Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[N:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:24][C:25]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=[CH:34][N:35]=1
Reactant: CCOC(=O)c1cccnc1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 95 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 50 mL round-bottom flask was charged with 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (2.0 g, 6.8 mmol), ethyl 2-(bromomethyl)nicotinate (2.3 g, 9.4 mmol), cesium carbonate (6.62 g, 20.3 mmol), potassium iodide (0.17 g, 1.0 mmol) and N,N-dimethylformamide (30 mL). The reaction mixture was stirred under nitrogen at 95° C. for 1 h, allowed to cool to ambient temperature and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 0% to 30% gradient of ethyl acetate in dichloromethane afforded ethyl 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate (2.4 g, 79%) as an off-white solid: MS (ES+) m/z 459.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:21])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 60 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
A 300 ml round-bottomed flask equipped with a Dimroth condenser was charged with 13.13 g (100 mmol) of L-isoleucine and 1000 ml of tetrahydrofuran. After the addition of 30.4 g (100 mmol) of bis(4-nitrophenyl) carbonate, the mixture was stirred at 60° C. for 20 hours. After evaporating the solvent, the residue was purified by column chromatography to obtain 8.3 g of N-(4-nitrophenoxycarbonyl)-L-isoleucine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.43 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [C:1]([C@:4]1([CH3:18])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)[NH2:2].C1COCC1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[C:1]([C@:4]1([CH3:18])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
Under a nitrogen gas flow, to a mixture of 11.0 g of tert-butyl (4S)-4-carbamoyl-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate and 170 ml of THF were added dropwise 11.0 ml of triethylamine and 8.0 ml of trifluoroacetic anhydride under ice-cooling, followed by warming to room temperature and stirring for 30 minutes. The reaction mixture was added to water, followed by extraction with ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 8.22 g of tert-butyl (4R)-4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:19]=[CH:18][S:17]/[C:16]/1=[N:20]\[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[C:26]([C:44]#[N:45])[CH:25]=1)(=[O:23])=[O:22])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].FC(F)(F)C(O)=O>C(OCC)(=O)C.ClCCl.C(O)C.CO>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[CH:19]=[CH:18][S:17]/[C:16]/1=[N:20]\[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[C:26]([C:44]#[N:45])[CH:25]=1)(=[O:22])=[O:23])=[O:2]
Reactant: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)/N=c2\sccn2COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1C#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)/N=c2\sccn2COP(=O)(O)O)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Di-tert-butyl [(2Z)-2-[({4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyanophenyl}sulfonyl)imino]-1,3-thiazol-3(2H)-yl]methyl phosphate, (Example 1040, 250 mg, 0.00036 mol) was dissolved in ethyl acetate (10 mL) and then trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 3 hours, then a further portion of trifluoroacetic acid (2 mL) was added and stirred at room temperature for 18 hours. The solvents were removed in vacuo and the residue was partitioned between tert-butylmethyl ether (30 mL) and water (40 mL) and a few drops of aqueous sodium hydroxide solution (2 molar). The aqueous layer was then acidified to pH 1-2 with aqueous hydrochloric acid (2 molar) to give a sticky cream precipitate which was dissolved in a mixture of dichloromethane, ethanol and methanol. This organic layer was dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give the crude product which was triturated with ethyl acetate to give the title compound as a buff powder, (85 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH:9]=1)[CH:7]=O.B(F)(F)F.CCOCC.C[Si](C)(C)[O:26][C:27]1[CH2:30][CH2:29][C:28]=1[O:31][Si](C)(C)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH:7]2[C:27](=[O:26])[CH2:30][CH2:29][C:28]2=[O:31])[CH:9]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Reactant: O=Cc1cc(Br)ccc1OC(F)(F)F
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(=O)C1c1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 5-bromo-2-trifluoromethoxybenzaldehyde (2.0 g, 7.43 mmol) in anhydrous dichloromethane (40 ml) at room temperature is added boron trifluoride etherate (1.13 ml, 8.92 mmol) then 1,2-bis(trimethylsiloxy)cyclobutene (2.86 ml, 11.2 mmol). The mixture is stirred at room temperature for 23 hours, followed by addition of distilled water (1.2 ml) and additional boron trifluoride etherate (14.1 ml, 112 mmol). After stirring for 24 hours at room temperature the reaction mixture is then quenched with saturated aqueous ammonium chloride solution (50 ml) and extracted with dichloromethane (2×50 ml). The crude product is extracted into 0.5 M aqueous potassium carbonate solution (×3), then the aqueous phase is acidified to pH 1 with concentrated hydrochloric acid. Final extraction with dichloromethane (×3) is followed by washing with brine then drying over magnesium sulfate. Filtration then concentration in vacuo gives a crude product which is purified by preparative reverse phase HPLC to afford 2-(5-bromo-2-trifluoromethoxyphenyl)cyclopentane-1,3-dione.
Reaction SMILES: C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O.[OH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]3[S:28][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][N:25]3[C:24]=2[CH:36]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH:19]([C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]3[S:28][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][N:25]3[C:24]=2[CH:36]=1)=[O:18]
Reactant: CCOC(=O)c1cn2c(nc3ccc(CO)cc32)s1
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn2c(nc3ccc(C=O)cc32)s1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Triethylamine (39.02 ml) and sulfur trioxide-pyridine mixture (55.71 g) were added to a DMSO (300 ml) solution of ethyl 6-hydroxymethylthiazolo[3,2-a]benzimidazole-2-carboxylate (19.34 g). The reaction mixture was stirred for 2 hours accompanied by exothermic reaction. After completion of the reaction, the reaction mixture was carefully added to saturated sodium bicarbonate aqueous solution. The insoluble matter was collected by filtration, washed with water and then dried by heating under a reduced pressure to obtain the pale ivory-colored title compound (19.10 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].Cl>C1COCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)OC(C)(C)C)cc2OC)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of Example 122K (3.5 g), and potassium trimethylsilanolate (1.70 g) in THF (250 mL) at room temperature was stirred for 18 hours, diluted with ethyl acetate (400 mL) and water (50 mL), and adjusted to pH 3 with 2N HCl. The organic phase was washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI (+)) m/e 357 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[C:19]2[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].C(NCC1(C(O)=O)C=CC2CCCCC=2C1)(OC(C)(C)C)=O>C(O)C.O>[C:1]([NH:8][CH2:9][CH:10]1[C:19]2[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)C(CNC(=O)OC(C)(C)C)CCC2
Agent: CC(C)(C)OC(=O)NCC1(C(=O)O)C=CC2=C(CCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCCc2ccc(C(=O)O)cc21

Procedure:
Part E--To a solution of methyl N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.50 g, 0.0016 mol) in ethanol (12.5 mL) was added, dropwise, a solution of sodium hydroxide (0.50 g) in water (12.5 mL). All was stirred a reflux over 4 hours. The reaction mixture was concentrated to half volume and then acidified to a pH equal to 1.0 using hydrochloric acid (1N). The residue was purified by flash chromatography using a gradient of hexane:ethyl acetate::1:1 to ethyl acetate to ethyl acetate: methanol::9:1 to give the racemic mixture of the title compound, N-(BOC)-2-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (0.19 g, 0.00062 mol, 39%) as a white solid. mp=172°-176° C.; 1H NMR (DMSO) d 7.8 (s, 1H), 7.65 (d, 1H, J=8.1 Hz), 7.15 (d, 1H, J=8.1 Hz), 7.1-7.0 (m, 1H), 3.2-3.1 (m, 2H), 3.0-2.7 (m, 4H), 1.8-1.6 (m, 4H), 1.4 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8].ClC1C=CC=CC=1C(C)CN([CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[CH2:6][N:5]([CH2:46][CH2:47][CH2:48][O:49][C:50]2[CH2:51][C:52](=[CH:56][C:57]([O:59][CH3:60])=[O:58])[CH:53]=[CH:54][CH:55]=2)[CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:23])([F:21])[F:22])[C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(Cl)cc2)C1
Yield: 33 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-chlorophenyl)propylamine in 33% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 568 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C:22](=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a suspension of 4-phenylpiperidine (2.12 g, 13.1 mmol) and 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.43 g, 13.1 mmol) in MeOH (60 mL) was added NaBH(OAc)3 (8.32 g, 39.3 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and stirred with saturated aqueous NaHCO3 (50 mL) for about 1 h. The organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give 3-(4-phenyl-piperidin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.3 g,) as a yellow oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.73 min; m/z: (M+H)+ 331.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:10]2[N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[N:12]=[N:13][C:9]=2[C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][N:29]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[C:28]1=[O:49].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[CH:15]1([CH2:14][N:11]2[C:10]3[CH:18]=[CH:19][C:7]([C:37]4[CH:38]=[CH:39][C:34]([CH2:33][N:29]5[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:49])=[CH:35][CH:36]=4)=[C:8]([C:20]([F:23])([F:22])[F:21])[C:9]=3[N:13]=[N:12]2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F)C(F)(F)F
Reactant: CN1C(=O)CN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C(F)(F)F)cc2)C1=O
Temperature: 25 °C

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yltrifluoromethanesulfonate [(Example 1, Step 9), 30 mg, 0.077 mmol], 3-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]imidazolidine-2,4-dione (38.2 mg, 0.116 mmol, 1.5 equiv), potassium phosphate (49.1 mg, 0.231 mmol, 3 equiv) and palladium tetrakis(triphenylphosphine) (8.91 mg, 0.007 mmol, 0.1 equiv) were combined in dioxane (2 mL) and water (0.2 mL) and heated at 90° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (15 mL, saturated aqueous) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (80:20 to 5:95; water with 0.05% trifluoroacetic acid:acetonitrile with 0.05% trifluoroacetic acid) to afford the titled compound: 1H NMR (400 MHz, CDCl3) δ 7.69 (1H, d, J=8.5 Hz), 7.34 (1H, d, J=8.5 Hz), 7.28 (4H, dd, J=8.8, 8.1 Hz), 4.58 (2H, s), 4.52 (2H, d, J=7.1 Hz), 3.74 (2H, s), 3.01 (3H, s), 1.40-1.32 (1H, m), 0.65-0.60 (2H, m), 0.48-0.44 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 444.1652 [(M+H)+; calculated for C22H21F3N5O2: 444.1642].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:13](=[S:14])[CH2:12][CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:19][CH2:20][CH2:21][S:14][C:13]1[C:8]([CH3:7])=[C:9]([CH:10]=[CH:11][CH:12]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: BrCCBr
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(SCCBr)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
30.3 g (0.22 mol) of potassium carbonate were added to 40.0 g (0.22 mol) of methyl 3-thio-2-methylbenzoate in 500 ml of acetone, and 82.6 g (0.22 mol) of 1,2-dibromoethane were added dropwise. After 10 hours of stirring at room temperature, the solvent was distilled off, the residue was taken up in water/ethyl acetate and the organic phase was dried and concentrated. The oil that remained was chromatographed over silica gel using ethyl acetate/cyclohexane=1/10.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](I)=[C:12]([O:14][CH3:15])[CH:13]=1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:56][C:57]1[CH:58]=[C:59]([SH:63])[CH:60]=[CH:61][CH:62]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:63][C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([F:56])[CH:58]=2)=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(Cl)ccc1I
Reactant: Fc1cccc(S)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(Cl)ccc1Sc1cccc(F)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A dry round bottomed flask was charged with KOtBu (1.903 g, 17.0 mmol), 5-chloro-2-iodoanisole (4.054 g, 15.1 mmol), Pd2dba3 (144 mg, 0.16 mmol), DPEPhos (176 mg, 0.33 mmol) and 3-fluoro-thiophenol (1.903 g, 17.0 mmol). The flask was evacuated and backfilled with Ar three times. Dry toluene (80 mL) was added and the mixture stirred at 95° C. for 2 h. The mixture was filtered through a pad of silica gel followed by adsorption onto silica gel. After purification by flash chromatography using silica gel, eluting with heptanes/EtOAc, 97:3, the title compound was obtained as a yellow oil (3.41 g, 85%).
Reaction SMILES: C(#N)C.S1(CCCC1)(=O)=O.[Na+].[Cl:12][C:13]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:14]=1[C:15]([C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([O-])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1)=[O:16].P(Cl)(Cl)([Cl:41])=O>O.CN(C)C(=O)C>[Cl:12][C:13]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:14]=1[C:15]([C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([Cl:41])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C(c1ccc(Oc2ccc(S(=O)(=O)[O-])cc2)cc1)c1cc(Cl)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 72 °C
Reaction time: 0.67 h

Procedure:
Solvent (300 mL of acetonitrile and 200 mL of sulfolane) was added to 215 g (about 400 mmol) of crude crystal of A—SO3Na. Furthermore, phosphoryl trichloride (245.3 g, 1.6 mol) was added and reacted at 70° C. Furthermore, 5 mL of N,N-dimethylacetamide was added, a yellow suspension was stirred for 40 minutes at 71 to 73° C., and the reaction liquid was cooled to 3° C. 1 L of cold water was added at a rate so that the temperature of the reaction liquid did not exceed 10° C. The deposit was filtered and collected, washed with cold water, and recrystallized with 350 mL of toluene to obtain 153 of white crystal of 4-[4-(2,5-dichlorobenzoyl)phenoxy]benzene sulfonic acid chloride (A—SO3Cl). Yield depending on A was 87%. Melting point is 130.5 to 131.5° C.
Reaction SMILES: [CH2:1]([N:4]([CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:30][CH3:31])[O:22][CH2:21]1)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15]C=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:2][CH3:3].COC1C=CC=C2C=1CC(NCCCCN1C(=O)C3C(CCC3)C1=O)CO2>>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10](=[O:19])[CH:11]2[CH:12]([CH2:15][CH2:17][CH2:18]2)[C:13]1=[O:14])[CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:30][CH3:31])[O:22][CH2:21]1)[CH2:2][CH3:3]
Reactant: CCCN(CCCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Agent: COc1cccc2c1CC(NCCCCN1C(=O)C3CCCC3C1=O)CO2
Product: CCCN(CCCCN1C(=O)C2CCCC2C1=O)C1COc2cccc(OC)c2C1
Yield: 78 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 2 by the compound of Example 11, the expected product is obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH2:21][NH2:22]>C(O)C>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([NH:21][NH2:22])[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: NN
Solvent: CCO
Product: CC[C@@H]1C(=O)N(C)c2cnc(NN)nc2N1C1CCCC1

Procedure:
Intermediate B and hydrazine (6 equivalents) in ethanol was heated in a microwave for 1 h at 120° C. The solvent was removed to give Intermediate B-2. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[C:10](=O)([O:16]C(C)(C)C)[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:11][C:10](=[O:16])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(N)c(O)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a stirred solution of 6-amino-m-cresol (5 g, 40.6 mmol) in DCM (100 mL) was added di-tert-butyl carbonate (9.4 ml, 40.6 mmol), under an argon atmosphere. The resulting mixture was stirred for 18 h at RT, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated to afford 9.1 g of the title compound as a black oil which was used as a crude material. HPLC: LtRet=4.86 min; LC-MS: m/z 224.3 [M+H]+.