Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:13]OCC)[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)[CH3:2].[N+:18]([CH2:21][C:22]([NH2:24])=[O:23])([O-:20])=[O:19].C([O-])(=O)C.[Na+].Cl>C(O)C>[N+:18]([C:21]1[C:22](=[O:23])[NH:24][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:13]=1)([O-:20])=[O:19]
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 79.3 %

Procedure:
Diethyl(ethoxymethylene)oxalacetate (5.63 g, 0.023 mol,) is dissolved under N2 atmosphere in 20 mL of absolute ethanol and cooled to 0° C. Nitroacetamide (2.00 g, 0.019 mol,) (S. K. Brownstein, J. Org. Chem 23, 113 (1958)) and sodium acetate (1.56 g, 0.019 mol,) are added and the mixture is stirred at room temperature for 15 hours. The suspension is diluted with 15 mL of absolute ethanol and acidified to pH 2 with concentrated HCl. The inorganics are removed by filtration and the filtrate is concentrated to an oily solid which is gravity chromatographed, first with methylene chloride and then 2% methanol in methylene chloride. The fractions are combined and stripped to give 4.28 g of the title product as a yellow solid, 78.4% yield, melting point 144°-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
A suspension of 18 (2.91 g, 8.68 mmol), Cs2CO3 (4.25 g, 13.02 mmol) and DMF (anhydrous, 40 mL) was stirred at room temperature for 1.5 h. To the mixture was then added methyl iodide (0.83 mL, 13.02 mmol), and stifling was continued for an additional 3 h at the ambient temperature. The mixture was then partitioned between water (150 mL) and dichloromethane (150 mL), aqueous layer was separated and washed with dichloromethane (3×300 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired methyl ester 19 (3.41 g, quant yield): 1H NMR (500 MHz, CDCl3) δ 1.26 (m, 12H), 1.47 (m, 2H), 1.52 (m, 2H), 2.28 (m, 2H), 3.16 (m, 2H), 3.66 (s, 3H), 5.10 (s, 2H), 7.32 (m, 5H); m/z (ESI) 350 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9]I.C(=O)([O-])[O-].[Ca+2].CCOCC>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(F)cc1I

Procedure:
A mixture of 22 g. of 4-fluoroaniline, 50 g. of iodine, 25 g. of calcium carbonate, 75 ml. of ether and 75 ml. of water is heated at reflux for 48 hours. The ether is removed by distillation and the excess iodine is destroyed by addition of sodium thiosulfate. Steam distillation and recrystallization from petroleum ether gives 4-fluoro-2-iodoaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH:8]([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:14](O)(=O)C.C(N)=N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][NH:10][CH:14]=[N:11]2)=[CH:12][CH:13]=1
Reactant: NCC(N)COc1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: Clc1ccc(OCC2CNC=N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 3-(4-chloro-phenoxy)-propane-1,2-diamine (0.19 g, 0.95 mmol) in ethanol (5 ml) was added formamidine acetate (0.1 g, 1.0 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield a light yellow oil (0.063 g, 32%); MS (ISP): 211.2 ((M+H)+).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl chloroformate (7.15 g, 50 mmol) and 1-octadecanol (13.53 g, 50 mmol) were suspended in chloroform (100 ml) at 0° C. Pyridine (3.96 g, 50 mmol) was added dropwise during 20 minutes, maintaining the temperature below 10° C. After stirring at room temperature for 24 hours the reaction mixture was washed four times with 1N hydrochloric acid, once with a saturated sodium bicarbonate solution and finally twice with water. The organic solution was dried with magnesium sulphate and the solvent was removed at reduced pressure. Yield: 19 g.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][CH3:26])=[CH:14][C:13]2=[O:27])[C:3]([OH:28])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (440 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (143 mg, 0.006 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (395 mg, 93%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([C:29]([F:28])([F:39])[F:40])[CH:31]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2cccc(C(F)(F)F)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-trifluoromethylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 63. ESI-MS m/e 395.4 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccnc(F)c1
Solvent: O
Solvent: CCOCCO
Product: Cc1ccnc(NN)c1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.33 g (30.0 mmol) 2-fluoro-4-methylpyridine are initially introduced into 40 ml 2-ethoxyethanol, 14.6 ml (15.0 g, 300 mmol) hydrazine hydrate are added to the solution and the mixture is stirred at the boiling point (150° C. bath temperature) for 16 h. Thereafter, the reaction solution is concentrated on a rotary evaporator, the residue is added to 100 ml water and the mixture is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:27]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[C:29](=[O:35])[CH2:28]2.[ClH:36]>C1CCCCC1.O1CCCC1>[ClH:36].[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:29]3([OH:35])[CH:30]4[CH2:33][CH2:34][N:27]([CH2:32][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Oc1ccc(-c2ccc(C3(O)CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of sec-butyllithium in cyclohexane (7.4 ml, 1.3M) was added dropwise, with stirring, to a solution of 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (2.9 g) in dry tetrahydrofuran (30 ml) under an atmosphere of argon at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (0.9 g) in dry tetrahydrofuran (12 ml) was then added over a period of 2 minutes. The mixture was stirred at -78° C. for a further 30 minutes and the mixture then allowed to warm to room temperature over 2 hours. Aqueous 2M hydrochloric acid (18 ml) was added to the reaction mixture, whilst keeping the temperature of the reaction mixture below 10° C. The aqueous layer was separated and washed with diethyl ether (2×20 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH 14. The mixture was extracted with warm ethyl acetate (50° C.) and the ethyl acetate phase separated, dried (Na2SO4) and evaporated. The residue was dissolved in dry tetrahydrofuran (20 ml) and added to a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1.6 ml, 1.0M). The mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, an excess of saturated ethereal hydrogen chloride solution was added to precipitate a solid which was crystallised from methanol/ethyl acetate to give as a colourless solid, 3-(4'-hydroxybiphenyl-4-yl)-3-hydroxy-quinuclidine hydrochloride (0.93 g), m.p. 270°-271° C., microanalysis, found: C, 66.5; H, 6.5; N, 4.1%; C19H21NO2.HCl.0.66H2O requires: C, 66.5: H, 6.8: N, 4.1%; NMR ([CD3 ]2SO): 1.4-1.6(1H, m), 1.7-1.9(2H, m), 2.3-2.4(2H, m), 3.1-3.4(5H, m), 3.8-3.9(1H, d), 5.9(1H, s), 6.9-7.5(4H, d of d), 7.6(4H, s), 9.6(1H, s); m/Z 296 (M+H).
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:13]1[C:8](=[O:7])[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:12]1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 53 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.10 g, 0.29 mmol) in a sealed tube, is added potassium carbonate (0.04 g, 0.58 mmol) and methyl iodide (0.1 mL, 1.7 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 100 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.23 g, 53%). 1H-NMR (DMSO) δ: 8.26, 8.12, 7.82, 7.59, 6.47, 4.73, 4.14, 3.77, 3.50, 3.42, 1.84
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([O:32][CH3:37])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:33][CH:34]=1
Reactant: CI
Reactant: O=C(COc1ccc(Cl)cc1)N1CCN(Cc2ccc(F)cc2)C(CC(O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1)c1ccccc1
Yield: 84.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine (0.051 g, 0.11 mmol) in anhydrous ether (5 mL) was added sodium hydride (0.006 g, 0.15 mmol). The resultant mixture was stirred at ambient temperature for 30 minutes, then methyl iodide (0.016 g, 0.11 mmol) was added. Once thin layer chromatography analysis showed complete consumption of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-2-phenylethyl)piperazine had occurred, the mixture was poured into water and extracted with two portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford 0.046 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-methoxy-2-phenylethyl)piperazine as a yellow oil: NMR (CDCl3) 7.3 (m, 9), 7.0 (m, 2), 6.9 (m, 2), 4.8 (m, 3), 4.2 (m, 2), 3.9-3.2 (m, 5), 3.1 (d, 2), 3.0 (s, 1), 2.9 (s, 1), 2.6 (m, 1), 2.4 (m, 1), 1.9 (m, 1) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C=O.[CH:17](O)=O>CO>[CH3:1][C@@H:2]1[N:7]([CH3:17])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=CO
Agent: C=O
Solvent: CO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 70 °C
Yield: 100.8 %

Procedure:
To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (50 g, 0.250 mol) in 500 mL of methanol was added formaldehyde (41.6 mL, 0.5 mol, 37% aqueous solution) and formic acid (33 mL, 0.874 mol) and the mixture was heated to 70° C. for 16 hours, then concentrated under reduced pressure. The resulting residue was taken up in EtOAc (500 mL), washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 54 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23)=[O:35]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CCl)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 10.2 g (0.030 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 8.3 ml (0.060 mol) of Et3N in 90 ml of CHCl3 was treated dropwise with a solution of 3.6 ml (0.045 mol) of chloroacetyl chloride in 20 ml of CHCl3 over ten minutes. The reaction mixture was stirred at room temperature for three hours, treated with an additional 1.2 ml (0.015 mol) of chloroacetyl chloride in 50 ml of CHCl3, and concentrated to dryness in vacuo. The residue was triturated three times with cold MeOH to give 8.3 g of product, mp 204°-205° C. dec.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][O:29][C:27](=[O:28])[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=3[CH:15]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-(4-Methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (D3) (6.35 g) was dissolved in dichloromethane (30 ml) and treated with trifluoroacetic acid (30 ml). The solution was stirred at room temperature for 2 hours, concentrated in vacuo and then twice co-evaporated with dichloromethane. The residue was dissolved in dichloromethane and washed with 10% aqueous sodium hydroxide, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (D4).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([CH3:38])([O:39][C:40]1[CH:45]=[CH:44][C:43]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:2][CH:3]=3)[O:8][C:9]=2[CH3:25])=[CH:42][CH:41]=1)[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Yield: 47 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-(2-biphenyl-4-yl—methyl-oxazol-4-yl)ethyl ester (14.9 g, 34.3 mmol), 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691 (6.15 g, 27.4 mmol) and Cs2CO3 (12.0 g, 36.8 mmol) was heated at 55° C. in DMF (110 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (600 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (6.25 g, 47%) as a colorless, viscous oil: Rf=0.48 in 35% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.67-7.64 (m, 4H), 7.46 (m, 2H), 7.38 (m, 1H), 6.83-6.77 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.97 (t, J=8.8 Hz, 2H), 2.37 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=9.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Ethyl 7-bromoheptanoate and 3,5-bis(trifluoromethyl) phenol were added to dimethylformamide (DMF). The solution was added with potassium carbonate and stirred at room temperature. The solution was added with water and extracted twice with ethyl acetate. After the organic layer was washed three times with water and dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography to obtain ethyl 7-(3,5-bis (trifluoromethyl)phenoxy)heptanoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([CH3:16])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[N:3]=1.[Cl-].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Zn+])=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:5]=[C:4]([C:9]([CH3:16])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[N:3]=1
Reactant: CC(C)(O[Si](C)(C)C)c1cc(Cl)nc(Cl)n1
Reactant: Clc1ccc(C[Zn+])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 50 °C
Yield: 71 %

Procedure:
To a solution of 2,4-dichloro-6-(1-methyl-1-trimethylsilanyloxy-ethyl)-pyrimidine (5.02 g, 18.0 mmol) in THF (60 mL) was added Pd(TPP)4 (0.83 g, 0.72 mmol). The solution was flushed with argon, and subsequently, a 0.5 M solution of 4-chloro-benzylzinc chloride in tetrahydrofuran (36 mL, 18.0 mmol) was added at 20° C. over 1-3 minutes. The reaction mixture was heated to 50° C. for 3 h under an atmosphere of argon. After cooling the mixture to 20° C., saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (2×30 mL) and the organic layers were washed with brine (2×30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residual oil was purified by chromatography on silica gel using heptane/0-30% ethyl acetate as eluent to afford the title compound (4.72 g, 71%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
4-Bromobenzene-1,2-diamine (0.5 g, 2.67 mmol), benzaldehyde (0.284 g, 2.67 mmol), and 4-methylbenzenesulfonic acid (0.046 g, 0.267 mmol) in DMF (8 mL) were combined and heated at 100° C. for 1 hour in a microwave reactor. The reaction mixture was subsequently diluted with EtOAc, washed with brine (4×100 mL), concentrated, and purified by CombiFlash® chromatography, eluting with a gradient of MeOH (0-30%) in DCM over 120 minutes. The product-containing fractions were combined and concentrated to give the title compound as light yellow liquid (0.48 g, 66%).