Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][OH:12].[C:13]([O-])(=O)C.[Na+].C([O-])([O-])OCC>C(O)(=O)C>[CH2:9]([C:7]1[CH:6]=[CH:5][C:4]2[N:3]([N:2]=[CH:13][C:11]=2[OH:12])[CH:8]=1)[CH3:10]
Reactant: CC(=O)[O-]
Reactant: CCc1ccc(CO)[n+](N)c1
Agent: CCOC([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1ccc2c(O)cnn2c1
Temperature: 140 °C
Yield: 42 %

Procedure:
A mixture of 3.8 g of 1-amino-5-ethyl-2-hydroxy methylpyridinium chloride, 2.5 g of sodium acetate, 25 ml of acetic acid and 8.9 g of ethyl orthoformate was refluxed for 4 hours in an oil bath at 140° C. After evaporated under vacuum, to the residue was added water. The mixture was brought to pH 11 by the addition of potassium carbonate and extracted with ethyl acetate. Ethyl acetate extract was then dried over anhydrous sodium sulfate, decolorized with charcoal and concentrated to dryness. After purification of the oily residue by silica gel column chromatography, eluted with chloroform, the light brown viscous oil that had a yellowish green fluorescence by irradiating of the long wave ultraviolet rays (3650 Å) was obtained. By recrystallization from chloroform-methanol, 1.36 g of the desired product, pale yellow needles, were obtained. Yield: 42.0%, mp 78°-79° C. The result of elemental analysis was illustrated in Table 3.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl.CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:39])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(OCCCS(=O)c2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a mixture of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio]benzimidazole-5-carboxylic acid (1.00 g) in dichloromethane (30 ml) and methanol (3 ml) stirring in ice-salt-water bath, was added m-chloroperbenzoic acid (80%, 503 mg) in a small portions below 0° C. Further stirring for an additional 15 minutes, the mixture was evaporated, and the residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from ethanol-water to give the title compound (540 mg, 52.1%) as colorless crystals, mp 173-175° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22]=1[CH3:31]>>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)[CH:28]=2)[NH:23][C:22]=1[CH3:31]
Reactant: CO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1[nH]c2ccc(N)cc2c1Cl
Product: CO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(Cl)c5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone and 3-chloro-2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 103. MS: 441.2/443.2; 407.2(MH+); HPLC Rf: 4.96 min.; HPLC purity: 98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Into a solution of 3-fluoro-4-nitro-benzoic acid (4.0 g, 21.6 mmol) in anhydrous CH2Cl2 (200 mL) at 0° C. was slowly added oxalyl chloride (2.45 mL, 28.0 mmol) and a drop of DMF. The solution was stirred and allowed to warm to RT overnight before concentrating under reduced pressure to give 3 (4.39 g, 100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26].C(N(CC)CC)C>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 37 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (35 mg, 0.115 mmol) in MeOH (3 mL), was added hydrazinecarboxamide hydrochloride (115 mg, 1.035 mmol). The solution was heated to 37° C. overnight. Triethyl amine (1 mL) was added and the solution was stirred at rt for 20 min. Solvents were removed in vacuo and the residue was diluted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 25 mg of the title compound in 57% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.85 (s, 1H), 8.89 (m, 1H), 3.36 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.17 (s, 2H), 2.32 (s, 3H). LCMS (method A): [MH]+=384, tR=4.09 min.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:46][CH2:47]2)=[CH:38][CH:37]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)N1CC(=O)Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
The 7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) suspended in propionitrile (1 mL). To this was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIEA (0.237 mL, 1.356 mmol) and 4-(4-chlorophenyl)piperidine hydrochloride (115 mg, 0.50 mmol). The reaction was stirred at 90° C. overnight. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered and dried in vacuum to afford the title compound (28.3 mg, 16%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.29-7.37 (m, 2H), 7.18-7.29 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.75-4.87 (m, 1H), 3.81 (s, 2H), 3.32 (d, J=12.9 Hz, 3H), 2.88 (d, J=11.1 Hz, 2H), 1.87-2.07 (m, 2H), 1.65-1.77 (m, 2H), 1.57 (dd, J=12.4, 3.3 Hz, 2H), 1.10 (d, 6H). [M+H] calc'd for C22H27ClN4O, 399. found, 399.
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[CH3:54][NH2:55]>C1(C)C=CC=CC=1>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11][CH:10]2[O:9][CH2:8][C:7]2[CH:46]=[CH:47][C:4]([C:2](=[O:3])[NH:55][CH3:54])=[C:5]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=2)=[CH:17][CH:18]=1
Reactant: CN
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 69b) in 1.0 ml of toluene is slowly added dropwise to 1.5 ml of methylamine solution (approx. 10M in ethanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (2:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:31][CH:32]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:24][CH2:23]2)=[O:21])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1O
Yield: 84.4 %

Procedure:
To a solution of 270 mg (0.45 mmol) of the amide compound in 5 ml of methanol was added 95 mg (0.5 mmol) of p-toluen esulfonic acid monohydrate,,and the mixture was heated and refluxed for 1 hour under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, a saturated aqueous solution of sodium hydrcgencarbonate was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected tc silica gel column chromatography, eluted with chlcroform - methanol, to give 200 mg (0.38 mmol) of N-[3-(3,5-dimethoxy-4-hydroxyphenyl) 2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR93##
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCCCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv) and piperidine (0.70 mL, 6.7 mmol, 12 equiv) in methylpyrrolidone (6.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (10.0 mL) and the resultant solids were filtered. The solids were purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to provide N-(4-mesitylthiazol-2-yl)-2-(piperidin-1-yl)isonicotinamide (87.2 mg, 0.20 mmol) as yellow solids in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J=5.1 Hz, 1 H), 7.15 (s, 1 H), 6.83-6.90 (m, 3 H), 6.79 (s, 1 H), 3.61-3.63 (m, 4 H), 2.31 (s, 3 H), 2.08 (s, 6 H), 1.57-1.67 (m, 6 H); ESI-MS: m/z 407.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]([O-])(=O)=O.[K+]>OS(O)(=O)=O>[Br:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.7 %

Procedure:
To a mixture of 5 g (30.5 mmol) of 4-hydroxy-3-nitrobenzonitrile in H2SO4 solution (50 mL of concentrated H2SO4+50 mL of H2O) at 25° C., 7.9 g (47.3 mmol) of potassium bromate were added in small portions cooling the flask with an ice-bath and maintaining the temperature between 25 and 35° C. After the addition was completed, the reaction was stirred at room temperature for 22 h and then filtered. The pale yellow solid was washed with water and dried to give 4.2 g (57%) of the title compound. M.p.: 162-164° C.; 1H NMR (CD3OD) δ 8.54 (d, 1H, J=2.0 Hz, H-6), 8.32 (d, 1H, J=2.0 Hz, H-2); 13C NMR (DMSO-d6) δ 153.9 (C-4), 140.8 (C-2), 138.2 (C-5), 130.1 (C-6), 117.0 (CN), 115.9 (C-3), 101.6 (C-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccccc3F)n2)ccc1F
Yield: 48 %

Procedure:
4,2′-Difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.115 g, 0.338 mmol) was coupled to 2-fluorobenzeneboronic acid (0.104 g, 0.743 mmol) by the method of Example 2 to give the title product as a pale yellow solid (63 mg): 8H (400 MHz, CDCl3) 7.27 (1H, q, J 1.3 Hz), 7.32-7.37 (1H, m), 7.43-7.48 (2H, m), 7.53-7.60 (3H, m), 8.24-8.29 (1H, m), 8.35-8.39 (2H, m), 9.67 (1H, s); m/z(ES+) 389 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:26]3[CH:27]=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (3′-hydroxy-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester (435 mg), 2,4-dichloropyrimidine (221 mg) and potassium carbonate (295 mg) in DMF (10 ml) is stirred at rt for 20 h. This mixture is quenched with brine and extracted twice with EtOAc. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the resulting crude product is purified on silica (90 g) with cyclohexane/EtOAc 80/20 to afford pure [3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH2:34][C:35]([NH2:37])=[O:36])[CH:27]=[CH:26]1.C(O[K])(C)(C)C>C1COCC1>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([C:4]3[C:3](=[O:23])[NH:37][C:35](=[O:36])[C:34]=3[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:33]=3[N:25]([CH3:24])[CH:26]=[CH:27]4)=[CH:7][NH:8]2)=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(OCc6ccccc6)ccc45)C(=O)NC3=O)c21
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a suspension of (6-benzyloxy-1H-indol-3-yl}-oxo-acetic acid methyl ester (1.0 g, 3.2 mmol) and 2-(1-methyl-1H-indol-7-yl)-acetamide (608 mg, 3.2 mmol) in 15 ml THF was added 3.5 equiv. of tBuOK in THF at 0° C. (11.3 ml of 1.0 M solution in THF) under N2. The mixture was stirred at r.t overnight, quenched with conc. HCl 5.0 ml, and neutralized with 5 N NaOH to PH=8. The mixture was extracted with ethyl acetate, and the extract was washed with saturated NaHCO3, brine and water, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography with Hexane:Ethyl acetate (1:1) to yield the title compound (700 mg) as orange solid, 74% yield. MS(m/z): 448.2 (M++1), 446.1 (M−−1); 1HNMR (DMSO-d6) 11.62 (s, 1H), 11.07 (s, 1H), 7.77 (d, J=1.80 Hz, 1H), 7.57 (m, 1H ), 7.26 (m, 5H), 7.21 (d, J=2.40 Hz, 1H), 6.94 (tri, J=6.00 Hz, 1H), 6.84 (m, 2H), 6.44(d, J=2.40 Hz, 1H), 6.16 (s, 1H), 4.97 (s, 2H), 3.62 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: OB(O)c1ccnc(F)c1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccnc(F)c4)nc3s2)cc1
Yield: 38 %

Procedure:
The titled compound (yield=38%, light yellow solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 2F (Example 2) and 2-fluoropyridin-4-ylboronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.49 (d, J=3.03 Hz, 2H) 4.78 (br. s., 1H) 7.59 (d, J=8.59 Hz, 2H) 7.91 (s, 1H) 8.06-8.16 (m, 3H) 8.27-8.36 (m, 2H) 8.38 (d, J=5.31 Hz, 1H) 13.11 (s, 1H); ESI-MS: m/z 423.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 4.19 mmol) in CH2Cl2 (10 ml) was added TFA (6 ml) at room temperature. After 4 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water to give 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetic acid (1.33 g, 100%) as a yellow powder. mp 243–245° C. (dec.); 1H-NMR (CDCl3) δ 2.24 (s, 3H), 3.47 (s, 2H), 6.99–7.08 (m, 3H), 7.28 (t, J=7.6 Hz, 1H), 7.44 (dt, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.3, 1.9 Hz, 1H), 8.13 (dd, J=6.1, 1.7 Hz, 1H), 8.61 (d, J=6.3 Hz, 2H); MS (ESI), m/z 319 (M++1), 321 (M++3); Anal. Calcd for C16H15ClN2O3.0.7TFA: C, 59.33; H, 4.65; Cl, 10.85; N, 8.57. Found: C, 59.23; H, 4.64; Cl, 10.90; N, 8.40.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NC1CCCC1
Product: CCc1cc(-c2cncc(C(=O)NC3CCCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and cyclopentyl amine to afford the title compound. MS: m/e=326 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+]>>[CH2:20]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C=CCCCCCCC
Reactant: Oc1ccc(S)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCSc1ccc(O)cc1

Procedure:
A 4-(nonylthio)phenol was prepared as follows. 63 Grams of 4-mercaptophenol and 5 grams of toluene sulfonic acid were heated to 60° C. Then 76 grams of nonene (approximately 55 percent 2,4-di-methyl-1-heptene) were added over a 38 minute period. The flask contents were neutralized with 5 grams of Na2CO3 in aqueous solution, decanted and stripped to a pot temperature of 180° C. at 26 millimeters of mercury. The product weighed 113 grams.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[O:37][N:36]=1>>[C:40]([C:38]1[O:37][N:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[CH:39]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)on4)c4ccccc43)cn12

Procedure:
The title compound was prepared starting from Intermediate 81d and (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see WO 2006/091671, which is incorporated herein by reference in its entirety) using analogous procedures to those described in Example 110 step c. LCMS (Method 5): Rt 4.67 min, m/z 544 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.44-1.57 (2H, m), 1.60-1.73 (2H, m), 1.74-1.86 (2H, m), 1.88-2.22 (4H, m), 2.86-2.94 (1H, m), 3.12-3.20 (2H, m), 4.86-4.95 (1H, m), 5.54 (1H, t, J=4.2 Hz), 6.40 (1H, s), 7.00 (1H, d, J=8.6 Hz), 7.21-7.26 (1H, m), 7.27-7.33 (1H, m), 7.34-7.42 (3H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.71 (1H, d, J=2.10 Hz), 9.31 (1H, s).