Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:20][C:21]1[CH:22]=[C:23]([C:27](=[O:32])[CH2:28][NH:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.[Pd]>[ClH:1].[CH2:2]([O:20][C:21]1[CH:22]=[C:23]([CH:27]([OH:32])[CH2:28][NH:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)CNCC)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(O)CNCC)c1

Procedure:
72 gm (0.15 mol) of the product obtained in step (a) were hydrogenated in 1.44 liters of methanol and in the presence of 5 gm of 5% palladium charcoal at 5 atmospheres and 60° C. After the absorption of hydrogen had ceased, the catalyst was filtered off, and the methanol was distilled out of the filtrate. The crystalline residue was stirred with acetonitrile, the mixture was vacuum-filtered, and the filter cake was recrystallized from ethanol, yielding 69 gm (95.% of theory) of the compound of the formula ##STR5## which had a melting point of 113° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+]([C:7]1[C:12]([CH3:13])=[CH:11][N+:10]([O-:14])=[C:9]([CH3:15])[C:8]=1[CH3:16])([O-])=O>CO>[CH3:1][O:2][C:7]1[C:12]([CH3:13])=[CH:11][N+:10]([O-:14])=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: C[O-]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)c[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of sodium methoxide, prepared from Na (8.62 g, 0.375 mol) and MeOH (500 ml), was added 4-nitro-2,3,5-trimethylpyridine-N-oxide (45.5 g, 0.25 mol). The reaction mixture was refluxed for 5 h, cooled to rt and most of the solvent removed in vacuo. The slurry was diluted with water (100 ml) and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl solution, dried (MgSO4) and the solvent removed in vacuo to give 4-methoxy-2,3,5-trimethylpyridine-N-oxide as a semi-solid (37.5 g, 90%).
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C@@H:9]2[O:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]12CC[CH:35]([CH2:36][CH2:37]1)[C@@H:34](O)[CH2:33]2>>[C:26]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C@@H:22]3[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:23]3)=[O:20])[CH2:10][C@@H:9]2[O:24][CH3:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCCCN1CC[C@@H](N(c2ccccc2)c2ccccc2)[C@@H](OC)C1
Reactant: O[C@H]1CN2CCC1CC2
Product: CO[C@H]1CN(CCCCCC(=O)O[C@H]2CN3CCC2CC3)CC[C@H]1N(c1ccccc1)c1ccccc1

Procedure:
esterifying the ethyl 6-((3S,4R)-4-(diphenylamino)-3-methoxypiperidin-1-yl)hexanoate with (R)-quinuclidine-3-ol to yield (R)-quinuclidine-3-yl 6-((3S,4R)-4-(diphenylamino)-3-methoxypiperidin-1-yl)hexanoate
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of COMPOUND 117 (51 mg, 0.10 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 137 as a white solid (48 mg, 85%) following work-up and purification. 1H NMR (CDCl3) δ 0.97-1.18 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.24 (s, 3H), 2.31 (s, 6H), 2.55 (t, 1H, J=10.5 Hz), 2.74-2.87 (m, 3H), 3.24-3.31 (m, 1H), 3.57-3.63 (m, 1H), 3.77 (s, 2H), 3.85-3.91 (m, 1H), 6.51 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.1 Hz), 6.93-7.05 (m, 3H), 7.43-7.52 (m, 4H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 14.53, 20.27, 22.20, 30.06, 31.46, 32.06, 40.96, 44.70, 49.60, 53.28, 57.84, 61.68, 113.66, 115.15, 120.06, 123.21, 128.42, 129.52, 130.36, 131.08, 131.64, 132.01, 135.21, 139.77, 143.16, 143.23, 147.35, 170.96, 171.27. ES-MS m/z 533 (M+H). Anal. Calcd. for C34H40N4O3.0.6H2O: C, 72.47; H, 7.37; N, 9.94. Found. C, 72.38; H, 7.25; N, 9.83.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]2([CH3:22])[O:21][CH:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH3:22])[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Product: COC(=O)C(O)C(C)(Oc1ccc(Br)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
51.9 g (0.3 mol) of 4-bromophenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are stirred for 8 hours at 100° C. and for 12 hours at room temperature. After the excess phenol has been distilled off, the residue is purified by flash chromatography (silica gel, 9:1 n-hexane/ethyl acetate). 7.2 g of a white solid are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[CH:31]([C@:33]1([CH3:48])[CH2:37][CH2:36][CH2:35][N:34]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:32].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:31]([OH:32])[C@:33]2([CH3:48])[CH2:37][CH2:36][CH2:35][N:34]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[CH:12][CH:11]=1)[CH3:9])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: C[C@@]1(C=O)CCCN1C(=O)OCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)[C@]2(C)CCCN2C(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
423 mg of the compound [1-1] and 508 mg of N,N,N′,N′-tetramethylethylene diamine were dissolved in 22 mL of tetrahydrofuran, the temperature of the solution was kept at −78° C., and then 1.09 mL of n-butyl lithium (2.66 M hexane solution) was added thereto. After stirring at the same temperature for 1 hour to obtain the resultant white suspension, 2.2 mL of a tetrahydrofuran solution prepared by dissolving 384 mg of the compound [63-3] was added thereto, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain benzyl (2S)-2-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]-2-methylpyrrolidine-1-carboxylate [634]. The compound [634] obtained was a mixture of two isomers, which was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 to 40/60) to obtain 199 mg of a low polarity compound (compound that eluted first under the above condition) [634a] (hereinafter, referred to as the compound [634a]) and 117 mg of a high polarity compound (compound that eluted afterwards under the above condition) [634b] (hereinafter, referred to as the compound [63-4b]). Here, the compound [634a] is a precursor of a compound [63], and the compound [634b] is a precursor of a compound [64] described later.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc([N+](=O)[O-])cc3)sc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc(N)cc3)sc21
Temperature: 90 °C
Yield: 7.9 %

Procedure:
To a solution of 6-(4-nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione (275 mg) in ethanol (15 ml) and water (1 ml) was added iron powder (82 mg) and ammonium chloride (78 mg). The mixture was heated at 90° C. for 6 h. and then allowed to cool to room temperature. The reaction was filtered and then evaporated before being partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, and then evaporated. The resultant oil was purified by normal phase HPLC (isohexane:ethyl acetate 80-0:20-100) to give the title compound (20 mg).
Reaction SMILES: ClC1C=C(C2SC(C(O)=O)=CC=2C2C=CC=C(C#N)C=2)C=C(F)C=1.[Br:25][C:26]1[CH:27]=[C:28]([C:38]([O:40]CC)=[O:39])[S:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1>>[Br:25][C:26]1[CH:27]=[C:28]([C:38]([OH:40])=[O:39])[S:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)s1
Agent: N#Cc1cccc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)c1
Product: O=C(O)c1cc(Br)c(-c2cccc(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 19A starting with the compound from Example 10A. 1.11 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(C(C)C)CC)(C)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([S:8]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNS(=O)(=O)c1cccc(I)c1
Yield: 42.9 %

Procedure:
(3-Iodophenyl)sulphonyl chloride (0.303 g) was stirred with glycinamide hydrochloride (0.122 g) and diisopropylethylamine (0.3 ml) in DMF (4 ml) at 21° for 24 h. The mixture was evaporated to dryness and applied to a silica Bond Elut Cartridge (10 g). The cartridge was eluted with CH2Cl2, Et2O and EtOAc. This gave the title compound (0.146 g), LCMS RT=2.36 min, ES+ve 341 (MH)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C([Sn](CCCC)(CCCC)[C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)CCC>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>[S:25]1[CH:26]=[CH:27][C:23]([C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=2)[O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])=[CH:24]1
Reactant: O=Cc1cccc(COc2cccc(Br)c2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(COc2cccc(-c3ccsc3)c2)c1
Yield: 76.7 %

Procedure:
1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and the solution was added to 5 ml of a tetrahydrofuran solution of phenolate, prepared from 1.5 g of 3-bromophenol and 0.36 g of 60% oily sodium hydride. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and water and ethyl acetate were added to the residue to extract it. The extract was worked up in a customary manner to give crude 3-(3-bromophenoxymethyl)benzaldehyde. When the same reaction as in Referential Example 12 was performed using 440 mg of the resulting aldehyde compound, 747 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 341 mg (yield 77%) of 3-[3-(3-thienyl)phenoxymethyl)benzaldehyde was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26])=[O:22])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CN(C)C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl sarcosinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]sarcosinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]sarcosine (M.P. 103° to 105°).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C([O-])([O-])=O.[K+].[K+].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.O>[N:37]1([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([N:14]4[CH:19]=[CH:18][C:17]([C:20]5[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=5)=[CH:16][C:15]4=[O:30])=[CH:11][CH:12]=3)[CH:7]=[N:6]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNC1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCN2CCCC2)c1
Temperature: 50 °C
Yield: 91.7 %

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded the intermediate 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (78 mg, 0.18 mmol) in DMF (1.0 mL) was added K2CO3 (0.12 g, 0.90 mmol), pyrrolidine (130 mg, 1.8 mmol) and KI (30 mg, 0.18 mmol), and the reaction was heated to 50° C. for 18 h. The reaction mixture was cooled and diluted with H2O (25 mL). The resulting solids were collected by filtration and washed with H2O (10 mL). The collected solid was dissolved in EtOAc (20 mL) and washed with brine (10 mL). The washed organic solution was dried over Na2SO4, filtered and concentrated to provide the title compound (77 mg, 91%): 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.77-7.74 (m, 5H), 7.60-7.42 (m, 3H), 6.92 (d, J=2.0 Hz, 1H), 6.53-6.51 (m, 1H), 4.51 (t, J=7.0 Hz, 2H), 2.48-2.44 (m, 6H), 2.16-2.12 (m, 2H), 1.79-1.77 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].CCO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Cl)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Ethyl 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylate (220 g, 401 mmol) was dissolved in 1.8 L of a 2:1 mixture of THF:EtOH. To the solution was added 4 N NaOH (150 mL, 600 mmol) and the reaction was stirred at ambient temperature for 2 hours. The mixture was concentrated to a solid residue, diluted with 1 L of water and 1 N HCl (700 mL, 700 mmol) was added. The resulting white solids were collected by filtration, washing with 2 L of water. The white solids were dried under high vacuum to give 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylic acid (207 g, 99% yield). MS (apci) m/z=520 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18]>C(#N)C>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(COc2cccc(C(N)=O)c2)cc1

Procedure:
3-hydroxybenzamide (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-cyanobenzyl bromide (0.138 g; 1 mmol). This was left to reflux for 5 hours.
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:26]=[N:27][C:28]([CH3:31])([CH3:30])[CH3:29])(Cl)[CH3:24])(=O)C>C(Cl)Cl.O>[C:28]([N:27]=[N:26][C:23]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH3:24])[CH2:22][CH2:21][CH2:20][OH:19])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CC(=O)OCCCC(C)(Cl)N=NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N=NC(C)(CCCO)Sc1ccc(C(C)(C)C)cc1
Temperature: 30 °C

Procedure:
To a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel was added 6.6 grams (0.1 mole) of 85% potassium hydroxide pellets and 130 mls of methanol. The mixture was stirred at 30° C. until the pellets dissolved. The resulting solution was cooled to 15° C. and with rapid stirring 16.6 grams (0.1 mole) of para-t-butyl-thiophenol were added while holding the temperature at 15° to 20° C. The mixture was stirred an additional 15 minutes at 15° C. and then 24.9 grams (0.1 mole) of 4-t-butylazo-4-chloropentyl acetate were added over 20 minutes while holding the temperature at 15° to 20° C. After the addition was complete, the mixture was stirred an additional hour at room temperature and then an additional 6.6 grams (0.1 mole) of 85% potassium hydroxide was added (to saponify the acetyl group). The mixture was stirred an additional 1 hour at room temperature, poured into 300 mls of water and the organic layer taken up in 100 mls of methylene chloride. The methylene chloride layer was separated, washed with 50 ml portions of water, 10% HCl, water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off on a rotary evaporator under reduced pressure. The resulting light orange liquid weighed 28 grams (83.5% crude yield). The infrared spectrum of the product contained a very broad strong OH band centered at 3350-3400 cm-1 and there was no carbonyl band.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15]2([CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:14](=[O:22])[NH:13][CH:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C:15]2([CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:14](=[O:22])[N:13]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:12]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(F)cc2)NC(=O)C12COCCOC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28 mg (0.66 mmol) sodium hydride were added to 0.23 g (0.6 mmol) tert-butyl-3-(4-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml DMF. After 5 min at RT 64 μl (0.91 mmol) methyl bromoacetate were added dropwise and then the reaction mixture was stirred for 1 h at RT. The reaction was poured onto ice water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-ethylaniline to yield 2-[(4-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: O=CCc1ccc(OC(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
A solution of (4-difluoromethoxyphenyl)-acetaldehyde 1.22 g, 6 mmol; from step (ii) above) in ethanol (20 mL) was cooled to 0° C. Sodium borohydride (0.27 g, 7.2 mmol) was added and the resulting reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 16 h. After concentration under reduced pressure, the residue was diluted with diethylether (50 mL) and 1 M HCl (50 mL). The phases were separated and the organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by two times repeated chromatography on silica gel. (Horizon™, flash system from Biotage™. Column: Flash 40+M, 40×150 mm. Eluent: Gradients from 25 to 40% ethyl acetate in heptane. Concentration in vacuo afforded 0.62 g (50%) of the sub-title compound as a light yellow oil.