Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 60 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (57 mg, 60%), which was obtained as a white solid after recrystallization from ethyl acetate/hexane. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:8](=[O:17])[C@H:7]([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:6]1)=[N+:2]=[N-:3].[BH4-].[Na+]>CO>[N:1]([CH2:4][C@@H:5]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:6][C@H:7]([CH2:8][OH:17])[CH2:18][CH2:19][CH2:20][Cl:21])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](CCCCl)C[C@H]1CN=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H](CO)CCCCl
Temperature: 27 °C

Procedure:
The (3R,5S)-tert-butyl 5-(azidomethyl)-3-(3-chloropropyl)-2-oxopyrrolidine-1-carboxylate (10.11 g, 31.9 mmol, 10. equiv) was dissolved in 200 mL of MeOH. Solid NaBH4 was added in ˜1 g portions at a rate to maintain the reaction temperature at ˜27° C. Subsequent portions of NaBH4 were added only after the previous charge had completely dissolved. After the addition of ˜3 g of NaBH4 (˜80 mmol, 2.5 equiv) over a 3 h period, LC/MS analysis showed >95% conversion to the desired alcohol. The residual hydride reagent was quenched by cooling the mixture to 0° C. and carefully adding 1.0 M HCl until H2 evolution ceased. The methanol was removed in vacuo and the mixture diluted with ˜200 mL of EtOAc. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with additional EtOAc and the combined organic layers washed with brine, dried over Na2SO4, filtered through a pad of silica and evaporated. This yielded ˜10 g of tert-butyl (2S,4R)-1-azido-7-chloro-4-(hydroxymethyl)heptan-2-ylcarbamate which possessed sufficient purity to employ in the subsequent step with no further purification.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:43][N:44]([CH3:75])[C:45](=[O:74])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([C:56]2([CH2:72][NH2:73])[CH2:61][CH2:60][N:59]([C:62]3[C:63]4[C:70]([CH3:71])=[CH:69][NH:68][C:64]=4[N:65]=[CH:66][N:67]=3)[CH2:58][CH2:57]2)=[O:55])[CH:48]=1>C(Cl)Cl.O>[CH3:75][N:44]([CH3:43])[C:45](=[O:74])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([C:56]2([CH2:72][NH:73][C:7](=[O:9])[CH2:6][C:5]3[NH:1][CH:2]=[N:3][CH:4]=3)[CH2:57][CH2:58][N:59]([C:62]3[C:63]4[C:70]([CH3:71])=[CH:69][NH:68][C:64]=4[N:65]=[CH:66][N:67]=3)[CH2:60][CH2:61]2)=[O:55])[CH:48]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(CN)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Reactant: O=C(O)Cc1cnc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c[nH]c2ncnc(N3CCC(CNC(=O)Cc4cnc[nH]4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
To a suspension of 2-(1H-imidazol-5-yl)acetic acid (0.238 g, 1.47 mmol) and HATU (0.372 g, 0.978 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (0.51 mL, 2.93 mmol). The resulting solution was allowed to stir for 20 min. at room temperature. To this solution was added the acetate salt of 3-(4-(aminomethyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate (from example 20, 0.500 g, 0.978 mmol) and N,N-diisopropylethylamine (0.17 mL) in CH2Cl2 (5 mL). The reaction was allowed to stir at room temperature for 6h, and then diluted with H2O (10 mL) and CH2Cl2 (20mL). The mixture was extracted with CH2Cl2 (2×10 mL), and the combined organics were washed with NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (3-10% MeOH:CH2Cl2) to afford the title compound (0.393 g, 72% yield) as a white solid. This solid was suspended in water, and acetic acid was added until the solution became clear. This solution was frozen and lyophilized to the di-acetate salt of the title compound (0.477 g).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:5]=1[C:6]([C:8]1[CH:9]=[N:10][O:11][C:12]=1[CH:13]1[CH2:15][CH2:14]1)=[O:7])([O-:3])=[O:2].[BH4-].[Na+]>C(O)C>[OH:7][CH:6]([C:5]1[CH:16]=[CH:17][C:18]([C:20]([F:22])([F:21])[F:23])=[CH:19][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]1[CH:9]=[N:10][O:11][C:12]=1[CH:13]1[CH2:15][CH2:14]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A mixture of 4-[2-nitro-4-trifluoromethylbenzoyl]-5-cyclopropylisoxazole (8.00 g) and sodium borohydride (0.53 g) in ethanol (250 ml) was stirred at room temperature for 2 hours. The solution was evaporated almost to dryness and the resultant solution was diluted with ethyl acetate. The solution was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ether and petroleum ether to give 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 294, 5.95 g) as an off white solid: m.p. 76° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[OH-].[Na+].[N:13](OC)=[O:14].OS(O)(=O)=O.N([O-])=O.[Na+]>CO.O>[OH:14][N:13]=[C:7]([C:8]#[N:9])[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1
Reactant: CON=O
Reactant: Cc1ccc(CC#N)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(C#N)=NO)cc1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
131.2 g (1 mol) of p-tolylacetonitrile are placed in a sulfonation flask and charged with 40 g (1 mol) of sodium hydroxide, dissolved in 325 ml of methanol. This solution is cooled in an ice bath to 0-5° C. At this temperature, 1 mol of gaseous methyl nitrite (prepared in situ by addition of 31.5 ml of conc. H2SO4, dissolved in 65 ml of water, to a solution of 83 g of NaNO2 in 50 ml of water and 53 ml of methanol (see Org. Synthesis 1979, 59, 95)) is introduced, with stirring, over 3 hours. The ice bath is then removed and the red solution is stirred overnight at room temperature. The methanol is distilled off on a rotary evaporator and the orange residue is then charged with water and toluene. The aqueous phase is separated, washed twice with toluene and acidified with conc. HCl. The resulting orange emulsion is extracted three times with ethyl acetate, the extracts are washed with water and dried over magnesium sulfate. After filtration, the solvent is distilled off and a yellowish-orange oil is obtained which solidifies upon standing. Recrystallisation from toluene gives 133.6 g (83% of theory) of α-hydroxyimino-4-methylbenzylcyanide as a beige solid having a melting point of 110.5-114.5° C. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OC)=O)[CH2:14][C@@H:13]1[CH3:22])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[CH3:22])=[O:10]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(Cl)c1Cl
Yield: 63.4 %

Procedure:
A solution of methyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 40, 3.4 g, 9.79 mmol), potassium hydroxide (3.84 g, 68.58 mmol), and hydrazine hydrate (3.6 mL, 68.58 mmol) in ethylene glycol (180 mL) was stirred for 60 h at 120° C. The reaction mixture was poured in to water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product, which was triturated with water (150 mL) to afford 3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.8 g, (63%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](I)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13].[CH3:15][N:16]1[C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:19][CH:18]=[N:17]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:20]2[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=2)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13]
Reactant: CCc1cc(N)c(C(=O)OC)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(C(=O)OC)cc1-c1ccnn1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
2-Amino-5-iodo-4-ethyl-benzoic acid methyl ester (280 mg, 0.92 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (409 mg, 1.2 equiv) were weighed in air and added to a flame-dried flask. [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (75 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred at 100° C. for 18 h (TLC control). The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-ethyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (163 mg, 68% yield) as a yellow solid. ESI-MS: m/z 260.3 [M+H]+, rt 6.37 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2cncc(F)c2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2cncc(F)c2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(5-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=417.2, tR (minutes, Method D)=0.68
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6].CCN(CC)CC>CCO>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[C:10]([F:22])=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCl)c1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCS2(=O)=O)c1F
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of methyl 3-{[(3-chloropropyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D145) (300 mg, 0.85 mmol, 1 equiv) in EtOH (30 ml) was added NEt3 (280 μl, 2 mmol, 2.3 equiv) and the resulting solution was refluxed for 1.5 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt/Et2O to give methyl 3-(1,1-dioxido-2-isothiazolidinyl)-2-fluoro-5-nitrobenzoate (D147) (150 mg, 55%) as a light tan solid which was used in the next step without further purification. [M+H+ NH3]+=336.3, RT=2.50 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[O:16][Si](C(C)(C)C)(C)C.C([Li])(C)(C)C.CCCCC.[CH:34]1([CH2:37][C:38](N(OC)C)=[O:39])[CH2:36][CH2:35]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Cl>C(OCC)C.O>[CH:34]1([CH2:37][C:38]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[OH:16])=[O:39])[CH2:36][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CON(C)C(=O)CC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: O=C(CC1CC1)c1ccc(O)cc1O
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Stir 1-bromo-2,4-bis-(tert-butyl-dimethyl-silanyloxy)-benzene (100 g, 240 mmol) in diethyl ether (1 L, anhydrous) at −60° C. and treat with 1.7M tert-butyllithium in pentane (290 mL, 493 mmol) via addition funnel over a 10 minute period. Stir for 15 min, then treat with 2-cyclopropyl-N-methoxy-N-methyl-acetamide (34 g, 237 mmol) in a minimum amount of ethyl ether. Remove cold bath, stir for 1 hr, treat with 1N aqueous hydrochloric acid (100 mL), and stir for an additional hour. Separate the layers and wash the organic layer with 1N aqueous hydrochloric acid (100 mL), brine, dry with magnesium sulfate, filter, and evaporate. Dissolve the residue in tetrahydrofuran (1 L), treat with 1N tetrabutylammonium fluoride solution in tetrahydrofuran (500 mL, 500 mmol), and stir for 3 hrs. Pour mixture into 1 L of water containing 120 mL of 5N hydrochloric acid, separate layers, and extract water layer twice with ethyl acetate. Wash organic layers with brine, dry with magnesium sulfate, filter, and evaporate. Chromatograph residue on silica gel (Biotage® Radial Compression fitted with a 75-L column) eluting with 25% ethyl acetate in hexanes to isolate the title compound (43 g, 94% yield). 1H NMR (CDCl3) δ 12.83 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 6.39 (m, 2H), 5.98 (s, 1H), 2.80 (d, J=4.0 Hz, 2H), 1.13 (m, 1H), 0.60 (m, 2H), 0.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:14])[CH:12]=[CH2:13])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC)c(OC)c1
Yield: 29.3 %

Procedure:
1,2-dimethoxybenzene (135 mg), acryloyl chloride (118 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from −40° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (55 mg).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:8][CH2:7]1)=O)=C.Cl.CO>>[CH:22]1([CH2:21][O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2/[CH:13]=[CH:12]/[CH:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C=COC(=O)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Agent: Cl
Solvent: CO
Product: C(=C/C1CCNCC1)\c1ccccc1OCC1CCCCC1
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
2.026 g of 1-(vinyloxycarbonyl)-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine was suspended in 20 ml of a 10% hydrogen chloride-methanol solution, and the mixture was stirred for 20 minutes under ice-cooling. After stirring for 15 minutes at room temperature, the mixture was heated under reflux for one hour 10 minutes. The solvent was evaporated, and to the residue was added an aqueous saturated sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and to the residue was added n-heptane. The insoluble matters were filtered off, and the filtrate was evaporated, to give 1.556 g of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=3)[NH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc2[nH]cc(Cn3ccnc3)c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc2[nH]cc(Cn3ccnc3)c2c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a well-stirred solution consisting of 3-(imidazol-1-ylmethyl)-5-methoxyindole (0.30 g.) dissolved in dry methylene chloride (30 ml.) at -70° C., there was added boron tribromide (0.38 ml.) in a dropwise manner. The resulting mixture was allowed to warm up and was then stirred at 20° C. for a period of five hours. Water (50 ml.) was then added to the spent reaction mixture, and the resulting aqueous layer was subsequently separated and washed with methylene chloride (using two-20 ml. portions). The washed aqueous layer was then made basic with solid sodium bicarbonate and evaporated to dryness. The residue obtained in this manner was next treated with boiling ethyl acetate (200 ml.), and the resulting organic solution was separated from the mixture by decantation and then evaporated to give a solid. Crystallization of the latter material from isopropanol/petroleum ether (b.p. 80°-100° C.) then gave pure 5-hydroxy-3-(imidazol-1-ylmethyl)-indole (yield, 0.10 g.), m.p. 169°-170° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[CH:19](Br)([CH3:21])[CH3:20].O>CS(C)=O>[CH:19]([O:7][N:8]1[C:9](=[O:18])[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:13])([CH3:21])[CH3:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (37 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture, isopropyl bromide (3.41 mL, 37.5 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-isopropyloxy-isoindole-1,3-dione (4.44 g, 86.6%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]#[C:9]Br.CCCCC>C(N(CC)CC)C.C(OCC)C>[O:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[N:8]
Reactant: N#CBr
Reactant: Oc1ccccc1
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#COc1ccccc1

Procedure:
To a oven dried 500 mL 3-neck round bottom flask equipped with a overhead stirring, a septa, a thermocouple and the nitrogen inlet, phenol (20.0 g, 0.210 mol), diethyl ether (Et2O, 290 mL) and cyanic bromide (BrCN, 23.0 g, 0.210 mol, 1.0 equiv) were added at room temperature. The resulting solution was cooled down to 0-3° C. before triethylamine (TEA, 61.9 mL, 0.442 mol, 2.1 equiv) was added dropwise via syringe over 25 min. The addition of triethylamine to reaction mixture was mildly exothermic and the reaction temperature went up to as high as 15° C. After addition of triethylamine, the reaction mixture became a white slurry which was stirred vigorously at 0° C. for 2 h at 5-15° C. When the reaction was deemed complete as confirmed by TLC and LCMS, the reaction mixture was diluted with pentane (150 mL, 1.30 mol). The precipitated triethylamine hydrochloride was filtered off and the salt was washed with diethyl ether and pentane (1 to 1 by volume, 200 mL). The filtrate was then concentrated under reduced pressure to remove the majority of the solvent, and the residue, which contains the crude cyanatobenzene (6), was directly used in the subsequent reaction without further purification assuming the theoretical yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[N:13]=[C:14]([C:33]2[O:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:36][N:37]=2)[C:15]([N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]([O:20][C:19](=[O:25])[N:18]([C:15]1[C:14]([C:33]2[O:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:36][N:37]=2)=[N:13][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:17][N:16]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: OB(O)c1ccccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccccc2Br)nc1-c1nnc(-c2ccccc2)o1
Temperature: 50 °C

Procedure:
A mixture of (2-bromophenyl)boronic acid (100 mg, 0.4979 mmol), tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (258.1 mg, 0.4979 mmol), potassium carbonate (206.5 mg, 1.494 mmol) and triphenylphosphane palladium (13.06 mg, 11.54 μL, 0.04979 mmol) in DMF (3 mL) was heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature and filtered through a Celite,™ pad. The pad was washed with ethyl acetate (1×10 mL) and the combined filtrates were washed with water (2×10 mL) and brine (1×10 mL), dried over MgSO4 and concentrated to leave the product as a solid which was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][CH2:30][CH2:31][S:32](=[O:35])(=[O:34])[NH2:33])[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.O.CCO>C1COCC1>[S:32]([CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:18]=1)(=[O:35])(=[O:34])[NH2:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
4-{4-[4-(3-Sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexane-carboxylic acid ethyl ester (590 mg, 1.176 mmol) and LiOH.H2O (493.5 mg, 11.76 mmol) were combined in THF (2.5 mL), H2O (2.5 mL), and EtOH (2.0 mL) and allowed to stir overnight at RT. 10% HV1 solution was then added and the product precipitated. The organic solvents were removed in vacuo and the remaining suspension was filtered, washed with water and the yellow solid dried to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclo-hexanecarboxylic acid (Compound 220, 550 mg, 99%).