Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:32]([O:39][C:40](=[O:41])[N:11]([CH2:10][CH:9]([OH:16])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:14])[CH3:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -1.5 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester (2) (24.50 g, 72.80 mmol, 1 equiv) and triethylamine (7.37 g, 72.80 mmol, 1 equiv) were dissolved in dichloromethane (500 mL). The solution was cooled to −1.5° C., followed by the dropwise addition of benzylchloroformate (12.40 g, 72.80 mmol, 1 equiv). The solution was stirred at 0° C. for 24 h. Due to the incompleteness of the reaction, benzylchloroformate (2.40 g, 14.07 mmol) and triethylamine (1.44 g, 14.23 mmol) were added to the solution. The solution was stirred at room temperature for 24 h. The solution was diluted with 2% Na2CO3 solution (300 mL) and the mixture was stirred for 10 min. The organic layer was separated, washed with water (2×) and saturated sodium chloride solution (1×). The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a yellow colored oil (34.30 g, 72.80 mmol, quantitative). LRMS (ES+): m/z 471 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([O:17][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1c2ccc(Br)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (2.00 g, 6.66 mmol), (4-fluorophenyl)boronic acid (1.865 g, 13.33 mmol), copper (II) acetate (1.33 g, 7.33 mmol), 4 Å molecular sieves (1 g), triethylamine (0.93 mL, 6.66 mmol), and pyridine (1.08 mL, 13.33 mmol) in dichloromethane (30 mL) was stirred opened to air at rt for two days. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-10% ethyl acetate-hexane) to afford methyl (S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (1.81 g, 69%) as a colorless film. MS (ESI, pos. ion) m/z 394, 396 [M+H]+.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1O.[OH-].[Na+]>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:6][CH3:7]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylsulfate (94.64 g) is added dropwise over a 40 minute period to a cooled stirred solution of 2,5-dichlorophenol (122.25 g) and sodium hydroxide (31.5 g) in water (300 ml). This mixture is stirred at room temperature for one hour then at reflux for 2 hours, then cooled to room temperature. The organic layer is separated and combined with ether extracts of the remaining aqueous layer. The ether solution is dried (saturated NaCl, Na2SO4, K2CO3) and the ether removed to give 2,5-dichloroanisole. Distillation gives a colorless liquid (115° C. at aspirator vacuum).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:3]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:3]=2)[CH2:32][CH2:31]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3ccc(Cl)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
222 mg of the product obtained in Stage 1 above and 302 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 208 mg of expected product is recovered.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.C1C=C(C([O-])=[O:32])C(C(O[O-])=O)=CC=1.[Mg+2].[OH2:39].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CCOC(C)=O>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:8]=1)(=[O:32])=[O:39]
Reactant: O
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)c3ccccc32)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cold solution of the compound from Step 1 (525 mg, 1.6 mmol) in CH2Cl2 (16 mL) and MeOH (1.6 mL) was added MMPP (1.09 g, tech. 80%, 1.76 mmol). The resulting suspension was stirred at r.t. for 3 hrs. The reaction was diluted with EtOAc and a 1:1 mixture of H2O and saturated aqueous NaHCO3 and extracted. The aqueous layer was extracted one more time with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated to dryness. The crude product was purified first by flash chromatography, eluted with EtOAc in hexane 35%, and then crystallized from EtOAc/Hexane (1:1, 20 mL) to give the title compound as a bright orange solid. m.p. 167-168° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])[C:5]=2[N:4]=[CH:3]1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].O.ClCCl>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]3[C:18]4[N:19]=[C:20]([NH:30][C@@H:25]5[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]5[NH2:31])[N:21]=[CH:22][C:17]=4[S:16][CH:15]=3)=[O:13])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c(NC(=O)c3csc4cnc(Cl)nc34)cccc21
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cnc2c(NC(=O)c3csc4cnc(N[C@@H]5CCCC[C@@H]5N)nc34)cccc21
Yield: 37.9 %

Procedure:
To a solution of 0.041 g (0.119 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid(1-methyl-1H-benzoimidazol-4-yl)-amide in 1.19 mL of dioxane was added 0.082 g (0.716 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.019 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (1-methyl-1H-benzoimidazol-4-yl)-amide as a light yellow solid. MH+/Z=422
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[CH2:3][CH2:4][C@@H:5]([C:21](=[O:47])[NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:24]1)[C@H:6]([CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:48][C:2]([F:1])([F:49])[CH2:3][CH2:4][C@@H:5]([C:21](=[O:47])[NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:24]1)[C@H:6]([CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:18])[F:19])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](CCCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 117.3 %

Procedure:
A solution of Intermediate 1C (62 mg, 0.090 mmol) in DCM (1 mL) was treated with TFA (1 mL). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated to dryness to afford Intermediate 1D (67 mg, 100%). HPLC: RT=3.011 min (CHROMOLITH® ODS 4.6×50 mm (3 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=634 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:21][CH:19]1[CH2:20][N:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]([F:6])([F:22])[F:23])=[N:9][N:10]=3)[N:13]=2)[CH2:18]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Methanesulfonyl chloride (0.929 mL, 12 mmol) was added dropwise to a stirred partial solution of 1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-ol (2.59 g, 10 mmol) and triethylamine (1.951 mL, 14 mmol) in DCM (17 mL) at 0° C. The solution was allowed to warm to ambient temperature and stirred for 30 minutes. The precipitate was collected by filtration, washed with a little DCM, a little ethanol and ether. It was dried under vacuum to afford 6-[3-(methanesulfonyloxy)azetidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.400 g, 71.2%) as a white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[C:67]([O:71][CH2:72][CH3:73])[CH:68]=[N:69][CH:70]=1>C1(C)C=CC=CC=1>[CH2:72]([O:71][C:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1)[CH3:73]
Reactant: C1CC2(CN1)CC1CCN2C1
Reactant: CCOc1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOc1cncc(N2CCC3(CC4CCN3C4)C2)c1
Temperature: 160 °C
Yield: 34.1 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg, 0.3 mmol) tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide (147 mg, 1.2 mmol), and 5-bromo-3-ethoxypyridine (73 mg, 0.36 mmol) in dry toluene (5 mL) was placed in a sealed tube under argon and heated at 160° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:C Cl3H:NH4OH (8:2:0.01, v/v) as the eluent, to give 28 mg (27%) of 1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as a viscous brown oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1.[I:26]I>O1CCCC1>[Br:16][C:17]1[CH:25]=[C:24]([I:26])[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Br)cc1I
Temperature: -25 °C
Reaction time: 16 h
Yield: 64775.4 %

Procedure:
n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was added over 1 h to a cooled (−25° C.) solution of 2,2,6,6,-tetramethylpiperidine (131 mL, 0.77 mol) in tetrahydrofuran (1 L). The mixture was left to stir for 16 h at −25° C. then cooled to −55° C. before addition of solid 6-bromonicotinic acid (50.0 g, 0.25 mmol). The mixture was allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was cooled to −70° C. then poured onto a pre-cooled (−70° C.) solution of iodine (188.5 g, 0.74 mol) in tetrahydrofuran (500 mL). The mixture was then poured into the original reaction vessel and the contents allowed to warm to ambient temperature and stirred for 1 h. The solvent was evaporated and the resultant residue dissolved in water (500 mL) and washed with dichloromethane (3×300 mL). The aqueous phase was separated and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. Aqueous sodium metabisulfite solution (20% w/w, 30 mL) was added and the solid which deposited was collected by filtration. The resultant solid was washed with water (75 mL) and pentane (75 mL) and dried at 75° C. under vacuum to furnish the title compound as a tan solid (53.1 g, 65%). 1H NMR (DMSO-D6, 300 MHz): 8.62 (s, 1H), 8.35 (s, 1H). LCMS (Method B): RT=2.16 min, M+H+=328/330.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ncc2cccc(-c3ccc(C#N)cc3)n12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ncc2n1C(c1ccc(C#N)cc1)CCC2

Procedure:
A solution of 1.1 g of 5-(p-cyanophenyl)-3-ethoxycarbonyl-imidazo[1,5-a]pyridine in 30 ml of ethanol is hydrogenated with 0.1 g of 10% Pd on charcoal at 1 bar for 2 h, filtered and evaporated to dryness. The resulting oil is partitioned between water and ethyl acetate. The organic phase is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on 40 g of silica gel with ethyl acetate to yield 5-(p-cyanophenyl)-3-ethoxycarbonyl5,6,7,8-tetrahydroimidazo[1,5-a]pyridine
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][N:32]([CH2:35][C@H:36]([C@H:39]([OH:41])[CH3:40])[CH2:37][OH:38])[C:31](=[O:42])[N:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH2:37][C@H:36]([CH2:35][N:32]2[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[N:30][C:31]2=[O:42])[C@H:39]([OH:41])[CH3:40])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)Nc1ccn(C[C@@H](CO)[C@@H](C)O)c(=O)n1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
DMTCl (0.79 g, 2.34 mmol) was added to a stirred solution of 46 (0.5 g, 1.96 mmol) in 20 ml of anhydrous pyridine. After being stirred at room temperature overnight the reaction was quenched with MeOH (2 ml) and concentrated to an oil. The oil was partition between dichloromethane and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resulting material was chromatographed on silica eluting with a gradient of methanol (5-7.5%) in ethyl acetate. Concentration of the pure product fractions afforded 0.99 g (90%) of 47 as a white amorphous solid. 1H NMR (DMSO-d6): δ 10.78 (s, 1H), 7.73 (d, J=7 Hz, 1H), 7.27 (m, 5H), 7.16 (m, 4H), 6.98 (d, J=7 Hz, 1H), 6.82 (m, 4H), 4.60 (d, J=5 Hz, 1H), 3.84 (d, J=7 Hz, 2H), 3.76 (m, 1H), 3.72 (s, 6H), 3.08 (m, 1H), 2.99 (m, 1H), 2.20 (m, 1H), 2.09 (s, 3H), 1.03 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[C:17]2[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])(=[O:23])=[O:22])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH3:34])[CH:18]=[C:17]2[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])(=[O:23])=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CN(CCOc1cccc2c(S(=O)(=O)c3ccccc3F)c[nH]c12)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1cccc2c(S(=O)(=O)c3ccccc3F)cn(C)c12)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A dry 25 mL flask equipped with a magnetic stirrer was charged with {2-[3-(2-fluoro-benzenesulfonyl)-1H-indol-7-yloxy]-ethyl}-methyl-carbamic acid tert-butyl ester (0.116 g., 0.258 mmol) and dimethylformamide (5 mL.) This solution was treated with sodium hydride (0.011 g. of 60% suspension in mineral oil, 0.284 mmol) and allowed to stir for 10 minutes under N2. Methyl iodide was then added via syringe in one portion. After 18 hours stirring at ambient temperature, the reaction mixture was extracted into 45 mL ethyl acetate and washed with water (2×45 mL). The organic fraction was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (85:15 hexanes:EtOAc to 70:30 hexanes:EtOAc) to give 45 mg of {2-[3-(2-fluoro-benzenesulfonyl)-1-methyl-1H-indol-7-yloxy]-ethyl}-methyl -carbamic acid tert-butyl ester as a clear oil: 1H NMR (CDCl3, 300 MHz) δ: 1.45 (s, 9H), 2.94 (s, 3H), 3.71 (m, 2H), 4.09 (s, 3H), 4.19 (m, 2H), 6.67 (d, 1H, J=7.7), 7.04 (m, 1H), 7.08 (t, 1H, J=8.0), 7.27 (td, 1H, J=7.6, J′=1.13), 7.44 (d, 1H, J=7.6), 7.49 (m, 1H), 7.74 (d, 1H, J=1.3), 8.15 (td, 1H, J=7.6, J′=1.8).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:4][C:3]1=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:55][C:56]1[CH:60]=[C:59]([C:61]([O:63][CH3:64])=[O:62])[N:58]([CH3:65])[CH:57]=1>CN(C=O)C.CCOCC>[CH3:65][N:58]1[C:59]([C:61]([O:63][CH3:64])=[O:62])=[CH:60][C:56]([NH:55][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3](=[O:20])[CH:4]=2)=[CH:57]1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)CCCCOC2=CC(=O)C(=O)c3ccccc32)cn1C
Reaction time: 0.08 h
Yield: 39.9 %

Procedure:
A solution of an acid 503 (334 mg, 1.22 mmol) in DMF (1.67 mL) was treated with HBTU (462 mg, 1.22 mmol) followed by DIEA (452 mg, 3.5 mmol) and stirred for 5 min. 3-Amino-1-methyl-5-methyloxycarbonylpyrrol hydrochloride (232 mg, 1.22 mmol) and DIEA (378 mg, 3 mmol) were added to the reaction mixture. The latter was stirred for 2 h, diluted with Et2O, the precipitate was removed, dissolved in CHCl3, washed with 3% HCl, H2O, aqueous NaHCO3, H2O again, dried (MgSO4) and purified by chromatography on alumina column (CHCl3/MeOH 80:1, 50:1). The product was triturated with Et2O/CHCl3 to obtain a yellow-red solid (200 mg, 40%); mp 122-123° C. (decomp.): MS (LSIMS, 3-NBA) 410 (M+), 237 (M+−173). 1H NMR (CDCl3) 8.08 (d, J=7.5 Hz, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.34 (s, 1H), 6.65 (d, J=2 Hz, 1H), 5.95 (s, 1H), 4.19 (t, J=5.53 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 2.46 (t, J=6.6 Hz, 2H), 1.90-2.15 (m, 4H).
Reaction SMILES: [Na].[CH2:2]([CH:4]([CH2:12][CH3:13])[CH2:5][CH2:6]C(OCC)=O)[CH3:3].[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[C:15]([O:17]CC)=O>C(O)C>[CH2:2]([CH:4]([CH2:12][CH3:13])[CH2:5][CH2:6][C:15](=[O:17])[C:14]([O:21][CH2:22][CH3:23])=[O:20])[CH3:3]
Reactant: CCOC(=O)CCC(CC)CC
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CCC(CC)CC
Yield: 50.7 %

Procedure:
In 100 ml of ethanol is dissolved 4.5 g of sodium, and 27.8 g of ethyl 4-ethylhexanoate and 29 g of diethyl oxalate are added to the solution, and the low-boiling substance is removed by evaporation under reduced pressure at about 70° C. for 40 minutes. After cooling, 500 ml of water and 300 ml of petroleum ether are added to the brown viscous residue, and the mixture is thoroughly shaken. The aqueous layer is separated off and the petroleum layer is extracted twice with 50 ml each of 1N sodium hydroxide solution. The extracts are combined, acidified slightly with concentrated hydrochloric acid and extracted twice with 200 ml each of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. One hundred and ten (110) ml of 10% aqueous dimethylsulfoxide and 10 g of sodium chloride are added to the oily residue, and the mixture is stirred at 160° C. for 2.5 hours. After the reaction mixture is cooled, 500 ml of water is added, followed by extraction with 300 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue is distilled under reduced pressure to give 16.4 g of ethyl 5-ethyl-2-oxoheptanoate as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1(O)[CH:16]=[CH:15][CH:14]=[N:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].C1C[O:33]CC1>>[CH2:1]([O:8][C:9]([NH:10][C:11]1[C:12](=[O:33])[N:13]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])[CH:14]=[CH:15][CH:16]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(O)C=CC=NC1)OCc1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16.2 g of benzyl-3-hydroxypyridin-3-yl-carbamate (66.4 mmol) are suspended in 900 mL of absolute THF and cooled to 0° C. under argon atmosphere and 2.92 g of NaH (60% in mineral oil, 73.1 mmol, 1.1 eq) are added. To the resulting solution after the end of gas emission (ca. 15 min) 13.7 mL of bromoacetic acid tert-butylester (89.7 mmol, 1.35 eq) are added. It is stirred still for 15 minutes at 0° C. and subsequently at RT overnight. The reaction mixture is filtered and the filtrate is concentrated in dryness. The residue is taken up in 5 mL of ethyl acetate and treated with ca. 50 mL of diethylether and the resulting suspension is precipitated in the refrigerator overnight. The crystals are filtered off and washed with a little amount of ether.