Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>ClCCl>[CH:1]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[CH3:11])=[O:3]
Reactant: O=CO
Reactant: Cc1ccccc1N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1NC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2-methylaniline (10.710 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with a mixture of hexanes/diethyl ether (2×10 mL) and then with hexanes (3×5 mL) to afford N-formyl-2-methylaniline 8b as a white solid (9.70 g, 72%). 1H NMR (CDCl3, 300 MHz): δ=9.03-8.18 (m, 2H, CHO, NH), 7.77-7.03 (m, 4H), 2.30-2.22 (m, 3H); 13C{1H}NMR (CDCl3, 75 MHz): δ=164.41, 160.32, 135.50, 134.99, 131.45, 130.82, 130.50, 129.87, 127.25, 126.80, 126.34, 125.84, 123.75, 121.32, 18.05, 17.99; HRMS (FAB+) calculated for C8H10NO [M]+ 136.0762, observed 136.0783.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1CCN1CCN(c2ccccc2)CC1

Procedure:
A mixture comprising 0.1 mol 2-(2-bromoethyl)nitrobenzene, 0.23 mol N-phenylpiperazine, and 300 cc absolute ethanol was heated for 15 hr with agitation and refluxing of the ethanol. The alcohol was then removed by evaporation. The residue of the evaporation was dissolved in water. This was then extracted with ether. The ether phase was washed with fresh water, and then dried over sodium sulfate, after which the ether was evaporated off. The excess N-phenylpiperazine was removed by distillation. The distillation residue was recrystallized in methanol, yielding 2-(4-phenylpiperazinylethyl)nitrobenzene with m.p.=76° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.O>ClCCl>[CH:14]12[O:6][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Reaction time: 18 h
Yield: 78.7 %

Procedure:
3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS2O5 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL×2). The organics were combined and washed with 5% aqueous K2CO3 solution (100 mL×3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to a stirred solution of 5% NaS2O5(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed <0.5 mg/mL peroxide. The layers were separated and aqueous layer washed with further DCM (2×50 mL). The combined organics were then dried (Na2SO4). and concentrated in vacuo to afford the crude product as a pale-gold oil. The crude product was purified by silica gel chromatography, (340 g Si), eluting with 30→80% EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil—benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (12.75 g, 54.7 mmol, 79% yield).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:28][CH:29]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)n(C)c2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a mixture of 4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}benzoic acid (270 mg) synthesized above, β-alanine ethyl ester hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (158 mg), triethylamine (287 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (151 mg, 45%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
A suspension of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone (22.3 mg, 0.0698 mmol, Example 325) and 1-(4-amino-piperidin-1-yl)-ethanone (14.9 mg, 0.105 mmol, prepared as described in U.S. Pat. No. 5,817,828) in isopropyl alcohol (2.5 mL) was heated at 120° C. in a sealed tube under microwave conditions for 0.3 to 1 hour. The resulting reaction mixture was evaporated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 1-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid (23.1 mg). MS (M+H)+, 384.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>ClCCl.O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:9][C:3]1[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(I)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(I)cc1CBr
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a mixture of 2-chloro-5-iodotoluene (4.07 g, 16.12 mmol), N-bromosuccinimide (3.16 g, 17.73 mmol) in dichloromethane (258 mL) and water (258 mL) was added 2,2′-azodiisobutyronitrile (0.132 g, 0.81 mmol). The reaction mixture was irradiated with a halogen sun lamp (150 watt) for 2 h and then cooled to room temperature. The two-phase reaction mixture was separated, and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were washed with water (2×150 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an orange oil (5.20 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Cl[CH2:12][CH:13]1[O:17][CH2:16][O:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:17]1[CH:13]([CH2:12][NH:4][C:3]2[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])[CH2:14][O:15][CH2:16]1
Reactant: ClCC1COCO1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: Cc1cc(C)c(NCC2COCO2)c(C)c1

Procedure:
2,4,6-Trimethylaniline (0.3 mole), 5-chloromethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 8 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxolan-5-ylmethyl)-2,4,6-trimethylaniline.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: Sc1cccs1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSc1cccs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a solution of thiophene-2-thiol (1.2 g, 10.3 mmol) in anhydrous DMF (30 mL) was added cesium carbonate (3.9 g, 12 mmol) and the resulting suspension was stirred for 15 min at ambient temperature, then treated with methyl bromoacetate (1.53 g, 10 mmol). The purple suspension was stirred for 1 h, then poured into water (30 mL) and extracted twice with 300 mL EtOAc. The combined organic extracts were washed with brine, dried, filtered, concentrated and the residue was purified via column chromatography eluting with 10% EtOAc/Hexanes to give 1.48 g (79%) of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1)=O>O1CCCC1>[C:7]([CH:9]=[CH:18][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)NC1CCCC(C=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(C=CC#N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.0 M potassium tert-butoxide in THF (2.0 mL, 2.0 mmol) was added diethyl cyanomethylphosphonate (0.30 mL, 1.8 mmol) dropwise at 0° C. and the mixture was stirred at 0° C. for 1 h. A solution of tert-butyl (3-formylcyclohexyl)carbamate (0.30 g, 1.3 mmol) in tetrahydrofuran (9.3 mL) was added dropwise, then cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, concentrated and purified on silica gel column (eluting with 0-30% EtOAc in hexanes) to give the desired product as a mixture of cis- and trans-isomer mixtures (0.12 g, 36%). LCMS calculated for C14H22N2O2Na (M+Na)+: m/z=273.2. Found: 273.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[CH:15]([Si:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])Cl)([CH3:17])[CH3:16].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][Si:18]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a mixture of 3,5-dichlorophenol (16.3 g, 100 mmol), imidazole (14.98 g, 220 mmol), and triisopropylchlorosilane (21.21 g, 110 mmol) was added DMF (200 mL) at room temperature. The resulting brown solution was stirred for 15 h and then it was diluted with water (500 mL). The organic compound was extracted into ethyl acetate (2×100 mL) and the combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was purified using an ISCO (400 g) column chromatography to obtain 31.1 g (97%) of (3,5-dichlorophenoxy)-triisopropylsilane as a colorless oil. EI(+)-HRMS m/e calcd. for C15H24Cl2OSi (M)+ 318.0973, obsd. 318.0971.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (500 mg, 2.47 mmol) was coupled to 3,5-dichloro-phenylboronic acid (473 mg, 2.47 mmol) acid using Method F to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]CCCCC)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1C1CCCCC1
Reactant: CCCCCCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc(C#Cc2ccc(Cl)cc2C2CCCCC2)cc1
Temperature: 100 °C

Procedure:
6.6 g (30.17 mmol) of 9, 7.28 g (30.17 mmol) of 1-bromo-4-hexylbenzene, 21.63 g (66.39 mmol) of caesium carbonate, 78 mg (0.3 mmol) of bis(acetonitrile)palladium(II) chloride and 431 mg (0.9 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl are dissolved in 90 ml of dioxane under nitrogen and heated at 100° C. overnight. 100 ml of water are added to the cooled solution, and the mixture is extracted twice with methyl t-butyl ether (100 ml). The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:54])([CH3:53])[CH2:42][O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C:41]([CH3:54])([CH3:53])[CH2:42][O:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([CH2:2][CH2:1][O:3][C:4]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[O:5])=[O:49])=[CH:46][CH:45]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)OCCC(=O)c2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Yield: 78.2 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (1.2 g) and 4-(2-tert-butoxycarbonylamino-2-methylpropoxy)benzoic acid (1.27 g) according to an analogous synthetic method to Preparation Example 154, the title compound (1.56 g) was obtained.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([O:18][CH3:19])=[CH:11][CH:12]=3)[C@:7]3([CH2:23][O:22][C:21]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[N:20]3)[C:6]=2[CH:5]=1)=[N+]=[N-].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.C1COCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([O:18][CH3:19])=[CH:11][CH:12]=3)[C@:7]3([CH2:23][O:22][C:21]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])=[N:20]3)[C:6]=2[CH:5]=1
Reactant: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: [Pd+2]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(N)ccc1O2

Procedure:
A solution of (S)—N-(2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide (0.410 g, 0.978 mmol) in ethanol (12 mL) and THF (8 mL) was stirred with palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (0.136 g, 0.978 mmol) under hydrogen at atmospheric pressure and RT for 2 hours. The catalyst was removed by filtration over a celite-pad, washed with ethanol (15 mL). The combined filtrates were concentrated to yield the crude product (104584-37-2). The product (S)—N-(2′-amino-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide was obtained as an off-white solid. MS (ESI pos. ion) m/z: 394 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:37]=[C:36]([Br:38])[C:22]([O:23][C@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:21]([Br:39])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O>[CH2:40]([O:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:37]=[C:36]([Br:38])[C:22]([O:23][CH:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:21]([Br:39])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(O)c3sc4ccccc4c23)cc1Br
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OCc3ccccc3)c3sc4ccccc4c23)cc1Br
Reaction time: 17 h
Yield: 100.7 %

Procedure:
To a solution of (R)-2-[4-(6-hydroxy-benzo[b]naphtho[2,3-d]thiophen-11-yl]-2,6-dibromo-phenoxy]-3-phenyl-propionic acid, methyl ester (0.50 g, 0.755 mmol) in dry N,N-dimethylformamide (5 mL) was added benzyl bromide (0.27 mL, 2.27 mmol, 3 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring about 17 hours the reaction was quenched with water (50 mL) and the organics were extracted with ether. The extracts were washed with water, and brine and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (97/3 petroleum ether/ethyl acetate) and the solvents chased with benzene and petroleum ether to provide the title compound as a pale yellow solid (0.572 g, 84%): NMR (CDCl3); δ8.30 (ddd, J=8, 1, 1 Hz, 1 H), 7.82 (ddd, J=8,1,1 Hz, 1 H), 7.68 (ddd, J=8, 1, 1 Hz, 2 H), 7.62 (dd, J=3, 2 Hz, 2 H), 7.60-7.55 (m, 2 H), 7.51-7.26 (m, 10 H), 7.16 (ddd, J=8, 7,1 Hz, 1 H), 6.81 (ddd, J=8, 1, Hz, 1 H), 5.34 (s, 2 H), 5.25 (dd, J=6, 2 Hz, 1 H), 3.76 (s, 3 H), 3.59 (septet, J =Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 750 (2%), 752 (3.5%), 754 (2.5%); Anal Calc. for C39H28Br2O4S: C, 62.25, H, 3.75, N, 0.00; Found C, 61.66, H, 3.53, N, 0.25.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1ccccc1-c1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2ccccc2C)cc1

Procedure:
The phenol from step A (1.72 g, 9.35 mmol), CS2CO3 (3.6 g, 10.5 mmol) and allylbromide (0.9 mL, 10.3 mmol) in DMF (47 nmL) were stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc, washed with water (3×), brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[C:23]1([C:29]2[N:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH2:31][CH2:32][NH:33][CH2:34]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[N:38][C:29]=4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:34]3)=[O:21])[C:4]=12.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-c2nccc3c2CCNC3)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ccnc4-c4ccccc4)C3)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.124 g, 0.413 mmol) and 5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, TFA (0.147 g, 0.454 mmol) in DMF (5 mL) was added Hunig's Base (0.5 mL, 2.86 mmol) followed by TBTU (0.172 g, 0.537 mmol). The solution was stirred at rt for 5 h and quenched with 5 mL of water. The solvent was removed under reduced pressure and the residue dissolved in DMF and passed through a plug of glass wool. The DMF solution was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure. The residue was further purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)ethane-1,2-dione, TFA (0.192 g, 0.314 mmol, 76% yield), was isolated as an off-white solid. LC/MS: m/z 494.12 (M+H)+, 0.878 min (method 6). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.40-12.47 (m, 1H) 9.24 (s, 1H) 8.47-8.58 (m, 1H) 8.25-8.32 (m, 1H) 7.87 (s, 1H) 7.30-7.63 (m, 6H) 4.75-4.96 (m, 2H) 3.59-3.88 (m, 5H) 2.78-2.99 (m, 2H) 2.48-2.52 (m, 3H).
Reaction SMILES: [S:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1)([CH3:4])(=[O:3])=[O:2].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:6]([O:5][S:1]([CH3:4])(=[O:2])=[O:3])=[CH:7][CH:8]=2)[C:12]1=[O:15])[CH:17]=[CH:18][CH3:19]
Reactant: C=CC(C)O
Reactant: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Yield: 50 %

Procedure:
A solution of 18.3 g of 6-mesyloxy-1-indanone, 16.7 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 400 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). In addition to 8.31 g of educt, there were obtained 11.3 g (50%) of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone as a yellow oil.