Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
Into a flask was introduced 251.0 g (1.65 mol) of methyl 4-hydroxybenzoate, 276.37 g (1.99 mol) potassium carbonate and 1200 g of acetone. This was refluxed for 45 min followed by the dropwise addition of 386.17 g (1.99 mol) of 1-octylbromide over a 1 hour period. The reaction mixture was refluxed for two days. Filtration of the cooled reaction mixture and evaporation of the filtrate gave an oil. This was taken up in ethyl acetate and extracted with 5% NaOH (2×100 ml) followed by water (2×100 ml). The organic layer was dried (MgSO4), concentrated, and transferred to a 1 L three necked flask. The contents of the flask was subjected to high vacuum distillation to remove the excess 1-octylbromide. The pot residue was essentially pure methyl 4-octoxybenzoate (376 g, 86%).
Reaction SMILES: [H-].[Na+].C(O/[N:7]=[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])\[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=1[OH:18])(=O)C.N#N.O>CN(C=O)C>[Cl:17][C:11]1[C:10]2[O:18][N:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[C:9]=2[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(/C(=N\OC(C)=O)c2cccc(F)c2F)c(O)c1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(-c3cccc(F)c3F)noc2c1Cl
Temperature: 45 °C

Procedure:
To a mixture of 1.4 g of NaH in 200 ml of DMF, a solution of 19 g of E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 200 ml of DMF is added dropwise in an atmosphere of N2. The mixture is stirred for one half hour and then warmed at 45° C. for one half hour. Water is added and a product precipitates and is filtered and dried giving 7-chloro-3-(2,3-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 184°-189° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[H-].[Na+].[CH3:9][S:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.Cl>O1CCOCC1>[CH:4]1([C:2](=[O:3])[CH2:1][C:15]([C:14]2[CH:20]=[CH:21][C:11]([S:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1ccc(SC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1ccc(C(=O)CC(=O)C2CC2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
Cyclopropyl methyl ketone (0.84 g) was added to a suspension of sodium hydride (80%, 0.3 g) in dioxane. The mixture was stirred for 20 minutes and ethyl 4-(methylsulphenyl)benzoate (1.0 g) was added. The mixture was stirred and heated at 45° C. for 1.5 hours and at 60° C. for 2 hours. It was left to stand at room temperature overnight. Hydrochloric acid (2M) was added and the mixture was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The flitrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give 3-cyclopropyl-1-[4-(methylsulphenyl)-phenyl]-propan-1,3-dione (0.59 g) as an orange solid, NMR (CDCl3) 1.0(m,2H), 1.2(m,2H), 1.8(m, 1H), 2.5(s,3H), 6.25(s,1H), 7.25(d,2H), 7.8(d,2H), 16.35(bs,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: O=C(O)c1cc(Cl)cnc1O
Product: CC(C)(C)c1cc(NC(=O)c2cc(Cl)cnc2O)cc(C(C)(C)C)c1
Yield: 59.1 %

Procedure:
Using 5-chloro-2-hydroxynicotinic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([F:13])[F:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([F:13])[F:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)cccc1OC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(Cl)cccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 2-chloro-6-difluoromethoxy-benzaldehyde (0.65 g; 3.15 mmol) in MeOH (10 mL) was added NaBH4 (357.13 mg; 9.44 mmol), at −15° C. After complete addition the mixture was allowed to warm to RT and stirred for 30 minutes. Subsequently, water (5 mL) was added and the volatiles were removed in vacuo. The residue was partitioned between Et2O and 5% aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford (2-chloro-6-difluoromethoxy-phenyl)-methanol (0.52 g), which was used as such.
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:10][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:8]([Se]C3C=CC=CC=3)[C@H:4]1[O:5][CH2:6][CH2:7]2.CC(N=NC(C#N)(C)C)(C#N)C.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[OH:1][CH2:2][C@:3]12[CH2:10][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:8][C@H:4]1[O:5][CH2:6][CH2:7]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1
Temperature: 81.5 °C

Procedure:
A 22-L four-neck round bottom flask equipped with mechanical stirrer, heating mantel, temperature probe, nitrogen inlet, and a reflux condenser with nitrogen outlet was purged with nitrogen for 30 min before use. The product of Step C (603.5 g, 1.46 mol, 1 eq), AIBN (241 g, 1.46 mol, 1 eq), tris(trimethylsilyl)silane (910 mL, 2.93 mol, 2 eq) and toluene (16.3 L) were added and the suspension was degassed with nitrogen purge through the suspension for 20 min. The reaction was heated to 80-83° C. for 1 h after which time the heat was shut off, and the reaction cooled to rt over 12-18 h. TLC showed the reaction was complete. The reaction was poured directly into a BIOTAGE dry 5-kg column that was eluted with 16 L of 50% EtOAc in heptane, followed by 32 L of EtOAc and provided the product of Step D of a golden thick oil, which slowly crystallized on standing. 1H NMR (CHLOROFORM-d) δ: 4.64 (brd. s, 1H), 4.07-4.25 (m, 2H), 3.89 (ddd, J=8.8, 7.2, 4.5 Hz, 1H), 3.53-3.67 (m, 3H), 2.17 (dd, J=13.3, 6.2 Hz, 1H), 1.98-2.06 (m, 1H), 1.86-1.97 (m, 1H), 1.68-1.81 (m, 2H), 1.46-1.56 (m, 2H), 1.44 (s, 9H). Calculated for C13H23NO4: 202.2 (M−55). found: 202.2.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[CH:7]=1>C(Cl)(Cl)Cl>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: CCCOc1ccc2c(O)cc(=O)oc2c1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc2c(O)c([N+](=O)[O-])c(=O)oc2c1

Procedure:
Fuming nitric acid (15 ml) was added to a stirred suspension of 4-hydroxy-7-n-propoxycoumarin (m.p. 216°-8°; 3.0g) in chloroform (300 ml) at room temperature over one hour. After a further hour, the solvent was removed in vacuo and 6N hydrochloric acid (60 ml) added to the residue. Filtration and recrystallisation from ethanol gave the product, m.p. 151°-2°, (C12H11NO6 requires C, 54.34; H, 4.18; N, 5.28. Found: C, 54.38; H, 4.28; N, 5.24).
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]1([F:26])[C@@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC(=O)OC2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>CN(C=O)C.CO>[C:1]([O:9][CH2:10][C@@:11]1([F:26])[O:12][C@H:13]2[N:18]3[CH:23]=[CH:22][C:21](=[O:24])[N:20]=[C:19]3[O:17][CH:14]2[C@@H:15]1[OH:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)c1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OC[C@@]1(F)O[C@@H]2C(Oc3nc(=O)ccn32)[C@@H]1O)c1ccccc1
Temperature: 110 °C
Yield: 68 %

Procedure:
The benzyloxy protected 4′-fluorouridine (A3, 2.8 g, 7.6 mmol) was dissolved in DMF (10 mL). Solid diphenylcarbonate (1.80 g, 8.42 mmol, 1.1 eq) was added followed by solid sodium bicarbonate (0.36 g, 4.56 mmol 0.6 eq). The mixture was stirred and heated to 110° C. under an argon atmosphere for 8.5 hours at which time the reaction was shown to be complete by tlc (silica gel, EtOAc:MeOH=4:1). The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in methanol, and was purified by CombiFlash® column chromatography (Silica gel; 0 to 100% EtOAc:Heptane to 2:1 EtOAc:MeOH) providing the desired material in 68% yield (A4, 1.8 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[O:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[O:34][C:33](=[O:35])[NH:32][N:31]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1-c1n[nH]c(=O)o1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1n[nH]c(=O)o1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 5-(6-chloro-2-methylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (101 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH2:7]OS(C)(=O)=O)[CH2:4][CH2:3]1.[CH2:13]([NH:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:7][C@@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)[CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCNCc1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1CCC(=O)N1
Product: O=C1CC[C@H](CN(CCO)Cc2ccccc2)N1
Temperature: 130 °C
Yield: 98.3 %

Procedure:
A mixture of (−)-methanesulfonic acid (R)-5-oxo-pyrrolidin-2-ylmethyl ester (10.53 g, 54.5 mmol) and 2-(benzylamino)ethanol (32.58 g, 215.5 mmol) was heated at 130° C. in a microwave oven (Personal Chemistry Emrys™ Optimizer) for 45 minutes. The residue was partitioned between water and DCM, the organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH 95/5 respectively) to afford the title compound as yellow oil (13.3 g, 98% yield).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[S:20][CH:19]=1>>[S:20]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[CH:19]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1csc2ncccc12
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3csc4ncccc34)N1C2
Yield: 73.9 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (6.7 g) and 3-aminothieno[2,3-b]pyridine (2.8 g) as the starting materials, (S)-3-[(thieno[2,3-b]pyrid-3-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (4.6 g) is obtained in the form of beige crystals, m.p.=145°-146° C.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Na+].[C:20]1([S:26][N:27]([CH2:33][CH2:34]OS(C)(=O)=O)[C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[C:20]1([S:26][N:27]([CH2:33][CH2:34][O:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[C:3]([F:2])[CH:16]=[C:15]([F:17])[CH:14]=3)=[CH:12][CH:11]=2)[C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CCOC(=O)N(CCOS(C)(=O)=O)Sc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1
Temperature: 0 °C

Procedure:
A solution of the sodium salt of 4-(3,5-difluorophenoxy)phenol (prepared from 4.3 g of 4-(3,5-difluorophenoxy)phenol and 0.8 g of a 55% dispersion of sodium hydride in mineral oil in 40 ml of dry dimethyl sulfoxide) is metered at a constant rate at +25° C. in the course of 5 hours to a solution of 6.5 g of ethyl N-phenylthio-2-methylsulfonyloxyethylcarbamate and 0.1 g of hydroquinone in 20 ml of anhydrons dimethyl sulfoxide, with stirring. The mixture is stirred for 5 more hours at room temperature. After this, the reaction mixture is poured into ice-water and extracted repeatedly with an ether/hexane mixture (1:4), and the combined organic phases are washed with water and dried over sodium sulfate. After the solvents have been distilled off in vacuo, the crude product is purified by chromatography, by which process ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate is isolated, nD20 : 1.5700.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18]I)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:24][C:23]1[CH:22]=[CH:21][C:27]([CH3:28])=[C:26]([CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:25]=1
Reactant: Cc1ccc(N)cc1I
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: Cc1ccc(N)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
Following the General Procedure of Description 15 (Part B), The zinc insertion product of (6c) was used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (1.21 g, 5.2 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (119 mg, 0.13 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (158 mg, 0.52 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with an ethyl acetate (EtOAc)/hexane mixture (EtOAc/hexane=7:3, v/v) furnished 1.15 g (61% yield) of the title compound (6d) as a yellow viscous oil. Rf˜0.28 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=8.1 Hz, 1H), 6.50-6.46 (m, 2H), 5.20-5.10 (br. m, 1H), 4.18-4.00 (m, 1H), 3.24 (br. s, 2H), 2.88-2.78 (br. dd, 1H), 2.70 (dd, 1H), 2.44 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.36 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.22 (s, 3H), 1.45 (s, 9H), 1.40 (s, 9H) ppm. LC/MS: Rt=1.433 min; ESI (pos.) m/z=365.20 (M+H+)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12]C)(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(NOC)C.[CH3:33][O:34][CH2:35]CONC>>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH2:15][CH2:33][O:34][CH3:35])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CNOCCOC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Agent: CCNOC
Agent: Cl
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OCCOC)c2O)c(=O)c1=O

Procedure:
This compound was prepared analogously to 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) by replacing N-ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) with O-(2-Methoxy-ethyl)-N-methyl-hydroxylamine (Intermediate K). [M+H]+ 435
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12]C(=O)[N:10]([C@H:14]([CH3:30])[CH2:15][C:16]3[C:24]4[C:19](=[C:20]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[CH2:9][NH:10][C@H:14]([CH3:30])[CH2:15][C:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)Nc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.4 %

Procedure:
To a solution of N-(3-((2R)-2-((5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolidin-3-yl)propyl)-1H-indol-7-yl)propanamide (28.4 mg, 0.0666 mmol) in ethanol (1 mL) is added a 5N aqueous sodium hydroxide solution (0.2 mL), and the mixture is stirred at room temperature for 15 hours, and further stirred at 60° C. for 11 hours. The ethanol is evaporated, and the resulting residue is separated into a saturated aqueous sodium hydrogen carbonate solution-and chloroform. The organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by preparative HPLC (water-aceto-nitrile-trifluoroacetic acid), and preparative thin layer chromatography (1st; a saturated ammonia solution in chloroform-methanol=10:1, 2nd; chloroform:methanol=10: 1) to give the title compound (3.3 mg, 12.5%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][C:9](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2=[N:18][NH:19][CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]2[CH2:6]1)=[O:4].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([N:19]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]2[CH2:6][N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:10][C:9](=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[N:18]1)(=[O:29])[CH3:28]
Reactant: CNC(=O)N1CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Reactant: CC(=O)OC(C)=O
Product: CNC(=O)N1CC(=Cc2ccccc2)C2=NN(C(C)=O)C(c3ccccc3)C2C1
Temperature: 0 °C

Procedure:
A suspension of 5 g of 2,3,3a,4,6,7-hexahydro-N-methyl-3-phenyl-7-(phenylmethylene)-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (the product of Example 55) in 50 ml of acetic anhydride is refluxed for four hours. The mixture is cooled and poured onto 250 ml of ice-water. The product is filtered and dried.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[F:13][C:14]([F:22])([F:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18]>>[CH3:18][C:17]1[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=[C:15]([C:14]([F:22])([F:21])[F:13])[CH:16]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Cl
Product: Cc1cc(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 1,1,1-trifluoro-2,4-pentanedione: MS (ESI) m/z 270 [M+H]+, 1H-NMR (CDCl3) δ 7.41-7.34 (4H, m), 6.45 (1H, s), 3.93-3.86 (211, m), 2.94 (2H, t, J=6.6 Hz), 2.34 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]=[C:54]1[NH:58][C@@H:57]([C:59](O)=[O:60])[CH2:56][CH2:55]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:59]([C@H:57]4[CH2:56][CH2:55][C:54](=[O:53])[NH:58]4)=[O:60])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)[C@H]1CCC(=O)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a DCM (10 ml) solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0° C. was added a solution of (R)-5-oxopyrrolidine-2-carboxylic acid (0.15 g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g, 1.17 mmol). The reaction was then stirred at room temperature for 1 hour and quenched with 20 ml aqueous NaHCO3, and extracted with DCM (2×30 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=20:1) to give the title compound (0.25 g, 43%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.80-5.65 (br s, 1H), 5.07 (br s, 1H), 4.33-4.16 (m, 3H), 2.46-2.22 (m, 3H), 2.05-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 0.93-0.92 (m, 2H), 0.66-0.62 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: CC(CC[OH:13])CCC1C=CC=CC=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>CCOCC>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([OH:13])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCO)CCc1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Phenoxanol (30.00 g, 0.168 mol) and pyridine (130 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -10° C. and to it is added p-toluenesulfonyl chloride (39.28 g, 0.202 mol) in portions via Gooch tubing so as to maintain the reaction temperature between -10°-0° C. After 3 h, water (20 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 275 mL of ether. The layers are separated and the organic layer is washed with 5M H2SO4 (75 mL), saturated CuSO4 solution (75 mL), water (2×75 mL) and saturated NaHCO3 solution (75 mL). After drying over MgSO4, the organic layer is filtered and concentrated to leave a light yellow liquid as phenoxanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:3])=O.C(C(C(C(O)=O)O)O)(O)=O.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1>>[OH:41][CH:42]1[CH2:45][N:44]([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:3])[CH2:43]1
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CNC1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC(O)C1
Yield: 68.7 %

Procedure:
In the same manner as in step c) in Example 3, 0.742 g of the title compound was prepared from 0.957 g of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 0.757 g of 3-hydroxyazetidine tartrate.