Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16].[CH2:19]([O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH3:20].[ClH:27]>C1C=CC=CC=1.C(O)C.C(OCC)C>[ClH:27].[CH2:19]([O:21][C:22]([NH:24][C:25]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[S:26])=[O:23])[CH3:20]
Reactant: CCOC(=O)N=C=S
Reactant: CCCCc1ccc(NC(=O)CN(C)C)c(N)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCc1ccc(NC(=O)CN(C)C)c(NC(=S)NC(=O)OCC)c1

Procedure:
Petroleum spirit (b.p. 60°-80° C; 50 ml) was added to a solution of N-(2-amino-4-n-butylphenyl)-2-dimethylaminoacetamide (4.98 g) in benzene (50 ml) and the solution stirred vigorously while ethoxycarbonyl isothiocyanate (2.65 g) was added dropwise, with external cooling, to maintain the temperature between 15° C. and 20° C. After ten minutes, the precipitated solid was filtered off and recrystallised from benzene to give crude 1-ethoxycarbonyl-3-(5-n-butyl-2-dimethylaminoacetamidophenyl)thiourea, m.p.152°-155° C. (with decomposition), which was then dissolved in the minimum of ethanol. Diethyl ether (200 ml) was added, followed by an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitated solid was filtered off and recrystallised from ethanol/ethyl acetate to give 1-ethoxycarbonyl-3-(5-n-butyl-2-dimethylaminoacetamidophenyl)thiourea hydrochloride (1.9 g), m.p. 174°-176° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][CH2:13][NH:14]1
Reactant: COC(=O)c1ccnc(Cc2c(F)cccc2F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2c(F)cccc2F)C1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
Methyl 2-(2,6-difluorobenzyl)isonicotinate (5.031 g, 19.11 mmol) was dissolved in acetic acid (49 mL) and platinum(IV) oxide (0.217 g, 0.96 mmol) was added. The mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 5 h. More platinum(IV) oxide (0.108 g, 0.48 mmol) was added and hydrogenation was continued for 1 h. Additional platinum(IV) oxide (0.108 g, 0.48 mmol) was added and the mixture was again hydrogenated for 1.5 h. More platinum(IV) oxide (0.108 g, 0.48 mmol) was added. After a total of 8.5 h the reaction mixture was filtered through celite and the catalyst was washed with MeOH. The eluate was concentrated and DCM and 1 M K2CO3 were added. The phases were separated and the organic phase was washed with brine before it was dried and concentrated to yield methyl 2-(2,6-difluorobenzyl)piperidine-4-carboxylate (5.01 g, 97%). MS m/z 270 (M+H)+
Reaction SMILES: FC(F)(F)C([N:5]([C:22]1[CH:41]=[CH:40][C:25]([C:26]([NH:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35]CC)=[O:34])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=O.C(O)C.[OH-].[Na+].Cl>O>[CH2:6]([NH:5][C:22]1[CH:41]=[CH:40][C:25]([C:26]([NH:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Nc2ccc(C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1

Procedure:
To a stirred solution of 3.62 g. of ethyl p-[p-(2,2,2-trifluoro-N-hexadecylacetamido)benzamido]benzoate in 72 ml. of ethanol was added a solution of 1.44 g. of sodium hydroxide in 18 ml. of water and the resulting mixture was heated under reflux for 30 min. The mixture was allowed to cool, acidified with dilute hydrochloric acid, and filtered. The white solid was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4](O)=O.C(OC(=O)C)(=[O:13])C.C(O)(=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][O:10][C:8](=[O:9])[C:7]1=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CN1CCOC(=O)C1=O
Yield: 77.1 %

Procedure:
A round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with N-methyliminodiacetic acid (25.0 g, 170 mmol, 1.0 equiv), acetic anhydride (85 mL, ˜850 mmol, ˜5 equiv.), and pyridine (274.9 μL, 3.4 mmol, 0.02 equiv). The flask was capped with a rubber septum which was pierced with an 18 gauge needle (alternatively a reflux condenser could be used). The reaction was lowered into a preheated 70° C. oil bath and stirred until the mixture became clear and dark orange (about 1.5 h). The acetic acid, pyridine, and remaining acetic anhydride were then removed by vacuum distillation (37° C. to 42° C. at 30 Torr). The resulting brown-black liquid was azeotroped three times with toluene (50 mL) to remove residual acetic acid and then transferred to an Erlenmeyer flask. To this flask was added enough diethyl ether to dissolve the crude N-methyl morpholine dione product (˜400 mL). The resulting mixture was filtered to remove a black-brown precipitate, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was then recrystallized from a minimum amount of hot diethyl ether to yield N-methyl morpholine dione (MIDA anhydride; 16.9 g, 131 mmol, 77%) as an off-white crystalline solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Agent: BrB(Br)Br
Product: O=C1c2ccccc2C(=O)N1CCN1CCCC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 2-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione dry chloroform (40 ml) was added boron tribromide (99%, 1.3 ml) at -10° C., under nitrogen. The reaction mixture was stirred for 10 mins in a cooling bath and 20 mins at ambient temperature. Crushed ice was added followed by 5:1-chloroform/2-propanol (10 ml). The layers were separated, and the aqueous phase was extracted with 5:1-chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 0.89 g (93%) of product, mp 172°-175° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23]C(C)C)[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:27](N(C)CCC(O)CCCC)[C:28]1C=CC=C[CH:29]=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Reactant: CCCCC(O)CCN(C)Cc1ccccc1
Product: CCCCC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, 1-(benzyl-methyl-amino)-heptan-3-ol affords the title compound: mass spectrum (ion spray) m/z=368 (M+1); 1H NMR (CDCl3) δ 8 7.45-7.41 (m, 2H), 7.29-7.19 (m, 7H), 6.80 (d, 1H), 4.56-4.51 (m, 1H), 3.47 (s, 2H), 2.55 (t, 2H), 2.20 (s, 3H), 2.01-1.91 (m, 2H), 1.90-1.63 (m, 3H), 1.45-1.29 (m, 4H), 0.89 (t, 3H).
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][CH:30]([C:36](OCC)=[O:37])[C:31](OCC)=[O:32].[OH-].[Na+]>O>[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH2:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][CH:30]([CH2:36][OH:37])[CH2:31][OH:32]
Reactant: CCOC(=O)C(Cc1cccc(Cc2nc(-c3ccc(C)cc3)oc2C)c1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc(Cc3cccc(CC(CO)CO)c3)c(C)o2)cc1
Yield: 73 %

Procedure:
To 30 ml of dry tetrahydrofuran, 854 mg of lithium aluminium hydride was added, and 3.94 g of diethyl 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylmalonate/10 ml of dry tetrahydrofuran was added dropwise with stirring under ice-cooling. The mixture was stirred for 1.5 hours at room temperature and cooled with ice-cold water. To the mixture were added dropwise 0.85 ml of water, 0.85 ml of 15% sodium hydroxide solution and 2.5 ml of water sequentially, and stirred for 15 minutes. The mixture was filtrated to remove insolubles, and the filtrate was concentrated. The residue was dissolved into ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform: methanol=20:1) to provide 2.32 g of the objective compound as colorless crystals. M.p. 114-115C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[CH3:4]>ClC(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1csc(C(C)=O)c1OC(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1csc(C(=O)CBr)c1OC(=O)c1ccccc1
Temperature: 22.5 °C
Yield: 77 %

Procedure:
A solution of 1.28 mL of bromine in 24 ml of tetrachloromethane was added dropwise to a solution of 7.23 g of Compound 1C in 72 mL of tetrachloromethane over a period of 10 minutes and stirred at reflux. After a further 5 minutes at reflux, the mixture was cooled to 20-25° C. The precipitated solid was collected by filtration and washed with cold tetrachloromethane to yield 7 g (77%) of Compound 1D, melting at 115-118° C. The compound was contaminated with impurities 1B and methyl 2-(2,2-dibromoacetyl)-3-benzoyloxythiophene-4-carboxylate (2% and 6% mol. respectively, determined by 1H-NMR spectroscopy). but could be used without further purification in the next reaction step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:10]I.[OH-].[K+]>CN(C)C=O>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
To a stirred solution of indole 7 (1.0 eq.) in dimethylformamide (4.4 mL/mmol) under argon was added iodine (1.98 eq.) and potassium hydroxide (1.0 eq.). The reaction mixture was stirred for 3 hours. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried. The solid was resubmitted to reaction conditions (dimethylformamide (4.4 mL/mmol) under argon, iodine (0.4 eq.) and potassium hydroxide (0.2 eq.) and stirred for 1 h) to convert the remaining starting material. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried to afford 3-iodoindole 8. Beige solid. 1H NMR (d6-DMSO, 400 MHz) δ 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 7.35-7.42 (m, 2H), 12.66 (s, 1H), 19F NMR (d6-DMSO, 376 MHz) δ −126.87, MS (ESI−) m/z=366.13 (M−H)− 100%, 368.15 (M−H)− 35%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]([CH2:14][CH2:15][O:16][CH3:17])[CH3:13])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C(O)(=O)/C=[CH:20]/[C:21](O)=[O:22]>C(O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:21](=[O:22])[CH3:20])[S:3][C:4]=1[N:12]([CH2:14][CH2:15][O:16][CH3:17])[CH3:13]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: COCCN(C)c1sc(N)nc1-c1ccco1
Solvent: CCO
Product: COCCN(C)c1sc(NC(C)=O)nc1-c1ccco1
Yield: 21.4 %

Procedure:
In a manner similar to that in Example 2, a free form of the entitled Compound was obtained from 2-amino-4-(2-furyl)-5-[N-(2-methoxyethyl)-N-methylamino]thiazole (160 mg, 0.63 mmol) obtained in Step 1 of Example 77, in place of Compound a. The resulting free form was dissolved in ethanol (5 mL), and fumaric acid (146 mg, 1.26 mmol) was added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound 83 (39.8 mg, 18%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9](=[O:40])[C:10]2[CH:15]=[C:14]([C:16]3[C:25]4[C:20](=[C:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=[CH:23][CH:24]=4)[C:19]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[N:18][N:17]=3)[CH:13]=[N:12][CH:11]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9](=[O:40])[C:10]1[CH:15]=[C:14]([C:16]2[C:25]3[C:20](=[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[N:18][N:17]=2)[CH:13]=[N:12][CH:11]=1
Reactant: CC1(C)OCC(CNC(=O)c2cncc(-c3nnc(NCc4ccccn4)c4c(-c5ccccc5)cccc34)c2)O1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CO)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 50 °C
Yield: 64 %

Procedure:
To N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(5-phenyl-4-((pyridin-2ylmethyl)amino)phthalazin-1-yl)nicotinamide (0.0200 g, 0.0370 mmol) was added TFA (0.00282 mL, 0.0370 mmol) at room temperature and was heated at 50° C. for 4 h. TFA was removed under reduced pressure and reaction mixture was diluted with saturated NaHCO3 (50 mL). The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 14 as described in general methods) to afford N-(2,3-dihydroxypropyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinamide (0.0120 g, 65%). LCMS (Condition 7): retention time 1.59 min, [M+1]=507.2. HPLC (Condition 25): retention time 5.23 min, Purity 97.90%. 1H NMR (400 MHz, DMSO-d6) δ 3.21-3.49 (m, 4 H), 3.63-3.72 (m, 1 H), 4.55-4.60 (m, 1 H), 4.66 (d, J=4.0 Hz, 2 H), 4.84 (br s, 1 H), 6.32 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.22 (dd, J=4.8 Hz, J=6.8 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.50-7.58 (m, 5 H), 7.68-7.73 (m, 2 H), 7.80 (dd, J=1.6 Hz, J=8.4 Hz, 1 H), 7.93 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.23 (d, J=4.8 Hz, 1 H), 8.51 (t, J=2.0 Hz, 1 H), 8.75 (t, J=5.6 Hz, 1 H), 8.98 (d, J=2.0 Hz, 1 H), 9.16 (d, J=2.0 Hz, 1 H).
Reaction SMILES: O.Cl(O)(=O)(=O)=O.[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]2([C:19](=[O:20])C2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-:24].[Na+].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]([CH2:19][OH:20])([OH:24])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CC12CCN(Cc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: OCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[OH-].[Na+]>CO>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To the round bottom flask containing compound 3 (720 mg, 2.15 mmol) is added MeOH (20 ml) followed by 1 N NaOH (12.9 ml, 12.9 mmol) and stirred overnight at room temperature at which point LCMS shows product peak at 321 (M+H). The reaction mixture is concentrated under reduced pressure to remove methanol. Acidified to pH around three with acetic acid. The mixture is then extracted with DCM and the organic is washed with water twice and once with brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to get white solid 4 (615 mg, 89% yield). HPLC shows compound 4 to be greater than 98% pure.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][O:3]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A solution of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (13.2 g) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of sodium hydride (8.0 g, 60% dispersion in oil) in tetrahydrofuran (150 ml) and the mixture was then treated dropwise with a solution of ethyl 4-chloroacetoacetate (16.5 g) in tetrahydrofuran (50 ml). The mixture was stirred at room temperature overnight and evaporated. The residue was quenched with 10% aqueous acetic acid and extracted twice into dichloromethane. The combined dichloromethane extracts were washed with saturated brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on SiO2 (100 g) using toluene plus 0-20% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (5.6 g) as an oil. This compound was used in Preparations 3 and 4 without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:3]=1
Reactant: Clc1ccc(I)cc1Cl
Reactant: Clc1ccnc2ccccc12
Product: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl

Procedure:
The title compound, m. p. 138-140° C., MS: m/e=308 (M+), was prepared from 4-chloro-quinoline and 3,4-dichloroiodobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:12]([C@H:16]1[CH2:20]OS(=O)(=O)[O:17]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C>CN(C)C=O.CO>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C@@H:16]([OH:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC(C)(C)[C@H](O)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A solution of 2.08 g (11.1 mmol) of 5,6-dichloro-1H-benzimidazole and 2.00 g (11.1 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide in 28 mL of N,N-dimethylformamide was stirred as 1.57 g (11.4 mmol) of potassium carbonate was added. The mixture was stirred at 60° C. for 18 h, and then cooled in an ice bath. A solution of 12 mL of acetyl chloride in 120 mL of methanol was then added. The reaction mixture was stirred for one day, and concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was concentrated, and the residue was slurried in ethyl acetate. The solid was isolated by filtration to yield 1.88 g of (2S)-1-(5,6-dichloro-1H-benzimidazol-1-yl)-3,3-dimethyl-2-butanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate to yield an additional 0.50 g (total yield 2.38 g, 74%) of the title compound. 1H-NMR (300 MHz, DMSO-d6): δ 8.29 (d, J=8 Hz, 2H), 7.90 (s, 1H), 7.86 (s, 1H), 4.96 (d, J=6 Hz, 1H), 4.39 (dd, J=14 Hz, J=2 Hz, 1H), 3.98 (dd, J=14 Hz, J=10 Hz, 1H), 3.32 (m, overlapping H2O), 0.95 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:16])[N:6]1[CH2:15][CH2:14][NH:13][CH2:12][CH:7]12.[CH:19](O)=O.C=O>O.C(=O)(O)[O-].[Na+]>[CH3:19][N:13]1[CH2:14][CH2:15][N:6]2[C:5](=[O:16])[C:4]3[C:8]([CH:7]2[CH2:12]1)=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:17])([F:1])[F:18]
Reactant: O=C1c2c(cccc2C(F)(F)F)C2CNCCN12
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN2C(=O)c3c(cccc3C(F)(F)F)C2C1
Temperature: 60 °C
Yield: 53.1 %

Procedure:
To a stirring solution of (±)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (60 mg, 0.23 mmol) in water (1 mL) was added formic acid (0.22 mL, 5.9 mmol) and formaldehyde (190 mg, 2.3 mmol; 37% sol. in water). The reaction flask was sealed with a rubber septum (no nitrogen inlet) and warmed to 60° C. The reaction was maintained at this temperature for 24 h and was then cooled. The reaction was then diluted with saturated aqueous sodium bicarbonate, washed with ethyl acetate (3×50 mL), and the combined organic layers were dried over sodium sulfate, filtered, an concentrated. The resulting residue was purified by radial chromatography (2% ammonium hydroxide in 8% methanol in dichloromethane) to afford the desired product (33 mg, 52%) as a pale yellow residue.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=1.Cl>Cl[Ni]Cl.C(OCC)C>[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Clc1ccc(Cl)cc1
Reactant: CCCCCCBr
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCc1ccc(CCCCCC)cc1
Reaction time: 3 h

Procedure:
Nitrogen was introduced into a flask (250 ml), and 10 ml of anhydrous diethyl ether was added, and 15 g of magnesium was added, and stirred. Hexyl bromide (0.61 mole) of 100 g mixed with 50 ml of diethylether was poured into a dropping funnel, and the mixture therein was slowly added into the flask over 1 hour. The reaction was carried out at 45° C. for 3 hours. The reaction product, Grignard, was poured into a dropping funnel. To the reactant was slowly added a mixture of 42 g of 1,4-dichlorobenzene (0.29 mol), 0.3 g of NiCl2 and 80 ml of diethylether, and the reaction was carried out at room temperature for 24 hours to obtain solid reaction product. 6 N HCl was slowly added so as to neutralize the solid reaction product, the product was extracted with diethyl ether and dried with anhydrous MgSO4, and the reaction product was separated by vacuum distillation (122° C./0.1 mmHg). The structure analysis of the compound was confirmed by 1H-NMR, which was shown in FIG. 3.