Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:37][CH2:36][CH2:35][CH2:34][NH:33][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:29]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCCO)c(C)sc5c4)c3s2)C1
Yield: 23.3 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with 3-amino-1-propanol (106 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (34 mg, 23%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.65 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.07 Hz), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.07, 8.85 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.13-3.82 (3H, m), 3.62 (2H, m), 3.50 (2H, m), 3.39-3.30 (2H, m), 3.27, 3.24 (3H, s), 2.60 (3H, s), 2.18-1.93 (2H, m), 1.71 (2H, quintet, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[O:10]1[CH:12]([CH2:13][CH3:14])[CH2:11]1>C(O)=O>[OH:10][CH:12]([CH2:13][CH3:14])[CH2:11][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: CCC1CO1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Solvent: O=CO
Product: CCC(O)Cn1c([N+](=O)[O-])cnc1C
Temperature: 10 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 2-methyl -5-nitroimidazole (127 g, 1.0 mol) and 88% formic acid will be cooled to 10° C. under stir, then 1,2-epoxybutane (360 g, 5.0 mol) will be added dropwise to above cold solution under the condition of 10° C. After the dropping, the reactants will be placed at room temperature overnight. The formic acid will be recovered under reduced pressure. To this residue, 100 ml of water will be added. The mixture will be filtered and the filter residue will be washed with water. The water phases will be combined, alkalified with 10 M sodium hydroxide aqueous solution up to pH 9. The solution will be placed in the cold room overnight for crystallization. The crystals will be collected, washed with water, and then dried. Crude product will be recrystallized from toluene to give 1-(2-hydroxybutyl)-2-methyl-5-nitro-1H-imidazole.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[N:19](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[OH:20]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=NO)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked one liter flask, fitted with a thermometer, a dropping funnel and a magnetic stirrer were placed 173 g. (0.9 mole) of benzyl acetoacetate [The benzyl acetoacetate was prepared as described by Baker et al., J. Org. Chem. 17, 91 (1952)] and 130 ml. of glacial acetic acid. The contents were cooled in an ice-salt bath and a solution of 69 g. (1 mole) of sodium nitrite in 130 ml. of water was added over a period of half an hour; the temperature was kept at 0° to 10° C. After the reaction mixture was stirred for one hour at room temperature, 400 ml. of water was added and the stirring was continued for an additional two hours. The reaction mixture was extracted three times with 200 ml. portions of diethyl ether. The diethyl ether extracts were combined, washed once with water, three times with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the diethyl ether solution was evaporated leaving 16 as a clear oil which solidified upon trituration with petroleum ether (30°- 60°) to give 186.5 g. (93.2%) of white solid. Its NMR spectrum was consistent with the assigned structure. Generally the product was used as such in subsequent reaction but it can be recrystallized from toluene, m.p. 81°- 82° C. ##STR143##
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[CH:21]=[O:22]>C1COCC1.ClCCl>[CH3:19][N:18]1[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:15]([CH:21]=[O:22])[C:16]([CH3:20])=[N:17]1
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nn(C)c(OCC(F)(F)F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.4 %

Procedure:
2,2,2-Trifluoroethanol (7.11 ml, 97.6 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (97.6 ml, 97.6 mmol) at 0° C. A solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (10.3 g, 65.1 mmol) in THF (28 ml) was added slowly to the solution at 0° C. The solution was allowed to warn to room temperature and stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and concentrated to give the product as a yellow oil (15.82 g, 109% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3): 2.42 (s, 3H, Me), 3.65 (s, 3H, Me), 4.93 (q, 2H, CH2), 9.72 (s, 1H, CH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cccc2c1C(CO)CN2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1cccc2c1C(COS(C)(=O)=O)CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
A solution of 17 (80 mg, 0.26 mmol) in 5 mL anhydrous CH2Cl2 was cooled to 0° C. and treated with Et3N (79 μL, 0.57 mmol). After 10 min, MsCl (40 μL, 0.52 mmol) was added and the reaction mixture was subsequently warmed to 25° C. and stirred for 3 h. The reaction solution was concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 30% EtOAc/hexane) yielded pure 18 (94 mg, 94%) as a colorless oil: 1H NMR (CDCl3, 250 MHz) δ7.49 (m, 1H), 7.15 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 5.19 (d, J=8.8 Hz, 1H), 5.17 (d, J=8.8 Hz, 1H), 4.58 (dd, J=3.6, 9.7 Hz, 1H), 4.21 (app t, J=8.9 Hz, 1H), 4.00 (m, 2H), 3.79 (m, 1H), 3.46 (s, 3H), 2,71 (s, 3H), 1.54 (s, 9H);13C NMR (CDCl3, 100 MHz) δ153.9, 152.1, 130.5, 110.2, 108.8, 107.7, 103.9, 94.4, 81.0, 69.9, 56.2, 51.1, 37.9, 37.2, 28.2; IR (film) νmax 2976, 1703, 1610, 1479, 1463, 1391, 1355, 1254, 1175, 1154, 1061, 952 cm−1; FABHRMS (NBA/CsI) m/z 520.0388 (C17H25NO7S+Cs+ requires 520.0406).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.Cl.[C:23]12([NH2:28])[CH2:27][CH:25]([CH2:26]1)[CH2:24]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:23]12([NH:28][C:12]3[N:11]=[C:10]([NH:9][C@@H:4]4[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]4)[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH2:27][CH:25]([CH2:26]1)[CH2:24]2
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Reactant: NC12CC(C1)C2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C#N)C[C@H]1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (446 mg, 1.437 mmol; synthesis described herein) in NMP (5 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (258 mg, 2.155 mmol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (1.255 mL, 7.18 mmol). The reaction was stirred at 80° C. for 4 h and then allowed to cool to ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-90% ethyl acetate in hexanes) to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (381 mg, 1.216 mmol, 85% yield). MS (ESI): m/z 314.0 [M+1]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)[C:18]#[N:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccc(-c2ccc3cccnc3c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccc(-c2ccc3cccnc3c2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 2-(4-(quinolin-7-yl)phenyl)acetonitrile (0.409 mmol) in carbon tetrachloride (2 mL) was degassed for three minutes with a stream of nitrogen. The solution was then treated with N-bromosuccinimide (0.450 mmol) and azobisisobutyronitrile (0.020 mmol). The reaction vessel was purged with nitrogen and sealed and the mixture was allowed to stir overnight in a 75° C. oil bath. The reaction mixture was then directly loading onto silica gel and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-80% ethyl acetate/hexanes) afforded the title compound (30 mg, 17%). MS(ES)+ m/e 322.9/325.0 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][CH2:36][OH:37]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)=[O:12])=[CH:32][CH:33]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Reactant: OCCBr
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCN(CCO)CC3)c2)cc1
Yield: 72.7 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.5 g (1.14 mmol) and 2-bromoethanol (0.214 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 76.2%, (M+1)=482+1.
Reaction SMILES: C(N[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)C.[CH:10]([N:13]([SiH3:17])C(C)C)(C)[CH3:11]>>[C:4]1([CH2:11][CH2:10][NH:13][SiH3:17])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)N([SiH3])C(C)C
Reactant: CCNc1ccccc1
Product: [SiH3]NCCc1ccccc1
Reaction time: 24 h

Procedure:
In a 500 ml Schlenk flask, 60.5 g (0.5 mol) N-ethylaniline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product phenylethylaminosilane was obtained by vacuum distillation. The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 2 and shows, among other things, peaks at 151, 150, 136, 120, 106, 93, and 77. The molecular weight of the phenylethylaminosilane was 151.28.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])Cl)=[CH:19][C:18]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(OCC)C>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([Si:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=3)([CH3:29])[CH3:28])=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: C[Si](C)(Cl)CCCc1ccc(F)c(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(CCCc1ccc(F)c(Oc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1.21 g (0.0060 mole) of 5-bromo-1,3-benzodioxole in 30 mL of dry diethyl ether that had been cooled to -78° C. was added during a 15 minute period 0.42 g (0.0065 mole) of butyllithium as a 2.5 M solution in hexanes. Upon completion of addition this mixture was stirred at -78° C. for one hour. During a 20 minute period 1.9 g (0.006 mole) of [3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylchlorosilane was added as the solution prepared in Part D. The reaction mixture was allowed to warm to room temperature and to stir for an additional hour. Water was added to the reaction mixture which was then extracted With diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure, leavinq a residue weighing approximately 3 g. This residue was passed through a column of silica gel, eluting with methylene chloride/hexane (1/9). This procedure yielded 1.0 g of (1,3-benzodioxol-5-yl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a clear, colorless liquid, compound 43 of Table 1. The ir spectrum and the proton, carbon, and fluorine nmr spectra were all consistent with the proposed structure.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([NH2:22])[N:10]([CH3:23])[N:9]=1)(=O)C.[Na].[Cl-].[NH4+]>C(O)C.O>[NH2:22][C:11]1[N:10]([CH3:23])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1N
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (100 mg) (Preparation 33) in ethanol (6 ml) at room temperature, was added sodium hydroxyde (10 mg). After one hour, the reaction was diluted with water (5 ml ) and an aqueous saturated solution of ammonium chloride (10 ml ). The mixture was extracted with ethyl acetate (3×6 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a white solid (85 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:15][CH2:16][C:17]([CH3:19])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:22]([O:21][C:14](=[O:20])[CH2:15][CH2:16][C:17]1([CH3:19])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:23]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCC1(C)OCCn2c1c(C)c1ccccc12
Reaction time: 12 h

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol (29.7 g., 0.17 mole), described in Example 1, ethyl levulinate (26.96 g., 0.187 mole) and p-toluenesulfonic acid (2.25 g.) in dry benzene (650 ml.) is refluxed with stirring for 12 hr. with hydrated alkalialuminum silicate (Molecular Sieves No. 4). The benzene solution is washed with 5% aqueous NaHCO3, followed by water. Concentrations of the solution gave a residue, which is passed through a silica gel column using 15% ethyl acetate in benzene to afford the ester, 3,4-dihydro-1,10-dimethyl1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, as an oil, γmaxCHCl5 1730 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C1COCC1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3F)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3ccccc3F)cccn2c1C(=O)O
Reaction time: 96 h
Yield: 100.7 %

Procedure:
To 2.16 g of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate were added 20 ml of THF, 40 ml of ethanol, and 20 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 4 days. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added thereto. The insoluble material was collected by filtration and dried to obtain 1.99 g of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.C(Cl)(Cl)(Cl)[Cl:15].S(Cl)(Cl)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:15]
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 55 °C
Yield: 98 %

Procedure:
Into a three-necked, round-bottom flask fitted with a stirrer, thermometer, reflux condenser and dropping funnel was added 250 g of 96% 2-(2,4,6-trichlorophenoxy) ethanol, 250 ml carbon tetrachloride and 4 g of benzyl-trimethyl-ammonium chloride. The mixture was heated to 55° C. and 146 g thionyl chloride was added dropwise over 1.5 hours. After the addition of the thionyl chloride the temperature of the reaction was slowly raised to 80° C. for a total reaction tme of 2.5 to 3 hours. The end of the reaction was determined by GLC. The mixture was cooled to 60° C. and water slowly added to decompose the excess thionyl chloride. The phases were separated and the organic phase was washed with a 10% sodium hydroxide solution until it reached a pH of 7. After an additional separation of the phases the organic phase was washed again with water. After a further separation of phases, the carbon tetrachloride was distilled off to yield an oil which slowly crystallized to form 257 g of 2-(2,4,6-trichlorophenoxy)-ethyl chloride in a purity of 96%-98% and yield of 98%.
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.C(O[CH:20]=[C:21]([CH3:24])[CH:22]=O)C.C[O-].[Na+]>CO>[CH3:24][C:21]1[CH:20]=[N:11][C:10]([C:9]2[CH:13]=[CH:14][C:6]([C:5]([F:15])([F:16])[F:4])=[CH:7][CH:8]=2)=[N:12][CH:22]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A sample of 4-trifluoromethylbenzamidine hydrochloride dihydrate (Maybridge, 15.2 g, 58 mmol) was dissolved in 100 mL of methanol and 3-ethoxy-2-methylacrolein (Janssen, 7.8 g, 64 mmol) was added. Sodium methoxide (25% solution in methanol, 14.7 mL) was added and the mixture was heated at 50° C. for 3 h. The cooled reaction mixture was then dded to 500 ml of ice water and stirred for 30 minutes. The white solid was filtered, air dried, dissolved in 300 mL of dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield, after trituration with hexanes, 12.5 g of the product as a white solid melting at 143-146° C. 1H NMR (CDCl3): δ2.37 (s, 3H), 7.73 (d, 2H), 8.53 (d, 2H), 8.66 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]=[C:5]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:8]1([CH3:13])[CH2:7][CH:6]=[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:3](/[CH:22]=[CH:21]/[C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)=[CH:2][CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2cccc3c2C(Sc2ccccc2)=CCC3(C)C)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 0.35 g (1.0 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalene (Compound A35) and 0.34 g (1.9 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, was added 0.066 g (0.2 mmol) of tri-o-tolylphosphine and then 0.025 g (0.1 mmol) of palladium(II) acetate. The reaction was heated at 90° C. for 2.25 h. The reaction was concentrated in vacuo. The residue was purified by flash chromatography (silica, 5% ethyl acetate in hexane), followed by recrystallization using EtOH to afford the title compound as white crystals.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH:22]=O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C@H:22]2[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(F)c(F)c3)OC2)CC1

Procedure:
A solution of 2.4 g (0.01 mol) of 2-[2'-(trans-4"-butylcyclohexyl)-ethyl]propane-1,3-diol, 2.8 g (0.01 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich) and 0.1 g of TsOH in 50 cm3 of dichloromethane was refluxed for 3 hours over a hot water bath with a Dean-Stark trap. The reaction solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.0 g (0.008 mol) of trans-2-(3',4'-difluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)-ethyl]-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR45## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.