Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([NH:24][C:19]3[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: O=C(O)c1ccc2c(Br)c[nH]c2c1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Product: O=C(Nc1ccccc1NC(=O)c1ccc2c(Br)c[nH]c2c1)OCC1CCN(c2ccncc2)CC1

Procedure:
Using the procedure described in Example 23, Part C, and purifying with preparative RPHPLC method A, N2-[1-(4-Pyridyl)-piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine(326 mg, 1.0 mmol) and 3-bromoindole-6-carboxylic acid (240 mg, 1.0 mmol) yielded the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24]C(=O)OCC3C=CC=CC=3)[CH3:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:24][C@@H:22]([CH3:23])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:36][CH:35]=2)=[N:19][CH:18]=1
Reactant: [H][H]
Reactant: C[C@@H](COc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)COc1ccc(Oc2ccc(O)cc2)nc1

Procedure:
Benzyl {(S)-2-[6-(4-benzyloxyphenoxy)pyridin-3-yloxy]-1-methylethyl}carbamate (118 mg, 0.24 mmol) were hydrogenated in ethanol over 5% of palladium on carbon at 5 bar hydrogen pressure. The catalyst was filtered off and the filtrate was concentrated: Yield: 43 mg (68%), M+H+: 261.13.
Reaction SMILES: Cl[C:2]1[N:29]=[CH:28][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[CH:3]=[CH:2][N:29]=[CH:28][C:5]=2[N:6]=[C:7]1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:17]=1
Reactant: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2)nc2cnc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2)nc2cnccc2c1=O
Yield: 43.7 %

Procedure:
6-Chloro-3-methyl-2-[4-(3-piperidin-1-ylpropoxy)phenyl]pyrido[3,4-d]pyrimidin-4(3H)-one (42.0 mg, 0.101 mmol) produced in Example 18 was dissolved in ethyl acetate (1 mL), and 10% palladium-carbon (11 mg, 0.0101 mmol) was added thereto and stirred in a hydrogen atmosphere at room temperature for 24 hours. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel column chromatography (chloroform/methanol=3/1) to obtain the intended compound (16.7 mg, 44%) as a colorless solid.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17][CH2:16]1.Cl>S(Cl)(Cl)=O.CN(C)C=O>[CH3:14][C:15]1([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[C:19]2[CH:20]=[C:21]([NH:25][C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=3)=[O:8])[CH:22]=[CH:23][C:24]1=2
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of monomethyl terephthalate (VIIIa) (2.86 g, 15.89 mmoles) in thionylchloride (50 mL) with 2 drops of N,N-dimethylformamide was allowed to stir at room temperature. The mixture became homogeneous within 30 minutes and was then concentrated in vacuo. The residue was then taken up in 30 mL of anhydrous pyridine and treated with 4,4-dimethyl-7-amino-1-tetralone (3.00 g, 15.9 mmoles). After 16 hours at room temperature 1N HCl was added to the mixture. It was extracted with ethyl acetate, washed with 1N HCl (4×200 mL) and washed with saturated sodium bicarbonate (2×200 mL). The organic phase was then separated, dried over magnesium sulfate, and concentrated in vacuo to give 5.07 g (Y: 91%) of the title compound; 1H-NMR (CDCl3): δ 8.27 (dd, J=8.7, 2.5 Hz, 1H), 8.19 (bs, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 2.70 (t, J=7.0 Hz, 3H), 2.00 (t, J=7.0 Hz, 3H), 1.38 (s, 6H); MS (DCI) m/e: 352 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:25][C:26]([CH3:28])=O>FC(F)(F)C(O)=O>[OH:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:26]([CH3:28])([CH3:25])[O:1][C:2]=2[CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(O)cc2O1
Reaction time: 24 h

Procedure:
A suspension of 2,4-dihydroxybenzoic acid (85.0 g) in trifluoroacetic acid (800 mL) was cooled in an ice/water bath as trifluoroacetic anhydride (500 mL) followed by the addition of acetone (100 mL). After the addition was complete, the ice/water bath was removed and the reaction mixture stirred for 24 hours before the volatiles were removed under vacuum using a rotary evaporator. The residue was cautiously added to a water/sodium bicarbonate suspension to afford a neutralized mixture. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with dichloromethane to afford the product (I-1a) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:30])[C:6]=2[CH2:5][CH2:4][CH2:3]1.O1CCOCC1.Cl>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:10]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:30])[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2c1c1cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc1[nH]c2=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCc2c1c1cc(OC3CCNCC3)ccc1[nH]c2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
The compound (70 mg, 0.17 mmol) prepared in step 1 was dissolved in 1,4-dioxane (3 ml), added with 3.7 N hydrochloric acid 1,4-dioxane solution. The resulting mixture was stirred overnight at room temperature and the precipitate was collected by filtration to obtain the title compound (56 mg, yield: 86%, brown solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(OC)c(OC)c1
Temperature: 12 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 919 g (6 mol) of 3,4-dimethoxyaniline in 5 L of methylene chloride was treated with 3.3 L of 2N sodium hydroxide. The reaction mixture was cooled to 12° C. and 603 mL (6.3 mol) of ethyl chloroformate was added at a rate to keep the temperature between 25°-30° C. The reaction mixture was stirred at room temperature for 2 hr and the layers were separated. The aqueous layer was extracted with 3×1500 mL of methylene chloride and the combined organic layers were dried over sodium sulfate and treated with Darco*. Evaporation gave an oil to which 3 L of ethyl acetate and 1 L of hexanes were added to crystallize the product. After cooling at 4° C. for 3 hr, the product was filtered and washed with 3×1 L of hexanes. Drying under vacuum gave 1133 g (84%) of the product, mp 75°-78° C. NMR (CDCl3) δ 1.30 (t, 3H, J=7 Hz, OCH2 --CH3), 3.83 (s, 6H, OCH3), 4.18 (q, 2H, J=7 Hz, OCH2 --CH3), 6.58 (br s, 1H, NH ), 6.70 (m, 2H, ArH), 7.12 (m, 1H, ArH).
Reaction SMILES: Cl.[C:2]([C:10]1[CH:11]=[C:12]([C@H:16]([NH2:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OS(O)(=O)=O.[S-:24][C:25]#[N:26].[Na+]>C1(C)C=CC=CC=1>[C:2]([C:10]1[CH:11]=[C:12]([C@H:16]([NH:18][C:25]([NH2:26])=[S:24])[CH3:17])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1cccc(C(=O)c2ccccc2)c1
Reactant: N#C[S-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(N)=S)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R)-1-[(3-benzoyl)phenyl]ethylamine hydrochloride (0.52 g, 2 mmol) in toluene (15 mL), conc. H2SO4 (3 mmol) and sodium thiocyanate (0.18 g, 2.2 mmol) were added and the resulting mixture was left stirring at room temperature for 30 min. The formation of a white precipitate was observed: then the mixture was refluxed for 4 h and left stirring at room temperature overnight. The organic phase was washed with H2O (3×mL), dried over Na2SO4, filtered and evaporated under vacuum to give the N-[(1R)-1-(3-benzoylphenyl)ethyl]thiourea a dark red oil (0.53 g) pure enough (GC-Ms analysis) to be used without any further purification.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:16][C:14]1[N:15]=[C:6]2[C:5]3[NH:4][C@H:3]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:2]([O:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:11](=[O:12])[C:10]=3[CH:9]=[CH:8][N:7]2[CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a of 0° C. cooled solution of 10.5 g (35.8 mmol) (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in dichloromethane (110 ml) is added 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride dissolved in dichloromethane (10 ml). The reaction is stirred for 2 h at 0° C. and warmed up to 25° C. and stirred for further 24 h. Afterwards 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride are added to this mixture and it is stirred for 18 h at 25° C. Subsequently the reaction is quenching by adding of water (100 ml). The organic layer is separated, washed with ammonia solution, washed with water two times, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from 2-propanol to provide 12.1 g (32.06 mmol/90%) of the title compound as a colourless solid with a melting point of 145–147° C. (2-propanol).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(=O)([O-])[O-:16].[Na+].[Na+]>Cl.O>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[C:3]([CH3:14])[C:2](=[O:16])[NH:11]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(C)c(Cl)nc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(C)c(=O)[nH]c2c1
Temperature: 110 °C
Yield: 71 %

Procedure:
A suspension of 3-chloro-6-methoxy-2-methylquinoxaline (Intermediate 162, 1.5 g, 7.21 mmol) in 5M HCl (30 mL) was heated to 110° C. for 1 hour. The reaction mixture was neutralized with saturated sodium carbonate solution, diluted with water and extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated to a small volume under reduced pressure. The precipitate was collected by filtration to give 1.0 g (71%) of product as an off-white solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=3)[N:14]=2)[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Oc4ccc(F)c(N)c4)n3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2nccc(-c3cn[nH]c3)n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (50 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) at 0° C. and the reaction stirred at RT for 12 h. The solvent was removed in vacuo, the residue was washed with ether and treated with saturated ammonia solution. The solid was collected via filtration and dried under vacuum to give 5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (15 mg, 43% yield). 1H NMR (300 MHz, MeOD) δ 8.44 (d, J=5.1 Hz, 1H), 8.23 (br s, 2H), 7.40 (d, J=5.4, 1H), 7.02 (dd, J=10.8, 8.7 Hz, 1H), 6.73 (dd, J=2.7, 7.2 Hz, 1H), 6.50 (m, 1H); MS (ESI) m/z: 272.2 (M+H+).
Reaction SMILES: [C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>O1CCOCC1>[C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccccc1N
Reactant: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 36.7 %

Procedure:
3-hexanoyl-4-chloro-8-methoxyquinoline (5 g, 0.071 mol) and o-toluidine (2 ml, 0.019 mol) were heated under reflux in 1,4-dioxan (50 ml) for 1 hour. The solvent was evaporated and the residue was taken up in dichloromethane, washed with 10% hydrochloric acid, water, sodium hydrogen carbonate solution and brine, dried and evaporated. Trituration with ethyl acetate/ether and recrystallisation from methanol-water gave 3-hexanoyl-4-(2-methylphenylamino)-8-methoxyquinoline as yellow needles (2.53 g, 45.3%), mp 94°-6° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([CH2:10][CH2:11][C:12]#[N:13])=[N:8][CH:9]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[N:8][CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1CCC#N
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cnc1CCCN
Yield: 145.2 %

Procedure:
Raney nickel (24 g) was added to a stirred solution under nitrogen of 5-nitro-2-(2-cyanoethyl)-3-methylpyridine (10.36 g) in ethanol (700 ml). Hydrazine hydrate (13.5 ml) in ethanol (30 ml) was added over 2.75 hr., followed by further additions of Raney nickel (15 g) and hydrazine hydrate (60 ml) over two days which included two periods of eight hours at 50° C. The solution was decanted off, filtered through a hyflo pad and concentrated to dryness to give a green oil (13 g). This oil was chromatographed on silica in ethylacetate/ethanol/0.880 ammonia 15:10:2 to give the title compound as an oil (8.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.5 mmol) in DMF (160 mL), was added iodomethane (35.7 g, 248 mmol) and sodium carbonate (26.3 g, 248 mmol). The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrates were concentrated under vacuum till dry and re-dissolved in ethyl acetate before washing with 5% sodium bicarbonate solution (700 mL) followed by 5M HCl solution (300 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-bromo-2-methyl-3-nitrobenzoate (16 g, 94.5%).
Reaction SMILES: P(Br)(Br)[Br:2].C(Cl)Cl.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[CH:17](O)[CH3:18]>O>[Br:2][CH:17]([C:10]1[C:9]([Cl:8])=[C:14]([F:15])[CH:13]=[CH:12][C:11]=1[F:16])[CH3:18]
Reactant: BrP(Br)Br
Reactant: CC(O)c1c(F)ccc(F)c1Cl
Solvent: ClCCl
Solvent: O
Product: CC(Br)c1c(F)ccc(F)c1Cl
Temperature: 0 °C
Yield: 78 %

Procedure:
Phosphorus tribromide (1.3 mL) and anhydrous CH2Cl2 (50 mL) were combined and then cooled over ice water for 20 minutes. The cooled solution was then added to a mixture of 1-(2-chloro-3,6-difluorophenyl)ethanol (2.71 g) and methylene chloride (50 mL), and the resulting mixture was stirred at room temperature for two (2) hours. The mixture was then poured into H2O and extracted into CH2Cl2. The organic phase was isolated, dried with magnesium sulfate, filtered, and concentrated to give the title compound (78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[OH:13].[H][H]>CO>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:13]
Reactant: COc1cc(CO)cc(OC)c1O
Reactant: [H][H]
Solvent: CO
Product: COc1cc(C)cc(OC)c1O
Yield: 65.7 %

Procedure:
310 g of 2,6-dimethoxyphenol, 300 g of 38 wt% formalin, and 810 g of 10% wt% aqueous sodium hydroxide were reacted for 60 hours at 25° C. under a pressure of 0 kg/cm2 -G, the reaction mixture was and then neutralized with sulfuric acid, to obtain 80 g of 2,6-dimethoxy-4-(hydroxymethyl)phenol. (Yield: 22 mol%) 25 g of the obtained 2,6-dimethoxy-4-(hydroxymethyl)phenol was reacted in 320 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 200° C. at 199 kg/cm2 -G, and 15 g of 2,6-dimethoxy-4-methylphenol was obtained. (Yield: 66 mol%) The yield on the basis of the amount of the raw material was 15 mol%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([CH:13]([NH2:16])[CH2:14][CH3:15])[CH3:12].Cl>O>[CH2:11]([CH:13]([NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:14][CH3:15])[CH3:12]
Reactant: CCC(N)CC
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Solvent: O
Product: CCC(CC)Nc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 158 g. of 1-chloro-2-nitrobenzene and 260 g. of 1-ethyl propylamine are refluxed together for 5 days. The solution is cooled and 500 ml. of water is added followed by 10 ml. of concentrated hydrochloric acid. The product separates out as an oil and is extracted with chloroform (2 × 200 ml.). The chloroform layer is dried over MgSO4 and evaporated to yield 190 g. (91%) of product.
Reaction SMILES: [CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([C:14]([C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][CH:30]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([CH2:14][C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][CH:34]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 109 grams of 2,5-bis(4-nonylbenzoyl)terephthalic acid 1500 mL of tetrahydrofuran, and 7.43 grams of 10% palladium on carbon (as a catayst)was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis(4-nonylbenzyl)terephthalic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].C1(C)C(C)=CC=CC=1.Br[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:31])[CH2:29][OH:30]>C(O)C>[S:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH3:31])[CH2:29][OH:30])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(Br)(CO)c1ccccc1
Reactant: Oc1ccc(C2CCSc3ccccc32)cc1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CC(CO)(Oc1ccc(C2CCSc3ccccc32)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 2.42 g. of 4p-hydroxyphenyl-thiochromane and 0.23 g. of sodium in 50 ml. of xylene is boiled for 3 hours. The mixture is allowed to cool to 20° C., 2.15 g. of 2-bromo-2-phenylpropanol in 10 ml. of xylene are added and the suspension is stirred for 6 hours at the boil, cooled and treated with 2 ml. of ethanol. The inorganic precipitate is filtered off, the filtrate is evaporated, the residue is taken up in ether and the solution is washed with NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and evaporated, to give 2-[4-(4-thiochromanyl)-phenoxy]-2-phenylpropanol, nD20 1.6172.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1ccc2ccccc2c1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(C(C)=O)ccc4ccccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (5 mg, yield 30%).