Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].O1CCOCC1.C([O-])(O)=O.[Na+]>Cl>[F:33][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Tert-butyl (4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate (0.100 g, 0.213 mol) was dissolved in HCl in dioxane (4 N, 3 mL, 12 mmol) and stirred at 40° C. for 1 h. The solutionwas then cooled, neutralized with saturated aqueous NaHCO3 solution to pH 7, and extracted with diethyl ether (2×10 mL). The combined organic layer was dried and concentrated to afford the title compound as a light tan solid (54 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H). 3.9 (br s, 2H); ESIMS m/z 371 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[C:20]([SH:22])[CH:21]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[NH:23][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[C:5]=1[S:22]2
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccc(Br)cc1S
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Br)cc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (5.94 g, 30 mmole) and 5-bromo-2-aminobenzenethiol, 6 (X=Br, 5.8 g, 30 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separetely recrystallized twice from MeOH and proves to be identical. An analytical sample of 4k, (R=Br), mp 201-203° C. occurs as light orange crystals; 2.24 g (56.7%).
Reaction SMILES: [CH:1]([C@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3].Cl.[OH2:11]>>[NH2:8][C@H:4]([CH:1]=[C:2]=[CH2:3])[CH2:5][CH2:6][C:7]([OH:9])=[O:11]
Reactant: C=C=C[C@@H]1CCC(=O)N1
Reactant: O
Agent: Cl
Product: C=C=C[C@@H](N)CCC(=O)O
Yield: 80 %

Procedure:
A solution of (5S)-5-(1,2-propadienyl)pyrrolidin-2-one (37) (1.1 g, 9.0 mmol), 5N HCl (10 mL) and H2O (4 mL) was heated to 80° C. for 18 hours. the solution was cooled, concentrated and neutralized to pH 6 with 1N NaOH. This solution was put on a Dowex 1×2-100 ion exchange column (OH) form. The column was rinsed with distilled H2O (800 mL) and the compound was removed with 0.5N acetic acid. Lyophilization gave (4S)-4-amino-5,6-heptadienoic acid as an off-white foamy solid (1.01 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[CH2:39][Cl:38])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CCl)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.52 g of the compound obtained in Example 5 step B), 25 ml of DCM and 0.5 g of pyridine were mixed. 0.54 ml of chloroacetyl chloride in 10 ml of DCM was then added over 5 minutes at 20° C. The reaction mixture was stirred for 2 hours at 20° C. and then concentrated under vacuum at 20° C. The residue was extracted with AcOEt and washed with water, then with 1N hydrochloric acid and then with water. It was dried over sodium sulfate and the solvent was evaporated off to give the expected product, which crystallized from isopropyl ether. m=0.6 g. M.p.=232° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:18])[C:12]=3[C:11]([I:19])=[CH:10]2)[CH2:6]1)=O.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:18][C:17]1[C:12]2[C:11]([I:19])=[CH:10][N:9]([C@@H:7]3[CH2:6][C@H:5]([CH2:3][OH:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: OC[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 45 °C
Reaction time: 0.83 h

Procedure:
To a solution of cis-3-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid methyl ester (2.15 g, 5.49 mmol) in CH2Cl2 (85 mL), cooled by dry ice/acetone, was added DIBAL (1M in toluene, 12.4 mL, 12.4 mmol) over 5 min. Note that the ester started precipitating at the low temperature; but upon adding the DIBAL solution, a clear, pale yellow solution formed. After 50 min, the dry ice/acetone bath was replaced with and ice/water bath. The reaction was quenched 2.5 h later by adding Na2SO4.10H2O. A very slow gas evolution occurred, even with vigorous stirring or sonication. MeOH (2 mL) was added at ambient temperature, and a precipitate slowly formed, which was filtered off and washed with 150 mL of 10% MeOH in CH2Cl2. The combined filtrate and washings were concentrated, the resulting solid was suspended in 80 mL of 10% MeOH/CH2Cl2, heated briefly to 45° C., and cooled to −20° C. overnight. The white solid was filtered off and dried in vacuo, yielding the title compound. The aluminum-containing precipitate was suspended in potassium sodium tartrate solution and extracted with CH2Cl2 (3×100 mL), the combined extracts were dried over MgSO4, filtered, and combined with the mother liquor of the white solid. This material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-7)→CH2Cl2:EtOAc 5:1 (8-32)→CH2Cl2:EtOAc 4:1 (33-43)] to give a second crop of the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.79 (brs, 1H), 2.40-2.53 (m, 3H), 2.59-2.71 (m, 2H), 3.74 (brs, 2H), 5.13-5.23 (mc, 1H), 7.60 (s, 1H), 8.60 (s, 1H). MS (ES+): m/z 364.0/366.0 (100/40) [MH+]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:7](O)=[O:8].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:5][C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:7]([Cl:3])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)Cl

Procedure:
5 g of thionyl chloride was added dropwise to a mixture of 6 g of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid, 80 ml of pyridine and 50 ml of chloroform under ice-cooling with stirring, followed by stirring for one hour to obtain a solution of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid chloride. 8 g of cyclohexylamine was added to the solution, and the mixture was stirred for one hour and poured into water. The mixture was rendered basic with sodium carbonate, and the organic layer was separated by filtration, washed with water and dried over magnesium sulfate. The solvent was distilled off and the resulting oily substance was purified by silica gel chromatography (eluted with chloroform-diethyl ether, 1:2 by volume). The resulting crystals were converted into the hydrochloride in the same manner as described in Example 4 and recrystallized from a mixture of ethanol and diethyl ether to obtain 4.5 g (51% yield) of N-cyclohexyl-2-methyl-3-[4-(3-pyridyloxy)phenyl]propenamide hydrochloride having a melting point of 162°-166° C.
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.S(=O)(=O)(O)[OH:15]>C(O)C>[O:15]=[C:3]1[NH:2][CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1CCC(=NO)CC1
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C1CCNC(=O)CC1

Procedure:
Ethyl 4-(hydroxyimino)cyclohexanecarboxylate was reacted in the presence of conc. sulfuric acid in ethanol to produce ethyl 7-oxoazepane-4-carboxylate.
Reaction SMILES: [C:1]([C:5](Cl)=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]1.CCN(CC)CC.O>C(Cl)Cl>[F:24][C:20]1([F:23])[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:14]2[CH:13]=[CH:12][C:11]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:10][C:9]=2[NH:8][C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:18][CH2:19]1
Reactant: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(NC(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of t-BuCOCl (7.6 g, 0.063 mol) in DCM (150 mL) was slowly added to a solution of N-(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)ethanesulfonamide (22 g, 0.063 mol) and Et3N (9.7 mL, 0.069 mol) in DCM (500 mL) at 0° C. The reaction mixture was stirred for 3 hrs. at 0° C. DCM (300 mL) and water (200 mL) were added. The organic layer was separated and washed with water (3×200 mL), brine and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (EtOAc:hexane 1:1) to provide the title product (23.3 g) as beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:45][C@@H:46]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:47]([O:49]C(C)(C)C)=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:44]=[CH:43][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([NH:45][C@@H:46]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:47]([OH:49])=[O:48])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@@H](C(=O)N[C@H](C(=O)O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)(phenyl)acetic acid (0.040 g, 0.065 mmol) was dissolved in CH2Cl2 (5 ml). tert-Butyl (2S)-amino(phenyl)acetate (0.016 g, 0.078 mmol) and N-methyl-morphiline (0.020 g, 0.195 mmol) were added. After 5 minutes, TBTU (0.027 g, 0.084 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). The pure fractions were concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (0.5 ml). The reaction mixture was stirred overnight at room temperature. The resulting acid was concentrated and the remaining trace of TFA was removed by co-evaporation with toluene (3 ml). The acid was dissolved in MeOH (3 ml) and NaBH (0.010 g, 0.260 mmol) was added. After 5 minutes, full conversion to the corresponding alcohol was obtained. The reaction was quenched by the addition of 1 ml of 0.1M NH4OAc buffer. Concentration followed by purification on preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase and freeze-drying of the pure fractions afforded the title compound (0.037 g, 76%) as a colourless solid. M/z: 750.6 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.87-2.94 (m, 2H), 4.25-4.28 (m, 1H), 4.58-4.78 (m, 3H), 5.01-5.07 (m, 2H), 5.65-5.74 (m, 1H), 6.94-7.39 (m, 22H), 8.53-8.72 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:26][O:27][C:28]([CH:30]1[CH2:37][CH:36]2[N:38]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:32]([CH2:33][CH:34](O)[CH2:35]2)[CH2:31]1)=[O:29].ClCCl.CO.N.[Mn]([O-])(=O)(=O)=O.[K+].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:26][O:27][C:28]([CH:30]1[CH2:37][CH:36]2[N:38]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:32]([CH2:33][CH:34]([O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])[CH2:35]2)[CH2:31]1)=[O:29]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: COC(=O)CN1C2CC(O)CC1CC(C(=O)OC)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN1C2CC(OC(=O)c3c[nH]c4ccccc34)CC1CC(C(=O)OC)C2
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
Indole-3-carboxylic acid (6.43 gr, 39.9 mmol) is added in portions to a solution of 5.33 mL (37.7 mmol) of trifluoroacetic anhydride in dichloromethane (172 mL) and under nitrogen atmosphere. The resulting suspension is left under stirring for 30 minutes. 7-hydroxy-9-methoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonan-3-carboxylic acid methyl ester (6 gr, 22.1 mmol) dissolved in dichloromethane (15 mL) is then added dropwise. Next, a catalytic amount of DMAP is added, and the suspension is then left under stirring for 4 h. Following that time, and once the limiting starting product has been used up as shown by thin-layer chromatography (dichloromethane/methanol/ammonia 90:10:1, which reveals potassium permanganate), water (50 mL) is added to the reaction mixture and the mixture is basified with a saturated aqueous solution of sodium bicarbonate. Following filtration to remove the remains of indole-3-carboxylic acid in excess, the resulting phases are separated. The organic phase is dried over magnesium sulphate and evaporated to dryness, to give 7-(1H-Indole-3-carbonyloxy)-9-methoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl ester as a white solid (8.20 gr, 89%) that can be used directly in the following synthesis step.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO>[OH:3][CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(C(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.9 %

Procedure:
To a cloudy solution of 7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (45 mg, 0.092 mmol) in tetrahydrofuran (4 mL) and methanol (12 mL) at 0° C. was added sodium borohydride (17.46 mg, 0.462 mmol) in one portion. The mixture was stirred at room temperature for 20 min and then the reaction was quenched with ice cold water (15 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with dichloromethane (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (10.9 mg, 0.022 mmol, 23.5% yield) as a white solid. LCMS (M+H)+=490.1. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.78 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.28 (dd, J1=8.0 Hz, J2=1.4 Hz, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 7.30 (m, 1H), 7.12 (m, 1H), 5.25 (s, 1H), 4.85 (m, 1H), 1.82 (s, 3H),
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][NH2:51]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:51][O:50][CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][O:44]3)=[O:20])=[CH:12]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
0.295 g of (E)-3-(1-phenylmethansulfonyl-1H-pyrrol-3-yl)-acrylic acid (compound B1), 0.152 g of N-hydroxybenzotriazole hydrate (HOBt′H2O) and 561 μl of triethylamine are dissolved in 20 ml of N,N-dimethylformamide (DMF) at room temperature. Afterwards it is added 0.601 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC?HCl) and stirred for 1 hour at room temperature. Then is added 0.152 g of O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine and stirred for 2 hour. The DMF is evaporated under high vacuo. Water is added and the mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane/methanol from 99:1 to 98:2 to give 0.189 g of the title compound as a pale grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[K+].O.Cl[CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][Cl:17]>C(O)(C)C>[Cl:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OC(CCl)CCCl
Reactant: Oc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: OC(CCCl)COc1ccccc1Cl
Temperature: 50 °C

Procedure:
To a mixture of 129 g (1 mole) of 2-chlorophenol, 60 g of potassium hydroxide, 100 ml of water and 400 ml of isopropanol was added 1.3 mole (185.9 g) of 1,4-dichloro-2-butanol with stirring at 50° C. The resulting mixture was heated in a steam bath at 65° C. overnight and extracted with 300 ml of isopropyl ether. The ether extract was washed successively with 1N sodium hydroxide, water and dried over sodium sulfate. The dried ether solution was concentrated and the oily residue was distilled under reduced pressure yielding 152 g of an oily substance (b.p. 130°-131° C./0.01 mm).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].C(Cl)Cl>CO>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:20](=[O:22])[CH3:21])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A 200 mL round bottom flask was charged with 125d (2.1 g, 12.9 mmol), triethylamine (5.5 mL, 38.7 mmol), acetyl chloride (1.1 mL, 15.5 mmol) and CH2Cl2 (100 mL). The mixture stirred at room temperature over night. After this time, the reaction mixture was concentrated under reduced pressure, and to the residue was added H2O (50 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL). The combined aqueous extracts were back extracted with 9:1 CH2Cl2:MeOH (2×50 mL). The combined organics were dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2—9:1 CH2Cl2:MeOH to afford a 84% yield (2.3 g) of 125e.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(C(C)=C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH2:11]=[C:12]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1)[CH3:16]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: C=C(C)c1c[nH]c(C(=O)OC)c1
Temperature: 140 °C
Yield: 68.79 %

Procedure:
Mix methyl 4-iodo-1H-pyrrole-2-carboxylate (1.5 g, 5.98 mmoles), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.01 g, 17.98 mmoles) 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf) (0.3 g, 0.06 mmoles), tris(dibenzylideneacetonyl)bis-palladium (Pd2(dba)3) (0.3 g, 0.06 mmoles), tripotassium phosphate (2.54 g, 11.95 mmoles) and methanol (12 mL). Heat the mixture in a sealed tube in a microwave at 140° C. for 30 minutes. Cool, filter the reaction mixture and wash sinter with methanol, evaporate the filtrate under reduced pressure and chromatograph on silica eluting with isohexane/dichloromethane (gradient elution, 100:0 to 0:100). Evaporate the fractions containing product to give methyl 4-(prop-1-en-2-yl)-1H-pyrrole-2-carboxylate. (0.679 g, 68.79% yield). MS (m/z): 166.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[Si:25]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: Nc1ccc(-c2cccc(CO)c2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
4.99 g of [3-(6-aminopyridin-3-yl)phenyl]methanol are placed in a round-bottomed flask and dissolved in 240 ml of tetrahydrofuran. 2.2 g of 1H-imidazole are added thereto, followed by 4.51 g of tert-butylchlorodimethylsilane, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolyzed with water and the organic phase, extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 7.0 g of compound are obtained.