with hydrogen peroxide being produced at the same time. The hydrogen peroxide in the working solution is separated out from the working solution by a process such as water extraction. The working solution from which the hydrogen peroxide has been extracted is returned into the hydrogenation step, whereby a cyclic process is formed.
Reaction SMILES: [C:1]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.Cl.Cl.CC1C=C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)N(C2C=CC=CC=2)N=1.Cl.[C:54]([NH:58][NH2:59])([CH3:57])([CH3:56])[CH3:55]>C(O)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[N:58]([C:54]([CH3:57])([CH3:56])[CH3:55])[N:59]=[C:3]([CH3:5])[CH:2]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)NN
Reactant: CC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n(C(C)(C)C)n1
Reaction time: 15 h
Yield: 18.9 %

Procedure:
1-Acetoacetyl-4-tert-butoxycarbonylpiperazine [product of Example 222 (1), 3.92 g] was dissolved in ethanol (300 mL), and tert-butylhydrazine hydrochloride (1.81 g) and molecular sieves 3A (10 g) were added thereto at room temperature. The mixture was stirred for 15 hr. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue was dissolved in pyridine (200 mL), and phosphorus oxychloride (3.0 mL) was added thereto at room temperature. The mixture was stirred for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with dilute hydrochloric acid to pH 3. The mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 1-tert-butoxycarbonyl-4-(1-tert-butyl-3-methyl-5-pyrazolyl)piperazine (886 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][NH:5]/[C:6](/[NH:18][C:19]1[NH:23][N:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:20]=1)=[N:7]/[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:33](=[O:34])[N:23]2[N:22]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:20]=[C:19]2[NH:18]/[C:6]/1=[N:7]\[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(/N=C(/NCc1ccc(F)cc1Cl)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: O=C(/N=c1\[nH]c2cc(C(F)(F)F)nn2c(=O)n1Cc1ccc(F)cc1Cl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
To a solution of (Z)—N-(((2-chloro-4-fluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-3,4-difluorobenzamide (50 mg, 0.11 mmol) in THF (1 mL) was added 1,1′-carbonyldiimidazole (CDI) (26 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Purification by silica chromatography (EtOAc:hexanes) provided the title compound (14 mg, 27% yield). HPLC (Method A): 11.1 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCNCC1

Procedure:
Mono-benzoylation of unsymmetric substituted piperazines (A and B in Scheme 33 represent, for example R14, R16, R18 and R20 once incorporated into a compound of Formula I) could be achieved by using one of the following procedures (Scheme 33), in which all the methods were exemplified by mono-alkyl substituted piperazines. (a) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature to afford a mixture of two regioisomers, which could be separated by chromatography (Wang et al, Ref.32 and 33(b), Scheme 34 eq. 06); (b) Benzoic acid was converted to its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine to provide the mono-benzoylpiperazines with the benzoyl group at the less hindered nitrogen (Adamczyk et al, Ref. 33(a), Scheme 34, eq. 07); (c) A mixture of piperazine and methyl benzoate was treated with dialkylaluminum chloride in methylene chloride for 24 days to yield the mono-benzoylpiperazine with the benzoyl group at the less hindered nitrogen (Scheme 34 eq. 08); (d) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by subsequent addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to afford mono-benzoylpiperazines with the benzoyl group at the more hindered nitrogen (Wang et al, Ref. 33(b), Scheme 34, eq. 09). When the substituent at position 2 was a ester or amide, the mono-benzoylation with benzoyl chloride occurred at the less hindered nitrogen of the piperazine with triethylamine as base in THF (Scheme 34, eq. 10).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].IC.[C:21](=O)([O-])O.[K+]>CN(C=O)C>[CH3:21][O:17][C:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1)=[O:18]
Reactant: O=C([O-])O
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of N-carbobenzyloxypyrrolidine-3-carboxylic acid (10.15 g, 40.72 mmol) and iodomethane (5.08 mL, 81.44 mmol) in N,N′-dimethylformamide (80 mL) was added powdered potassium hydrogen carbonate (8.15 g, 81.44 mmol) and the reaction mixture stirred at ambient temperature for 5 hours. The mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel using 5-50% ethyl acetate in hexane to give the title compound (10.59 g, 99%). MS(DCI): m/z 264 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH2:4]1)[CH3:2].O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:14]1[C:9]([NH:8][C@@H:7]2[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:31][S:32]([CH:35]3[CH2:37][CH2:36]3)(=[O:33])=[O:34])[CH2:6]2)=[C:10]2[CH:20]=[CH:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=3)(=[O:22])=[O:23])[C:11]2=[N:12][CH:13]=1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 75 °C
Yield: 98.4 %

Procedure:
To a suspension of N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.172 g, 0.314 mmol) in EtOH (6 mL) was added tin (II) chloride dihydrate (0.142 g, 0.628 mmol). The reaction mixture was heated at about 75° C. for about 15 h. Tin (II) chloride dihydrate (0.128 g, 0.565 mmol) was added and the reaction mixture was heated at about 70° C. for about 40 min then heated at about 80° C. for about 3 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1N aqueous NaOH (10 mL), water (10 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure. EtOH (10 mL) was added and the mixture was concd under reduced pressure to give N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.160 g, 98%) as a yellow oil: LC/MS (Table 1, Method n) Rt=0.75 min; MS m/z 518 (M+H)+.