Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:21]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]3)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: OCC1CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Yield: 156.9 %

Procedure:
A solution of piperdin-3-yl methanol (0.342 g, 2.97 mmol), 1-(4-chloro-phenyl)-cyclopentylcarboxylic acid (1.0 g, 4.45 mmol), diisopropylethyl amine (1.9, 15.00 mmol) in dichloromethane (7 mL) was stirred at room temperature. PyBroP (2.07 g, 4.45 mmol) was added and the reaction mixture continued stirring at room temperature. After 12 h the reaction mixture was quenched with 10% KOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The crude material was purified using silica gel chromatography (95:5 hexane:ethyl acetate) to yield the desired compound (1.50 g). C18H24ClNO2, LRMS (m/z)=322 (MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C1(C)C=CC=CC=1.[Cl-].[NH4+].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:10][C:4]1[CH:3]=[C:2]([C:20]#[N:21])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Br)cc1F
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C#N)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (20 g, 100 mmol), zinc cyanide (7 g, 60 mmol) and tetrakis(triphenyl-phosphine)palladium (4.6 g, 4 mmol) in DMF (100 mL) was heated at 80° C. for 4 hr. Toluene (300 mL) and saturated aqueous ammonium chloride (300 mL) were added and the layers were separated. The organic layer was washed once with saturated aqueous ammonium chloride and twice with brine. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography, eluting with a gradient of hexanes to 30% EtOAc/hexanes (11 g, 75%).
Reaction SMILES: [OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C(O)(c2nccs2)C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cccc(OCc2ccc3ccccc3n2)c1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
A mixture of 2-[1-hydroxy-1-(3-hydroxyphenyl)-2,2,2-trifluoroethyl]thiazole (0.33 g), 2-chloromethylquinoline hydrochloride (0.22 g), potassium carbonate (0.5 g) and dimethylformamide (5 ml) was stirred at ambient temperature for 24 hours. The mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with chloroform/ethyl acetate (9/1 v/v) to give 2-[1-hydroxy-1-[3-(quinol-2-ylmethoxy)phenyl]-2,2,2-trifluoroethyl]thiazole (0.15 g, 30%), m.p. 177° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1OC.O.[NH2:13]N>O>[NH2:13][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COc1cnn(C)c(=O)c1Cl
Solvent: O
Product: Cn1nccc(N)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
9.14 g (52 mmoles) of intermediate 4b are placed in mL hydrazine monohydrate. The reaction medium is agitated for 3 h at 80° C. then diluted in 100 mL water and extracted with CH2Cl2 then with AcOEt. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2—AcOEt, gradient 100:0 to 0:100 over 50 min). 4.17 g of intermediate 4c are thus obtained in the form of an orange-like solid (yield 63%). TLC silica 60 F 254 Merck, CH2Cl2—AcOEt: 50:50, Rf=0.16.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36](O)=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[NH4+].[NH4+].C[N:50](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O.O>[NH2:50][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:19][CH:18]=2)[N:26]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cc2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
2-(2-(2-(2-((4-(4-(tert-Butoxycarbonyl)morpholin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (190) (39 mg, 0.066 mmol) was dissolved in DMF (3 mL) and ammonium carbonate (38 mg, 0.40 mmol), HATU (28 mg, 0.073 mmol) and DIPEA (0.046 mL, 0.27 mmol) were added. The yellow mixture was stirred at room temperature for 18 hours then added to water (30 mL) and brine (10 mL). The mixture was extracted with ethyl acetate (3×30 mL), and the combined ethyl acetate phases washed with brine (50 mL), dried over sodium sulfate and evaporated. The residue was chromotographed (4 g deactivated* silica cartridge, 0-100% 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I91) (23.3 mg, 60% yield) as a colourless glass; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.78 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.31-7.19 (m, 5H, overlaps with CHCl3), 5.58 (s, 1H), 5.42 (s, 1H), 4.40 (d, J=8.5 Hz, 1H), 4.08-3.84 (m, 3H), 3.74-3.63 (m, 3H), 3.16-3.00 (m, 5H), 2.85 (s, 1H), 1.48 (s, 9H). LCMS Method C: rt 6.29 min; m/z 586.1 [M+H]+, 530.1 [M-tBu+2H]+, 608.1 [M+Na]+; m/z 584.1 [M−H]−. * cartridge deactivated by treating with 3 volumes of 1% isopropylamine in ethyl acetate followed by rinsing with a 3 volume gradient of 100-0% of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.
Reaction SMILES: C[C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[OH-].[Na+].O=O.[Na].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>[Cu].[Mn].[Fe]>[O:3]=[CH:2][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [Cu]
Agent: [Fe]
Agent: [Mn]
Product: COc1cc(C=O)ccc1O
Temperature: 180 °C

Procedure:
Two-gram samples of acetovanillone were separately placed in a batch type reactor vessel with 100 gr of 2N NaOH so that the ratio of NaOH to acetovanillone was 4:1. The reactor vessel was heated to about 180° C. and pressurized with either air or air enriched to 40% oxygen to the pressures indicated in Table 1. The reaction was allowed to proceed for the time indicated in Table 1. In some cases, as indicated in Table 1, sulfates and oxides of the transition elements copper, manganese and iron were employed as catalyst and in one case sodium-m-nitrobenzene sulfonate abbreviated as NAMNO. The resulting oxidation products were analyzed by gas chromatography and yields of vanillin (Van), are reported in Table 1.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].[H-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][O:28][C:7]1[CH:8]=[CH:9][C:10]([C:12]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=3[C:19]([Br:27])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:11][C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCCBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(=O)CCCOc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Yield: 51.5 %

Procedure:
A solution of 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.30 g, 0.81 mmol), 4-bromobutyric acid, methyl ester (1.5 mL, 13.0 mmol), 60% sodium hydride (0.09 g, 2.3 mmol), potassium carbonate (1.0 g, 7.2 mmol), and anhydrous benzene (2 mL) was heated at 100° for 36 h. Purification by chromatography with hexanes/ethyl acetate gave the title compound as a solid (0.23 g, 52%): NMR (DMSO-d6): δ 8.18 (d, J=8 Hz, 1H), 7.62 (ddd, J=2,6,8 Hz, 1H), 7.50-7.41 (m, 2H), 7.16-7.04 (m, 3H), 4.11 (m, 2H), 3.63 (s, 3H), 3.31 (quintet, J=8 Hz, 1H), 2.57 (t, J=7 Hz, 2H), 2.42 (s, 3H), 2.07 (quintet, J=7 Hz, 2H), 1.95 (m, 2H), 1.74-1.45 (m containing a singlet at δ 1.56, 9H); MS(EI): [M+], 1 bromine isotope pattern, 550/552.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 mL) was added conc. sulfuric acid (3 mL), and the mixture was heated for 5 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.99 g).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:37]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cccc(-c2cccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)c2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2cccc(C(O)(c3c[nH]cn3)C(C)C)c2)c1
Yield: 68.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide (0.781 g) and pyridine hydrochloride (290 mg), the title compound (315 mg) was obtained as colorless powder crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C1C[O:30][CH2:29]C1>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][C:29](=[O:30])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1CN(c1ccccc1)C(=O)O2
Temperature: 25 °C

Procedure:
A solution of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 50 mg, 0.163 mmol) in THF (2 mL) was treated at rt with lithium aluminum hydride (50 mg, 1.317 mmol) and the mixture was heated at reflux for 2 h. It was then cooled to rt and carefully treated with saturated aqueous ammonium chloride (2 mL). The mixture was diluted with DCM (60 mL) and washed with water (5 mL) and brine (5 mL), dried and concentrated to give the 4-bromo-3-methyl-2-((phenylamino)methyl)phenol (45 mg). Without purification, this material was dissolved in DCM (3 lM) and treated with carbonyldiimidazole (30.5 mg, 0.188 mmol) and DMAP (2.091 mg, 0.017 mmol) at rt and the mixture was stirred for 1 h. The mixture was diluted with DCM (60 mL) and washed with NaHCO3 (aq) (5 mL) and brine (5 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 50:50 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (25 mg). 1H NMR (400 MHz, chloroform-d) δ 7.33-7.57 (6H, m), 6.88 (1H, d, J=8.88 Hz), 4.82 (2H, s), 2.30 (3H, s). Mass spectrum m/z 318, 320 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(C(O)CO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(O)CO)c1
Yield: 119.6 %

Procedure:
1-(3-Nitrophenyl)ethane-1,2-diol (10 g) was dissolved in MeOH (100 ml). 10% Pd/C (1.3 g) was added the mixture hydrogenated at 40 psi H2 for 1 hour. The reaction mass was filtered through hyflo and concentrated to give the crude title compound (10 g, 92%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16](Cl)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:31])[CH2:29][CH3:30])[C:22]=1[NH2:23])[CH3:20]>>[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([O:31][C:16](=[O:17])[CH2:15][CH:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:29][CH3:30])[C:22]=1[NH:23][C:16](=[O:17])[CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: O=C(Cl)CC1c2ccccc2Oc2ccccc21
Reactant: CCc1cccc(C(O)CC)c1N
Product: CCc1cccc(C(CC)OC(=O)CC2c3ccccc3Oc3ccccc32)c1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 21, but using 2.2 equivalents of 2-(9H-xanthen-yl)acetyl chloride and one equivalent of 2-ethyl-6-(1-hydroxypropyl)aniline, the title compound was obtained as a foam-like material.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.390 g. of caprylic acid chloride as in Example 1. The 0.671 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.586 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl octanoate obtained melts at 77.5°-77.9° and is liquid crystalline (monotrope) upon cooling to 74.1°. UV (EtOH): ε272 = 26,500.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:25])[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[O:18][CH2:19][CH2:20]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([N:14]([CH3:13])[CH3:25])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(OCCO)c1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Product: COC(=O)c1nc(Br)ccc1OCCOc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Polystyrene bound PPh3 (0.77 g at 1 mmol/g, 0.77 mmol, 1.5 eq) was added to a solution of methyl 6-bromo-3-hydroxypicolinate (0.119 g, 0.51 mmol) and 2-(3-(dimethylamino)phenoxy)ethanol (39B) (0.093 g, 0.51 mmol) in dry DCM (5 mL). To this was added diethyl azodicarboxylate (0.134 mg, 0.77 mmol) dropwise, and the reaction mixture was stirred at rt for 4 hours, filtered to remove the resin, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 75:25-60:40, to provide the desired product methyl 6-bromo-3-(2-(3-(dimethylamino)phenoxy)ethoxy)picolinate (39C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][C:7]=1[Br:22]
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(C2CCC(=O)CC2)cc1Br

Procedure:
The title compound was prepared from 4-(4-amino-phenyl)-cyclohexanone (as prepared in the previous step) by bromination with NBS according to the procedure in Example 4, step (b), replacing CH3CN with CH2Cl2. Mass spectrum (ESI, m/z): Calcd. for C12H14NOBr, 268.0/270.0 (M+H). found 268.3/270.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)=[N:2]1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:29]
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
Compound 64 (60 mg, 0.13 mmol), iron powder (364 mg, 6.50 mmol) and ammonium chloride (35 mg, 0.65 mmol) were added to ethanol (1.0 mL) and water (1.0 mL) at room temperature, stirred at 50° C. for 1 hour and then the reaction mixture was filtered through Celite. The filtrate was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 69 (11 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7](Cl)=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cscc1Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)c1cscc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, a solution of 4-chlorothiophene-3-carboxylic chloride (13.5 g, 0.075 mol) in 30 ml of dioxane is dripped into a solution of aniline (7.7 g, 0.083 mol) in pyridine (160 ml). The mixture is stirred for 12 hours at room temperature and concentrated to dryness, and the residue is taken up in dichloromethane. The organic phase is extracted with aqueous citric acid solution, sodium bicarbonate solution and water, dried and concentrated to dryness. Yield: 16.7 g, 94%; m.p. 119°-121° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]([O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH3:35])[C:31](O)=[O:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]([CH:8]1[C:16]([CH3:17])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]1[C:31](=[O:32])[C@@H:30]([NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28])[CH2:34][CH3:35])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C1Nc2ccccc2C1(C)C
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCNC(=O)C1N(C(=O)[C@H](CC)NC(=O)OCc2ccccc2)c2ccccc2C1(C)C
Temperature: 0 °C
Reaction time: 22 h

Procedure:
3,3-Dimethylindoline-2(R/S)-carboxylic acid butylamide (1.000 g, 4.08 mmol) and N-benzyloxycarbonyl-2(S)-aminobutyric acid (1.451 g, 6.12 mmol) were dissolved in dry tetrahydrofuran (25 ml). The solution was cooled to 0° C. and triethylamine (2.44 ml, 13.78 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (2.338 g, 9.183 mmol) were added. The mixture was stirred at room temperature for 22 hours and ethyl acetate (40 ml) was then added, and the mixture was washed with 3N hydrochloric acid (3×50 ml), 5% sodium bicarbonate (3×50 ml) and water (50 ml) and dried over sodium sulphate. After removing the solvent, several successive purifications by chromatography on a column of silica gel gave the product in the form of an off-white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH2:27])=[CH:23][N:22]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(O)ccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21

Procedure:
Heat a mixture of N-Boc-1-aminomethyl-indan-5-ol (1.13 g, 4.29 mmol), 6-chloronicotinamide (671 mg, 4.29 mmol, K2CO3 (889 mg, 6.43 mmol), and DMSO (10 ml) at 100° C. for 19 hours. Pour the reaction mixture into saturated aqueous NH4Cl and extract with EtOAc. Wash extract with brine, dry (MgSO4) and concentrate to a brown foam. Purify on silica gel (30% EtOAc/DCM) to obtain [5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acid tert-butyl ester (847 mg) as a light yellow solid. 1HNMR (CDCl3): 8.61 (s, 1H), 8.17 (d, 1H), 7.24 (d, 1H), 7.00 (s, 1H), 6.95 (m, 3H), 6.03 (br s, 2H), 4.65 (br s, 1H), 3.48 (m, 1H), 3.31 (m, 2H), 2.98-2.83 (m, 2H), 2.30 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H).