Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:38](=[O:39])[CH2:37][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)COc3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and phenoxyacetyl chloride.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12](O)=[O:13].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12]([N:22]([O:23][CH3:24])[CH3:21])=[O:13]
Reactant: CNOC
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.082 mL, 7.81 mmol) was added to a stirred solution of 4,4,5,5,5-pentafluoropentanoic acid (1.00 g, 5.21 mmol), N,O-dimethylhydroxylamine hydrochloride (0.559 g, 5.73 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.998 g, 5.21 mmol) in dry DCM (5.35 mL) at 25° C. under N2. The reaction was stirred at 25° C. overnight. The reaction was diluted with CH2Cl2 (60 mL) and washed consecutively with 1N aq. HCl (2×), satd aq. NaHCO3, dried (Na2SO4) and concentrated in vacuo to give the desired product, as a colorless liquid. 1H NMR (500 MHz, CHCl3-d): δ 3.72 (s, 3H); 3.21 (s, 3H); 2.74 (t, J=7.8 Hz, 2H); 2.51-2.37 (m, 2H). m/z=236.2 (M+H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(OC(C)(C)C)=O.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH2:36])=[CH:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1

Procedure:
Compound 59a was prepared from compound 3a and 4-(N—BOC-amino)phenylboronic acid using the methods described in the Example 1, Step G, followed by the TFA deprotection of the resulting product. Mass Spectrum LCMS, ESI (pos.) Calcd. for C27H26N6O: 451.2 [M+H]. found 451.5.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example 1c, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[C:11](=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)/[C:12]#[N:13].C1COCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15](/[CH:14]=[C:11](/[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:38]4[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:36]([O:35][CH3:34])[CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)\[C:12]#[N:13])[CH:16]=1
Reactant: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(Br)cc12
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(-c2ccc3[nH]cc(/C(C#N)=C/c4cccnc4)c3c2)cc(OC)c1OC
Temperature: 50 °C

Procedure:
To a solution of (Z)-2-(5-bromo-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (180 mg, 0.56 mmol, 1.0 eq.) in anhydrous and degazed THF (6.0 mL) were added, under an argon atmosphere, K3PO4 (236 mg, 1.11 mmol, 2.0 eq.), PdCl2(dppf)*CH2Cl2 (41 mg, 0.056 mmol, 0.1 eq.) and 3,4,5-trimethoxyphenylboronic acid (235 mg, 1.11 mmol, 2.0 eq.). The reaction apparatus was protected from light and the mixture was heated at 50° C. for 16 hours, and then, quenched with a saturated aqueous ammonium chloride solution, after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over MgSO4, and then, evaporated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluent: heptane/AcOEt, 40/60 to 30/70) to afford, after trituration with diethyl ether, the compound (38) as a yellow solid (145 mg, 63%). IR νmax (cm−1): 2216 (νCN), 3307 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 3.70 (3H, s, 11′-methoxy), 3.88 (6H, s, 10′- and 12′-methoxy), 6.96 (2H, s, H9′ and H13′), 7.55 (3H, m, H6′, H7′ and H5″), 7.88 (1H, m, H4′), 7.93 (1H, s, H3), 8.24 (1H, s, H2′), 8.35 (1H, d, J4″-5″=7.9 Hz, H4″), 8.59 (1H, d, J6-5″=4.9 Hz, H6″), 9.01 (1H, s, H2″), 11.84 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 56.5 (10′- and 12′-methoxy), 60.5 (11′-methoxy), 105.3 (C9′ and C13′), 108.4 (C2), 111.4 (C3′), 113.2 (C7′), 118.2 (C2′), 118.6 (C1), 122.9 (C6′), 124.1 (C5″), 124.5 (C3a′), 128.4 (C4′), 131.4 (C3″), 133.6 (C11′), 134.2 (C7a′), 135.2 (C4″), 137.2 (C3), 138.0 (C8′), 150.1 (C6″), 150.5 (C2″), 153.6 (C10′ and C12′); ESI-MS: m/z 412.2 ([M+H]+), 434.1 ([M+Na]+); HRESI-MS: m/z 434.1481 (calcd for C25H21N3O3Na+, 434.1481).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:8])(=O)C.[OH-].[Na+].C1(C)C=CC=CC=1.C(O)(=O)C>CO>[SH:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CCOC(=O)CCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)CCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product from part (a) (1.02 g., 3.02 mmole) in methanol (6 ml.) is chilled (ice/methanol) and to it, under nitrogen, is added 1N sodium hydroxide (6.35 ml.) over 15 minutes. The mixture is stirred for 3 hours while warming to room temperature (TLC indicates incomplete reaction), and additional 1N sodium hydroxide (3.0 ml.) is added in one portion. After stirring for an additional 3 hours at room temperature, the mixture is concentrated to approximately 1/2 volume in vacuo, and the residue is partitioned between water (50 ml.) and ethyl acetate (30 ml.). The aqueous layer is washed with ethyl acetate (30 ml.), adjusted to a pH of about 2 with concentrated hydrochloric acid, and extracted again with ethyl acetate (3×20 ml.). These organic layers are pooled, washed with water and brine (30 ml. each), dried (Na2SO4), and concentrated in vacuo to yield 0.71 g. of (±)-3-[[2-(mercaptomethyl)-1-oxo- -phenylpropyl]amino]propanoic acid as a white solid; m.p. 76°-82°. TLC (silica gel, toluene/acetic acid; (4:1) Rf =0.37, minor spot at 0.07.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CO)CC3
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 9-bromo-5-hydroxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (3 g, 9.65 mmol) and triethylamine (1,28 g, 12.67 mmol) in THF (200 mL) was added methanesulfonyl chloride (1.44 g, 12.57 mmol) at -20° C. The mixture was stirred for 1.5 h at the same temperature and triethylamine (0.6 mL) and methanesulfonylchloride (0.4 mL) were added. The mixture was further stirred for 1 h at -20° C. and for 30 min at 0° C. and poured into water (500 mL). The mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate (500 mL×3). The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 1 to 5% acetic acid/ethyl acetate to give 2.42 g of the title compound (64%): mp 125°~130° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.05 (bs, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 4.97~5.06 (m, 1H), 4.28 (d, 2H, J=7.5 Hz), 3.20 (s, 3H), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.27 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:21]4[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cncc(S(N)(=O)=O)c3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (270 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (216 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (20 mg, 5%). MS (ISP) 495.0 [(M+H)+], 497 [(M+2+H)+]; mp 282° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][CH2:6]2)#[N:2].BrC1C=C2C(=CC=1)C(=O)OC2.[F:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.[Mg].[BH4-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CC#N.O.CCOCC>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:10]=1[CH:8]([C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)[OH:9])[C:1]#[N:2]
Reactant: N#Cc1ccc2c(c1)COC2=O
Reactant: Fc1ccc(Br)cc1
Agent: O=C1OCc2cc(Br)ccc21
Agent: [Al+3]
Agent: [BH4-]
Solvent: CCOCC
Solvent: CC#N
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1

Procedure:
In particular, step (a), consisting of the treatment of 5-cyanophthalide with a 4-fluorophenylmagnesium halide, occurs according to a classical Grignard reaction procedure, for example under the conditions described in Example 1 of U.S. Pat. No. 4,136,193 for the 5-bromophthalide, by treating 1.05-1.35 equivalents of a Grignard solution, titred at 15-20%, said solution being prepared from p-fluorobromobenzene and magnesium turnings in an ether, for example in tetrahydrofuran, with 5-cyanophthalide and by adding said Grignard reagent in the amount capable of consuming practically the whole starting 5-cyanophthalide. In practice, the operator controls the course of the reaction by HPLC [column: Develosil C18 4.6×250 mm, 5μ; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aqueous NH4H2PO4+H3PO4 at pH=2.85/B: CH3CN/H2O=9/1 (v/v)] and stops it when 2-3% of unreacted 5-cyanophthalide remains. The product thus obtained is directly submitted to the next step (b) consinsting of a reduction with an agent reducing ketones to alcohols for example with NaBH4, or with LiAlH4 as described in Example 3 of U.S. Pat. No. 4,136,193, to obtain the corresponding 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[C:18]([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([C:3]1[S:17][C:6]2[N:7]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:32][CH:33]=3)[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2sc(CC)cc2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate (200 mg, 0.8 mmol), 4-(2-t-butoxycarbonylphenyl)benzyl bromide (300 mg, 0.9 mmol) and cesium carbonate (650 mg, 2.0 mmol) in DMF (10 ml) was stirred at 60° C. for 3 hours and further at 100° C. for an additional hour. After cooling, the reaction mixture was poured into water followed by extraction with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated to dryness. The resulting residue was purified by flash column chromatography on silica gel to give 258 mg (62%) of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]2[O:26][CH2:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30](=[O:31])[C:24]=2[CH:23]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO>CCOCC.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:20][CH2:21][C:22]3[CH:37]=[CH:36][C:25]4[O:26][CH2:27][C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[C:30](=[O:31])[C:24]=4[CH:23]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: O=C1c2ccccc2COc2ccc(CCN3CCC(O)(c4ccc(Cl)cc4)CC3)cc21
Yield: 34.6 %

Procedure:
A mixture of 3 g (0.014 m) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 4.65 g (0.014 m) of 2-(6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1, 1.96 g (0.014 m), of K2CO3, 30 ml of methanol and 30 ml of absolute ethanol was refluxed overnight. The yellow reaction mixture was filtered and evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4), filtered and evaporated to afford a solid. Trituration with ether gave 2.17 g (35%) of 4-(4-chlorophenyl)-1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-4-hydroxypiperidine, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[NH:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[C:43]4[C:48](=[CH:47][CH:46]=3)[NH:40][CH:41]=[CH:42]4)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)CCN2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4[nH]ccc4c3)c2)c1CCC(=O)OCC
Yield: 7.8 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 5-indolineboronic acid (170 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-ethoxy-5-(1H-indol-5-yl)-phenoxy]-hexyl}-phenoxy]-butyric acid ethyl ester (25 mg, 8%) as a light yellow oil: ES(+)-HRMS m/e calcd for C39H49NO7 (M+Na)+ 666.3401. found 666.3399.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Br:17]N1C(=O)CCC1=O>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:17])=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cccc(OC)c1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(Br)c(OC)c1-c1ccccn1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 2 using 1,3-Dimethoxy-2-(Pyrid-2-yl) benzene 37 and N-bromosuccinimide to yield 38.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH:8]1([C:11]([NH:13][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([OH:17])=O)=[O:12])[CH2:10][CH2:9]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH:8]1([C:11]([NH:13][CH:14]([C:15](=[O:17])[CH3:1])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])[CH2:9][CH2:10]1
Reactant: CCOC(=O)CC(NC(=O)C1CC1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(NC(=O)C1CC1)C(C)=O
Temperature: 90 °C
Yield: 70 %

Procedure:
DMAP (5 g, 0.041 mol) and acetic anhydride (306 g, 3 mol) were added to a suspension of 2-[(cyclopropylcarbonyl)amino]-4-ethoxy-4-oxobutanoic acid (Preparation 85, 229 g, 1 mol) in freshly-distilled pyridine (1.5 L). The reaction was heated at 90° C. for 2 hours before concentrating in vacuo at 60° C., azeotroping with toluene. The residue was purified by silica gel column chromatography eluting with 2% methanol in chloroform to afford the title compound (70%) that was taken directly on to the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].C(N(C(C)C)C(C)C)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41]([O:40][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:42])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride salt (1510.00 mg; 3.91 mmol; 1.00 eq.) in DCM was added Ethyldiisopropylamine (2.81 ml; 15.64 mmol; 4.00 eq.) and stirred for 5 mins. N-(Benzyloxycarbonyloxy) succinimide (1169.26 mg; 4.69 mmol; 1.20 eq.) was then added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, washed with water, 5% NaHCO3 aq and brine. The organic layer was dried and concentrated. The residue was subjected to SNAP column (100 g), eluted with 20-80% EA in hexane to afford the title compound (1310 mg, yield 74.9%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(C)C)cc1
Yield: 73.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-isopropylphenylboronic acid (0.082 g; 0.5 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.074 g (73%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:19]1[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=1)[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:30]([O:32][CH3:33])=[O:31].CCCCCC>C(Cl)Cl.CCOC(C)=O>[CH:25]([N:23]1[C:22](=[O:28])[CH:21]=[CH:20][C:19]([CH:10]([NH:9][C:30](=[O:31])[O:32][CH3:33])[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:24]1)([CH3:26])[CH3:27]
Reactant: CC(C)n1nc(C(N)C(=O)c2ccccc2)ccc1=O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)NC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Reaction time: 0.5 h

Procedure:
Under ice-cooling, a solution of triethylamine (16.8 ml) of CH2Cl2 (30 ml) was added dropwise to a suspension of 6-(1-amino-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone hydrochloride (15.42 g) and methyl chloroformate (4.65 ml) in CH2Cl2 (155 ml) and stirred at the same temperature for 30 minutes. The mixture was washed with water, 1N HCl and sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (30:70 v/v) to give methyl [1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]carbamate as a syrup (15.78 g), which was identical to the authentic sample (the product of Preparation 5) by IR, MS and NMR spectra.