Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][CH2:6]2.[CH:13]([O-])=O.[Na+].C=O.O>C(O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][N:7]([CH3:13])[CH2:6]2
Reactant: O=C[O-]
Reactant: Oc1cc2c(cc1O)CNC2
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CN1Cc2cc(O)c(O)cc2C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
15.39 g (66 mmol) of 5,6-dihydroxyisoindoline hydrobromide and 4.48 g (66 mmol) of sodium formate were dissolved in 100 ml of a 50% formic acid aqueous solution, and then 5.17 ml (70 mmol) of 37% formalin was added thereto. The mixture was stirred at 80° C. for 4 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of water and subjected to active carbon treatment. The active carbon was filtered off, and the filtrate was stirred under cooling with ice, and adjusted to pH 8.0 with a saturated sodium hydrogen carbonate aqueous solution, and then it was stirred at the same temperature for about 30 minutes. The precipitates were collected, and washed with water to obtain yellowish green primary crystalline powder. This powder was combined with secondary crystalline powder obtained from the filtrate, and after an addition of 300 ml of water, stirred for 30 minutes. The insolubles was collected to obtain 7.87 g (yield: 72.3%) of the above identified compound.
Reaction SMILES: [CH3:1][C:2]([Cl:15])([CH3:14])[CH2:3][CH2:4][CH:5]1[N:9]([CH3:10])[S:8](=[O:12])(=[O:11])[NH:7][C:6]1=[O:13].[C:16]1([S:22][CH2:23]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:16]1([S:22][CH2:23][N:7]2[C:6](=[O:13])[CH:5]([CH2:4][CH2:3][C:2]([CH3:1])([Cl:15])[CH3:14])[N:9]([CH3:10])[S:8]2(=[O:12])=[O:11])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1C(CCC(C)(C)Cl)C(=O)NS1(=O)=O
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CN1C(CCC(C)(C)Cl)C(=O)N(CSc2ccccc2)S1(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
A mixture of 4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2.5 g, 9.81 mmol), phenylthiomethyl chloride (2.18 g, 13.74 mmol) and tetrabutylammonium bromide (0.369 g, 1.145 mmol) suspended in 150 ml of DMF was heated at 100° C. for 18 hours. After adding additional TBAB (0.369 g), the mixture was stirred at 95° C. for 4 hours, cooled, and poured into ice/water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (15% ethyl acetate in hexane) to afford 1.396 g (39%) of 2-phenylthiomethyl-4- (3-methyl-3-chlorobutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2C(Cl) (CH3)2 ; R3 =CH3) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][N:19]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
2,6-Dichlorobenzoyl isocyanate (2.2 grams; 0.01 mole) and 5-chloro-2-aminopyridine (1.3 grams; 0.01 mole) were mixed in about 50 ml. of ethyl acetate, at room temperature, and the reaction mixture was stirred overnight (about 18 hours) at room temperature. Solvent was then evaporated, water was added, and the product was extracted with ethyl acetate. The ethyl acetate was evaporated, and the product recrystallized from ethanol, m.p., 211°-215° C. Elemental analysis showed the following:
Reaction SMILES: [CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16](SC)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3].[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].C(OC([C@@H]1CCN(CC2C=CC=C3C=2C(NC2C=CC=C(OC)C=2)=NC=N3)C[C@@H]1C(OC)=O)=O)C=C>CO>[CH2:1]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[C:32]([C:30]#[CH:31])[CH:33]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:26]([O:28][CH3:29])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: C#Cc1cccc(N)c1
Reactant: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(SC)c23)C[C@@H]1C(=O)OC
Agent: C=CCOC(=O)[C@@H]1CCN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)C[C@@H]1C(=O)OC
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](C(=O)OCC=C)[C@@H](C(=O)OC)C4)c23)c1

Procedure:
Compound 18A was prepared from 15B and 3-ethynylaniline in a similar way as 15C. It has an analytical HPLC retention time=2.353 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=500+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCC([O-])(C)C.[Na+].O=[C:32]1[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]1.[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:2][O:3][CH:4]=[C:32]1[CH2:35][CH:34]([C:36]([O:38][CH3:39])=[O:37])[CH2:33]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CC(=O)C1
Agent: CCC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: COC=C1CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of methoxymethyltriphenylphosphonium chloride (1350 g, 3.90 mol) in anhydrous benzene (12 L), a solution of sodium tert-pentoxide (435 g, 3.90 mol) in anhydrous benzene (4 L) was added slowly under nitrogen atmosphere. The resulting red solution was stirred for 15 minutes at ambient temperature. Then, a solution of methyl 3-oxocyclobutanecarboxylate (250 g, 1.95 mol) in anhydrous benzene (1 L) was added slowly and the reaction mixture was heated at 70° C. for 2 hours. Saturated aqueous ammonium chloride (˜4 L) was added to the reaction mixture and extracted with diethyl ether (5 L). The organic layer was washed with water (5 L×2), brine (5 L), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (mesh 60-120; eluent: 10% diethyl ether in hexane) to afford the title compound as a pale yellow liquid. 1H NMR (300 MHz, CDCl3): δ 2.89-2.92 (m, 2H), 2.96-3.0 (m, 2H), 3.14-3.17 (m, 1H), 3.56 (s, 3H), 3.70 (s, 3H), 5.81-5.83 (m, 1H). GC-MS: [M]+ m/z=156.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])([O-:3])=O.C(OC([CH:21]=[CH:22][CH2:23][NH2:24])=O)(C)(C)C>CC(C)=O>[NH2:24][CH2:23][CH:22]1[O:3][N:1]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:21]1
Reactant: CC(C)(C)OC(=O)C=CCN
Reactant: CC(C)(C)OC(=O)CCC[N+](=O)[O-]
Solvent: CC(C)=O
Product: NCC1CC(CCC(=O)O)=NO1

Procedure:
The racemic product is prepared starting from tert.-butyl 4-nitrobutyrate and N-tert.-butoxycarbonylallylamine in analogy to Example 12. After cleavage of the protecting groups, it is taken up in acetone and the betaine is precipitated by adjusting the pH to 6 by means of conc. aq. ammonia. The melting point is 201° C. (with dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[N:7]([CH2:17][C@@H:18]([OH:53])[C@@H:19]([NH:29][C:30](=[O:52])[C:31]1[CH:36]=[C:35]([C:37](=[O:48])[NH:38][CH:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH3:40])[CH:34]=[C:33]([C:49](=[O:51])[CH3:50])[CH:32]=1)[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:54])[N:7]([CH2:17][C@@H:18]([OH:53])[C@@H:19]([NH:29][C:30](=[O:52])[C:31]1[CH:32]=[C:33]([CH:49]([OH:51])[CH3:50])[CH:34]=[C:35]([C:37](=[O:48])[NH:38][CH:39]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH3:40])[CH:36]=1)[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(C(=O)NC(C)c3ccc(F)cc3)c2)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)NC(C)c3ccc(F)cc3)cc(C(C)O)c2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
[(2R,3S)-3-{3-Acetyl-5-[1-(4-fluoro-phenyl)-ethylcarbamoyl]-benzoyl-amino}-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-methoxy-benzyl)-carbamic acid tert-butyl ester (10 mg, 0.0134 mmol) was dissolved in MeOH (0.1 mL) and sodium borohydride (0.68 mg, 0.0179 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The organic layer was separated and concentrated under vacuum to give the title compound (10 mg): HPLC retention time: 2.243 min (method A). MS (ESI) (M+H)+ 750.40.
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Cl:1][C:9]1[CH:8]=[C:7]([C:10]([Cl:11])([Cl:12])[Cl:13])[CH:6]=[CH:5][C:4]=1[Cl:3]
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: ClCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Temperature: 0 °C
Yield: 75.6 %

Procedure:
Chlorine gas was passed into a mixture of 115 g (0.5 mol) of p-chlorobenzotrichloride and 0.8 g (6 mmol) of aluminum chloride for 8.5 hours at 60° to 80° C. The mixture was then worked up by adding 200 ml of ice-cooled dilute hydrochloric acid to the reaction mixture, filtering off the solid constituents, separating off the organic phase from the filtrate, washing the organic phase five times with, in each case, 100 ml of water, then drying it over calcium chloride and subsequently distilling it over a packed column of 60 cm in length and having a silvered casing of glass. In this procedure, 100 g (75.6% of theory) of 3,4-dichlorobenzotrichloride (purity 99%) of boiling point 87° to 97° C./0.22 mm Hg were obtained. The purity and the structure of the product were unequivocally determined by a gas chromatogram and by a nuclear-magnetic resonance spectrum.
Reaction SMILES: C1(C=CC(C2C=CC=CC=2)=O)C=CC=CC=1.BrC1C=CC(C)=CC=1.[CH3:25][N+:26]([CH3:28])=[CH2:27].[I-].[ClH:30].CN(C)[C:33](C)([CH:42]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1)[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[ClH:30].[CH3:27][N:26]([CH2:28][CH:33]([CH:42]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:43]1[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=1)[C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:25]
Reactant: C=[N+](C)C
Reactant: Cc1ccc(C(c2ccccc2)C(C)(C(=O)c2ccccc2)N(C)C)cc1
Agent: Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C(C=Cc1ccccc1)c1ccccc1
Product: Cc1ccc(C(c2ccccc2)C(CN(C)C)C(=O)c2ccccc2)cc1

Procedure:
The synthesis was carried out according to the procedure of Example 38 and the chalcone derivative was reacted with 4-bromotoluene. The Eschenmoser salt was then added in an equimolar amount. The yield of (2RS)-(3RS)-2-dimethylamino-methyl-1,3-diphenyl-3-p-tolylpropan-1-one hydrochloride was 0.7 g (41%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OCCCBr)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-hydroxyphenylacetate (11.3 g, 0.068 mole) in 300 mL of anhydrous toluene was treated with 3-bromopropanol (12.2 g, 0.088 mole). Polymer bound triphenylphosphine (36.0 g, 0.108 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture reacted for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (16.9 g, 0.084 mol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered and the solid washed with 100 mL toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 15.8 g (81% yield) of the title compound as an oil:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[CH2:16](B(O)O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)CCc1ccccc1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc2ccc(CCc3ccccc3)cc2c1
Temperature: 130 °C
Yield: 45.6 %

Procedure:
To a 2-5 mL microwave vial fitted with a stirbar was added methyl 6-bromoquinoline-3-carboxylate (0.25 g, 0.94 mmol), phenethylboronic acid (0.282 g, 1.88 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.0773 g, 0.094 mmol), and potassium carbonate (0.39 g, 2.82 mmol). The vial was capped and 1,4-dioxane (4 mL) and water (1 mL). The contents of the vial were heated in a microwave at 130° C. for 0.5 h. The vial was cooled to room temperature and opened. The contents were partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes to 75/25 hexanes/ethyl acetate gradient) to afford the desired product (0.125 g, 36%). LC-MS: (FA) ES+ 292.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.COC(C)(C)C>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=2)[CH:21]=[N:20]1
Reactant: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (160 g, 488 mmol) was dissolved under Ar in N,N-dimethylformamide (1.5 L) before 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (143 g, 687 mmol), potassium carbonate (160 g, 1.16 mol), and water (130 mL) were added. The solution was degassed and tetrakis-(triphenylphosphine)palladium(0) (24.0 g, 20.8 mmol) was added. The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was poured onto water (5 L) and extracted with ethyl acetate (1×3 L, 2×1 L). The combined organic extracts were washed with brine (1 L), the volume was reduced in vacuo to ca. 2 L and dried over sodium sulfate. The resulting filtrate was further reduced in vacuo until precipitation occurred and a homogeneous slurry was formed. Tert-butyl methyl ether (1 L) was then added in portions to the distillation, keeping the overall volume constant (solvent exchange). The suspension was cooled to 5° C. (ice bath) and filtered. The precipitate was washed with tert-butyl methyl ether (500 mL) and dried in vacuo to provide 141 g of the title compound as brown crystalline solid (88%). MS (ESI & APCI): m/z=330.1 [M+H]. 1H NMR (CDCl3, 600 MHz): δ 2.54 (t, J=7.4 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H), 5.39 (bs, 1H), 5.52 (bs, 1H), 7.56 (s, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 7.73 (bs, 1H), 7.77 (d, J=0.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>C(#N)C.C(O)(C)C>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cn1
Reactant: NCC(O)CO
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(NCC(O)CO)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.5 g (0.003 mol) 6 and 0.3 g (0.003 mol) triethylamine in 10 ml acetonitrile is added 0.32 g (0.0035 mol) 3-amino-1,2-propanediol (10) in 10 ml iso-propanol. After stirring for 18 hours at room temperature the solvent is removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel eluting with 10% methanol/chloroform. Pure 12 has Rf 0.4 and is a pale yellow solid, m.p. 185°-7°.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([N:18]3[CH2:17][C@@H:16]4[CH2:21][C@H:19]3[CH2:20][N:15]4[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:26]=2)=[N:4][CH:3]=1
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Temperature: 85 °C
Yield: 105.3 %

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2.26 g, 8.14 mmol), 4-((1S,4S)-5-Isopropyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamine (2.07 g, 8.95 mmol, 1.10 equiv.) and DiPEA (4.3 mL, 24.42 mmol, 3.00 equiv.) are mixed in isopropanol (28 mL) under nitrogen. The reaction is heated to 85° C. until completion of the reaction (typically 5 h). The solvent is removed under vacuum and the residue is partitioned between 60 mL aqueous sodium phosphates buffer (pH 7) and 200 mL DCM, the organic layer is washed with 60 mL satd. NaCl, dried on anhydrous Na2SO4, filtered and evaporated in vacuo to yield the title compound (3.67 g) as a green-black foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:13][CH2:14]3)[C:6]=2[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc2c1c(C)nn2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CC2)c2nc(Cl)cc(C(=O)O)c12

Procedure:
To a solution of methyl 6-chloro-1-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (370 mg, 1.393 mmol) in ethanol (30 mL) was added 1N sodium hydroxide (1.393 mL, 1.393 mmol) and heated at reflux for 2 hours. The solvent was removed in vacuo, the residue dissolved in 20 mL of water, and acidified with acetic acid. The contents were extracted with EtOAc (4×30 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The product was collected as 297 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-1.43 (m, 4 H), 2.55 (s, 3 H), 3.63-4.15 (m, 1 H), 7.52 (s, 1 H), 14.18 (br. s., 1 H). LCMS(ES) [M+H]+252.4
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:8])[O:5]CC)C.CO.O>C(Cl)(Cl)(Cl)Cl>[CH:19]1([NH:18][CH:9]([P:10](=[O:11])([OH:14])[OH:17])[P:4](=[O:3])([OH:5])[OH:8])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: CCOP(=O)(OCC)C(NC1C=CCCCC1)P(=O)(OCC)OCC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: O=P(O)(O)C(NC1C=CCCCC1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.1 %

Procedure:
2.5 ml of trimethylsililiodide was added dropwise to an ice-cold solution of 1.55 g of tetraethyl(2-cycloheptenyl)aminomethylene-bis(phosphonate) in 25 ml of carbon tetrachloride. Then, the mixture was stirred at room temperature for 2.5 hours. 2 ml of methanol and 1 ml of purified water were added to the ice-cold reaction solution and it was concentrated under reduced pressure. To the obtained residue were added methanol and acetone to give a white solid. The residue was recrystallized from water-methanol to give 0.39 g of (2-cycloheptenyl)aminomethylenebis(phosphonic acid) as colorless crystals in the form of needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH2:20][OH:21]>C(Cl)CCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[CH:20]=[O:21]
Reactant: O=S(=O)(c1ccc(Br)c(CO)c1)n1ccc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: O=Cc1cc(S(=O)(=O)n2ccc3ccccc32)ccc1Br
Yield: 72.7 %

Procedure:
To a solution of [2-Bromo-5-(indole-1-sulfonyl) phenyl] methanol (4.73 grams, 12.92 mmol) (obtained from preparation 2) in ethylene dichloride (75 mL) was added manganese dioxide (8.92 grams, 102.5 mmol). The reaction mass was heated to reflux temperature and maintained under reflux for 3 hours while monitoring the progress of the reaction by TLC. After completion of the reaction, the reaction mass was filtered through hyflow bed and the bed was washed with ethylene dichloride (2×10 mL). The clear filtrate was concentrated under reduced pressure to obtain technical product. The technical material was triturated with of n-hexane (2×15 mL), decanted the solvent and dried under reduced pressure to obtain 3.42 grams title product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:28])[CH2:24][O:23][C:22]3=[O:29])=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:30][C:17]1[CH:16]=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:31])[CH:20]=[CH:19][C:18]=1[N:21]1[C@H:25]([CH2:26][O:27][CH3:28])[CH2:24][O:23][C:22]1=[O:29]
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1F
Temperature: 25 °C
Yield: 99.9 %

Procedure:
(R)-4-[3-Fluoro-4-(4-methoxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (506 mg) described in Preparation Example 93 was dissolved in ethyl acetate (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added and the mixture was stirred at room temperature. Under ice-cooling, the reaction mixture was neutralized with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and extracted once with ethyl acetate and the aqueous layer was extracted with twice with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (390 mg).