Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:37])[CH:3]([OH:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(#N)C>[NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)nc2C1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Yield: 62.6 %

Procedure:
Oxidation of tert-butyl 2-(3-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamoyl)pyridin-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (88 mg, 0.174 mmol) as described in example 1.4 and purification by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) gave 55 mg of an amorphous solid; ESI-MS [M+H]+: 505.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.83 (m, 1H), 8.52 (m, 1H), 8.15 (m, 1H), 8.06 (m, 1H), 7.84 (m, 1H), 7.72 (m, 1H), 7.44 (m, 1H), 7.23 (m, 4H), 7.17 (m, 1H), 5.26 (m, 1H), 4.35 (m, 2H), 4.18 (m, 1H), 4.0 (m, 1H), 3.09 (m, 1H), 2.73 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[C:9]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCNC1=O

Procedure:
A solution of 6-2 (28.0 g, 98 mmol), Mg(CIO4)2 (4.3 g, 20 mmol), and CH3CN (400 mL) was heated at 50° C. for 3 hr. The cooled solution was diluted with CHCl3 and then washed with 1N HCl, sat. naHCO3, and brine, dried (Mg S4), and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes→EtOAc) gave 6-3 as a yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([Br:29])=[CH:12][C:11]=1[OH:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([Br:29])=[CH:12][C:11]=1[O:30][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCOc1cc(Br)c(O)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(Br)c(OCc2ccccc2)cc1Br
Temperature: 50 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
Benzyl bromide (3.8 ml, 0.031 mol) was added drop wise to a stirred solution of 2,5-dibromo-4-dodecyloxy phenol (a) (6.95 g, 0.015 mol) and anhydrous K2CO3 (3.28 g, 0.023 mol) in 700 ml of absolute ethanol at 40-50° C. The reaction mixture was stirred for 10 h at 50° C., progress of the reaction was monitored using TLC, cooled to RT and evaporated to remove the solvent. An equal volume of distilled water was added to the residue and the mixture was stirred for one hour at 0° C. The resulting precipitate was collected by filtration, washed with water, and dried in vacuum. Recrystallization was done in methanol to get 80% yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[C:22]([C:23]([O:25]C)=O)=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[NH4+:28]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[O:15][C:16]4[C:22]([C:23]([NH2:28])=[O:25])=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(CN4CCNCC4)c3)oc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
Methyl 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (79 mg, 0.23 mmol) and ammonium water (64.4 mg, 1.84 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide (12 mg, yield 13%). 1H-NMR (400 MHz, DMSO-d6) δ 2.91 (s, 4H), 3.21 (s, 4H), 4.20 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.67 (s, 2H), 7.81-7.97 (m, 4H), 8.31 (s, 2H); LC-MS (ESI) m/z 337 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[C:8](=[O:9])[N:7]([CH3:10])[N:6]([CH3:11])[C:5]=1[CH3:12])([O-])=O.Cl.[OH-].[Na+]>[Zn].O>[NH2:1][C:4]1[C:8](=[O:9])[N:7]([CH3:10])[N:6]([CH3:11])[C:5]=1[CH3:12]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N)c(=O)n(C)n1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2.8 g. 4-nitro-1,2,3-trimethylpyrazolin-5-one in 8.4 ml. concentrated hydrochloric acid and 3 ml. water is added dropwise, with cooling, to a suspension of 6.4 g. zinc dust in 5 ml. water, the reaction temperature thereby being kept between 25° and 30° C. The reaction mixture is then further stirred for 2 hours at 60° C., whereafter the reaction mixture is poured on to ice and rendered alkaline with 5N aqueous sodium hydroxide solution. The precipitated zinc salts are filtered off with suction, the mother liquor is substantially evaporated and the residue is shaken out several times with chloroform. After drying the organic phase over anhydrous sodium sulphate, it is evaporated in a vacuum, the desired product thereby crystallising. Yield: 0.93 g. (40% of theory).
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15](=[O:32])[NH:16][C:17]2[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([O:25]C(C)C)=[O:24])=[CH:19][C:18]=2[CH3:31])=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].O.Cl>C(O)(=O)C>[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15](=[O:32])[NH:16][C:17]2[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][C:18]=2[CH3:31])=[O:13])=[CH:33][CH:34]=1)(=[NH:6])[NH2:7]
Reactant: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C(=N)N)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC(=O)O)ccc1NC(=O)NC(=O)c1ccc(C(=N)N)cc1
Reaction time: 72 h
Yield: 63.8 %

Procedure:
A mixture of isopropyl 4-[3-(4-amidinobenzoyl)ureido]-3-methylphenoxyacetate, acetate salt (500 mg), water (50 ml), 50% aqueous acetic acid (1.5 ml) and 2N HCl (1.5 ml) was stirred and heated to 90°-100° C. until all the solids had dissolved. The hot solution was then quickly filtered and the filtrate was heated to 80°-85° C. and stored at that temperature for 3 days. The mixture was cooled and the solid was collected, washed thoroughly with water, methanol and with ether. The solid was suspended in refluxing methanol/dichloromethane, 4:1 (50 ml). The insoluble material was collected, washed with hot methanol and with ether and dried to give the title compound (250 mg), as a pale yellow solid: NMR Spectrum (DMSO-d6 +CF3CO2H) 2.30 (3H, s), 4.66 (2H, s), 6.81 (1H, dd), 6.89 (1H, d), 7.78 (1H, d), 7.97 (2H, d), 8.24 (2H, d), 9.17 (2H, br s), 9.48 (2H, br s), 10.51 (1H, s), 11.25 (1H, s); m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.25 H2O: C, 55.0%; H, 5.26%; N, 14.3%; found: C, 54.9%; H, 5.3%; N, 14.2%.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:13]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:11]=1.[C:36](=O)([O:39]C)[O:37][CH3:38]>>[CH3:38][O:37][C:36](=[O:39])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:13]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 4.4 mL, 7.92 mmol) was added slowly to a stirred solution of 4-methyl-2,6-bis-(4-trifluoromethylphenyl)-pyridine (1.37 g, 3.6 mmol) under N2 at −78° C. After 30 minutes, dimethyl carbonate (720 μL, 8.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes The reaction was quenched with saturated aqueous NH4Cl (10 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (10-50% CH2Cl2 in heptane) to give the product as a white solid (1.38 g, 87%). 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.91 Hz, 4H), 7.76 (d, J=7.91 Hz, 4H), 7.72 (s, 2H), 3.80 (s, 2H), 3.77 (s, 3H). MS m/e 440.2 (M+H)
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)=[O:7])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCOCC1.C(Cl)Cl.CO>[Cl:38][C:10]1[N:9]=[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:12]=2[CH:11]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NNC(C)=O)c12
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3nnc(C)o3)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N′-acetyl-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (48 mg, 0.091 mmol) was taken up in 1,4-dioxane (1.0 ml) and Burgess reagent (39.1 mg, 0.164 mmol) was added. The reaction mixture was stirred at 100° C. for 1 hour. Room temperature was attained. The reaction mixture was diluted with DCM and MeOH and was concentrated in vacuo while loading onto silica gel. The products were then purified by MPLC 0-25% EtOAc/hexanes to give 2-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-5-methyl-1,3,4-oxadiazole (43B). MS: [M+H]+ m/z 508.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CS(C)=O>O>[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([C:8]3[N:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: CNc1ncnc(-c2cccnc2Cl)n1
Reactant: O=C(O)c1cc(O)ccc1F
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncnc(-c2cccnc2Oc2ccc(F)c(C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine (6.90 g, 31.1 mmol), 2-fluoro-5-hydroxybenzoic acid (4.9 g, 31.1 mmol) and Cs2CO2 (20.3 g, 62.2 mmol) was added DMSO (25 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified (pH˜4) with TFA and the resulting solid was filtered, washed with water and dried to yield 2-fluoro-5-[3-(4-methylamino-[1,3,5]triazin-2-yl)-pyridin-2-yloxy]-benzoic acid. MS m/z=342 [M+1]+. Calc'd for C16H12FN5O3: 341.30.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(C)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3-chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (51.1 mg, 77% yield). 1HNMR (500 MHz, CDCl3) δ: 12.09 (1H, s), 7.92 (1H, t, J=5.50 Hz), 7.39 (1H, t, J=8.24 Hz), 7.28 (1H, d, J=1.22 Hz), 7.17 (1H, d, J=7.63 Hz), 7.10 (1H, dd, J=7.63, 1.53 Hz), 6.62 (2H, d, J=8.24 Hz), 4.49 (2H, d, J=6.40 Hz), 3.76 (6H, s), 3.28 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C22H23ClN3O5 (M+H): 444.1326; found: 444.1327.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH2:26]([OH:35])[CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]O>ClCCl>[OH:35][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: OCCOCCOCCO
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: ClCCl
Product: O=C(OCCOCCOCCO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of triethylene glycol (0.9 g) in dichloro-methane (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloro-methane-ethyl acetate; 2:1) to provide, after crystallization from ethyl acetate-hexane, 0.36 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2-[2-(2-hydroxyethoxy)ethoxy]ethyl ester as a colorless solid, mp 70°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[F:42][CH:43]1[CH2:46][NH:45][CH2:44]1>CN1CCCC1=O>[F:42][CH:43]1[CH2:46][N:45]([C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:9]=3)[N:12]=2)[CH2:44]1
Reactant: FC1CNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(N3CC(F)C3)c21
Temperature: 150 °C

Procedure:
150 mg (0.155 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (2.7 ml) in a reaction vessel suitable for a microwave, and 0.423 ml (2.430 mmol) of N,N-diisopropyl ethylamine and 270 mg (2.420 mmol) of 3-fluoroazetidine hydrochloride were added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 30 mg of the title compound was obtained (40% of theor.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH:16]([CH3:17])[C:12]=2[C:11]=1[C:19](O)=[O:20])=[O:8].Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:24])[F:25])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH:16]([CH3:17])[C:12]=2[C:11]=1[C:19]([N:31]1[CH2:32][C:29]([F:33])([F:28])[CH2:30]1)=[O:20])=[O:8]
Reactant: FC1(F)CNC1
Reactant: CC1OCc2sc(NC(=O)c3cc(Cl)ccc3C(F)(F)F)c(C(=O)O)c21
Agent: Cl
Product: CC1OCc2sc(NC(=O)c3cc(Cl)ccc3C(F)(F)F)c(C(=O)N3CC(F)(F)C3)c21

Procedure:
The title compound was prepared from the product of Example 53A and commercially available 3,3-difluoroazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.4 Hz, 3H), 4.30-4.53 (m, 4H), 4.89-5.01 (m, 2H), 5.18-5.27 (m, 1H), 7.82-7.95 (m, 3H), 11.60 (br s, 1H). MS (ESI+) m/z 481 (M+H)+. Anal. calcd. for C19H14ClF5N2O3S: C, 47.46; H, 2.93; N, 5.83. Found: C, 47.38; H, 2.52; N, 5.72.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:12])([N+:9]([O-])=O)[CH3:8]>CO.[Ni].O>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:8])([NH2:9])[CH3:12]
Reactant: CN(C)CCNCC(C)(C)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CN(C)CCNCC(C)(C)N
Reaction time: 24 h

Procedure:
To a solution of N1,N1-dimethyl-N2-(2-methyl-2-nitropropyl)ethane-1,2-diamine (23.2 mmol) in MeOH (20 ml) was added a slurry of Raney Nickel in H2O (1 ml). The vessel was pressurized with H2 (500 psi) and the suspension stirred for 24 h. The mixture was filtered through Celite, then 0.45 um PTFE, and concentrated in vacuo. ESI/APCI (pos) expected for C8H21N3: 159.17. Found: 160 (MH+).
Reaction SMILES: N[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3O)[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1.CC(OC(N(C)C)N(C)C)(C)C.C1(C)C=CC=CC=1>CN(C)C=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:12]3)[CH:9]=[N:10][C:5]=12
Reactant: Nc1nc(O)c2ncc([C@@H]3N[C@H](CO)[C@@H](O)[C@H]3O)c-2[nH]1
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Temperature: 67.5 °C
Yield: 86.8 %

Procedure:
To a solution of the product from Example 1.2 (0.88 g) in N,N-dimethylformamide (5 ml) was added tert-butoxy bis(dimethylamine)methane (1.5 ml) and the solution was heated at 65-70° C. for 1 h. Toluene (20 ml) was added and the solution was washed (×3) with water, dried and concentrated to dryness. The residue was dissolved in tetrahydrofuran/acetic acid/water (1:1:1 v/v/v, 40 ml) at room temperature. After 1.5 h chloroform (50 ml) was added and the mixture was washed with water (×2), aqueous sodium bicarbonate, and then dried and evaporated to dryness. Chromatography of the residue gave (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-(1-cyano-2-hydroxyethenyl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (3) (0.68 g)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13]C(=O)OC(C)(C)C)[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:21]>CO>[ClH:21].[Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:10][CH:11]([NH2:13])[CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2Br)C1
Agent: Cl
Solvent: CO
Product: NC1CC(Oc2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl (3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see PREPARATION 7B; 342 mg, 1 mmol) was added 4 M HCl in MeOH (50 mL). The solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (223 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 243 calc. for C9H11BrN2O 242.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([SH:16])[S:15][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[SH:16][C:14]1[S:15][C:11]2[CH:10]=[C:9]([N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:27](=[O:28])[CH2:26][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: Sc1nc2ccc(NCc3ccccc3)cc2s1
Reactant: O=C(Cl)COc1ccccc1
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)N(Cc1ccccc1)c1ccc2nc(S)sc2c1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
Into a 13×100 mm screw cap Pyrex® vial were added 6-[(phenylmethyl)amino]-1,3-benzothiazole-2-thiol (30.6 mg, 0.11 mmol), poly(vinylpyridine) (25 mg, 0.22 mmol), phenoxyacetyl chloride (25 μl, 0.18 mmol), and THF (2 ml). The vial was purged with Ar, capped, and shaken for 24 h. Amino silica gel (200 mg, 166 mmol) was added, and the suspension was shaken an additional 6 h. The suspension was filtered, and purified by preparative TLC (developing with 35% EtOAc in hexanes) to afford the title compound as a white powder (33.8 mg, 76%); 1H NMR (DMSO-d6) δ=4.48 (s, 2H), 4.83 (s, 2H), 6.73 (d, 2H), 6.88 (t, 1H), 7.27-7.15 (m, 9H), 7.57 (s, 1H); ESIMS: m/z 405 (M−H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=[O:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=[O:17])[CH:6]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To the material of Step 2 (4.8 g, 0.0205 mol) in THF (25 mL) at −78° C., was added the lithium bis(trimethylsilyl)amide (20.5 mL of a 1M in THF solution). The diethyl oxalate (3 g, d=1.076 g/mL, 2.8 mL, 0.0205 mol) was then added and the reaction mixture was allowed to warm to room temperature and stir overnight. The slurry was then filtered to give an orange solid. 6.1 g (MW=334.28 g/mol, 90% yield). LC/MS m/z=335 (m+1).