Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[N:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:13][CH:12]=3)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:27][CH:26]=2)=[CH:33][CH:32]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)CCC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-benzoylamino)-propionic acid methyl ester (isomer 1, 80 mg, 0.15 mmol) is dissolved in the tetrahydrofuran (1 mL) and sodium hydroxide solution (5 M, 1.0 mL, 5 mmol) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with 5N HCl, diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound is used without further purification. MS (ES): 515.2 [M−H]−, the structure was also confirmed by proton NMR.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:19]=[CH:18][C:9]2[CH2:10][CH2:11][CH:12]([C:16]#[N:17])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4].C(O)C>O>[OH:15][C@H:14]1[C:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:19]=[CH:18][C:9]=2[CH2:10][CH2:11][C@H:12]([C:16]#[N:17])[CH2:13]1
Reactant: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#C[C@H]1CCc2ccc([N+](=O)[O-])cc2[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
10 g of sodium borohydride were added over 5 minutes under nitrogen to a mixture of 20 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile, 200 ml of ethanol and 20 ml of water and the mixture was stirred for one hour at room temperature and then evaporated to dryness under reduced pressure. 400 ml of water were added to the residue and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 18 g of raw product which were chromatographed over silica gel. Elution with a 9-1 ethyl acetate-triethylamine mixture yielded 2 fractions. The first fraction of 6.5 g of trans product occured in the form of a yellow oil with an Rf = 0.65 which was crystallized from ethyl acetate to obtain 4.5 g of trans 5-hydroxy-3-nitro-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile in the form of white crystals melting at 160° C. The second fraction of 7.9 g of cis product occured in the form of a yellow oil with a Rf = 0.55 which crystallized from ethyl acetate to obtain 6.5 g of cis 5-hydroxy-3-nitro-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile in the form of white crystals melting at 142° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10]C=C2[C:3]=1[CH:4]=[CH:5]C=[C:7]2[CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33]([O:37]C(NC(NC(OC(C)(C)C)=O)=N)=O)(C)(C)[CH3:34].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.O>[CH3:34][CH2:33][O:37][C:12]([CH3:7])=[O:13].[CH3:10][CH2:11][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OCc1cccc2c(Br)cccc12
Reactant: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 243.9 %

Procedure:
(5-Bromonaphthalen-1-yl)methanol (275 mg), PPh3 (456 mg, 1.5 eq.), and 1,3-bis(t-butoxycarbonyl)guanidine (601 mg, 2 eq.) in 5 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.34 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H2O were added, and the solution was concentrated. Chromatography achieved using ISCO max gradient 20% EtOAc/hexane yielding product as a white solid (493 mg, 90% yield). 1H NMR (400 MHz) (CDCl3) δ 9.47 (bs, 2H), 8.11 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.46 (t, J=16 Hz, 1H), 7.28 (t, J=16 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 5.62 (s, 2H), 1.36 (s, 9H), 1.07 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ160.83, 154.95, 135.04, 131.95, 129.89, 126.71, 126.26, 126.16, 123.71, 122.87, 122.73, 84.19, 79.03, 45.10, 28.23, 27.61.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1.O>O1CCOCC1>[F:35][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of methyl 4-(1-(4,4-difluoro-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (enantiomer 1) (D137a) (140 mg, 0.28 mmol) in dioxane (3 ml) and water (3 ml) LiOH H2O (47 mg, 1.12 mmol) was added and the mixture was left stirring at RT for 16 hrs. Dioxane was evaporated off then acetic acid was added to the aqueous layer until the solution reached the value of p≈4. The solid was filtered off and dried under vacuum to afford the title compound (E18) (90 mg)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10]N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]2[C:5]=1[C:13]1[CH2:12][CH2:19][CH2:17][C:15](=[O:16])[C:14]=1[NH:10]2
Reactant: O=C1CCCCC1=O
Reactant: NNc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CO
Product: O=C1CCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Temperature: 60 °C
Yield: 98.4 %

Procedure:
(2,5-Dichlorophenyl)hydrazine hydrochloride (0.3 g, 1.40 mmol) was dissolved in MeOH (3 mL) and 1,2-cyclo hexadione (0.15 g, 1.40 mmol) was added and the mixture heated to 60° C. for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was diluted with water, neutralized with NaHCO3 solution and extracted with EtOAc (3×15 mL). The combined organic extracts were concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to provide the title compound (0.35 g, 11.8%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.92 (bs, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 3.36 (t, J=6.2 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:23][NH:22][CH2:21][CH2:20][N:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C(OCC)(=O)C>C1COCC1>[C:31]1([S:37]([N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:18]([C:14]3[CH:13]=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[CH2:23]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccccc1N1CCNCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-(3′-methanesulfonyl-biphenyl-3-yl)-1-o-tolyl-piperazine hydrochloride (58 mg) in THF (1 mL) sodium hydride (12.3 mg, 60% in mineral oil) was added. After stirring for 30 min at room temperature, benzenesulfonyl chloride was added at 0° C. and stirring was continued at room temperature overnight. Water and ethyl acetate was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 2:1,) yielded 4-benzenesulfonyl-2-(3′-methanesulfonyl-biphenyl-3-yl)-1-o-tolyl-piperazine (55 mg, 42%) as colorless oil, MS: 547.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH:18]1([NH:22][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCC1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a solution of 4-(4-acetylpiperazin-1-yl)benzaldehyde (150 mg, 0.64 mmol) and cyclobutylamine (75 mg, 0.77 mmol) in dichloroethane (1.5 mL) was added sodium triacetoxyborohydride (216 mg, 0.96 mmol), followed by acetic acid (0.055 mL, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then quenched with 1 N aqueous NaOH, diluted with dichloromethane and the dichloromethane layer was isolated with a phase-separator cartridge and concentrated to give 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg). The product was used without purification. LCMS (m/z) ES+ 288 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[S:27][C:28]([CH2:31][N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:30]=2)=[CH:20][N:19]=1)([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[S:27][C:28]([CH2:31][N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[CH:20][N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CCCCN
Reactant: CCCCN(CCCC)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Product: CCCCN(CCCC)Cc1ccc(Cc2cnc(NCCCCc3ncccc3OC)[nH]c2=O)s1

Procedure:
Reaction of 4-(3-methoxypyridyl)butylamine with 2-nitroamino-5-(5-di-n-butylaminomethyl-2-thienylmethyl)-4-pyrimidone gives 2-[4-(3-methoxypyridyl)butylamino]-5-(5-di-n-butylaminomethyl-2-thienylmethyl)-4-pyrimidone.
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH2:18][CH:19]=[CH2:20])(=[O:16])=[O:15])=[CH:9][CH:8]=1>O.Cl>[ClH:5].[NH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14]([NH:17][CH2:18][CH:19]=[CH2:20])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: C=CCNS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCNS(=O)(=O)Cc1ccc(NN)cc1
Reaction time: 1.33 h

Procedure:
A solution of sodium nitrite (1.06 g) in water (2.5 ml) was added dropwise to a stirred suspension of the product from stage (b) (3.5 g) in 5N hydrochloric acid (28 ml) between -8° and -3° under nitrogen and stirring was continued at ca -3° for 80 min. The mixture was filtered, and the clear yellow filtrate was added dropwise from an ice-cooled, jacketed dropping funnel to a stirred solution of stannous chloride dihydrate (17.5 g) in concentrated hydrochloric acid (17.5 ml) between -2° and +1° over 35 min. After warming up to 10° over 15 min, the mixture was filtered, and the residue was washed with concentrated hydrochloric acid (4×30 ml) and dry ether (4×30 ml) and dried to give the title compound as a very pale yellow solid (2.44 g), m.p. 163°-166°, containing 5% inorganic material.
Reaction SMILES: [Cl-].[CH2:2]([O:4][N:5]=[C:6]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3].C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH2:2]([O:4][N:5]=[C:6]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O-:29])=[O:28])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3cccc(N(C)C)c3)CS[C@H]12)c1nsc(N)n1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3cccc(N(C)C)c3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
A mixture of diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate chloride (syn isomer) (0.42 g) and anisole (1 ml) in trifluoroacetic acid (3.5 ml) was stirred for 15 minutes under cooling in an ice bath. The mixture was poured into diisopropyl ether (10 ml) and a resulting precipitate was filtered. The powder was dissolved in water and subjected to column chromatography on a non ionic adsorption resin "Diaion HP 20" (10 ml). After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluates containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.12 g), mp 129° to 138° C. (dec.).
Reaction SMILES: C1(C2[O:11][C:10](=[O:12])[NH:9]C2=O)C=CC=CC=1.C(=O)([O-])N.[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20]>>[C:18]([OH:28])(=[O:27])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].[C:10](=[O:11])([OH:12])[NH2:9].[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20]
Reactant: O=C1NC(=O)C(c2ccccc2)O1
Agent: NC(=O)[O-]
Agent: O=C(O)[C@H](O)c1ccccc1
Product: NC(=O)O
Product: O=C(O)C(O)c1ccccc1

Procedure:
According to the present invention, the carbamyl derivative of D(-) madelic acid can be advantageously prepared by the stereoselective enzymatic hydrolysis of the corresponding 5-phenyl-2,4-oxazolidinedione. A further considerable advantage of the process according to the present invention is that the enzymatic reaction substrate recemises spontaneously under the hydrolysis conditions, so that at the end of the reaction the carbamate of the D-mandelic acid is obtained in a stoichiometric quantity with respect to the starting substrate. The reaction scheme is as follows: ##STR5## D(-) mandelic acid is then obtained from the D-mandelic acid carbamate by hydrolysis in an acid environment.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].OS(O)(=O)=O>O>[CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@@H:9]2[O:14][C@@H:13]([CH2:15][NH2:16])[C@H:12]([OH:17])[C@@H:11]([OH:18])[C@@H:10]2[OH:19])[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: NC[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@@H](O)[C@H](O)[C@H]1O
Yield: 113.6 %

Procedure:
Kanamycin sulfate (20.0 g) was dissolved in 200 mL of water. This was loaded on a column prepared with 400 g of AMBERLITE IRA-140 resin (6.4 cm×17.5 cm). The column was eluted with water, and the appropriate fractions were collected and lyophilized to give 18.9 g of kanamycin A (free base) (18).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[CH3:29])=[CH:16][C:15]=1[F:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:35]=[O:36]>>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:35]=[O:36])=[C:21]2[CH3:29])=[CH:16][C:15]=1[F:30])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (3 mL) was added to anhydrous dimethylformamide (6 mL) and the mixture allowed to stir at room temperature for 15 min. A mixture of 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole (1.03 g, 3.1 mmol) in dimethylformamide (10 mL) was added and the mixture heated to 80° C. and held for 18 hr. The reaction mixture was poured onto ice and adjusted to a pH of 7 by the addition of 2 N NaOH. The mixture was extracted with ethyl acetate (2×100 mL), the organic layer washed with water and brine and dried over MgSO4, and evaporated to provide the product as a dark solid. Purification by silica gel chromatography (25% EtOAC-hexanes) provided a white solid (0.84 gr, 76%): mp 166-168-152° C.; 1H NMR (DMSO-d6): δ 2.55 (3H, s), 5.30 (2H, s), 7.04 (1H, d, J=6.9 Hz), 7.19-7.28 (2H, m), 7.23-7.52 (7H, m), 7.44 (2H, dd, J=6.0 Hz, J=1.4 Hz), 7.59 (1H, dd, J=11.7 Hz, J=2.5), 8.17 (1H, dd, J=7.0 Hz, J=1.0), 10.20 (1H, s) Hz; MS m/z (M+H)+ 360: Anal. for C23H18FNO2 (0.1H2O): Calc'd: C, 76.48; H, 5.08; N, 3.88. Found: C, 76.39; H, 4.81; N, 3.69
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:17][CH:18]2[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]2=[O:25])[N:3]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[C:4]([NH:17][CH:18]3[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]3=[O:25])[N:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(Nc3ccc(OC)cc3)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 18.5 h
Yield: 57.1 %

Procedure:
A suspension of 5-[4-chloro-6-(4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-3-methyl-imidazolidine-2,4-dione (Example 1.10, Part A) (50 mg, 0.14 mmol), p-methoxyaniline (25 mg, 0.21 mmol) and potassium carbonate (48 mg, 0.34 mmol) in anhydrous DMF (5 mL) was stirred under a nitrogen atmosphere for 18.5 h. The reaction mixture was diluted with water and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated, and the crude product was purified by column chromatography (silica; dichloromethane:ethyl acetate starting with a solvent ratio of 10:1 and increasing the polarity to dichloromethane:methanol, 10:1) to afford the product as a pale yellow solid (36 mg, 58%). δH (300 MHz, (CD3)2CO) 8.14 (br s, 2H, NH), 7.60 (br s, 4H, ArH (ortho to NH attach)), 7.43 (br s, 1H, NH), 6.91 (d, J 8.7 Hz, 1H, NH), 6.85 (d, J 9.0 Hz, 4H, ArH (ortho to O attach)), 5.91 (d, J 7.8 Hz, 1H, CH), 3.77 (s, 6H, OCH3), 2.86 (br s, 2.0H, NCH3), 2.73 (br s, 1.0H, NCH3). Mass spectrum (ESI) m/z 451 (37%, MH+).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([Cl:22])=[O:21]>O1CCOCC1>[ClH:22].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:21]
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cccc3F)n2)CC1
Product: Cl
Yield: 80.3 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 200 mg, 0.907 mmol), 2,6-difluorobenzoyl chloride (125 μL, 0.998 mmol), and 1,4-dioxane (10 mL) to yield 289 mg (80%) of the title compound: mass spectrum (ion spray): m/z=361.3 (M+1); Analysis Calcd for C19H23N4OF2Cl.0.5H2O: C, 56.22; H, 5.96; N, 13.80. Found: C, 56.49; H, 5.80; N, 14.15. mp 308° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:26]I.[Cl-].[NH4+]>C1COCC1>[I:26][C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A solution of 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (2.0 g, 9.0 mmol) in THF (50 ml) was cooled to −78 C under a nitrogen atmosphere. To this was added tert butyl lithium (5.9 ml) in pentane (1.7M, 10 mmol). After 10 minutes iodine (2.53 g, 10 mmol) in THF (10 ml) was added and the reaction mixture was stirred for a further 30 minutes before allowing to warm to ambient temperature followed by stirring for 12 hours. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 20-100% dichloromethane in hexane to give the product as a solid (0.96 g, 30%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=12.[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:14][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccn2ccnc2c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of Methyl imidazo[1,2-a]pyridine-7-carboxylate (3.8 g, 21.6 mmol, 1.0 equiv) in DMF (20 ml) was added N-iodosuccinimide (5.8 g, 26 mmol, 1.2 equiv) and the resulting mixture was stirred for 2 h at room temperature. The brown slurry was diluted with water, 10% w/v sodium thiosulfate and sodium carbonate (1M) and the resulting white solid was removed by filtration, washed with ether and dried to afford 4.7 g of product. MS: [M+H]+ 303; 1H NMR (400 MHz, Me-d3-OD): 8.44 (1H, d), 8.25 (1H, s), 7.88 (1H, s), 7.61 (1H, dd), 3.95 (3H, s).