Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:46][CH:45]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
First, 3.4 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 3.3 g of 2,3-difluoro-4'-[16-hydroxyhexadecyl]oxybiphenyl, 2.3 g of triphenylphosphine, and 50 ml of tetrahyrofuran were placed in a 100 ml flask. Then, 1.5 g of diethyl azodicarboxylate was added dropwise to the reaction mixture at 5° C. Thereafter, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 5.9 g of 16-[2,3-difluorobiphenyl-4'-yl]oxyhexadecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 92.1%). The compound thus obtained had a purity of 98.3% by HPLC.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:6])[CH2:4][CH3:5].C(N(CC)CC)C.Br[CH2:15][CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH:23]([NH:35][C:36](=[O:40])[O:37][CH2:38][CH3:39])[CH:24]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:38]([O:37][C:36](=[O:40])[NH:35][CH:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][C:17]([CH2:16][CH2:15][S:6][CH2:3][CH2:4][CH3:5])=[CH:18][CH:19]=2)[CH:24]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH3:39]
Reactant: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCSCCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (4.73 mg, 0.177 mmol) in 3 ml dry DMF under N2 was added 1-propanthiol (0.012 ml, 0.133 mmol, dissolved in 1 ml dry DMF). The reaction was stirred at room temperature for 2 h, followed by addition of triethylamine (0.019 ml, 0.133 mmol) and ethyl 7-(2-bromoethyl)-1-(3-chlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (40 mg, 0.089 mmol, dissolved in 2 ml dry DMF). The mixture was stirred at room temperature over night, the solvent evaporated, the residue re-dissolved in ethyl acetate, washed with water, citric acid, NaHCO3 and brine and filtered. The solvent was evaporated to obtain 31 mg of an off white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1OC

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3,4-dimethoxyaniline (78.3 mg, 0.51 mmol). The title compound was obtained as a yellow solid (25.0 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.54 (1H, m), 9.00 (2H, m), 8.67 (1H, m), 7.30 (1H, m), 7.22 (1H, m), 6.94 (1H, m), 3.72 (6H, s). MS m/z: 484.24, 486.25 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13](I)=[CH:12][C:11]=2[F:19])[CH:6]=[C:7]([F:9])[CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.C([Li])CCC.[OH-].[Na+]>C1COCC1>[F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([B:21]([OH:26])[OH:22])=[CH:12][C:11]=2[F:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1I
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1B(O)O
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A RBF was charged with 3′-(difluoromethyl)-2,5′-difluoro-4-iodo-5-methoxy-1,1′-biphenyl (770 mg, 1.944 mmol), triisopropyl borate (0.580 mL, 2.53 mmol) and THF (9.719 mL). The flask was cooled to 78° C. for 10 min, then n-butyllithium solution, 2.5m in hexanes (1.011 mL, 2.53 mmol) was added drowpise over 1 min. The colorless solution turned green then yellow. After 30 min at 78° C., 2N aq. NaOH (10 mL) was added. The resulting biphasic mixture was stirred for 10 min, and partitioned between water (20 mL) and ether (50 mL). The layers were separated, and the ethereal layer was extracted with water (2×10 mL). The combined aqueous extracts were washed with ether (10 mL), and then were acidified with 6N aq. HCl (10 mL). The resulting aq. mixture was extracted with DCM (3×20 mL). The combined DCM layers were dried over sodium sulfate, filtered, and concentrated to give (3′-(difluoromethyl)-2,5′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (111 mg, 0.353 mmol, 18.18% yield) as white solid. m/z (ESI) 315.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:39])[CH2:19][C:20]([CH2:37]Cl)=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:54].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:39])[CH2:19][C:20]([CH2:37][I:54])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)C2=C(CCl)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To the solution of (5R,6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (5 g, 6.28 mmol) in Acetone (50 mL) was added sodium iodide (1.176 g, 7.85 mmol) and the mixture was stirred at rt for 2 h. Solvent was removed under vacuum, the residue was chromatographed to give (5R,6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (4.5 g, 5.07 mmol, 81% yield). LCMS: (M+H)+: 887.6
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.CN(C=O)C.[Cl:17]N1C(=O)CCC1=O>CCOC(C)=O>[Cl:17][C:7]1[C:8]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cc2sccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1[nH]c2ccsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a 20 mL vial fitted with a magnetic stir bar at 25° C. was added 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.1 g, 0.599 mmol, 1 equiv) and 2 mL of anhydrous DMF. N-chlorosuccinimide (NCS) (0.08 g, 0.599 mmol, 1 equiv) was subsequently added and the reaction vessel contents stirred for 1 h at 25° C. before heating the reaction vial to 55° C. for 12 h. The reaction was then allowed to cool to 25° C. and was diluted with EtOAc (10 mL). The resulting mixture was then washed with water) 3×5 mL). The organic phase was dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The resulting residue was dissolved in a small volume of methanol, filtered through a 0.45 micron syringe filter, and further purified via preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min) afforded the desired 6-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 70 (5.5 mg, 5%). LC/MS m/e 199.9 (M−H). tR of product: 2.3-2.7 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.41 (d, J=5.32 Hz, 1H), 6.97 (d, J=5.27 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=2)[CH:8]=1
Reactant: COCCOc1ccc2c(O)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Temperature: 85 °C

Procedure:
8-Chloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinolin-4-ol (2.16 g, 5.8 mmol) was dissolved in POCl3 (20 mL) under an atmosphere of nitrogen. The reaction was heated to 85° C. for 4 hours. The reaction was cooled to 0° C. and quenched with water. A saturated solution of sodium bicarbonate in water was used to neutralize the reaction. The reaction was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and was concentrated. 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline (1.87 g, 82%) was purified by silica gel chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]2[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.O>CS(C)=O>[CH3:16][O:15][C:13]([C:11]1[C:10]2[C:17](=[O:22])[CH:18]([Br:23])[CH2:19][CH2:20][CH2:21][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)=[O:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole 1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(1.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether. The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR (CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H) Step 2: A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H), 8.28 (br s, 1H)8.56 (d, 2H)
Reaction SMILES: NCCOCCOCC1NC(C)=C(C(OC)=O)C(C2C=CC=C(Cl)C=2Cl)C=1C(OCC)=O.Cl[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42].[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.[K]>CN(C)C=O>[C:43]1(=[O:53])[N:47]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOCCOCCCl
Agent: CCOC(=O)C1=C(COCCOCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCO

Procedure:
The subject of the present invention is also the process for preparing the (-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethylformamide in the heated state, to form 2-[2-(2-phtalimidoethoxy)ethoxy]ethanol the compound of the formula XIV: ##STR14## which is converted by means of Jones reagent to 2-[2-(2-phtalimidoethoxy)ethoxy]acetic acid, the compound of the formula XV: ##STR15## which is treated with carbonyldiimidazole and Meldrum's acid in the presence of pyridine in methylene chloride to obtain the compound of formula XVI: ##STR16## which is then reacted with (R)-2-phenyl-2-methoxyethanol, the compound of formula XVII: ##STR17## to obtain the β-keto ester of formula XVIII: ##STR18## which is condensed in the presence of ammonium formate in ethanol with a benzylidene compound of formula XIX: ##STR19## to obtain (4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XX: ##STR20## and then: either: this compound is subjected to the action of aqueous sodium bicarbonate solution, in solution in acetonitrile, to obtain (4R,4'R/4S,4'R)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine, the compound of formula XXI: ##STR21## which is treated, after separation by HPLC, with a mixture of glyme and sodium ethylate to obtain a mixture containing (-)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, the compound of formula XXII: ##STR22## and its homolog substituted at the 5-position with an ethoxycarbonyl radical,
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:6]=1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])O.[Na+].O>O1CCCC1CO>[N:24]1[C:3]([C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:6]=2)=[CH:2][N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=12
Reactant: CC(C)(C)OC(=O)n1nc(C(=O)CBr)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: OCC1CCCO1
Product: CC(C)(C)OC(=O)n1nc(-c2cn3ccccc3n2)c2cc([N+](=O)[O-])ccc21
Yield: 43.7 %

Procedure:
A total of 0.88 g of tert-butyl 3-(2-bromoacetyl)-5-nitro-1H-1-indazolecarboxylate was dissolved in 10 ml of tetrahydrofuran-methanol (1:1), and 240 mg of 2-aminopyridine and 210 mg of sodium hydrogencarbonate were added, followed by heating under reflux for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and the solvent was removed. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:7), to give 0.38 g of the title compound as a pale yellow powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:9]([CH3:22])([CH3:21])[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (2 ml) was added to a stirred solution of 4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) and triethylamine (2 ml) in methylene chloride (25 ml) at ambient temperature, stirring was continued for 1 hr concentrated to dryness, triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give 1-benzyl-4-carbethoxyamino-3,3-dimethyl piperidine as oil. Yield 1.3 g (62%), C17H26N2O2, m/z 291 (M+1), PMR (CDCl3): 0.98 (s, 3H), 1.2 (t, 6H), 1.78 (m, 2H), 2.42 (m, 2H), 2.82 (m, 2H), 3.6 (d, 2H), 3.9 (m, 1H), 4.1 (q, 2H), 4.8 (bs, 1H), 7.54 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (8.5 g), water (15 mL) and sodium bicarbonate (10.6 g). The mixture was heated to about 100° C. and maintained at the same temperature for about 20 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 30° C. followed by addition of water (50 mL) and ethyl acetate (25 mL). The mixture was stirred for about 10 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL). Total organic layer was washed with water (50 mL). The organic layer was subjected to complete distillation under vacuum at 55° C. followed by addition of ethyl acetate (5 mL). The mixture was stirred for 20 minutes followed by addition of n-hexane (75 mL). The mixture was further stirred at room temperature for solid separation followed by isolation of solid by filtration and washing with n-hexane (10 mL). The solid isolated was subjected to drying under vacuum at 60° C. for 3 hours to afford the title compound in about 91% yield having HPLC purity of about 99.18%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].Cl[CH2:10][CH:11]([OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[NH:13][CH2:12][CH:11]([OH:22])[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(CCl)CNc1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
19.9 Grams (0.293 mol) of imidazole and 54.7 g (0.304 mol) of sodium methylate solution (30% in methanol) are mixed and concentrated to dryness at 50° C./12 Torr. 80 Ml of dimethylformamide are added to the thus-formed imidazole sodium salt. The mixture is heated to 110° C. and a solution of 50 g (0.197 mol) of N-(3-chloro-2-hydroxypropyl)-3,4-dichloroaniline in 100 ml of dimethylformamide is added dropwise at this temperature over a period of 30 minutes. This addition finished, the reaction solution is further heated and refluxed for 2 hours. The solution is then cooled to 90° C. and 650 ml of water are added. The reaction mixture is left standing for 12 hours. The solid precipitant is filtered off, washed with water and dried at 50° C./12 Torr. For purification the substance is recrystallized under filtration with active charcoal from 100 ml ethyl acetate to yield 22 g of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole, M.P. 98°-100° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cu](C#N)[C:13]#[N:14]>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 58.9 %

Procedure:
2,5-Dibromo-3-nitropyridine (3.80 g, 13.4 mmol) and copper cyanide (2.42 g, 26.8 mmol) were mixed, and stirred under heat at 150° C. for 2 hours. After cooled to room temperature, the contents were filtered, and the residue was washed with acetone. The mother liquid was concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to obtain the intended compound (1.80 g, 59%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:34][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and 2-methoxyethanol in dioxane and DMF. ES-MS m/e (%): 467 (M+Na+, 24), 445 (M+H+, 100).