Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH3:12])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a mixture of 112a (9.0 g, 51 mmol), and Et3N (18.6 mL, 51 mmol) in DCM (100 mL) was added TsCl (9.77 g, 51 mmol). The mixture was stirred at rt for 4 h and concentrated. The residue was diluted with EA, washed with water. The organic layer was dried and concentrated to give 2-(tert-butoxycarbonyl(methyl)amino)ethyl 4-methylbenzenesulfonate 112b (10.0 g, 61%) as light yellow oil. ESI-LCMS: m/z=230.0
Reaction SMILES: [Br-].[C:2]1([CH:8]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:23])[C@@H:19]([NH:20][CH:21]=[O:22])[C@H:16]3[S:15][CH:14](C[P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50](=O)(O)[O-].[Na+].[CH:55](=O)[C:56]#[C:57][CH2:58][CH3:59]>ClCCl>[CH:21]([NH:20][C@@H:19]1[C:18](=[O:23])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])=[C:13](/[CH:59]=[CH:58]\[C:57]#[C:56][CH2:55][CH3:50])[CH2:14][S:15][C@H:16]12)=[O:22]
Reactant: O=C([O-])O
Reactant: CCC#CC=O
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CC(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)S[C@H]12
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC#C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1

Procedure:
A stirred solution of (6R,7R)-[4-diphenylmethoxycarbonyl-7-formamidoceph-3-em-ylmethyl]triphenylphosphonium bromide (15.00 g) (preparation described in British Patent Specification No. 1342241) in dichloromethane (250 ml) was treated with saturated sodium bicarbonate solution (75 ml). After a few minutes, 2-pentynal (3.28 g) was added, in one portion, and the mixture was stirred for ca 19 h. The two layers were separated and the organic phase was washed with 2N hydrochloric acid (250 ml), water (250 ml) and brine (250 ml) and dried (sodium sulphate). The solvent was removed and the residue was purified by chromatography (750 g silica gel). Elution with ethyl acetate:dichloromethane (1:19→1:14) gave the title compound as a solid (1.72 g); νmax (CHBr3) 3410 (NH), 2200 (C≡C), 1783 cm-1 (β-lactam); τ(CDCl3) values include 1.76 (H-CO), 3.26 (--CH=CH--C≡C), 3.54 (NH), 4.14 (7H), 4.42 (--CH=CH--C≡C), 4.98 (6H), 7.66 (C≡C--CH2 13 ).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=[O:4])=[O:3].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([Cl:18])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-chlorosulfonyl-4-fluoro benzoic acid (2.5 g, 10 mmol) in methylene chloride at 0° C. is added oxalyl chloride (1.33 g, 11 mmol), followed by the addition of 1 drop of N,N,-dimethylformamide. The reaction mixture is warmed up to room temperature and stirred for an additional 4 h. The solvent is removed, and the residue is dried under vacuum for 1 hr to obtain the title compound as an oil, which is used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C=[O:20].[CH:21]([OH:23])=[O:22]>>[C:12]([OH:20])(=[O:11])/[CH:13]=[CH:14]/[C:21]([OH:23])=[O:22].[CH3:21][N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][O:11][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][CH2:9]3)[CH2:14]1
Reactant: C=O
Reactant: O=CO
Reactant: Fc1ccc(OCC2CNCCO2)c2c1CCC2
Product: CN1CCOC(COc2ccc(F)c3c2CCC3)C1
Product: O=C(O)/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To 180 mg of 2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine were added 1 ml of a 35% aqueous formaldehyde solution and 1 ml of formic acid, and the mixture was stirred at 80° C. for 7 hours, followed by concentration under reduced pressure. The concentrate was neutralized by addition of 20 ml of a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with three 20 ml portions of ethyl ether. The ethyl ether solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was dissolved in 20 ml of ethyl ether, and a solution of 42 mg of fumaric acid in 1 ml of methanol was added thereto while stirring. The precipitated salt was collected by filtration, washed with ethyl ether, and dried to give 123 mg of 4-methyl-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine fumarate.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1C2C(=CC=CC=2)CNC1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:43][CH:44]([CH3:48])[C:45](Cl)=[O:46]>O.C(Cl)Cl>[Cl:43][CH:44]([CH3:48])[C:45]([N:4]1[CH2:3][CH:2]([CH3:1])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:46]
Reactant: CC(CN)c1ccccc1
Reactant: CC(Cl)C(=O)Cl
Reactant: O=C(Cl)c1ccccc1
Agent: CC1CNCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2cnccc2c1
Solvent: O
Solvent: ClCCl
Product: CC(Cl)C(=O)N1CC(C)c2ccccc2C1c1ccccc1

Procedure:
By procedures described in Example 1 (Method A), β-methyl-phenethylamine and benzoyl chloride were converted to 4-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 4.0 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 2 ml 2-chloropropionyl chloride was added dropwise to the mixture. The mixture was stirred for 15 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (150° C. @ 0.1 mm Hg) to provide a product having the elemental analysis reported in Table I.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 14-1, 61.1 mg, 0.136 mmol) was dissolved in anhydrous dichloromethane (1 mL), and triethylamine (44 μL, 0.319 mmol) and methanesulfonyl chloride (13 μL, 0.168 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for hours and 15 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (68.3 mg) as a colorless amorphous product. (Yield 98%)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:37])([F:36])[C:29]1[C:33]([CH:34]=[O:35])=[CH:32][NH:31][N:30]=1.Cl>CN(C=O)C.O>[CH:34]([C:33]1[C:29]([C:28]([F:37])([F:27])[F:36])=[N:30][N:31]([CH2:2][C:3]([NH:5][C:6]2[S:10][C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[C:7]=2[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4])[CH:32]=1)=[O:35]
Reactant: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 49 %

Procedure:
2-(2-Bromoacetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.91 g, 8.06 mmol) was dissolved in DMF (25 mL) and potassium carbonate (2.23 g, 16.11 mmol), followed by 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (1.39 g, 8.46 mmol), added. The mixture was stirred at 60° C. for 25 min after which time the reaction mixture was diluted with water (˜800 mL), then acidified with 5 N HCl until pH 1. During acidification a free flowing solid was obtained which was collected by filtration. NMR analysis indicated ˜60-70% purity of desired product. The solid was successfully triturated with a mixture of DCM/ether to give a light beige solid which was collected by filtration. The mother liquor was concentrated and a second batch obtained using a similar process. The batches were combined to yield the title product (1.76 g, 3.95 mmol, 49%).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:23]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL), diethylamine (63.4 mg, 0.87 mmol, 2.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 117 mg (80%) of methyl 3-(diethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][C@@H:47]2[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]2)(=O)=O)=CC=1.CCOC(C)=O>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH2:46][C@@H:47]4[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]4)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1c(OC[C@@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 60 °C

Procedure:
To a suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (84.5 mg, 0.180 mmol) and potassium carbonate (104.5 mg, 0.7561 mmol) in DMF (3 mL), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (103.6 mg, 0.3618 mmol) in DMF (2 mL) was added and the reaction mixture was heated to 60° C. for a total of 23 h. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 gram] and purified using the Teledyne/ISCO system [RediSepRf 12 g Gold Silica], eluting with a 5-20% EtOAc:heptane solvent system. Fractions containing product were combined and concentrated in vacuo. The material obtained was dissolved in MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions containing product were pooled together and concentrated in vacuo, affording the title material as a clear and colorless film. 1H NMR (400 MHz, CDCl3): δ=8.43 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.02 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.92 (q, J=7.0 Hz, 1H), 4.31 (quint, J=5.7 Hz, 1H), 3.97 (dd, J=8.3, 6.6 Hz, 1H), 3.91 (dd, J=9.0, 5.9 Hz, 1H), 3.65 (br s, 1H), 3.46 (br s, 1H), 1.76 (d, J=7.1 Hz, 3H), 1.69 (s, 9H), 1.36 (d, J=5.3 Hz, 6H). MS (ES+): m/z 605.30/606.98/608.99 (23/61/9) [MH++Na]. HPLC: tR 4.15 min (ZQ3, nonpolar—5 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:36]([C:31]1([CH2:34][CH3:35])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1)[CH3:37]
Reactant: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCNCC2)CC1
Reaction time: 0.33 h

Procedure:
(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (59 mg, 0.1148 mmol) produced in Example (50b) was dissolved in a mixed solvent of dichloromethane (0.7 mL)-water (1 drop). Trifluoroacetic acid (0.177 mL, 2.296 mmol) was added thereto followed by stirring for 15 hours and 20 minutes under the same conditions. Aqueous solution of potassium carbonate was added to the reaction mixture to make the mixture basic. The mixture was then extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a crude product of (S)-1-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine as a brown oil. This was directly used without purification for the following reaction.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O:8]=[C:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](CCO)=[CH:14][CH:13]=1.O1CCCC1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9](=[O:8])[CH3:21])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)COc1ccc(CCO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(CCOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1.96 g of acetic anhydride were added, whilst ice-cooling, to a mixture of 3.1 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 50 ml of anhydrous tetrahydrofuran and 2.53 g of pyridine, and the resulting mixture was stirred at room temperature for 3.5 hours. At the end of this time, 12.5 g of pyridine and 9.8 g of acetic anhydride were added, whilst ice-cooling, and the mixture was allowed to stand at room temperature for 1 day, after which the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give the title compound having an Rf=0.71 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
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##
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.O=S(Cl)[Cl:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCBr

Procedure:
A solution of 11-bromoundecanoic acid (10.00 g, 37.7 mmol) dissolved in CH2Cl2 (30 mL) was slowly added to a solution of SOCl2 (7.0 mL, 94.0 mmol) in CH2Cl2 (25 mL). The mixture was refluxed for 5 h, then concentrated in vacuo to give 11-bromoundecanoyl chloride, which was used without further purification:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 0.21 g (0.44 mmol) 6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide and 1.0 ml (9.0 mmol) 1-methylpiperazine was heated at 120° C. for 2 h. After cooling to room temperature the mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 0.25 g of crude product. Flash chromatography gave 0.17 g (70%) of the title compound. MS m/e (%): 552 (M+H+, 100)
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].I[CH2:30][CH2:31][CH3:32]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:30][CH2:31][CH3:32])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCCI
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: CCCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)cc1

Procedure:
The product from Example 33A and 1-iodopropane were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Reaction time: 16 h
Yield: 56 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (150 mg, 0.34 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) were taken up in dimethylformamide (3 ml). HATU (195.2 mg, 0.51 mmol) and N,N-diisopropylethylamine (110.4 mg, 0.86 mmol) were added at room temperature and the reaction mixture was stirred for 16 h (monitored by LC-MS). To the reaction, water was added (10 ml) and the mixture was stirred for 5 min. Thereafter, the aqueous mixture was extracted with ethyl acetate (2×15 ml) and the combined extracts were washed with water (3×10 ml), dried and concentrated under reduced pressure. The obtained crude product was purified by normal silica gel column chromatography (100-200 mesh) using 30% ethyl acetate in hexane as mobile phase to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (333) (130 mg, 56%) as a yellow sticky solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:18])C(=O)C1.O>C(Cl)Cl>[Br:18][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.91 g, 38 mmol) in DCM (250 mL) was added NBS (7.93 g, 44 mmol). The suspension was stirred at room temperature for 3 hours. Water (200 mL) was added to the reaction mixture. The mixture was sonicated for 5 min. The solid was collected by filtration and washed with water, then taken into 100 mL of MeOH. The suspension was sonicated for 3 min. The solid was collected by filtration as the desired product (6.47 g, 72%). LCMS[M+1]: 232.