Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:27][CH2:28]Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([O:14][CH3:15])=[O:13])[CH2:28][CH2:27]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCBr
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mL (1.0 m, 2 Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of 1-bromo-2-chloroethane in 100 mL dry THF were reacted as described in Preparation 11, except that the reaction mixture was stirred for one hour at ambient temperature before work-up. This reaction yielded 4.21 g of a brown oil. This material was purified via silica gel chromatography eluting with a gradient solvent of hexanes to hexanes/EtOAc 19:1 to yield the title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C. Calculated for C15H20O2: Theory: C, 77.37; H, 8.81 Found: C, 77.54; H, 8.68.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23]([O:25]CC)=[O:24].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:18]=[CH:19][C:4]([N:1]2[C:21]([CH2:28][CH2:29][CH3:30])=[C:22]([C:23]([OH:25])=[O:24])[N:3]=[N:2]2)=[CH:5][CH:6]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
4-Azido-N-benzylbenzamide obtained in Example 58a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.71 g, 4.70 mmol, 91.3%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[S:4]
Reactant: NNC(N)=S
Reactant: CN(C)C(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)C(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 92.4 %

Procedure:
Thiosemicarbazide (2.75 g, 30.2 mmol) was added to a solution of 4-oxo-N,N-dimethyl-4-phenyl-butyramide (3.80 g, 18.5 mmol), prepared in the previous step, in 65 ml of methanol plus 5 ml of 1 N HCl plus 5 ml of water and the reaction stirred at room temperature for 28 hours. The solid present was collected by filtration to give 4.76 g of a white solid. The solid was triturated with water and then dried to give the title compound (4.53 g, 88%) as a white solid, mp 173-175° C.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:3]1[C:2]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Reactant: Cc1ccccc1N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cnc(Nc3ccccc3C)c(Cl)c2C#N)c1
Temperature: 180 °C

Procedure:
A mixture of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (50 mg, 0.179 mmol, from Step 3 of Example 128) and o-toluidine (384 mg, 3.58 mmol) in DMSO (1 mL) was heated to 180° C. under microwave for 1 h. LCMS and HPLC analysis indicated that the reaction was ˜25% complete. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with 1 N HCl (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave 3-chloro-5-(3-methoxyphenyl)-2-(o-tolylamino)isonicotinonitrile as yellow solid, assumed as TFA salt (7 mg, 8% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1H, s), 7.38-7.54 (2H, m), 7.28-735 (1H, m), 7.15-7.27 (2H, m), 7.07-7.14 (2H, m), 6.97-7.05 (1H, m), 3.87 (3H, s), 2.27 (3H, s); MS (ES+) m/z: 350 (M+H); LC retention time: 3.848 min (analytical HPLC Method A).
Reaction SMILES: CO[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C@@H]3[C@@H](CC[C:20]=2[CH:21]=1)[C@H]1[C@@](C)([C@@H](OCOC)CC1)CC3.COCCl.[CH3:31][C@@:32]12[C@@H:40]([OH:41])[CH2:39][CH2:38][C@H:37]1[C@@H:36]1[CH2:42][CH2:43][C:44]3[CH:49]=[C:48]([OH:50])[CH:47]=[CH:46][C:45]=3[C@H:35]1[CH2:34][CH2:33]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:3][O:4][CH2:5][CH2:21][CH2:20][CH2:8][CH2:7][CH2:6][C@@H:43]1[CH2:42][C@@H:36]2[C@H:35]([CH2:34][CH2:33][C@@:32]3([CH3:31])[C@H:37]2[CH2:38][CH2:39][CH:40]3[OH:41])[C:45]2[CH:46]=[CH:47][C:48]([OH:50])=[CH:49][C:44]1=2
Reactant: COCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]12
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCCCCC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)c2ccc(O)cc21
Reaction time: 18 h

Procedure:
(8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene—Chloromethyl methyl ether (7.0 mL, 92.0 mmol) is added to a solution of β-estradiol (5 g, 18.4 mmol) and diisopropylethylamine (16.0 mL 92 mmol) in 100 mL of THF. The reaction mixture is heated to reflux and stirred for 18 hours. The THF is removed in vacuo, and the yellow/brown oil is partitioned between water and CH2Cl2. The organic layer is separated, washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give a golden oil. Purification by silica gel column chromatography (10% EtOAc/Hex) affords the title compound as a viscous, clear oil (5.7 g, 86%).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[CH2:23][OH:24].CC([O-])(C)C.[K+]>CS(C)=O>[OH:24][CH2:23][CH2:22][O:25][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCCO
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of tert-butyl (3R)-4-(3-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate* (35 g, 0.11 mol), ethylene glycol (100 g, 1.61 mol) and t-BuOK (25 g, 0.22 mol) in DMSO (150 g) was stirred at 50° C. for 3 h. After this time, the reaction mixture was partitioned between EtOAc (500 g) and water (500 g) and sodium chloride (20 g) was added. The organic layer was concentrated in vacuo to furnish 32.5 g (87%) of the title product. HPLC purity: 75%. HRMS m/z calcd for C16H26N4O4 (M)+ 338.1954, found 338.1959. *Described in WO 00/76984, Example 172, Step 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121–128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+. Anal. calc. for C21H21FN2O4S.0.50 H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=[O:22].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[O:32]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][C:18]1=[O:20])([CH3:1])[C@@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 5α-androst-2-en-11one 17β-carboxylic acid (1.397 g.) and m-chloroperbenzoic acid (850 mg.) in chloroform (20 ml.) was stirred at room temperature for 3.25 hr. and then diluted with chloroform (75 ml.) prior to washing with 10% aqueous sodium bicarbonate and water. The chloroform solution was dried, filtered and evaporated to give a foam (1.04g.) which, after preparative t.l.c. afforded the pure title compound as a foam; [α]D + 69°, (c 0.3).
Reaction SMILES: [Li][NH2:2].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:12])[CH3:11].Cl.C([O-])(O)=O.[Na+]>COCCOC>[CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:2])([CH3:12])[CH3:11]
Reactant: [Li]N
Reactant: CC(C)c1ccccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccccc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
(CyPF-t-Bu)PdCl2 (73.0 mg, 100 mmol), LiNH2 (2.30 g, 100 mmol) and 1-Bromo-2-i-propylbenzene (1.99 g, 100 mmol) were weighed into a 100 mL round bottom flask with a stirring bar. DME (20.0 mL) was then added. The flask was sealed with a cap and wrapped tightly with electrical tape. The reaction mixture was stirred for 24 h at 90° C. The reaction mixture was allowed to cool to room temperature before pouring into ice water (50.0 mL). To this mixture was added aqueous HCl (100 mL, 1.0 M). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHCO3 (50.0 mL). After extraction with CH2Cl2 (3×50.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by column chromatography, eluting with hexane/ethyl acetate (70/30) to give 1.11 g (82%) of 2-i-propylaniline as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][OH:22])=[CH:12][C:7]=2[O:6][CH2:5]1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([OH:22])[C:30](=[O:31])[O:32][CH3:33])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CON=C1COc2cc(OCc3ccccc3NO)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON=C1COc2cc(OCc3ccccc3N(O)C(=O)OC)ccc21
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A solution of 4.8 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxyamine and 1.3 g of pyridine in 50 ml of dichloromethane was cooled to 0° C. 1.4 g of methyl chloroformate was dropped into the solution. The temperature was slowly elevated to room temperature, and the reaction was further carried out for 8 hours. After the completion of the reaction, the reaction liquid was washed with a dilute aqueous hydrochloric acid solution and aqueous NaCl solution and then dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the obtained residue was dissolved in a mixed solution of 30 ml of methanol and 20 ml of tetrahydrofuran. 1.4 g of anhydrous potassium carbonate was added to the obtained solution, and they were stirred for 4 hours. Water and diethyl ether were added to the reaction solution, and the resultant mixture was neutralized with a dilute aqueous hydrochloric acid solution. After the extraction with diethyl ether, the extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.9 g of methyl N-[2-(3-methoxyimino-2,3-dihydrobenzofuran-6-yloxymethyl)phenyl]-N-hydroxycarbamate [1H-NMR (CDCl3) (ppm): 3.77 (3H, s), 3.93 (3H, s), 5.03 (2H, s), 5.13 (2H, s), 6.49-7.50 (m)].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[CH3:13][C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=[C:17](N)[C:16]=2[CH:15]=1>CN1C(=O)CCC1.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[NH:8][CH2:9][CH2:10][N:11]([C:17]2[C:16]3[CH:15]=[C:14]([CH3:13])[S:23][C:22]=3[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=2)[CH2:12]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: COCCCC[C@H]1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Temperature: 211 °C

Procedure:
Heat in a 211° C. oil bath, a stirring solution of (S)-2-(4-methoxybutyl)-piperazine 0.086 g, 0.49 mmol), and 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.114 g, 0.49 mmol) in NMP (1 mL) for 4 h. Cool to room temperature, dilute the solution with brine (15 mL) and extract with EtOAc (3×30 mL). Concentrate the organic layers under reduced pressure to a volume of 20 mL and wash with 75% brine (4×20 mL). Dry the organic layer over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 10% (33% 2 M NH3 in MeOH/64% EtOH)/CH2Cl2. Combine the purified fractions, concentrate under reduced pressure, azeotrope with CH2Cl2/hexanes and place under vacuum to give the title compound: brown solid (0.036 g), mass spectrum (m/e):385.08 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>CN(C=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1ccc(Br)s1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccn2)s1
Temperature: 80 °C

Procedure:
To methyl 5-bromo-thiophene-2-carboxylate (2 g), tri-2-furylphosphine (400 mg), and tris(dibenzylidineacetone)dipalladium(0) (400 mg) was added DMF (50 mL), 2-(tributylstannyl)pyridine (4 g) and TEA (1 mL) The mixture was heated at 80° C. for 7 hours, cooled and partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate, and the extract was dried, filtered and concentrated. The concentrate was flash chromatographed on silica gel with a 20-70% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Oc1ccccc1
Product: COc1ccc(CC(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a solution of 2-(4-methoxyphenyl)acetic acid (10 g, 0.06 mol) in PPA (20 mL) was added dropwise phenol (5.6 g, 0.06 mol) under an inert atmosphere. The mixture was then stirred at 80° C. for 1 h, quenched with cold water and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the crude product which was purified via silica gel column chromatography to afford 1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (3 g, 20%) as a pale yellow solid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:15][C:16]([OH:18])=O)[CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][NH2:36])[CH2:30]2)=[N:27][CH:28]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]([CH3:13])[CH3:14])[CH2:15][C:16]([NH:36][CH2:35][CH:31]2[O:32][CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:38])([F:37])[F:21])=[CH:28][N:27]=3)[CH2:30]2)=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCC1CN(c2ccc(C(F)(F)F)cn2)CCO1
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cn2)CCO1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.1 %

Procedure:
2-(4-Fluoro-N-isopropylphenylsulfonamido)acetic acid (108 mg, 0.39 mmol), (4-(5-(trifluoromethyl)pyridin-2-yl)morpholin-2-yl)methylamine dihydrochloride (131 mg, 0.39 mmol) and TEA (0.22 mL) were combined in dichloromethane (6 mL). To this stirred solution was added BOP reagent (174 mg, 0.39 mmol). The mixture was stirred at room temperature for 6 h. Solvents were evaporated and the residue was extracted with ethyl acetate and water, washed with sodium bicarbonate solution and dried. Solvents were evaporated. The residue was purified by ISCO flash column chromatography (0% to 100% ethyl acetate in hexanes) to give a white powder (160 mg, 79%). [MH]+=519.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([Cl:15])[C:13]=1Cl.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][C:13]2[C:12]([Cl:15])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]=2[Cl:7])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Yield: 98.7 %

Procedure:
To a mixture containing 28.02 g (0.203 mole) of anhydrous potassium carbonate and 30.26 g (0.134 mole) of 3,4,5-trichloro-1-nitrobenzene in 300 ml dry DMF under an atmosphere of nitrogen and at room temperature was added 30.04 g (0.168 mole) of 4-chloro-1-naphthol. The flask was then placed in an oil bath which was heated. An internal reaction temperature of 105° C. was reached and maintained for 20 hours. After cooling the reaction mixture to room temperature most of the DMF was removed under vacuum. The residue was taken up in 1.5 L of 1:1 EtOAc to Et2O and 300 ml of H2O. The layers were separated and washed twice with 5% NaOH, twice with H2O, and finally once with a saturated aqueous NaCl solution. After drying over anhydrous Na2SO4 removal of the solvents afforded 48.73 g of a dark brown solid. This was recrystallized twice from hexane-ethyl acetate to afford 15.84 g of pale yellow needles; mp 121.5°-123° C. NMR (COCl3): δ6.18 (d, J=8 Hz, 1H), 7.25 (d, J=8 Hz 1H) 8.4-8.7 (m, 2H), 8.0-8.5 (m, 4H, contains 8.25 [S]).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Cl:14])[C:10]=2[O:9]1
Reactant: OB(O)c1ccccc1Cl
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.078 g, 40%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 163-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 16, 118 mg) was dissolved in dry dichloromethane (18 mL). The reaction mixture was cooled down in an ice bath. Triethylamine 0.327 mL, 2.350 mmol) was added. Then a solution of triphosgene in dry dichloromethane (46.5 mg, 0.157 mmol) dissolved in 7 mL of dichloromethane was added. The reaction was stirred at 0° C. for 10 min under argon. A saturated aqueous solution of NaHCO3 was added (18 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×15 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 12 g cartridge) eluting with a gradient cHex/EOAc from to 100/0 to 60/40 during 20 min and 60/40 during 30 min. This afforded the title compound (91 mg).
Reaction SMILES: [I:1][C:2]1[C:10]([NH2:11])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5].C1(=O)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])C(=O)C2=CC=CC=C12>>[I:1][C:2]1[C:10]([NH:11][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH2:18])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Product: NCCCCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I

Procedure:
The same procedure is used as for Compound I, using 2,4,6-triiodo-3-amino-benzoic acid as iodo starting material and ε-phthalimidocaproic acid chloride.