Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1ccccn1

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) was added slowly to a stirred and chilled (10°-15° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in 50 ml of dry dimethylformamide. The reaction mixture was heated between 60°-90° C. for 5 hours. The solution of the acyl chloride was added dropwise under a nitrogen atmosphere to a stirred, chilled (10°-15° C.) solution of 2-aminopyridine (1.77 g, 0.019 mole), and triethylamine (1.90 g, 0.019 mole) in 75 ml of dry dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, diluted with water to the cloud point, and seeded. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum at 70° C. for 2 hours, then at 60° C. overnight togive 1.0 g (20%) of crystals, mp 190°-191° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: Cl
Product: COC(=O)c1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min (Method A); 1H NMR (CDCl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:42])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[C:25]4[N:30]=[CH:29][S:28][C:26]=4[N:27]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:51]>>[N:11]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[C:25]4[N:30]=[CH:29][S:28][C:26]=4[N:27]=3)[CH:17]=2)=[O:42])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1.[ClH:51]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)cc1OC
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)N4CCCNCC4)c3)nc3scnc23)cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a stirred solution of 4-{3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoyl}-[1,4]-diazepane-1-carboxylic acid tert-butyl ester (130 mg, 0.22 mmol) in 10 mL of CH2Cl2 was added slowly CF3COOH (4 mL) at room temperature. Then the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.), then 1M HCl (0.5 mL) was added and stirred, then solvents were removed under reduced pressure to give [1,4]diazepan-1-yl-{3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-phenyl}-methanone as HCl salt (35 mg, 30.2%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.18 (s, 1H), 9.38 (s, 1H), 9.05 (brs, 2H), 8.46-8.44 (m, 2H), 7.86 (s, 1H), 7.60-7.59 (m, 2H), 7.42 (dd, 1H, J1=8.7 Hz, J2=2.7 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.85 (brs, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.44 (brs, 2H), 3.30 (brs, 2H), 3.20 (brs, 2H), 2.02-1.96 (m, 2H). LC-MS: 491.2 [M+H]+, tR=1.51 min. HPLC: 99.24% at 214 nm, 98.23% at 254 nm, tR=4.65 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2.[H-].[Na+].[Na].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:13]
Reactant: COc1cccc2c1CCC(=O)N2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC(=O)N2CCCCl
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of 5-methoxy-3,4-dihydrocarbostyril (53.1 g, 0.3 mole) in 200 ml of dimethylformamide (DMF) was added portionwise 60% sodium hydride in oil (19.2 g, 0.4 mole) at room temperature, and the mixture was stirred for 30 minutes. To the thus-obtained solution of the sodium salt of 5-methoxy-3,4-dihydrocarbostyril in DMF was added 1-bromo-3-chloropropane (94 ml, 0.6 mole). The mixture was stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 59 g of 1-(3-chloropropyl)-5-methoxy-3,4-dihydrocarbostyril as colorless needles.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C)C=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: OCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
Sodium hydride (99 mg, 4.14 mmol) was added to a solution of 3-phenyl-1-propanol (564 μL, 4.14 mmol) in N,N-dimethylformamide (15 mL) while cooling in ice, and the mixture was stirred for 30 min while cooling in ice. A solution of 2-fluoro-5-nitropyridine (500 mg, 3.45 mmol) in N,N-dimethylformamide (5 mL) was added thereto. The mixture was warmed to room temperature and stirred for 19 hr. Subsequently, sodium hydride (99 mg, 4.14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was heated to 85° C., stirred for 1.5 hr, and further stirred at room temperature for 2 hr. Water was added to the reaction mixture while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to afford 5-nitro-2-(3-phenylpropoxy)pyridine as a brown solid (440 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[NH2:29])([CH3:11])([CH3:10])[CH3:9].[Cl:31][CH2:32][C:33](Cl)=O>ClCCl.CO>[C:8]([O:12][C:13](=[O:30])[NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=[C:33]1[CH2:32][Cl:31])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 55.5 %

Procedure:
Triethylamine (9 mL, 64.7 mmol) was added to a solution of tert-butyl[3-(3-aminoquinolin-4-ylamino)propyl]carbamate (13.65 g, 43.1 mmol) in dichloromethane (150 mL). Chloroacetyl chloride (3.8 mL, 47.5 mmol) was added dropwise over a period of 10 minutes. The reaction mixture was stirred at ambient temperature over the weekend and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 1:1 water:saturated aqueous sodium bicarbonate. The organic layer was washed with brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 14.1 g of crude product as a brown foam. The foam was dissolved in a mixture of dichloromethane (15 mL) and methanol (0.5 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The cartridges were eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 5% methanol in 1:1 ethyl acetate:hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 8.96 g of tert-butyl[3-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light brown foam.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:33][CH3:34])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:40](N1CCCCC1)=[O:41]>C(OCC)C.O1CCCC1>[CH2:1]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:33][CH3:34])=[C:13]([CH:40]=[O:41])[C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2Cc1ccccc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1C=O)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2Cc1ccccc1

Procedure:
A solution of 4.93 g (10.0 mmol) of 10-benzyl-4-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 7.5 ml of n-butyllithium solution (1.6M in hexane) and 1.47 g (13.0 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The 10-benzyl-3,7-dimethoxy-6-(tert.-butyl-dimethyl-silanyloxymethyl)phenothiazine-4-carbaldehyde obtained was dissolved in 50 ml of tetrahydrofuran and reduced with 10.0 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The reaction mixture was worked up and chromatographed analogously to that described in 4.1.1.ea. After drying in a high vacuum 3.72 g (71.9%) of 10-benzyl-6-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-phenothiazin-4-yl-methanol were obtained as an amorphous white solid. MS:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH3:15])[CH:6]=1)=[O:4].C1COCC1.[OH-].[Na+]>CO>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)[CH3:15]
Reactant: CCn1cc(C(=O)OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1cc(C(=O)O)c2ccccc21

Procedure:
A solution of 1-ethyl-1H-indole-3-carboxylic acid methyl ester (1.8 g, 8.8 mmol) was stirred in a 1:1 mixture of THF:MeOH (40 mL), and to this was added 2N NaOH (20 mL). The reaction was heated at reflux for 4 hours. The reaction mixture was partially evaporated to remove the THF, MeOH and the remaining material diluted with water (20 mL) and acidified to pH=2 with 1N HCl. The mixture was extracted with dichloromethane (100 mL), dried over sodium sulfate and evaporated under reduced pressure to give the title compound as a white solid, which was used directly in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[N:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)O
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A mixture of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester (0.6 g, 10.96 mmol), and solid NaOH (2 g, 50 mmol) in ethanol (5 mL) and water (1 mL) was refluxed for 1 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was acidified with a 6N HCl solution. Then, the product was extracted with EtOAC (3×25 mL) and the organic extracts were dried and concentrated to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.43 g, 78%) as white solid. Mass Spec. LCMS 318 (M+1).
Reaction SMILES: [C:1]1([C@H:7](NC[C@@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCC[C@H](CN[C@H](C)c1ccccc1)CC(=O)O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(S,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.6 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1N hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (R)-1,1′-bi-2-naphthol (1.25 g) having 95% ee.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH3:20])([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:20][C:10]1([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C(=O)N2CCCC2)CCNC1
Yield: 79.3 %

Procedure:
A solution of 3-methyl-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (330 mg, 1.17 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed to give (3-Methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone as a white solid (169 mg, 79%). 1H NMR (400 MHz, CHCl3-d): δ 3.55-3.40 (m, 5 H); 3.06-2.92 (m, 2 H); 2.32-2.20 (m, 2 H); 2.01-1.82 (m, 5 H); 1.71 (m, 1 H); 1.33 (s, 3 H).
Reaction SMILES: [I-:1].[NH+]1C=CC=C[CH:3]=1.[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:9].CI.C(NC1C=CC=CC=1CCC1C=CC=CN=1)=O>>[I-:1].[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[CH3:3])=[O:9]
Reactant: c1cc[nH+]cc1
Reactant: COc1ccc(NC=O)c(CCc2ccccn2)c1
Agent: O=CNc1ccccc1CCc1ccccn1
Agent: [I-]
Solvent: CI
Product: COc1ccc(NC=O)c(CCc2cccc[n+]2C)c1
Yield: 95 %

Procedure:
The pyridinium iodide is obtained by treating 2-(2-formamido-5-methoxyphenethyl)pyridine with methyl iodide according to the procedure described in Example 2c for 2-(o-formamidophenethyl)pyridine. Analytically pure 2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide is obtained in a yield of 95% and has a melting point of 184°-186.5°C. (corr.).
Reaction SMILES: C([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27](OC)=[O:28])[N:26]=[C:10]12)C1C=CC=CC=1.Cl.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][C:37]=1[CH3:44]>CO.[Pd]>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:27]([C:25]2[N:26]=[C:10]3[CH:9]([NH:8][CH3:33])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]3[C:23](=[O:32])[C:24]=2[OH:31])=[O:28])=[CH:38][C:37]=1[CH3:44]
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Reactant: Cc1cc(CN)ccc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C(=O)OC(C)(C)C)CCn2c1nc(C(=O)NCc1ccc(F)c(C)c1)c(O)c2=O
Temperature: 25 °C

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate prepared as described in Step 4, was dissolved in MeOH, treated with 1 N HCl (1 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. MS (ES) C16H24N4O6 requires 368. Found: 369 (M+H+). The crude organic product was taken in methanol and treated with 1.2 eq. of 4-fluoro-3-methyl-benzylamine and resulting mixture was refluxed overnight. After cooling to room temperature, evaporation of volatiles under reduced pressure yielded title product which was directly taken in the next step. MS (ES) C23H30FN5O5 requires 475. Found: 476 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].NCCC(O)=O>C(O)CCC>[N+:13]([C:16]([CH3:17])=[CH:11][C:9]1[S:10][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc(-n2ccnc2)s1
Reactant: CC[N+](=O)[O-]
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc(-n2ccnc2)s1)[N+](=O)[O-]

Procedure:
Similar to example 4(a), the reaction is carried out with 60 g 5-(1-imidazolyl)-thiophene-2-aldehyde (EPA No. 112 987), 23.1 g nitroethane, 2 4 g β-alanine and 210 ml n-butanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O([C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:9])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=C(O)CCCCCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
6-Aminohexanoic acid (1.47 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered then washed with ethanol, giving crude 9-(5-carboxypentyl) aminoacridine.Yield 2.4 g (78%).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: CC(=O)Cl
Reactant: Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
41.0 mg (0.12 mmol) of rac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-amino-1-benzothiophene-2-carboxamide dihydrochloride and 36.8 mg (0.36 mmol) of triethylamine are dissolved in 1.5 ml of DMF. At 0° C., 14.3 mg (0.18 mmol) of acetyl chloride are added, and the mixture is stirred at RT overnight. The reaction mixture is purified by preparative HPLC. 29 mg (63% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([CH3:18])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[CH:7][CH:6]=1.Cl>P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH3:18])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[CH:9][CH:10]=1.[CH3:18][C@@H:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[CH:7][CH:6]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)[C@H](C)c1ccc(C(=O)c2cccs2)cc1
Product: C[C@H](C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Temperature: 22 °C
Reaction time: 48 h

Procedure:
To 100 mg crude Candida cylindracea lipase (Sigma L1754 Type VII, 500 units/mg solid) in 4 mL 0.2 M phosphate buffer, pH 7.0, was added 200 mg (±)-α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid methyl ester (suprofen methyl ester). The resulting suspension was gently stirred with a magnetic stirrer for 48 hours at 22° C. The reaction mixture was acidified to pH 1.0 with 1 N HCl and exhaustively extracted with ethyl acetate three times. The combined organic extract was dried over sodium sulfate and was then evaporated to dryness. The residue was chromatographed over a silica gel (MN Kieselgel 60) column (0.8×15 cm). Elution of the column with a solvent system consisting of ethyl acetate-hexane (1:5) gave unreacted (R)-α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid methyl ester, [α]D25 =-54.7° (c=3.9, CHCl3), ee>0.90, and (S)-α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid, [α]D25 =+43.5° (c=2.1, CHCl3), ee>0.95. The optical purity expressed as enantiomeric excess (ee) is determined by proton magnetic resonance spectroscopy of the methyl ester in the presence of the chiral lanthanide shift reagent, Eu(hfc)3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].NC(CO)CO.Cl[C:23]1[C:24]([CH2:30][CH3:31])=N[CH:26]=[CH:27][C:28]=1Cl.C(=O)C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[N:6][CH:5]=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:14][O:15][CH:26]([C:27]2[CH:31]=[CH:30][CH:24]=[CH:23][CH:28]=2)[O:13][CH2:12]1
Reactant: CCc1nccc(Cl)c1Cl
Reactant: CCc1nccc(NC(CO)CO)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(CO)CO
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nccc(NC2COC(c3ccccc3)OC2)c1Cl

Procedure:
2.3 g (10 mmol) of 5-chloro-6-ethyl-4-(1,3-dihydroxy-2-propylamino)-pyridine (prepared analogously to Example A from 2-amino-1,3-propanediol and 3,4-dichloro-2-ethyl-pyridine) and 5.0 g of benzaldehyde were heated with 2.1 g of p-toluenesulfonic acid hydrate in 40 ml of toluene, using a water separator, until the evolution of water had ended. Working up and purification were carried out analogously to Example A. the chromatography over silica gel (ethyl acetate) gave initially 0.6 g of trans isomer (18.8% of theory), melting point: 139-140° C., and then 2.4 g of cis isomer (75.2% of theory), melting point 119-120° C.