Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].O(C(C)(C)C)[K].[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1>CS(C)=O.O>[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:23])[NH:2][OH:3])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc(Br)o2)cc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N=C(NO)c1ccc(-c2ccc(Br)o2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled suspension of hydroxylamine hydrochloride (17.25 g, 0.25 mol) in DMSO (150 ml) was added portionwise KO-t-Bu (28.0 g, 0.25 mol) and the mixture was stirred under nitrogen for 30 min. 2-Bromo-5-(4-cyanophenyl)furan (17.37 g, 0.07 mol) was then added and the mixture was stirred overnight at room-temperature. The resulting solution was diluted with excess water to give 2-bromo-5-[4-(N-hydroxyamidino)phenyl]furan as an off-white solid, which was collected and washed with water. Yield: 19.45 g, 99%; mp 162-164° C. 1H NMR (DMSO-d6): 5.84 (broad s, 2H), 6.71 (d, J=3.6 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 9.70 (s, 1H). IR (cm−1): 3475, 3369, 3209 (broad), 1639, 1482, 1341, 1017, 927, 787. The intermediate amidoxime (38.9 g, 0.138 mol) was dissolved in a mixture of DMSO (60 ml) and dioxane (300 ml) and with chilling was treated with a solution of LiOH hydrate (11.61 g, 0.277 mol) in water (60 ml). At room temperature, the resulting suspension was then treated dropwise via an addition funnel with dimethyl sulfate (26.18 g. 0.208 mol) over the course of ˜30 min. Following the addition, the mixture became slightly warm and the solids dissolved. After stirring overnight, the mixture was diluted with excess water and extracted with EtOAc. Purification of the residue by column chromatography on silica gel eluting with 10% EtOAc in hexane gave the slightly impure product, which was further purified by recrystallization from MeOH/water in multiple crops to give an off-white solid, mp 116-117° C. Yield: 28.0 g, 69%. 1H NMR (DMSO-d6, an apparent mixture of stereoisomers): 3.74 (2s, 3H), 6.09 (broad s, 2H), 6.72 (2d, J=3.6 Hz, 1H), 7.09 (2d, J=3.6 Hz, 1H), 7.70 (m, 4H). IR (cm−1): 3459, 3312, 3177, 2957, 2935, 2901, 2818, 1634, 1403, 1051, 910, 842, 785.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14]3[C:9](=[CH:10][C:11]([CH2:16][OH:17])=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1.[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3]1[C:15]2[C:14]3[C:9](=[CH:10][C:11]([CH:16]=[O:17])=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1-c1ccc(CO)cc1C2=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1cccc2c1-c1ccc(C=O)cc1C2=O
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
To a stirred suspension of 1.85 g (7.69 mmol) of carbinol from Step E in 50 mL CH2Cl2 was added 270.1 mg (0.769 mmol) of tetrapropylammonium perruthenate. After stirring for 5 minutes, 1.35 g (11.5 mmol) of solid N-methyl-morpholine-N-oxide was added all at once, and the resulting mixture stirred further for 5 minutes. The dark solution was passed over a column of florisil eluted with CH2Cl2-EtOAc (10:1) to give 1.42 g of the title aldehyde as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](=[O:45])[NH:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([O:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH2:37]CCN5C=CN=C5)=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:46]>O1CCOCC1>[ClH:46].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([NH:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([O:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:17][NH:21][CH:20]([CH3:22])[CH3:19])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:45])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2nc3ccc(OS(=O)(=O)c4ccc(NCCCn5ccnc5)cc4)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CC4CCNCC4)sc3c2)cc1
Yield: 88 %

Procedure:
2nd step: A solution of 103 mg of 4-({6-[4-(3-imidazol-1-ylpropylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}methyl)piperidine-1-carboxylic acid tert-butyl ester, 2 ml of dioxane and 2 ml of 4N hydrochloric acid in dioxane is stirred for 3 hours at room temperature. The precipitate obtained is filtered off and washed with dioxane and ethyl ether to give 110 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-(2-piperid-4-ylacetylamino)benzothiazol-6-yl ester hydrochloride (white powder) in a yield of 88%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.C1(C)C(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=CC=1>CC#N>[N+:39](=[C:16]([C:15]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:40]
Reactant: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Reactant: Cc1ccccc1S(=O)(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-(4-morpholinylmethyl)phenyl)-3-oxopropanoate (Preparation 6, 5.00 g) and triethylamine (2.48 mL) in 50 mL CH3CN cooled to 0° C. is added toluenesulfonyl azide (3.51g, prepared according to Org. Prep. Proc. Intl., 1981, 13, 112) in 10 mL CH3CN. The reaction is stirred at 0° C. for 15 mnin then at room temperature for 2 h. The reaction is concentrated (below 50° C.). 2N NaOH (25 mL) is added. The aqueous layer is extracted with CHCl3 (3×). The combined organic layers are washed, dried and concentrated to yield 4.68 g (86%) of the desired product as a yellow oil. Physical characteristics are as follows: 1H NMR (CDCl3) δ 7.52, 7.44, 7.06, 4.24, 3.75, 3.55, 2.50, 1.24; MS (ESI+) for C16Hl8FN304 m/z 336.1 (M+H)+.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][O:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15](/[CH:20]=[CH:21]/[C:22]([CH2:24][C:25](/[CH:27]=[CH:28]/[C:29]2[CH:37]=[C:34]([O:35][CH3:36])[C:32]([OH:33])=[CH:31][CH:30]=2)=[O:26])=[O:23])[CH:14]=1.O/C(/C=C/C1C=CC(O)=C(OC)C=1)=C\C(=O)/C=C/C1C=CC(O)=C(OC)C=1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:2]([O:19][C:18]1[CH:17]=[CH:16][C:15](/[CH:20]=[CH:21]/[C:22](=[O:23])/[CH:24]=[C:25](\[OH:26])/[CH:27]=[CH:28]/[C:29]2[CH:30]=[CH:31][C:32]([OH:33])=[C:34]([O:35][CH3:36])[CH:37]=2)=[CH:14][C:13]=1[O:12][CH3:11])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: COc1cc(/C=C/C(=O)/C=C(O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(O)=C/C(=O)/C=C/c2ccc(OC(=O)c3cccnc3)c(OC)c2)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
To a solution of nicotinoyl chloride hydrochloride [296] (0.725 g, 4.0 mmol, 1.5 eq) in THF (30 ml) was added TEA (1 ml, x mmol, y eq) drop-wise at 0° C. A solution of curcumin, (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one [4151] (1.0 g, 2.7 moles, 1.0 eq) and pyridine (1 ml) in THF (10 ml) was then added at the same temperature. The reaction temperature was gradually increased to RT. The reaction mixture was stirred for 20 h at RT. Reaction was monitored by TLC. The reaction mixture was diluted with EtOAc (200 ml), washed by saturated NaHCO3 solution (75 ml) and water (100 ml) successively. The EtOAc layer was separated, dried with sodium sulphate and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography using (2% MeOH: DCM, 100-200 mesh) get the desired product, 4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxyphenyl nicotinate [307] as yellow solid (0.30 g, 23%).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([CH:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[NH:14][N:15]=[CH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[NH:6][C:7]=1[CH3:12])[CH3:19]
Reactant: Cc1[nH]c(C(C)(C)C)nc1C=O
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1nc(C(C)(C)C)[nH]c1C

Procedure:
A 6.17 gm. portion of 2-tert-butyl-5-methyl-4-imidazolecarboxaldehyde and 4.20 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 226°-228.5° C.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:13][CH2:14]1
Reactant: CCc1cccc(C2CC2)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cccc(C2CC2)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=327.4 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-6-ethyl-benzoic acid (intermediate T).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of (1RS,2SR)-2-[(benzylamino)methyl]-1-(3,4-dichlorophenyl)propane-1,3-diol (11.6 g) in THF (100 mL) were added tert-butylchlorodimethylsilane (5.63 g) and imidazole (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (10.9 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][F:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH2:18][F:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCCCF)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCCCF)nc1Cl
Yield: 116.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (127d) (0.84 g, 3.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.41 g, 2 mmol), WSC hydrochloride (0.77 g, 4 mmol), HOBt (0.41 g, 3 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.01 g of the title compound as a colorless solid (100%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.Cl.[O:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:30][NH:29][CH2:28]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:29]3[CH2:30][CH:27]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:28]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1CC(C2CNC2)CCO1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.173 g, 0.65 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.138 g, 0.78 mmol) and 4 Å molecular sieves (0.9 g) in DCE (7 mL). The reaction mixture was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.274 g, 1.29 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 2-Chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as a white foam (0.117 g, 45%). LCMS (Method A): RT=2.40 min, [M+H]+ 407.2
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:5])C.[OH-].[Na+].Cl>CCO>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:30]=[CH:29][C:28]([C:23]2[C:22]([C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:9][CH2:8][N:7]([CH2:6][C:4]([OH:5])=[O:3])[CH2:12][CH2:11]4)=[CH:14][CH:15]=3)=[O:21])=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)CN1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-phenyl]-amide (4.6 g) in EtOH (80 mL) was added 1N sodium hydroxide and the mixture was stirred under reflux for 2 hours. The solution was cooled at room temperature, acidified with concentrated HCl and evaporated to dryness. The solid residue was purified by flash chromatography eluting with CH2Cl2/MeOH/Et3N (70/30/0.2) and the solid was recrystallized from EtOH to give the title compound (4.2 g) as white crystals.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][CH2:14][C:13]=2[CH:20]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:18][C:16]1([CH3:19])[O:15][CH2:14][C:13]2[CH:20]=[C:9]([OH:8])[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]=2[O:17]1
Reactant: Cc1c(OCc2ccccc2)cc2c(c1C)OC(C)(C)OC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(O)cc2c(c1C)OC(C)(C)OC2
Yield: 89.4 %

Procedure:
To a solution of 6-benzyloxy-2,2,7,8-tetramethyl-4H-benzo[1,3]dioxine (86 mg, 0.29 mmol) in 10 mL EtOH was added Pd/C (15 mg, 10%). It was stirred in a hydrogen atmosphere for 1.5 h and filtered. The solution was concentrated and the crude product was purified on silicagel column chromatography to afford 2,2,7,8-tetramethyl-4H-benzo[1,3]dioxin-6-ol as a white solid (54 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 6.28 (s, 1H), 4.77 (s, 1H), 4.76 (s, 2H), 2.17 (s, 3H), 2.13 (s, 1H), 1.55 (s, 3H), 1.54 (s, 3H); 13C-NMR δ (ppm): 147.1, 142.9, 126.1, 122.7, 116.6, 107.5, 99.1, 60.9, 24.8, 11.9, 11.5.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5](=[O:27])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:34](=[O:36])[CH3:35])=[CH:10][C:9]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)COc1ccc(N)cc1C(=O)NCc1ccc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)COc1ccc(NC(C)=O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
A solution of [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester (0.13 g, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL, 0.2 M) along with pyridine (0.05 mL, 0.05 g, 0.61 mmol). This mixture was cooled to 0° C. before treatment with acetic anhydride (0.10 mL, 0.098 g, 0.95 mmol). After stirring at room temperature for 24 h, the reaction mixture was diluted ethyl acetate and sucessively washed with 2 N HCl, saturated aq NaHCO3 and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give [4-acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester (0.125 g, 87%): 1H NMR (DMSO-d6, 300 MHz) δ 89.95 (br s, 1 H), 8.94 (br t, J=5.7 Hz, 1 H), 7.98 (d, J=2.7 Hz, 1 H), 7.74 (dd, J1=9.0 Hz, J2=3.0 Hz, 1 H), 7.42–7.24 (m, 2 H), 7.22–7.02 (m, 2 H), 5.88 (m, 1 H), 5.30 (dd, J1=17.1 Hz, J2=1.8 Hz, 1 H), 5.21 (dd, J1=9.0 Hz, J2=1.8 hz, 1 H), 4.97 (s, 2 H), 4.64 (br d, J=5.4 Hz, 2 H), 4.55 (br d, J=6.0 Hz, 2 H), 2.00 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[S:29]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:28])(=[O:31])=[O:30]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-(2-hydroxyethyl)-3-carboethoxy-4-methylpyrrole-2-acetate (101.7 g) in 800 ml of dry methylene chloride at -10° C. was treated with 56 ml of triethylamine followed by addition dropwise 31 ml of methanesulfonyl chloride. After 30 minutes of stirring at room temperature, 250 ml of water was added and the organic layer separated and washed with water (3×300 ml ), dried over Na2SO4 and evaporated under reduced pressure to yield 121.3 g of ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methyl-pyrrole-2-acetate as white crystals from ethylacetate hexane, m.p. 66°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4].[OH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[OH:17])=[O:29])[CH2:7][N:6]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CCC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CCC(C)(C)C

Procedure:
(2S,4S)-1-(3,3-Dimethyl-butyl)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-amino-1-(3,3-dimethyl-butyl)-pyrrolidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C23H31N2O4 [(M+H)+] 399.0, obsd. 399.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:11]1[N:19]=[CH:18][C:17]2[NH:16][C:15]3[N:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]5)=[CH:26][CH:25]=4)=[CH:23][C:14]=3[C:13]=2[CH:12]=1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:19]=[CH:18][C:17]3[NH:16][C:15]4[N:20]=[CH:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)=[CH:23][C:14]=4[C:13]=3[CH:12]=2)[CH:2]=1
Reactant: OB(O)c1ccccn1
Reactant: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(-c6cccnc6)cc5c4c3)cc2)CC1
Temperature: 140 °C
Yield: 11.2 %

Procedure:
To a mixture of pyridine-2-boronic acid (27 mg, 0.22 mmol), 6-bromo-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (55 mg, 0.11 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9 mg, 0.011 mmol) in acetonitrile (1 mL) and saturated aqueous sodium carbonate solution (1 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was partitioned between DCM and water and the phases were separated using a hydrophobic frit and the organic phase evaporated. The residue was purified HPLC (C18 column, 50-98% MeCN in water (containing 20 mM triethylamine) over 30 minutes and the fractions containing pure product combined and concentrated then freeze-dried to afford the title compound (6 mg, 11%). 1H NMR (CDCl3 plus CD3OD, 400 MHz): 9.22 (dd, J=2.3, 0.8 Hz, 1H), 9.05 (d, J=1.1 Hz, 1H), 8.86-8.83 (m, 2H), 8.59-8.56 (m, 2H), 8.48-8.44 (m, 1H), 7.73-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 3.64 (s, 2H), 3.11-3.03 (m, 2H), 2.17-2.04 (m, 3H), 1.93-1.85 (m, 2H), 1.74-1.61 (m, 2H). LCMS (Method A): RT=5.43 min, M+H+=488.