Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CCCCCCCCCCC/C=C\CCCCCCCC.[CH:25]1[CH:30]=[C:29]([CH2:31][C:32]([O-:34])=[O:33])[C:28]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:43])=[CH:27][CH:26]=1.[Na+]>C(O)C>[CH:25]1[CH:26]=[CH:27][C:28]([NH:35][C:36]2[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:43])=[C:29]([CH2:31][C:32]([OH:34])=[O:33])[CH:30]=1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
A rectal suppository comprising erucic acid, beeswax, and the medicine diclofenac was prepared as follows: About 8.08 kg of micronized sodium diclofenac was added to a homogenous melt containing about 122.34 kg of erucic acid and about 13.57 kg of beeswax at a temperature of about 75° C. The medicine and suppository base was mixed gently until homogenous and the ethanol evaporated then poured into a mold. Upon cooling the suppository was removed from the mold.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCNCC
Product: CCCCCCCN(CC)C(=O)CCC(=O)O

Procedure:
In a manner similar to Preparation 4, react ethyl(heptyl)amine with succinic anhydride to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([NH2:23])[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
(R)-tert-Butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (3.79 g, 10.02 mmol) was dissolved in ethanol (75 mL) and added to a flushed hydrogenation flask containing Pd/C (380 mg, 0.411 mmol). The resultant mixture was flushed with nitrogen/vacuum 3 times, then stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was flushed from hydrogen atmosphere with nitrogen/vacuum three times. To this solution Celite (33 g) was added and stirred for 2 min. then filtered under vacuum. The solution was concentrated under vacuum to give a crude product that was purified on a 100 g SNAP cartridge using SP4 column chromotography. The column was eluted with 0-6% 2M NH3 in MeOH in DCM over 25CV. The appropriate fractions were combined and concentrated in vacuo to give a product that was further purified using SP4 column chromotography on a 100 g SNAP cartridge. The column was eluted with 0-100% EtOAc in cyclohexane over 15CV followed by 100% EtOAc 5CV followed by 0-6% 2M NH3 in MeOH in DCM over 15CV. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a pink solid (1.26 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33].O.Cl>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([O:27][C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:33])[C:23]([O:25][CH3:26])=[O:24])=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1
Reactant: COC(=O)[C@H](O)CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of methyl (R)-(-)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxy-pentanoate (3.15 g) in pyridine (50 ml) was added 4-nitrophenyl chloroformate (2.3 g), in limited amounts, at room temperature. The mixture was stirred for one hour. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained methyl (R)-(+)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-(4-nitrophenoxycarbonyloxy)pentanoate (4.3 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([Br:24])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2ccc(=O)n(Cc3ccccc3)c2c1O
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (50 mg, 0.16 mmol) and N-bromosuccinimide (30 mg, 0.17 mmol) in 0.5 mL of CH2Cl2 was refluxed for 3 h. Solvent was evaporated, and the residue was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 26 mg of the title compound as a pale yellow solid. MS: (+) m/z 387.14, 389.13 (M-1, 79/81Br).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][C:20]1([CH3:26])[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][C:20]1([CH3:26])[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1(C)CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE, m.p. 64°-67° C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 204.5°-207.5° C. (dec.) (corr.), in a 30% overall yield.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(COC)OC>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccncc23)c1
Yield: 93.6 %

Procedure:
A solution of 500 mg of 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine, 131 mg of 3-fluorophenylboronic acid, tetrakis(triphenylphosphine)palladium(0) and 537 mg of barium hydroxide octahydrate in a mixed solution of 18 mL of dimethoxyethane and 3 mL of water was stirred at 80° C. for 2 hours. The solution was diluted with ethyl acetate and water, followed by filtration through Celite. The organic layer of filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3-dichloromethane:n-hexane=1:2-1:1-dichloromethane:methanol 100:1), to afford 399 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([C:16]3([C:19]4[CH:29]=[CH:28][C:22]5[O:23][C:24]([F:27])([F:26])[O:25][C:21]=5[CH:20]=4)[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:9][C:8]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].CO>[CH:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([C:16]3([C:19]4[CH:29]=[CH:28][C:22]5[O:23][C:24]([F:27])([F:26])[O:25][C:21]=5[CH:20]=4)[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:9][C:8]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1C1=CCCCC1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1C1CCCCC1
Reaction time: 16 h

Procedure:
N-(6-Cyclohexenyl-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (82.4 mg, 0.200 mmol) was added to a flask containing 20 mg of 10% palladium on carbon under an atmosphere of argon. Methanol (5 mL) was added and then the reaction atmosphere was replaced with an atmosphere of hydrogen. The mixture was stirred vigorously for 16 hours. The atmosphere was then replaced with argon. The mixture was filtered, evaporated to dryness, and then purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-cyclohexyl-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 414.2. found; 415.1 (M+1)+ Retention time 1.78 minutes.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)(=[O:4])=[O:3].Cl>ClCCl>[NH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of tert-butyl trans-4-[(methylsulfonyl)amino]cyclohexylcarbamate (990 mg, 3.39 mmol) (preparation 32) in dichloromethane (25 ml) at room temperature was saturated with hydrogen chloride gas. The reaction mixture was stirred at room temperature for 2 hr and the solvent then removed under reduced pressure to give a colourless solid. The solid was triturated with diethyl ether and then suspended in ethyl acetate and exposed to ultrasonic agitation for 5 min. The remaining solid was filtered off to give the title compound (0.6 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10]C(=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:13]([O:18][CH3:19])([O:16][CH3:17])OC>CO.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:19][O:18][C:13]1([O:16][CH3:17])[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(OC)(OC)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
To a solution of ethyl-4-oxocyclohexane carboxylate (23.4 mL, 147 mmol) and p-TsOH (0.25 g, 1.31 mmol) in 25 mL MeOH was added HC(OMe)3 (24.10 mL, 220 mmol) dropwise. The reaction was stirred at rt for 15 h and 1.5 g of anhydrous Na2CO3 was added. The reaction was stirred at rt for another 30 min and filtered. TEA (0.18 mL, 1.31 mmol) was added to the filtrate and the resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL), washed with water (4×30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 20% EtOAc:hexanes) to afford the title compound (32 g, 100% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.15 (q, J=7.1 Hz, 2H), 3.21 (s, 3H), 3.18 (s, 3H), 2.41-2.28 (m, 1H), 2.08-1.96 (m, 2H), 1.91-1.79 (m, 2H), 1.77-1.61 (m, 2H), 1.43 (td, J=12.9, 4.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)CCC>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Product: COC(=O)c1nc(-c2ccc(F)cc2)c2nc(-c3ccccc3)oc2c1O

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tributyl(4-fluorophenyl)stannane under conditions analogous to example A-3b. MS: (+) m/z 364.9 (M+1).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)C1C=CC=CC=1.[ClH:18]>[Pd]>[ClH:18].[OH:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Agent: [Pd]
Agent: Cl
Product: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
(3R, 4R, 5R)-3-Benzyloxy-4-hydroxy-5-hydroxymethyl-piperidine, (12, 0.527 g, 2.2. mmol) was dissolved in 0.5M HCl (5.3 ml) and ethanol,(50 ml), 5% palladium charcoal (300 mg) was added. The mixture was hydrogenated at 101 kPa and 20° C. for 18 h. The reaction mixture was filtrated and concentrated to give the product in 93% (0.375 g) yield. 13C-NMR (50 MHz, D2O):δ70.7 and 68.1 (C-3 and C-4); 58.6 (C-5'); 46.2 and 44.4 (C-2 and C-6); 40.6 (C-5). 1H-NMR (500 MHz, D2O, PH<1, ref. HOD 4.63 ppm):δ3.72 (dd, 1H, H-5b', J5a',5b' =11.5, J5,5b' =3.3 Hz); 3.67 (ddd, 1H, H-3, J3,2ax =11.2, J3,4 =8.9, J3,2eq =4.9 Hz); 3.64 (dd, 1H, H-5a', J5a',5b' =11.5, J5,5b' =6.2 Hz); 3.43 (ddd, 1H, H-2eq, J2eq,2ax =12.7, J2eq,3 =4.9. J2eq,6eq =2.0); 3.42 (dd, 1H, H-4, J4,5 =10.5, J4,3 =8.9 (Hz); 3.41 (ddd, 1H, H-6eq, J6eq,6ax =13.4, J6eq,5 =3.8, J6eq,2eq =2.0 Hz); 2.87, 12.7, J2ax,3 =11.2 Hz); 1.86 ppm (ddddd, 1H, H-5). If necessary the piperidine could be chromatographed using ethanol/NH4OH (25% aq) 10:1 to give the free piperidine [α]D20 =+19.6° (c 0.85, EtOH). MS (CI, NH3): m/z 148 (M+H+). Anal. Calc. for C6H13NO3 : C,48.97; H, 8.90; N, 9.52. Found: C, 48.46; H, 9.33; N, 9.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)CBr
Reactant: COc1ccc(N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(OC)cc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.53 g (10 mmol) of 2,4-dimethoxyaniline and 2.76 g (20 mmol) of potassium carbonate in 10 mL of DMF are added 1.53 g (10 mmol) of methyl bromoacetate. The mixture is stirred at 60° C. for 3 h, then allowed to cool to RT. The mixture is poured into water and extracted with EtOAc. The organic phase is washed with water, brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue is chromatographed using CH2Cl2 as the eluant to give (2,4-dimethoxyphenylamino)-acetic acid methyl ester as an oil: 1H-NMR (CDCl3) δ 6.46 (d, J=2.20, 1H), 6.41-6.38 (m, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][N:6]=1.[Se](=O)=[O:31]>C(OCC)(=O)C>[CH2:22]([O:21][C:19]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([C:4](=[O:31])[C:3]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:2]=2[F:1])=[N:6][CH:7]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cnc(Cc2cc(OC)ccc2F)c2cc(OC)c(OC)cc12
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cc(OC)ccc2F)c2cc(OC)c(OC)cc12

Procedure:
The above 1-(2-fluoro-5-methoxybenzyl)-4-ethoxycarbonyl-6,7-dimethoxyisoquinoline was dissolved in ethyl acetate (25 ml) and selenium dioxide was added (723 mg). The mixture was refluxed for 1 hr until all starting material was consumed. The solution was filtered through a layer of Celite and the filtrate was concentrated. The residue was purified through a flash column chromatography using hexane and ethyl acetate (3/1 ratio) to give 1-(2-fluoro-5-methoxybenzoyl-6,7-dimethoxyisoquinoline-4-caboxylic acid ethyl ester (1.28 g). This ester (200 mg, 0.48 mmol) was suspended in 10 ml of methanol and 1N sodium hydroxide solution (2.0 ml) was added. The mixture was refluxed for 30 minutes and the solution was loaded to a preparative HPLC for purification to give 1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (138 mg). ES-MS calcd for C20H16FNO6 (m/e) 385.36, obsd 386.2 (M+H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[NH:10][C:11]=1[C:12]([O:14]CC)=[O:13])([CH3:6])[CH3:5].Cl>CC(C)=O>[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[NH:10][C:11]=1[C:12]([OH:14])=[O:13])([CH3:6])[CH3:5]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Temperature: 10 °C
Yield: 94.5 %

Procedure:
100 ml of 10% aqueous sodium hydroxide solution were added into a solution of 20 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate in 200 ml of acetone. The mixture was refluxed for 3 hours. After cooled to 10° C., pH of the reactant was adjusted to 6.4 using concentrated hydrochloric acid, solids precipitated. The precipitation was filtered, collected, washed with water, then dried to give 16.7 grams of whitish solid 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylic acid (formula III), resulting in a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([CH2:16][NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:17]([CH2:16][CH:13]2[CH2:15][CH2:14]2)[CH2:18][CH2:19][CH3:20])[N:7]=1
Reactant: CCCNCC1CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)OC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, 10.00 g; 48.3 mmol) in dry THF (200 ml) was treated dropwise over 1 hour with a solution of N-(cyclopropylmethyl)propane-1-amine (6.92 ml; 48.3 mmol) and triethylamine (7.37 ml; 53.1 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 18 hours. Water (200 mL) was poured into the reaction mixture, which was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under vacuum to afford the crude product, which was precipitated from MTBE (50 mL) to give the title compound as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[C:3]1=[O:13].Cl[CH2:15][CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOCC>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:15][CH2:16][S:17][C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[C:3]1=[O:13]
Reactant: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Reactant: ClCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c2cn(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 50 °C
Reaction time: 41.7 h

Procedure:
1,3-Dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione) (step 2)(10 g, 55.8 mmol), (2-chloroethyl)(trityl)sulfane (step 1) (20.81 g, 61.4 mmol), potassium iodide (1.853 g, 11.16 mmol) and caesium carbonate (36.4 g, 112 mmol) were suspended in anhydrous dimethylacetamide (250 mL), forming a dark orange suspension. The vessel was evacuated and back-filled with N2 (×3) and stirred under nitrogen at 50° C. for 41.7 h. The reaction was cooled to room temperature and decanted slowly into a stirring water (800 mL) and EtAcO (200 mL) mixture. The layers were separated and the aqueous extracted with EtOAc (4×100 mL). The solids present where collected by reduced pressure filtration (solid 1). The combined organics were washed with water (4×100 mL), brine (2×100 mL), dried (Na2SO4) and filtered under reduced pressure. The organic solvent was evaporated under reduced pressure to afford a pale yellow solid, which was suspended in Et2O (200 mL) and stirred at room temperature for 10 mins; the pale tan solid was then collected by reduced pressure filtration (solid 2). The solid collected from the extraction mixture (solid 1) was washed with water (100 mL), EtOAc (100 mL) and stirred in Et2O (100 mL) for 10 mins at room temperature and collected by reduced pressure filtration. Both solids were dried under vacuum at 50° C. for 16 h. Both crops were then blended to afford the title compound as a tan solid;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)[N:4]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:1][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15]4)=[CH:12][CH:13]=3)[N:4]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C1CCN(c2ccc(-c3noc(CN)n3)cc2)C1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CNCc2nc(-c3ccc(N4CCC(N(C)C)C4)cc3)no2)cc1

Procedure:
{1-[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl)pyrrolidin-3-yl}dimethylamine was reacted with p-anisaldehyde by method D. The product with the molecular weight of 407.23 (C23H29N5O2) was obtained in this way; MS (ESI): 408.30 (M+H+).
Reaction SMILES: N[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1C(O)[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C(#N)C1[C:20](=CC=CC=1)[NH2:21]>>[O:17]=[C:12]1[CH2:11][CH2:10][CH2:15][C:2]([C:3]2[C:8]([NH2:9])=[C:7]([CH:6]=[CH:5][CH:4]=2)[C:20]#[N:21])=[CH:13]1
Reactant: Nc1c2c(nc3ccccc13)CC(O)CC2O
Reactant: N#Cc1ccccc1N
Product: N#Cc1cccc(C2=CC(=O)CCC2)c1N

Procedure:
To gain entry into the 9-amino-1,2,3,4-tetrahydroacridin-1,3-diol series, i.e., to prepare diols of formula 15, an anthranilonitrile 10 is condensed with a 5-(phenyldialkylsilyl)-1,3-cyclohexanedione 11 to afford a 3-(oxocyclohex-1-enyl)-2-aminobenzonitrile 12, which is cyclized to a 9-amino-3-(phenyldialkylsilyl)acridinone 13 and, in turn, converted to a 9-amino-3-hydroxyacridinone 14 and reduced to a diol 15.