Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1C(O)=O>CN(C)C1C=CN=CC=1.CC(O)(C)C>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1c(F)cc(F)c(F)c1F
Temperature: 40 °C
Yield: 56.3 %

Procedure:
Di-tert-butyl carbonate (3.63 g, 16.7 mmol) was added to a mixture of 2,3,4,6-tetrafluorobenzoic acid (1.60 g, 8.88 mmol), 4-dimethylaminopyridine (102 mg, 0.83 mmol) in tBuOH (20 mL) and heated at 40° C. for 16 hours. The reaction mixture was quenched with aqueous 1M HCl and extracted with EtOAc. Combined organics were washed with aqueous 1M NaOH, then brine and evaporated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford the title compound as a colourless oil (1.25 g, 59% yield):
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([Li])CCC.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15]>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccccc1F
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1CNc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 2-fluoroaniline (6.8 mL, 70 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and treated with n-butyllithium (31 mL of a 2.5 M solution in hexanes, 77 mmol). After 1 h, the reaction mixture was treated with a solution of 2-nitrobenzylbromide (15.1 g, 70 mL) in tetrahydrofuran (50 mL), and warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl ether (500 mL), and washed with H2O (500 mL), and evaporated. Flash chromatography (SiO2, 5-20% ethyl acetate/hexanes) provided 2-fluoro-N-(2-nitrobenzyl)aniline (13.4 g) as a yellow solid:
Reaction SMILES: [Br:1]C(Br)(Br)Br.[CH3:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].C(Br)(Br)Br>O1CCCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:7]([CH3:6])([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: BrC(Br)Br
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(Br)C(=O)OC
Yield: 87.5 %

Procedure:
A solution of 3.25 g tetrabromomethane (10 mmol), 1.46 g dimethyl methylmalonate (10 mmol), and 100 mg tetra-n-butylammonium fluoride trihydrate (0.316 mmol) in 5 mL tetrahydrofuran (THF) was stirred for 10 min at 24° C. Gas chromatographic analysis of the resulting mixture showed that it contained 87% yield of both dimethyl α-bromo-α-methylmalonate (1.97 g) and bromoform (2.2 g).
Reaction SMILES: C(OC(=O)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:7]1=2)C.[OH-].[Li+].C(O)(=O)C.[Br:29]N1C(=O)CCC1=O>C(O)(C)C.O>[Br:29]/[CH:5]=[C:6]1/[C:7]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]/1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc2c(c1)OCc1ccccc1/C2=C\Br
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a suspension of (3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidene)-acetic acid ethyl ester (0.23 mol, 69.5 g) in isopropanol (725 mL) add a solution of lithium hydroxide (0.53 mol, 12.0 g) in water (125 mL) and warm to 70° C. for 4 h. Allow the mixture to cool to 40° C. and then treat with glacial acetic acid (0.44 mol, 25 mL). After stirring for 15 min, add N-bromosuccinimide (0.25 mol, 44 g). Bubbling ensues, the temperature rises to 45° C., and solids form after a few min. Stir the mixture at 40-45° C. for one hour and cool to room temperature. Add sodium bisulfite (4.5 g) in water (150 mL), saturated aqueous sodium bicarbonate (150 mL), and water (450 mL). Filter the resulting suspension and rinse with cold 1:1 isopropanol/water (300 mL). Dry the solid at 60° C./20 mm Hg overnight to obtain the title compound (65.8 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 4.9-5.4 (br d, 2H), 6.63 (dd, 1H), 6.77 (dt, 1H), 7.13 (s, 1H), 7.32-7.46 (m, 4H), 7.52 (dd, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.[NH2:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].CCO>O.Cl>[ClH:1].[C:3]1([CH2:2][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1
Reactant: CC(N)(CO)CO
Reactant: ClCc1ccc2cccc3c2c1-c1ccccc1-3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(CO)(CO)NCc1ccc2cccc3c2c1-c1ccccc1-3
Yield: 43.8 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added crude 1-chloromethylfluoranthene (3C, 13.01 g, 52 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 5.46 g, 52 mmol), K2CO3 (MCB, 14.37 g, 0.104 mol) and abs. EtOH (300 mL). The reaction was stirred at reflux overnight, filtered hot, and the solvent removed by rotary evaporation to give a crude dark oil. This was acidified with 1N HCl and dissolved in H2O, filtered, basified with 5N NaOH solution and filtered to give a crude white solide. The material was dissolved in ethanolic HCl solution, filtered and precipitated with Et2O. Filtration followed by crystallization (abs. EtOH/Et2O, 1:4) gave after filtration and drying a 43.8% yield of 2-[(1-fluorantheneylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride 0.3 H2O, mp 185-188 (dec), (C,H,N,Cl).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH2:11][CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:7][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)[CH2:11][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(C1CCCCC1)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2[nH]ncc2cc1NC1CCN(CC2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of the N-[1-(cyclohexylcarbonyl)-4-piperidinyl]-1H-indazol-5-amine (0.301 g, 0.92 mmol) obtained in Example 18 in tetrahydrofuran (2 ml) was added to a solution of lithium aluminum hydride (0.071 g, 1.88 mmol) in tetrahydrofuran (2 ml) at 0° C. and stirred at 0° C. for 1 hour. The reaction solution was cooled on an ice-water bath, followed by adding thereto water (0.07 ml), a 2N-aqueous sodium hydroxide solution (0.14 ml) and water (0.21 ml) in that order. The resulting mixture was stirred and then filtered by the use of Celite. Then, the filtrate was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in ethyl acetate and stirred. Thereafter, the solid was collected by filtration and dried under reduced pressure to obtain N-[1-(cyclohexylmethyl)-4-piperidinyl]-1H-indazol-5-amine (0.121 g, 73%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][CH2:9][OH:10])C.Cl>CCOCC>[CH3:11][C:7](=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[O:3]
Reactant: CCOC(C=CC(C)=CCO)OCC
Agent: Cl
Solvent: CCOCC
Product: CC(C=CC=O)=CCO

Procedure:
100 g. of 1,1-diethoxy-4-methyl-2,4-hexadien-6-ol are shaken for 20 minutes with 200 ml. of ether and 10 ml. of 3N hydrochloric acid and then treated with 20 g. of potassium carbonate, filtered, and the 4-methyl-6-hydroxy-2,4-hexadien-1-al, which is obtained almost quantitatively, is used without isolation in ethereal solution for the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH2:9]O)=[C:6]([CH2:11][CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39].C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[Br:39][CH2:9][CH2:8][C:7]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]=1[CH2:11][CH3:12]
Reactant: CCc1nn(-c2ccccn2)c(CC)c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1nn(-c2ccccn2)c(CC)c1CCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 2-(3,5-diethyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-ethanol (0.68 g, 2.78 mmol) and triphenylphosphine (1.09 g, 4.18 mmol) in DCM (20 mL) and cool to 0° C. Add a solution of carbon tetrabromide (1.39 g, 4.18 mmol) and triethylamine (0.77 mL, 5.56 mmol) in DCM (5 mL) dropwise. Warm the reaction mixture to room temperature and stir for 3 hr. Dilute with diethyl ether (20 mL) and filter. Concentrate filtrate and purify using silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate, to give the title preparation as an oil (0.8 g, 93%): 1H-NMR (400 MHz, CDCl3) δ 8.39 (m, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.15 (m, 1H), 3.39 (m, 2H), 3.08 (q, 2H), 2.98 (m, 2H), 2.64 (q, 2H), 1.28 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (S)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 15 cm), eluting with ethyl acetate and collecting 15 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylpropionyl]-4-perhydroisoindolone (1 g) is obtained in the form of a white meringue. [α]D20 =-231° (c=1, methanol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20](C5C=CN=C(OC)C=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.[CH3:36][OH:37]>C(C#N)(C)=O>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:10]5[CH:7]=[CH:6][C:36](=[O:37])[NH:15][CH:13]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)ccc2C)ccn1
Reactant: CO
Agent: CC(=O)C#N
Agent: C[Si](C)(C)I
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 55 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
To a slurry of 1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (25 mg, 0.062 mmol) in AcCN (1.5 mL) was added TMS-I (35.45 μL, 0.24 mmol) and stirred at 55° C. for 7 h. The reaction was diluted with methanol (1.0 mL) and stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum, and taken into ethyl acetate (10 mL. The organic solution washed with sodium bisulphate (2×2 ml) water (2×3 mL), dried over sodium sulphate and concentrated under vacuum. The solid was stirred with methanol (1.0 mL) at 40° C. for 10 min and collected by filtration, washed with methanol (1.0 mL) and dried under vacuum to yield 18.0 mg (74%) of the desired product. ESI-MS m/z calc. 387.4. found 388.2 (M+1)+. Retention time 1.32 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20]Br.[OH-].[Na+]>CO>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: Fc1ccccc1CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(CCc3ccccc3F)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 2-fluorophenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.14 (2H, t, J=6.9 Hz), 4.29 (2H, t, J=7.0 Hz), 7.13 (2H, m), 7.27 (2H, m), 7.58 (1H, d, J=4.0 Hz), 7.63 (1H, s), 7.80 (1H, s), 8.25 (1H, s), 8.62 (1H, d, J=4.9 Hz). [M+H] Calc'd for C17H14FN3O2, 312. Found, 312.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)[O:8][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccc(O)cc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 4.4 %

Procedure:
4-Hydroxybenzoic acid (35 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:13][C@H:14]([NH:16]C(=O)C)[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3]>Cl>[NH2:16][C@H:14]([CH3:15])[CH2:13][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: COc1ccc(C[C@@H](C)NC(C)=O)cc1S(N)(=O)=O
Agent: Cl
Product: COc1ccc(C[C@@H](C)N)cc1S(N)(=O)=O

Procedure:
Intermediate XI (10.5 g) is boiled in 5% HCl (250 ml) under a reflux condenser for 16 to 18 h. The course of the reaction is controlled with TLC detecting the starting substance. After the reaction is complete, the reaction mixture is concentrated to about ⅓ of its volume, then, a saturated solution of sodium carbonate (50 ml) is slowly added dropwise under stirring. After the addition, pH˜10 is controlled and the reaction mixture is stirred for 0.5 hour, then let to crystallize at 0° C. The precipitated crystals are sucked off and the filtrate is concentrated to ½ of its volume and let to crystallize at 0° C. Both fractions (4 g+8 g) of white to brownish crystals are combined and re-crystallized from water. The yield is 7.52 g (80%).
Reaction SMILES: [H-].[Li].[Al].[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[CH:15][N+:16]([O-])=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.O>[NH2:16][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([Cl:4])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])C=C1CCCN1Cc1ccc(Cl)cc1
Agent: [Al]
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCCN1Cc1ccc(Cl)cc1
Yield: 80.3 %

Procedure:
500 ml of anhydrous tetrahydrofurane and 23.4 g (0.615 mol) of the double hydride of lithium and aluminum are introduced into a reactor equipped with a mechanical stirrer, and a solution of 27.3 g (0.108 mol) of 1-p-chlorobenzyl-2-nitromethylene-pyrrolidine in 1,000 ml of tetrahydrofurane is then added slowly. The reaction mixture is heated at the reflux temperature for 12 hours and then cooled, and 53 ml of water are added dropwise, followed by 53 ml of 20% strength sodium hydroxide solution and finally 53 ml of water. The precipitate is filtered off and extracted with 500 ml of ether. The ether solution is combined with the filtrate and dried over magnesium sulphate, the solvents are evaporated and the residue is distilled under reduced pressure. 19.5 g (yield: 80.2%) of 2-aminomethyl-1-p-chlorobenzyl-pyrrolidine distilling at 118°-120° under a pressure of 0.06 mm of mercury are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COC(=O)c1ccc(OC)c(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO)cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reaction time: 0.5 h
Yield: 47 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(2-methoxy-5-methoxycarbonylphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-37, 50.2 mg, 0.102 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 ml), and lithium aluminum hydride (6.8 mg, 0.18 mmol) was added thereto at 0° C. After the reaction mixture was stirred at same temperature for 30 minutes, ethyl acetate (1 mL) and water (1 mL) were added thereto successively. Moreover ethyl acetate (10 mL) and water (10 mL) were added and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (29.8 mg) as a pale yellow solid. (Yield 47%)
Reaction SMILES: [C]=O.C=O.[C:5]([OH:9])(=[O:8])[CH2:6][CH3:7].C([O:14][CH2:15][C:16]([OH:18])=[O:17])(=O)CC>O>[C:16]([OH:18])(=[O:17])[CH2:15][OH:14].[C:5]([OH:9])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)OCC(=O)O
Agent: C=O
Agent: [C]=O
Solvent: CCC(=O)O
Solvent: O
Product: O=C(O)CO

Procedure:
FIGS. 1 and 2 present two, non-limiting embodiments or the instant invention described herein in detail. In a first embodiment of the invention as laid out in FIG. 1, Carbon Monoxide Stream 1, Aqueous Formaldehyde Stream 2, and Propionic Acid Stream 3 are fed to Hydrocarboxylation Reactor 50 which comprises a fixed bed, solid catalyst (not shown). The Effluent Stream 4 comprises the esters of glycolic and propionic acid including 2-propionoxyacetic acid and (2′-(propionyloxy)acetoxyacetic acid. Effluent Stream 4 and Water Stream 8 are fed to Hydrolyzer 55. Hydrolyzer 55 is operated at sufficient temperature, pressure, and residence time to produce Hydrolyzed Mixture Stream 9 comprising glycolic acid, propionic acid, and water. Hydrolyzed Mixture Stream 9 is extracted with Hydrophobic Solvent Stream 11, such as methyl tertiary-butyl ether, in Extractor 60, to produce Organic Extract Stream 10 and Aqueous Raffinate Stream 12. Organic Extract Stream 10 can be separated into Propionic Stream 3 and Hydrophobic Solvent Stream 11 in Separator 70. Separator 70 can be, for example a distillation column. Propionic Acid Stream 3 is recycled to Hydrocarboxylation Reactor 50 and Hydrophobic Solvent Stream 11 is recycled to Extractor 60.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a 0° C. solution of the acid from Example 1, Step 2 (900 mg, 2.24 mmol) in 10 mL of DMF was added iodomethane (0.18 mL, 2.89 mmol) followed by potassium carbonate (326 mg, 2.36 mmol). The mixture was warmed to room temperature, stirred 3 h, then poured into water and extracted with ether. The organic extracts were washed with water and brine, dried over Na2SO4 and evaporated to give 953 mg of the title compound.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[C:5](=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO>[CH3:15][O:14][C:11]1[CH:10]=[C:5]2[C:4](=[CH:13][CH:12]=1)[C:3](=[O:16])[O:8][C:6]2=[O:7]
Reactant: COC(=O)c1ccc(OC)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 4-methoxyphthalic acid dimethyl ester (3.1 g, Fluka, U.S.A.) in 10 mL methanol and 35 mL of a 1 M solution of aqueous sodium hydroxide was heated to reflux for 3 hours. The solution was allowed to cool to rt, acidified to pH 2 with 1 M hydrochloric acid, and extracted three times with ethyl acetate. The organic extractions were combined, dried over magnesium sulfate, and reduced in vacuo to cleanly yield 2.43 g of the corresponding diacid. The diacid (1.43 g) and 1.9 mL of acetic anhydride were dissolved in tetrahydrofuran and heated to reflux for 16 hours. The solvent was evaporated to give 5-methoxy-isobenzofuran-1,3-dione (1.25 g).