Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:35])[CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CI
Reactant: COc1ccc2[nH]cc(-c3cc4c(OC)ncnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(OC)ncnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [448 mg, Reference Example 5] in dimethylformamide (20 mL) was added the sodium hydride (44 mg, 60% dispersion in oil) and methyl iodide (156 mg) under inert atmosphere. The solution was stirred for 1 hour at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (30:70, v/v) to give the title compound (260 mg) as an amorphous solid. MS: 464 [MH]+. LCMS (Method B) RT=4.39 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CNc2cc(C(F)(F)F)cc(Cl)n2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccccc3C(F)(F)F)n2)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine (7.26 g, 22.9 mmol, prepared as described in STEP A above) in DME (100 mL) and water (50 mL) was treated with 2-trifluoromethylphenylboronic acid (5.66 g, 29.8 mmol), and Cs2CO3 (11.2 g, 34.4 mmol). The resulting mixture was degassed via heating under a stream of Ar. Cl2Pd(dppf).DCM (1.13 g, 1.38 mmol) was added, and the mixture was heated to 80° C. for 4 h. The cooled mixture was diluted with water (100 mL) and extracted twice with EtOAc (150 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield (4-methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]amine as a yellow oil, which solidified upon standing. 1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.8 Hz, 1H), 7.57-7.63 (m, 1H), 7.47-7.55 (m, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.85-6.91 (m, 3H), 6.57 (s, 1H), 5.11 (t, J=5.2 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N2OF6: 427.1 (M+H); Measured: 427.2.
Reaction SMILES: [OH-].[Na+].O.CO.[CH3:6][C:7]([CH3:21])([CH:14](Cl)[CH2:15][C:16](Cl)([Cl:18])[Cl:17])[CH2:8][C:9]([O:11]CC)=[O:10]>CCOCC>[CH3:6][C:7]1([CH3:21])[CH:14]([CH:15]=[C:16]([Cl:18])[Cl:17])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: CCOC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixed solution of 12.0 parts of sodium hydroxide, 40 parts of water and 60 parts of methanol was added dropwise under reflux 31.0 parts of ethyl 3,3-dimethyl-4,6,6,6-tetrachlorohexanoate and, after the dropwise addition had been completed, the mixture was stirred at that temperature for 2 hours. The reaction mixture was then distilled under reduced pressure to remove the methanol, and the residue was neutralized with hydrochloric acid and extracted with diethyl ether. From this ether layer was obtained 19.2 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 92%) which had the following properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5](=[O:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].C1(C)C=CC(S([N:23]=[N+:24]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N+:23]=[N-:24])[C:5](=[O:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11]
Reactant: COC(=O)CC(=O)CCC=C(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)CCC=C(C)C
Yield: 89.3 %

Procedure:
In accordance with the process of Example 1, 3-oxo-7-methyl-6-octenoic acid methyl ester (0.54 g; 2.93 m mol), triethylamine (0.30 g; 2.93 m mol) and p-toluenesulfonyl azide (0.61 g; 2.93 m mol) were used as starting materials to obtain 0.55 g of 2-diazo-3-oxo-7-methyl-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([Cl:18])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Cl)C1
Reaction time: 1.5 h

Procedure:
1-tert-Butyloxycarbonyl-azetidine-3-carboxylic acid (345 mg) in dry dichloromethane (10 ml) was treated with oxalyl chloride (254 mg; 0.175 ml) and N,N-dimethylformamide (1 drop). The solution was stirred for 1.5 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was dissolved in toluene (10 ml), and the toluene was evaporation under reduced pressure to give 1-tert-butyloxycarbonyl-azetidine-3-carbonyl chloride as a colourless oil. The oil was dissolved in dichloromethane (6 ml) and the solution was treated with silver cyanate (525 mg). The mixture was stirred for 10 minutes, and then mutilin 11-trifluoroacetate (535 mg) in dichloromethane (9 ml) was added. The mixture was stirred for 20 hours. Ethyl acetate (50 ml) was added and the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (20 ml) and saturated sodium chloride solution (20 ml). The solution was dried (sodium sulphate) and the solvent was removed under reduced pressure to yield a colourless gum. The gum was chromatographed on silica gel using 1:4 to 1:2 ethyl acetate/hexane to give the title compound as a colourless gum (485 mg); 1H NMR (CDCl3) inter alia 1.43 (9H, s), 3.93 (1H, quin, J 7.2 Hz), 4.98 (1H, d, J 6.9 Hz), 4.14 (4H, m), 5.23 (1H, d, J 17.5 Hz), 5.29 (1H, d, J 11.2 Hz), 5.58 (1H, d, J 8 Hz), 6.31 (1H, dd, J 17.5, 11.2 Hz), 7.57 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1.CNCCNC>N1C=CC=CC=1.C(Cl)Cl.[Cu]I>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:19]2[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]2)=[CH:3][CH:4]=1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: CNCCNC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
A solution of the product from Example 8F, 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135° C. for 16 hours. The reaction mixture was cooled and diluted with DCM (10 mL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL×2), and H2O, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz, 1H). MS (DCI—NH3) m/z 310 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([NH:38][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (125 mg) in dimethylformamide (2 mL) were added 1-hydroxybenzotriazole (96.4 mg), benzylamine (0.063 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (137 mg). The mixture was stirred for 3 hours at 20° C. The resulting mixture was diluted with ethyl acetate and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with methanol to give N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (150 mg) as a solid substance.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23]C)=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[S:28][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Yield: 79 %

Procedure:
Methyl 3-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoate (127 mg, 0.3 mmol) was heated in a 25% MeOH—H2O solution at 90° C. for 3 h in the presence of LiOH—H2O (12.7 mg, 0.3 mmol). The solvent was removed under reduced pressure; the residue was dissolved in MeOH and filtered. The filtrate was evaporated to collect product in 79% yield (97 mg). 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.92 (s, 1H), 7.85 (d, 1H), 7.50 (s, 1H), 7.42 (d, 1H), 7.33 (t, 1H), 4.11 (m, 1H), 3.59 (s, 2H), 2.98 (d, 2H), 2.20 (t, 2H), 2.00 (d, 2H), 1.68 (m, 2H); MS (ESI) m/z: Calculated for C19H20ClN4O2S, 403.1; Observed: 403.2 (M++1).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>CC1C=CC=CC=1C.O.[Pd]>[N:11]1([C:2]2[C:10]3[NH:9][CH:8]=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Brc1cccc2nc[nH]c12
Reactant: C1CNCCNC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: c1cc(N2CCCNCC2)c2[nH]cnc2c1
Temperature: 25 °C

Procedure:
A suspension of 4-bromobenzimidazole (42 mmol), homopiperazine (256 mmol) and NaOt-Bu (59 mmol) in dry o-xylene, under N2, is treated with a catalytic amount of Pd (OCOCH3)2.P(t-Bu)3 (P/Pd=4), heated at 120° C. for 3 hr, cooled to room temperature and diluted with water. The aqueous mixture is extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography to give 4-(homopiperazin-1-yl)benzimidazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:8]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccnc1
Reactant: ClCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(COc2cccnc2)cc1
Reaction time: 8 h

Procedure:
9.5 g (10 mMol) 3-Hydroxy-pyridine and 9.45 ml (10 mMol) benzylchloride are dissolved in 50 ml CH2Cl2 at rt. 0.5 g Adogen 464® (Aldrich 63393-96-4) are added followed by dropwise addition of 50 ml of aq. NaOH solution (40% wt). The resulting yellow solution is stirred overnight, leading to formation of a white precipitate. The insolubles are filtered off and the filtrated is diluted with CH2Cl2 and H2O. The phases are separated and the aq. phase is repeatedly extracted with CH2Cl2. Combined organic extracts are dried, concentrated and the residual crude product is purified by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) to give the title compound as a yellow oil: MS: [M+1]+=186; 1H MNR (CDCl3): δ ppm 8.42 (s, 1H), 8.26 (s, 1H), 7.55-7.38 (m, 5H), 7.30-7.19 (m, 2H), 5.17 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[F:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Reactant: FCCNc1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (336 mg, 1.2 mmol) and (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) (383 mg, 2.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (491 mg, 3.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with 2 N HCl (10 mL), water (2×10 mL) and aqueous potassium carbonate solution (2×5 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 40 mg (10%) of 6-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 9) as white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.13 (3H, t, J=9 Hz, N(CH2CH3)2), 1.30 (3H, t, J=9 Hz, N(CH2CH3)2), 1.55-2.14 (4H, m, 2- and 3-CH2), 2.78-2.86 (2H, m, 1-CH2), 3.36-3.67 (4H, m, N(CH2CH3)2), (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.60 (2H, dm, J=41 Hz, NCH2CH2F), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15]>C(Cl)(Cl)(Cl)Cl>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Cl:1]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
Chlorine gas was passed through a stirred solution of 4-amino-3-cyanotrifluoromethyl-benzene (5 g) in carbon tetrachloride (75 ml) until the absence of starting material was confirmed by gas liquid chromatography. Flow of the gas was then stopped and evaporation of the solvent under reduced pressure gave 4-amino-3-chloro-5-cyano-trifluoromethyl benzene as an orange solid (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNCC4CC4)c23)ccc1OCc1ccccn1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)CC1CC1
Yield: 58 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(cyclopropylmethyl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 58% yield; NMR spectrum (DMSO-d6) 0.16-0.27 (m, 2H), 0.36-0.52 (m, 2H), 0.97-1.06 (m, 1H), 2.00 (s, 3H), 3.24-3.29 (m, 2H), 3.93-4.02 (m, 2H), 4.33-4.56 (m, 2H), 5.31 (s, 2H), 7.13-7.18 (m, 1H), 7.21-7.29 (m, 1H), 7.31-7.40 (m, 2H), 7.54-7.62 (m, 2H), 7.69-7.79 (m, 1H), 7.86-7.92 (m, 1H), 7.93-7.96 (m, 1H), 8.44 (s, 1H), 8.61 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 518.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[Cl:12][C:13]1[N:18]=[C:17]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C
Yield: 98 %

Procedure:
To a solution of 4-methoxyphenylboronic acid (3.0 g, 19.7 mmol) and 2,4 dichloropyrimidine (5.9 g, 39.0 mmol) in dry acetonitrile (120 mL) was added a 0.4 M solution of Na2CO3 (120 mL) followed by Pd(PPh3)4 (400 mg, 0.35 mmol). The suspension was degassed and heated at 90° C. for 16 h, cooled down and concentrated to produce a precipitate which was collected by filtration, washed with water, dried and purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 5/95) to afford the title compound 17 (4.25 g, 19.3 mmol, 97% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:31][CH2:30][CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:29][CH2:28]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Yield: 20.2 %

Procedure:
Using a similar procedure to that described in Example 8, Part B, 2-chloro-N-(4-chlorophenyl)pyridine-3-carboxamide (125 mg, 0.47 mmol), 1-(4-pyridyl)piperidin-4-ylmethylamine (90 mg, 0.47 mmol), and triethylamine (0.07 mL) yielded 40 mg (24%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:27])C.[Li+].[OH-]>>[CH2:29]([O:28][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:27])[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid as colorless liquid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([CH2:24][C:25]([O:27]C)=[O:26])[O:13][N:12]=2)=[CH:7][CH:6]=1>>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([CH2:24][C:25]([OH:27])=[O:26])[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2noc(CC(=O)O)c2-c2ccc(OC)cc2)cc1
Temperature: 40 °C

Procedure:
To 15 ml of 2% aqueous solution of sodium hydroxide was added 1.77 g of methyl [3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetate obtained in Reference Example 1 and the mixture was stirred at 40° C. over night. After completion of the reaction, the reaction mixture was washed with ether twice, and thereto was added 5 ml of 10% HCl while cooling with ice. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, giving the above-identified compound as white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:47]=[CH:46][CH:45]=[CH:44][C:22]=4[O:23][CH:24]([CH2:41][CH2:42][CH3:43])[C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:47]=[CH:46][CH:45]=[CH:44][C:22]=4[O:23][CH:24]([CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)O
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of diphenylmethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanoate (2.30 g) in a mixed solvent of tetrahydrofuran (30 ml) and methanol (15 ml) was added 1N sodium hydroxide solution (6.8 ml) at room temperature. The solution was stirred for two hours and concentrated under reduced pressure. The residue was diluted with water and acidified with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanoic acid (901 mg).