Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.[F:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1.ClCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][F:29])[CH2:37][CH2:36]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCCN1CCN(CCF)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Diisopropylazodicarboxylate (921 mg, 4.56 mmol) was added portionwise, at room temperature, to a stirred suspension of 4-chloro-6-methoxyquinazolin-7-ol (800 mg, 3.80 mmol), 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (794 mg, 4.18 mmol) and triphenylphosphine (1.4 g, 5.34 mmol) in THF (20 ml). The reaction was stirred 1 hr. before adding triphenylphosphine (1.4 g), di-tert-butylazodicarboxylate (1.05 g, 4.56 mmol) and dichloromethane (10 ml). The reaction was stirred for a further 1 hr. then evaporated and purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent then on alumina (neutral) using 10% methanol in dichloromethane as eluent to give 4chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (696 mg, 48%) as a colourless solid; NMR Spectrum:(CDCl3) 2.13 (quintet, 2H), 2.55 (m, 10H), 2.67 & 2.76 (dt, 2), 4.06 (s, 3H), 4.30 (t, 2H), 4.53 & 4.64 (dt, 2H), 7.36 (s, 1H), 7.38 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21].B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 71.1 %

Procedure:
By the method used in Example 1, Part D, 1.16 g (3.27 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-methoxy-2-propyl-1H-indole was O-demethylated by treating it with 13 mL of 1M BBr3 /CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 794 mg (71% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:18][CH2:17][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A cold solution (0° C.) of N-Boc-D-phenylalaninol (0.53 g, 2.09 mmol) in anhydrous methylene chloride (20 mL) was treated sequentially with methanesulfonyl chloride (360 mg, 3.14 mmol) and triethylamine (0.32 g, 3.14 mmol). The reaction was stirred at 0° C. for 2 hr, quenched with 1M hydrochloric acid (2×25 mL) and extracted with methylene chloride. The combined extract was washed with saturated sodium bicarbonate (1×25 mL), and brine (1×25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto silica gel and applied to a column prepacked with silica gel. The title compound was eluted from the column with hexane:ethyl acetate (60:40, v:v) to furnish titled compound (352 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C(C)=CC=CC=1.C1COCC1>[C:2]1([C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C:3]2[C:24]3[C:19]4[C:18](=[CH:17][CH:16]=[C:15]5[C:20]=4[C:21]4[C:12](=[CH:11][CH:10]=[C:9]6[C:22]=4[C:23]=3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8]6)[CH:13]=[CH:14]5)[CH:1]=1
Reactant: c1cc2ccc3ccc4ccc5ccc6ccc1c1c2c3c4c5c61
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Reaction time: 4 h
Yield: 82 %

Procedure:
A Friedel-Crafts acylation of coronene was performed using the procedure of Clar and Zanders J. Chem. Soc. 2, (1958) 1577-1579, with the Coronene (100mg; FIG. 1, compound I) and succinic anhydride (73.4mg) were placed in a 10ml round-bottomed flask. Aluminum chloride (400mg) was dissolved in 3ml of nitrobenzene and injected slowly into the round-bottomed flask. The flask was then flushed with nitrogen and sealed. The mixture was stirred for four hours and cold 2M HCl (8ml) was added and the solution boiled for 10 minutes. A greenish-yellow precipitate was obtained. The crystals were filtered, washed with benzene, methanol and 2M HCl, and dried overnight under vacuum. The product (108mg; 82% yield) was recrystallized from xylene and judged pure using TLC analyses (Rf=0.53), using 50% ethanol/50% THF (v/v) as the developing solvent with silica gel G (40 micron) as the support medium. The keto-acid (FIG. 1, compound II) had a melting point of 243° C. IR and NMR analysis gave spectra consistent with the structure of the molecule, and in xylene had an absorption band at 444 nm, with ε340 in THF=24,914±80M-1 cm-1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N+:33]=3[O-:9])=[CH:28][CH:27]=2)=[O:38])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccn3)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cccc[n+]3[O-])cc2)CC1
Reaction time: 24 h

Procedure:
At −10° C., metachloroperbenzoic acid (789 mg) was added to a solution of 1-tert-butoxycarbonyl-4-[4-(2-pyridyl)benzoyl]piperazine (517 mg) in dichloromethane (dichloromethane: 8 ml). The resulting mixture was stirred for 24 hours, followed by dilution with dichloromethane. A small amount of an aqueous sodium thiosulfate solution and saturated saline were added to the dilute solution. The organic layer so separated was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=20:1), whereby the title compound (415 mg, 77%) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH:15]2[C:27](OCC)=[O:28])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH:15]2[CH2:27][OH:28])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 8 h
Yield: 103.2 %

Procedure:
A 3.06 g portion of lithium aluminum hydride in 130 ml of dry ether, with argon bubbling through the solution, was stirred at room temperature. A solution of 24.5 g of 1,4-bis(phenylmethyl)-2-piperazinecarboxylic acid, ethyl ester in 125 ml of dry ether was added, the mixture was heated at reflux for 5 hours and then cooled. A 40 ml portion of 40% aqueous potassium hydroxide followed by 80 ml of saturated aqueous potassium carbonate were added dropwise, under argon. The mixture was allowed to stand overnight, after stirring for one hour. The ether layer was removed and saved, then the remainder filtered. The filtrate was extracted several times with ether. The ether solutions were combined, dried, filtered and evaporated, giving 22.15 g of 1,4-bis(phenylmethyl)2-piperazinemethanol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(Br)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: BrCc1cccc(Br)c1
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC

Procedure:
50 g (0.2 mol) of 3-bromobenzyl bromide and 33.2 g (0.2 mol) of triethyl phosphite were heated at 140° C. for 2 hours, during which ethyl bromide was distilled off. The product was distilled over a 30 cm Vigreux column.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reaction time: 0.33 h

Procedure:
Mesyl chloride (106 μL, 1.37 mmol) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.242 mmol) and triethylamine (225 μL, 1.62 mmol) in DCM at 0° C. After 20 min, the reaction mixture was diluted with DCM, washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-14a. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 3.20-3.60 (m, 3H), 3.17 (m, 1H), 3.05 (s, 3H), 2.65 (m, 1H), 2.07 (m, 1H), 1.74 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.CO>O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A mixture of trityl candesartan cilexetil (20 g, 23.45 mmol), methanol (200 ml), and water (1 ml) was gently refluxed for about 16–17 h. The reaction progress was monitored by HPLC. The solution volume was reduced by evaporation under reduced pressure (30 mbar) at a temperature of 55° C. to 60° C. to obtain viscous oil of candesartan cilexetil as a residue.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CCCCCCCCCCCCC.[C:41](=O)=[O:42].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(OCCCCCCCC)N>C(OCC)C.C(#N)C>[CH2:1]([N:9]=[C:41]=[O:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=O
Reactant: CCCCCCCCN
Agent: CCCCCCCCCCCCC
Agent: CCCCCCCCOC(N)=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A Fischer-Porter bottle was charged with 0.65 g (5 mmol) of octyl amine, 2.74 g of BEMP (10 mmol), 25 mL of acetonitrile and 184 mg (1 mmol) of tridecane as an internal standard. The bottle was pressurized to 80 psig with carbon dioxide and the solution was stirred for 30 min. at room temperature. A second Fischer-Porter bottle was charged with 0.71 mL (5 mmol) of trifluoroacetic anhydride and 25 mL of acetonitrile then pressurized to 80 psig with CO2. The two solutions were cooled to 0° C. in an ice bath for 10 minutes after which time the octyl carbamate solution was added rapidly to the trifluoroacetic anhydride solution. An aliquot was taken after five minutes and diluted with diethyl ether prior to G.C. analysis which indicated a yield of 83% octyl isocyanate. The reaction mixture was allowed to warm slowly to room temperature and aliquots were taken periodically for G.C. analysis. A maximum yield of 85% octyl isocyanate was obtained after ca. 30 minutes.
Reaction SMILES: [C:1](=[O:3])=O.[CH2:4]([NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH2:4]([N:12]=[C:1]=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCN
Reactant: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCN=C=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (30 mL) solution containing octylamine (n-OctylNH2) (0.04 mol, 5.2 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.04 mol, 10.2 g) and triethylamine (0.08 mol, 8.0 g) at -10° C. (ice and salt bath) for 1 h at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.04 mol, 6.2 g) in 30 mL dichloromethane. After stirring for ca. 30 min at -10° C. the reaction mixture turned yellow-brown and a ppt. formed. The crude reaction was filtered and the filtrate concentrated in vacuo. The residue was extracted with 2×100 mL diethyl ether. The ether layers (light yellow) were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, octyl isocyanate, at 42°-44° C. (3.9 g, 63%) of 99% purity as by GC. IR (neat) 2274 cm-1. 1H NMR (in CDCl3) δ 3.23-3.29 (t, 2H), 1.54-1.63 (m, 2H), 1.23-1.40 (br, 10H), 0.84-0.90 (t, 3H) ppm.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([CH3:3])[CH3:1]
Reactant: C=CC
Reactant: Cc1ccccc1
Product: CC(C)Cc1ccccc1
Reaction time: 6 h

Procedure:
In a 300 ml autoclave equipped with a magnetic stirrer, Solid Base A (2.81 g) and toluene (80 g) were charged under nitrogen and then liquid propylene (70 ml) was injected under pressure. The reaction was carried out at 160° C. for 6 hours while stirring to produce isobutylbenzene (hereinafter referred to as "IBB").
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH2:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH:29][C:17]([C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]2[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:12]1)=[O:19]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(Cl)cc3Cl)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (100 mg, 0.377 mmol) was added [(2,4-dichlorophenyl)methyl]amine (82 mg, 0.47 mmol), DMAP (10 mg, 0.08 mmol) and EDCl (108 mg, 0.56 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered and the filtrate concentrated. The crude product was purified by HPLC to provide 55 mg (0.13 mmol, 35% yield) of the desired material as a single major racemic diastereomer. MS (ES+): m/e 423.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16]>CO>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:18][N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (1 N, 2.3 mL) was added dropwise to 4-formyl-benzoic acid methyl ester (0.33 g) and nitromethane (0.11 ml) in 5 mL methanol at 0° C. The solution was acidified after 0.5 h and a precipitate was formed. The precipitate was isolated by filtration to give 228 mg of 4-(2-nitro-vinyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>CO>[OH:4][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Solvent: CO
Product: CCOC(=O)C[C@@H](C)O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Ethyl acetoacetate (7.5 g) and dry methanol (25 mL) were mixed and deoxygenated with flowing nitrogen for five minutes. The catalyst [(R)—Ru(BINAP)Cl2]2NEt3 (0.1 mol %) was added along with 2N HCl (0.1 mol %). The mixture was transferred to a standard Parr reactor apparatus and flushed by evacuating and refilling with hydrogen several times. The apparatus was heated at 50° C. with stirring under 100 psi of hydrogen for 16 h. After completion of reaction (monitored by TLC) the reaction was cooled and concentrated under reduced pressure. The residue was subjected to column chromatographic purification with petroleum ether/ethyl acetate (9:1 v/v) to get pure (R)-alcohol 43 as a colorless liquid.
Reaction SMILES: [H][H].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[C:6]1[N:11]=[C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]2=[N:8][CH:7]=1)=[O:13].[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>[Pd]=O>[S:20](=[O:22])(=[O:21])([OH:24])[OH:23].[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[CH:6]1[NH:11][C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]=2[NH:8][CH2:7]1)=[O:13]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Reactant: [H][H]
Agent: O=[Pd]
Agent: O=S(=O)(O)O
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1

Procedure:
Ten milligrams of palladium oxide was dispersed into 10 ml of 5% aqueous sulfuric acid solution, and then the catalyst was activated with hydrogen gas. Then, 10 ml of 5% aqueous sulfuric acid solution containing 50 mg of biopterin was added to the above dispersion. After the catalytic reduction was conducted by agitating the resulting mixture for 3 hours under normal temperature and normal pressure in a hydrogen atmosphere, the catalyst was filtered off from the reaction mixture to give a sulfuric acid solution of tetrahydrobiopterin having a (6R)/(6S) ratio of 70/30 as measured by HPLC.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:20][C:19]([F:22])([F:21])[C:18]1[C:13]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: C[Si](C)(C)c1cccc(N)c1
Product: FC(F)(F)c1cccnc1N1CCNCC1
Yield: 90.1 %

Procedure:
Compound A-07 can be synthesized according to method 1. Just of Scheme 1, R1 is —CF3; R2 is —H; R3 is p-SiMe3. More specifically, compound 1 is 2-chloro-3-(trifluoromethyl)pyridine (2 g); compound 2 is piperazine; the synthesized compound 3 is 1-(3-(trifluoromethyl)-2-pyridyl)piperazine (2.3 g, yield about 90.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[K+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:11])([CH3:12])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H). To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00 g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) is added dropwise maintaining the temperature below 10° C. under nitrogen. The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH (4.6 mL) and H2O are added. The solution is extracted with AcOEt, and the organic layer is washed with H2O, dried over MgSO4, and concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid (850 mg, quant.); 1H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.98 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>[Pd].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1N
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Palladium on carbon catalyst (10% Pd, ˜200 mg) was added cautiously, as a slurry in methanol (10 ml), to a solution of 3-nitroanthranilic acid (2.44 g, 13 mmol) in methanol (120 ml), and the mixture was stirred under a hydrogen atmosphere for 2 hours until the absorption of gas ceased. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to dryness under reduced pressure to afford the crude product. Purification by column chromatography on silica gel, with dichloromethane:methanol (4:1) as eluent, gave 2,3-diaminobenzoic acid as a red solid (1.34 g, 66%). vmax/cm−1 3433.73, 2882.02, 2602.30 and 1658.99; δH (d6-DMSO, 200 MHz) 5.8-7.4 (4H, br s, 2×NH2), 6.45 (1H, t, Ar-5H), 6.75 (1H, d, Ar-4H), 7.20 (1H, d, Ar-6H); δC (d6-DMSO) 110.31, 115.45, 118.33, 120.55, 135.03, 140.36, 170.68; m/z (EI) 152 (M+), 134, 106, 79.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of tartaric acid (0.75 g) in 2-propanol (35 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.