Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH3:19]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH3:19])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(BOC-amino)-5-bromopyridine (3.06 g) in THF (50 mL) was added sodium hydride (538 mg) and the reaction stirred at room temperature for 20 min. Then, iodomethane (0.84 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted into dichloromethane (3×30 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A stirred solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from benzene-ligroin was accomplished by adding magnesium sulfate to absorb the water which separated from the wet product. After filtering and cooling the hot filtrate, the precipitated solid was collected by filtration to yield 4.1 g (85.2%) of white crystals, m.p. 144°-145° C.
Reaction SMILES: F[B-](F)(F)F.C(N(C(C)C)[CH:10]=[N+:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])(C)C.CC(C)([O-])C.[K+].[C:27]([O:31][C:32]([N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C@H:35]1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(=O)C>C1COCC1>[C:27]([O:31][C:32]([N:34]1[C@H:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:46]=2)[CH2:36]/[C:37](=[CH:10]\[N:11]([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])/[C:38]1=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)N(C=[N+](C(C)C)C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate (2.13 g, prepared according to Example 11) is added to a 1 M solution of potassium-tert-butoxide in THF (5.69 ml). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at 60° C. for 1 h. The mixture is then cooled to room temperature and diluted by addition of 10 ml isopropyl acetate. The mixture is then filtered through silica and concentrated in vacuo to afford (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Spectroscopic data as for Example 19, Method 1.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[CH:16]([NH2:18])=[O:17]>>[CH3:15][C:2]1[O:17][CH:16]=[N:18][C:3]=1[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: NC=O
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Product: COC(=O)c1cccc(-c2ncoc2C)c1
Temperature: 130 °C

Procedure:
A mixture of methyl 3-(2-bromo-propionyl)-benzoate (5.42 g) and formamide (3.6 ml) was heated to 130° C. for 5 h. The mixture was cooled and partitioned between H2O and AcOEt. The organic layer was dried over Na2SO4 and evaporated and the residue was purified by chromatography on silica gel (AcOEt/hexane 1:4 as eluent) to give 1.8 g methyl 3-[5-methyl-oxazol-4-yl]-benzoate as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[C:4]([C:17](=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N:9][C:10]([Cl:26])=[CH:11][CH:12]=2)=[C:4]([CH:3]=1)[C:17]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:23]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide (420 mg, 1.096 mmol) in 15 mL of DCM was added dropwise phosphorus oxychloride (301 μL, 3.29 mmol) followed by 2 drops of DMF. After stirring at rt for 1 h, the reaction was quenched with sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=10:1 to 5:1 to 3:1) gave 5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:15]2[CH:25]=[C:19]3[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]3[C:17](=[O:26])[N:16]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Cl)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-chloro-3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[C:22]1([C:28]#[C:29][C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:38]=2)[C:35](O)=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[CH3:40][NH:41][O:42][CH3:43]>O1CCCC1>[CH3:43][O:42][N:41]([CH3:40])[C:35](=[O:36])[C:34]1[CH:38]=[C:30]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:31]=[N:32][CH:33]=1
Reactant: CNOC
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (3.86 g, 20.2 mmol) and diisopropylethylamine (7.0 mL, 40.3 mmol) to a suspension of 5-phenylethynylnicotinic acid (3.0 g, 13.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.97 g, 20.2 mmol) in tetrahydrofuran (100 mL) and stir at room temperature overnight. Concentrate the reaction mixture, dissolve the residue in ethyl acetate and wash sequentially with an aqueous solution of phosphate buffer (pH=7) and a saturated aqueous solution of sodium chloride. Dry the organic layer over magnesium sulfate, filter and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes, to give the title compound as a pale yellow solid (2.4 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([OH:18])=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:26]2[N:25]=[CH:24][N:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(F)c(O)cc1F)OCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Reaction time: 2 h
Yield: 89 %

Procedure:
Benzyl(2,5-difluoro-4-hydroxyphenyl)carbamate (4.90 g) was dissolved in N,N-dimethylformamide (30 ml), then 4,6-dichloropyrimidine (2.61 g) and potassium carbonate (3.63 g) were added thereto at room temperature, followed by stirring for 2 hr. Water (90 ml) was added to the reaction mixture to precipitate crystals. The crystals were collected by filtration and washed with water (30 ml, 6 times). The crystals were hot air-dried at 60° C. for 2 days to provide the titled compound as pale brown crystals (6.108 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]([CH3:15])[C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCC1=O.C1COCC1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)/[N:11]([CH3:15])[C:10]2=[O:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: O=C1CCCN1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Temperature: 65 °C
Yield: 86.3 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C18H11Cl2N3O2: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.
Reaction SMILES: NCCC1C=CC(O)=CC=1.C1C(C(O)CN)=CC=C(O)C=1.[CH:22]1[C:27]([C@@H:28](O)[CH2:29][NH2:30])=[CH:26][C:25]([OH:32])=[C:24]([OH:33])[CH:23]=1>>[NH2:30][CH2:29][CH2:28][C:27]1[CH:22]=[CH:23][C:24]([OH:33])=[C:25]([OH:32])[CH:26]=1
Reactant: NC[C@H](O)c1ccc(O)c(O)c1
Agent: NCC(O)c1ccc(O)cc1
Agent: NCCc1ccc(O)cc1
Product: NCCc1ccc(O)c(O)c1

Procedure:
Tyramine (TA), octopamine (OA) and norepinephrine (NE), naturally occurring monoamines that have a similar structure to DA, were tested together with DA for their ability to inhibit 3H-DA uptake. The concentration range of an unlabeled competitive inhibitor was selected according to the expected IC50 value. The IC50 values obtained were 0.39±0.11 μM for TA, 1.92±0.28 μM for OA, 4.10±1.02 μM for DA and 22.04±2.94 μM for NE. The apparent Ki values (calculation based on Cheng et al., (1973) Biochem Pharmacol 22:3099) were 0.35±0.10 μM for TA, 1.74±0.25 μM for OA, 3.72±0.92 μM for DA and 20.04±2.67 μM for The rank order of apparent Ki on OA/TAT for potential substrates was: TA<OA<DA<NE.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.C(N(CC)CC)C.CC([O:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:36])[C:34]1[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:28]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A slurry of 58.6 g (0.355 mol) of 2-(4-aminophenyl)propionicacid and 500 ml of methylene chloride was treated with 90.11 ml (77.13 g, 0-710 mol) of trimethylsilyl chloride and was heated to reflux for 120 min. The reaction mixture was cooled to 0° C. and treated with 184.44 ml (107.77 g, 1.065 mol) of triethylamine. After stirring for 5 minutes, this mixture was treated with a solution of 70.45 g (0.355 mol) of O-acetylsalicyloyl chloride and 150 ml of methylene chloride. The reaction mixture was warmed to 25° C. and stirred for 64 hr. The volatiles were removed in vacuo. The residue was stirred in 2N aqueous sodium hydroxide for one hour and acidified with 2 M aqueous sulfuric acid. The solid was recrystallized twice from ethanol/water to give a tan solid. Isolation by filtration afforded 53.05 g of (52% yield) of 2-(4-(N-salicyloyl)aminophenyl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C)C=O.[Cl:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[Cl:19]
Reactant: O=[N+]([O-])c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole in 140 ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) of N-chlorosuccinimide followed by stirring at room temperature overnight. A 10% aqueous solution of sodium thiosulfate was added thereto followed by extracting with ethyl acetate. The organic layer was washed with water and brine successively, dr dried over magnesium sulfate and concentrated to dryness to give 14.84 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[NH2:43])[CH2:33][CH2:32]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:43][C:42]3[CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=[C:40]([O:39][CH2:38][CH2:37][N:34]4[CH2:33][CH2:32][O:31][CH2:36][CH2:35]4)[CH:41]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: Nc1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN4CCOCC4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (70.9 mg, 0.172 mmol) and 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (50 mg, 0.172 mmol) in pyridine (5 mL) was added T3P® (50% in EA, 0.3 mL) dropwise and the mixture was stirred at 25° C. for 1 h. The mixture was quenched with cold water (20 mL), extracted with DCM/MeOH (10:1, v/v, 20 mL×3). The organic layer was dried over Na2SO4 and concentrated to give an off white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide (80 mg, 0.111 mmol, 64.5% yield): 1H NMR (400 MHz, CD3OD): δ 7.94 (d, J=1.8 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.45-7.35 (m, 6H), 6.95-6.88 (m, 3H), 5.35 (s, 2H), 4.20-4.10 (m, 4H), 3.80 (s, 2H), 3.78 (s, 3H), 3.73-3.66 (m, 4H), 2.81 (t, J=5.4 Hz, 2H), 2.59 (d, J=4.2 Hz, 4H), 1.41 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 684 (M+H).
Reaction SMILES: FC1C=C(F)C=CC=1C(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:16]1[O:25][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=2[N:15]=1
Reactant: Cc1cc(NC(=O)c2ccc(F)cc2F)c(OC(=O)c2ccc(F)cc2F)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1cc2nc(-c3ccc(F)cc3F)oc2cc1C
Yield: 63.1 %

Procedure:
A suspension of 2-(2,4-difluorobenzamido)-4,5-dimethylphenyl 2,4-difluorobenzoate (90 mg, 0.22 mmol) and 4-methylbenzenesulfonic acid (82 mg, 0.43 mmol) in xylene (2 mL) was heated at reflux for 16 h. After cooling, the solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:15 v/v to afford 36 mg (64%) of the title compound (LCMS RT=7.81 min, MH+ 260.0)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[CH3:16].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Oc1ccccc1
Yield: 68.6 %

Procedure:
A solution of 4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (150 mg), phenylboronic acid (190 mg), copper (II) acetate (189 mg) and TEA (0.22 mL) in dichloromethane (4 mL) was stirred for 6 h. The reaction was diluted into ethyl acetate, washed with 1N hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. The resulting oil was flash chromatographed (10% DEE/petroleum ether) to afford 4-(3-phenoxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (130 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.C(C1C(=O)C(Cl)=C(Cl)[C:31](=[O:32])C=1C#N)#N>O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[CH:31]=[O:32]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (250 mg, 0.55 mmol) in H2O (5.5 mL) is treated with DDQ (369 mg, 1.6 mmol) in EtOAc (0.5 mL), and stirred at rt for 2 h. The mixture is diluted with EtOAc (50 mL), washed with brine (50 mL), and extracted with saturated aqueous NaHCO3 (3×50 mL). The aqueous layer is acidified to pH 2 with HCl (conc.) and washed with Et2O (50 mL). The aqueous layer is neutralized with 10% aqueous NaOH and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by triturating in Et2O to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-formyl-indol-1-yl)-amide (87 mg, 43%). MS: 376 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.53 (s, NH, 1H), 10.00 (s, 1H), 9.34 (m, 1H), 8.81 (m, 1H), 8.66 (s, 1H), 8.48 (m, 1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 7.27 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CC(C)=O.O>[CH:1]1([S:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][CH3:19])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of cyclopropanesulfonamide (Li, J. et al; Synlett 2006, 5, 725-728) (800 mg, 6.60 mmol) in acetone (25 ml) was added potassium carbonate (2.738 g, 3 eq, 19.81 mmol) and ethyl chloroformate (1.075 g, 1.5 eq, 9.90 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was poured into water and made acidic (pH 1) with cone HCl then extracted with EtOAc. The extract was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% EtOAc in hexanes) afforded 374 as a colourless oil (800 mg, 63%). 1H NMR (DMSO, d6) 11.47 (s, 1H), 4.10 (q, J=10.27 Hz, 2H), 2.90 (m, 1H), 1.19 (t, J=7.24 Hz, 3H), 1.039 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CS[C:11](=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH3:12]>O1CCOCC1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]1[N:3]2[N:4]=[C:5]([CH2:7][CH3:8])[CH:6]=[C:2]2[N:1]=[C:11]([CH3:12])[N:13]=1
Reactant: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCc1cc(N)n[nH]1
Solvent: C1COCCO1
Product: CCc1cc2nc(C)nc(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A mixture of 3-amino-5-ethylpyrazole (10.3 g, 39.3 mmol) and N-(1-(methylthio)ethylidene)-2,4-dichloro-benzamide (4.0 g, 35.7 mmol) in anhydrous dioxan (20 mL) was stirred at reflux temperature under a nitrogen atmosphere for 16 h. After being cooled to ambient temperature, the reaction mix was concentrated in vacuo and the residue was treated with dichloromethane. The resulting suspension was filtered and the filtrate was concentrated in vacuo to afford an oil (1.5 g, 14% yield): NMR (CDCl3, 300 MHz): δ 7.62 (d, 1H, J=8), 7.59 (d, 1H, J=2), 7.45 (dd, 1H, J=8,2), 6.42 (s, 1H), 2.82 (q, 2H, J=8), 2.73 (s, 3H), 1.30 (t, 3H, J=8).