Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N(C)C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:23][C:24]2[C:29]3[C:30]4[CH2:38][CH2:37][C:36]5[C:32](=[CH:33][N:34]([CH2:39][CH2:40][OH:41])[N:35]=5)[C:31]=4[S:42][C:28]=3[N:27]=[CH:26][N:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.Cl[S:44]([NH2:47])(=[O:46])=[O:45]>[Cl-].[Na+].O>[S:44](=[O:46])(=[O:45])([O:41][CH2:40][CH2:39][N:34]1[CH:33]=[C:32]2[C:36]([CH2:37][CH2:38][C:30]3[C:29]4[C:24]([NH:23][C:10]5[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]6[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=6)=[C:8]([Cl:7])[CH:9]=5)=[N:25][CH:26]=[N:27][C:28]=4[S:42][C:31]=32)=[N:35]1)[NH2:47]
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To 5 mL DMA cooled to 5° C. was added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethanol (100 mg, 0.19 mmol) followed by chlorosulfonyl amine (221 mg, 1.9 mmol). The mixture was stirred with warming to rt over a 2 h period, after which time stirring was halted. The entire mixture was poured onto cold brine (10 mL), upon which precipitation of a solid occurs. The mixture was filtered, and the filtrate extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude residue was purified by reverse phase HPLC. The product fractions were combined and diluted with CH2Cl2 (50 mL), and neutralized with NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to afford the final pure product (30 mg, 26%) as a white solid. 1H-NMR (DMSO-d6) δ 8.40 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.59 (s, 2H), 7.51 (dd, 1H), 7.40 (dd, 1H), 6.91-7.11 (m, 4H), 5.21 (s, 2H), 4.38 (br s, 4H), 3.32 (t, 2H), 2.90 (t, 2H); LCMS RT=3.45 min; [M+H]+=601.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>>[CH3:32][C:26]1[CH:25]=[CH:24][C:23]2[C:22]([O:21][CH2:20][CH2:19][C:7](=[C:4]3[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][C:13](=[O:17])[NH:14]4)=[CH:10][CH:9]=3)=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]=1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: O=C1Cc2ccc(C=C3CCNCC3)cc2N1
Product: Cc1ccc2c(OCCC(=C3CCNCC3)c3ccc4c(c3)NC(=O)C4)cccc2n1

Procedure:
The title compound was prepared from 6-(piperidin-4-ylidenemethyl)-1,3-dihydroindol-2-one and 5-(2-bromoethoxy)-2-methylquinoline using a similar method to that of Description 11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([N:19]3[CH2:23][CH:22]4[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:21]4[CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH:21]4[CH2:26][NH:25][CH2:24][CH:22]4[CH2:23]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1C1CC(c2csc(N3CC4CNCC4C3)n2)=NO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-carboxylate (i.e. the product of Step C) (0.6 g, 1.26 mmol) in dichloromethane (15 mL) cooled to 0° C. was added trifluoroacetic acid (2 mL, 26.93 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 3 h, and then concentrated under reduced pressure. The resulting material was dissolved in water (50 ml) and basified by the addition of sodium hydroxide (10%) to pH 12, and then extracted with chloroform (3×50 mL). The combined organic extracts were concentrated under reduced pressure to provide the title product as a white-gummy solid (0.42 g).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:41]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
WSC (2.87 g, 15 mmols) and HOBt (2.03 g, 15 mmols) were added to a DMF (20 ml) solution of 2,6-diisoproylaniline (1.97 g, 10 mmols) and 5-bromopentanoic acid (2.71 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.4 g (41%) of 5-bromo-N-(2,6-diisopropylphenyl)pentanamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[CH2:17](O)C>ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCO
Reactant: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: ClCCl
Product: CCC(=O)N(C)c1cc([N+](=O)[O-])ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of 340 mg of N1-(2-methaxy-5-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (2) in 20 mL of ethanol containing 5% w/w of Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) for 1.5 h. The contents of the flask were passed through a short pad of celite and washed with MeOH. The filtrate was evaporated under reduced pressure and crude amine obtained was carried over to the next reaction without further purification. Thiocarbodiimidazole (260 mg, 1.46 mmol) was added to the crude amine in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, and concentrated. The crude product was then purified by flash chromatography on silica gel to give N1-(5-isothiocyanato-2-methoxyphenyl)-)-N1, N2, N2-trimethylethane-1,2-diamine (3) (110 mg, 0.42 mmol, 31%).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:19]2[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[Cl:56][C:57]1[N:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1>C(Cl)Cl>[Cl:56][C:57]1[N:62]=[CH:61][C:60]([S:63]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[N:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:28])([F:29])[F:27])[C:30]([F:33])([F:31])[F:32])=[CH:23][N:24]=3)[C@@H:13]([CH2:12][N:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]2)(=[O:65])=[O:64])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 55.9 %

Procedure:
A 5-mL vial was charged with (R)-tert-butyl 4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrimidin-2-yl)-3-((N-phenylmethylsulfonamido)methyl)piperazine-1-carboxylate (0.214 g, 0.348 mmol, Example 233, Step 5), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The mixture was stirred at room temperature for 35 min and then concentrated. CH2Cl2 (2 mL) and triethylamine (0.50 mL, 3.6 mmol) were added and the mixture was stirred at room temperature for 10 min. 6-chloropyridine-3-sulfonyl chloride (0.0910 g, 0.429 mmol, Organic Process Research & Development 2009, 13, 875) was then added in potions and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and purified by column chromatography (50 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.134 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][NH2:23]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[O:14])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccn1)c1ncc2cccnc2c1O

Procedure:
To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added 1-pyridin-2-ylmethanamine (0.029 g, 0.270 mmol) and the mixture was heated to reflux for 16 hours. The solution was reduced to a smaller volume and refluxed for 4 additional hours. The solvent was removed under reduced pressure and the residue redissolved in DMF and filtered and the solution was purified by preparative HPLC (Gilson semipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D., C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9](O)=[O:10])[CH3:8])=[O:5])[CH3:3].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1COCC1.CC(O)C.C(OCC)(=O)C>[CH:18]1[C:17]2[CH:16]([CH2:15][O:14][C:12](=[O:13])[NH:1][C@H:2]([C:4](=[O:5])[NH:6][C@H:7]([C:9](=[O:10])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=3)[CH3:8])[CH3:3])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(CO)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of Fmoc-Ala-Ala-OH (1 g, 2.61 mmol, Eq: 1.00) and (4-aminophenyl)methanol (483 mg, 3.92 mmol, Eq: 1.5) in THF (20 ml) was treated with EEDQ (970 mg, 3.92 mmol, Eq: 1.5). The solution was stirred over night at room temperature. The mixture was diluted with 10% 2-propanol/ethyl acetate (100 mL) and the solution was washed with KHSO4 5%/K2SO4 10% (2×), water (1×) and brine (1×), dried over MgSO4 and evaporated in vacuo. The residue was sonicated in diethyl ether for several minutes and the solid was collected by filtration to obtain the product (1.27 g, 1.2 mmol) as light brown solid. MS (ISP): (M+H) 488.3.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B15 was prepared following the general procedure reported for B10 using A1 and (R)-2-methylpyrrolidine. Yield: 31.5 mg (9%), colorless amorphous solid. MS (ES) C15H20N6O2S requires: 348. found: 349 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCCO)C>[Cu].[Cu-]=O.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[Cl:12])[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Nc1ccccc1Cl
Agent: O=[Cu-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccc(Cl)cc1Nc1ccccc1Cl
Temperature: 130 °C
Reaction time: 48 h
Yield: 29.2 %

Procedure:
In a 250 mL round bottom flask, 2-bromo-4-chloro-benzoic acid (10 g, 42.5 mmol), 2-chloroaniline (8.49 g, 7.0 mL, 66.6 mmol), potassium carbonate (9.39 g, 68.0 mmol), copper (0.092 g, 1.44 mmol) and copper (I) oxide (0.126 g, 0.88 mmol) were combined with 2-ethoxyethanol (20 mL). The mixture was heated to 130° C. for 4 hr. The mixture was cooled to room temp. and 150 mL of water was added. The slurry was stirred at room temperature for 2 days. The slurry was filtered and rinsed with 2-ethoxyethanol. The pH of the filtrate was adjusted to 7 using 4N HCl and the solid was filtered off. The green solid was then air-dried for 4 hr. to give 4-chloro-2-(2-chloro-phenylamino)-benzoic acid (3.5 g, 29% yield). The material was used in the next step without further purification. MS calcd. for C13H9Cl2N3O2 [(M−H)−1]280.0, obsd. 280.0.
Reaction SMILES: FC1C=NC2C=CC=C(N)C=2C=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[C:22]([CH2:25][C:26]([OH:28])=O)[CH:21]=[CH:20][CH:19]=2.[Br:29][C:30]1[C:31]([C:36]2[NH:40][CH:39]=[N:38][N:37]=2)=[C:32]([NH2:35])[S:33][CH:34]=1>>[Br:29][C:30]1[C:31]([C:36]2[N:40]=[CH:39][NH:38][N:37]=2)=[C:32]([NH:35][C:26](=[O:28])[CH2:25][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH:24]=[C:15]([F:14])[CH:16]=[N:17]3)[S:33][CH:34]=1
Reactant: O=C(O)Cc1cccc2ncc(F)cc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: Cl
Agent: Nc1cccc2ncc(F)cc12
Product: O=C(Cc1cccc2ncc(F)cc12)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared by converting 3-fluoroquinolin-5-amine (850 mg, 5.24 mmol) into 2-(3-fluoroquinolin-5-yl)acetic acid hydrogen chloride (76 mg, 315 umol) and reaction with 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (34 mg, 139 umol) as outlined in Example 1.68., above. Method [8] retention time 2.46 min by HPLC (M+206). 1H NMR (300 MHz, CDCl3) δ 12.35 (s, 1H), 8.89 (d, J=2.7 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.07 (dd, J=9.3 and 2.7 Hz, 1H), 7.83 (m, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.59 (s, 1H), 6.93 (s, 1H), 4.33 (s, 2H).
Reaction SMILES: C[Mg]Cl.[CH2:4]([CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:5][CH2:6][CH2:7][CH3:8].[C:15](O)(=O)C.O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:15][C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC1CCCC1=O
Reactant: CC(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCCC1(C)O
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A 3-L reaction flask was charged with methylmagnesium chloride (MeMgCl) solution in tetrahydrofuran (THF) (800 mL, 2.4 mol) and THF (500 mL). The reaction flask was cooled to 5-10° C. 2-Pentyl-cyclopentanone (370 g, 2.4 mol) (prepared as above in EXAMPLE I) was fed into the reaction mixture over an hour. The reaction was aged for 4 hours and then neutralized with acetic acid (CH3COOH) (160 g) while the temperature was maintained at 5-10° C. The reaction mixture was poured into H2O (3 L) and toluene (1 L). The organic layer was separated and fractional distilled to afford 1-methyl-2-pentyl-cyclopentanol (245 g) having a boiling point of 150-152° C. at 3 mmHg.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([OH:22])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.C(=O)(O)[O-].[Na+].[C:33]([O:40][CH2:41]I)(=[O:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(OCC)(=O)C>O.CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([O:22][CH2:41][O:40][C:33](=[O:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Reactant: CCCCCC(=O)OCI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Yield: 55.5 %

Procedure:
7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn-isomer: 1.5 g.) and sodium bicarbonate (0.56 g.) were dissolved in water (50 ml.) at room temperature with stirring and lyophilized. A solution of iodomethyl hexanoate (0.93 g.) in dimethylformamide (5 ml.) was added dropwise to a solution of the product obtained above in dimethylformamide (15 ml.) at -5° C. and stirred at the same temperature for 30 minutes. Ethyl acetate (50 ml.) and water (100 ml.) were added to the resultant solution and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml.) twice. The extracts were combined with the ethyl acetate layer, washed with a saturated aqueous solution of sodium bicarbonate three times and a saturated aqueous solution of sodium chloride three times in turn, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. After washing the concentrate with n-hexane (50 ml.), n-hexane (50 ml.) and diethylether (25 ml.) were added to the residue and allowed to stand in a refrigerator overnight. The precipitating powder was collected by filtration, washed with n-hexane and dried to give a mixture (1.0 g.) of n-hexanoyloxymethyl 7-(2-[2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer) and n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-2-cephem-4-carboxylate (syn-isomer.)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>CC(C)=O>[CH:15]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCNCC1
Reactant: Clc1cnccn1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2cnccn2)CC1
Temperature: 120 °C

Procedure:
Chloropyrazine (2.3 g, 20 mmol) and triethylamine (3 g, 30 mmol) were mixed in acetone (8 mL) in a 20 mL microwave vessel. 1-Isopropylpiperazine (2.8 g, 22 mmol) was added and the reaction mixture was heated for 3300 seconds at 120° C. in a microwave oven. The reaction mixture was evaporated and the residue was purified on a silicagel column with dichloromethane/MeOH (9:1) as eluent. Yield: 1.64 g solid 4-isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][C@H:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[C:19](O)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:71][CH2:70]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([CH:75]2[CH2:80][CH2:79][N:78]([C:19](=[O:20])[C@H:18]([NH:17][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([N:8]4[CH2:7][CH2:6][C:5]5[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=5[NH:3][C:2]4=[O:1])[CH2:14][CH2:13]3)=[O:16])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:77][CH2:76]2)[CH2:71][CH2:70]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3ccc4c(c3)CCCC4)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 500 mg (1.02 mmol) (R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic acid, 350 mg (1.09 mmol) TBTU, 0.19 mL (1.08 mmol) ethyldiisopropylamine and 30 mL THF was stirred for 30 min at RT, then combined with 195 mg (1.06 mmol) 1-methyl-4-piperidin-4-yl-piperazin and stirred overnight. The reaction mixture was poured onto 100 mL of a 15% K2CO3 solution and extracted twice with DCM. The combined organic extracts were dried, evaporated down under reduced pressure and the residue was purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of 1-(4-Fluoro-phenyl)-5-(5-nitro-pyridin-2-yloxy)-1H-indazole (0.28 g, 0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-ylamine as a colorless solid. 1H NMR (CD3OD, 400 MHz): δ 8.96 (d, 1H, J=2.8 Hz), 8.58 (dd, 1H, J=2.8, 9.2 Hz), 8.25 (s, 1H), 7.6-7.8 (m, 3H), 7.66 (1H, d, 2.4 Hz), 7.3-7.2 (m, 3H), 7.19 (d, 1H, J=9.2 Hz) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([O:25]CC)=[O:24])=[C:13]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH2:1]([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[C:13]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Yield: 5.6 %

Procedure:
To a suspension of ethyl [7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate (0.514 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was added a 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixture was heated at reflux for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 2) furnished 0.027 g (5.5%) of the title compound as a light yellow solid.