Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH2:23][CH2:24][CH2:25][C:21]=2[C:20]([C:26](=[NH:29])[NH:27][NH2:28])=[N:19]1>C(O)C>[F:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH2:23][CH2:24][CH2:25][C:21]=2[C:20]([C:26]2[N:27]=[N:28][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:29]=2)=[N:19]1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2c1CCC2
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1O
Yield: 15.6 %

Procedure:
218 mg (1.13 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 5 ml of ethanol and heated to reflux. Subsequently, 205 mg (0.75 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidohydrazide suspended in 5 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 48 mg of the target compound were obtained (purity 54%; 8% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)CC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(O)ccnc2c1
Solvent: CCC(=O)O
Product: COc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 7-methoxyquinolin-4-ol (5.0 g, 28.5 mmol) and propionic acid (50 mL) was heated to reflux. Nitric acid (3.2 mL of 70%, 50 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was refluxed for 2 hrs and then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with cold ethanol followed by hexanes and then dried to provide 3.9 g of 7-methoxy-3-nitroquinolin-4-ol as a gray solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=[C:25]1[O:29][C:27](=[O:28])[CH2:26]1>>[C:27]([O:23][CH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:18]1)(=[O:28])[CH2:26][C:25]([CH3:24])=[O:29]
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 96.3 %

Procedure:
4-Benzhydryl-1-piperazinepropanol was reacted with diketene in the same manner as Reference Example 2-(1) to give 3-(4-benzhydryl-1-piperazinyl)propyl acetoacetate as an oil. Yield 96.3%. NMR(CDCl3)δ: 1.62-1.98(2H, m), 3.40(2H, s), 4.16(2H, t, J=6.8), 4.20(1H, s), 7.10-7.49(10H, m).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:22][C:23]=2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:15][CH:14]=1.O>C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:22][C:23]=2[CH2:24][CH2:25][CH2:26][OH:27])=[CH:17][CH:18]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
Lithium aluminium hydride (185 mg) was gradually added to a tetrahydrofuran (20 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid (1.47 g) at room temperature. After the mixture was stirred for 1 hour, water (2 ml) was added to the reaction mixture with cooling with ice, and stirred for further 30 minutes. Diethyl ether (50 ml) was added to the reaction mixture, which was then dried (MgSO4), and the insoluble substances were removed by filtration. The resulting filtrate was concentrated, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (435 mg, 31%). This was recrystallized from dichloromethane-isopropyl ether to give colorless prisms. mp 128-129° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CCCCCc1ccccc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
t-butyl diethylphosphonoacetate (18 g; 70 mmol) is dissolved in dry THF (250 mL) and cooled to -40° C. NaH (60% in oil; 2.8 g; 70 mmol) is added and the reaction is warmed to 0° C. Gas evolution is controlled with cooling and then stirred at 20° C. for 30 minutes. 5-Phenylpentanal (11.3 g; 70 mmol) is added and the reaction stirred 20 minutes. The reaction is concentrated to half volume and petroleum ether (500 mL) is added. The reaction is washed with 100 mL water, 100 mL 0.5 N HCl, NaHCO3, brine and dried (MgSO4). The solution is concentrated in vacuo to obtain t-butyl 7-phenylhept-2-enoate which is used directly in Step C.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[C:1]1([S:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(CSc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a chloroform (10 mL) solution of (4-phenylsulfanylmethyl-phenyl)-methanol (1 g, 4.34 mmol) described in Manufacturing Example 206-1-2 was added manganese dioxide (3.77 g, 43.4 mmol), which was stirred for 15 hours at room temperature. The manganese dioxide was removed with a Celite bed, and the filtrate was concentrated under a reduced pressure to obtain the title compound (990 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CN(C)C(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (380 mg, 1.16 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl(methyl)carbamate (400 mg, 1.1 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([N:61]=[N:62][C:63]2[CH:81]=[CH:80][C:66]([C:67]([O:69][C:70]3[CH:79]=[CH:78][C:73]([O:74][CH:75](O)[CH3:76])=[CH:72][CH:71]=3)=[O:68])=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:76][CH2:75][O:74][C:73]2[CH:78]=[CH:79][C:70]([O:69][C:67](=[O:68])[C:66]3[CH:80]=[CH:81][C:63]([N:62]=[N:61][C:58]4[CH:59]=[CH:60][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=4)=[CH:64][CH:65]=3)=[CH:71][CH:72]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: CC(O)Oc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCOc3ccc(OC(=O)c4ccc(N=Nc5ccc([N+](=O)[O-])cc5)cc4)cc3)c2)cc1

Procedure:
A solution of 0.6 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethanol and 0.04 g of 4-dimethylaminopyridine is reacted with 0.2 g of N,N'-dicyclohexyldicarbodiimide and 20 ml of dichloromethane in an analogous manner to Example 1 to give (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[C:28]([CH:33]=O)=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:33][C:28]2[C:27]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)(=[O:25])=[O:26])=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:6]1[CH3:15]
Reactant: O=Cc1ncccc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-(4-fluorobenzenesulfonyl)pyridine-2-carbaldehyde.
Reaction SMILES: [OH:1][CH:2]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:19]1([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:1][CH:2]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[CH2:20][CH2:21]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)(C)C(O)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(C)C(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-hydroxy-4,4-dimethylpentyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (39% yield). 1H NMR (500 MHz, CDCl3) δ 8.18, 8.05, 7.74, 7.63, 7.56, 7.36, 6.99, 4.05, 3.92-3.67, 3.45-3.32, 3.26, 1.76, 1.55, 0.88. MS (ES+) m/z 494 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:42][C:43]1[CH:48]=[C:47]([CH2:49][OH:50])[CH:46]=[CH:45][N:44]=1>CO>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([O:50][CH2:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([Cl:42])[CH:48]=4)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (115 mg, 0.254 mmol) and 1M solution of potassium tert-butoxide in tert-butanol (0.80 mL, 0.80 mmol) was added 2-Chloro-4-pyridinemethanol (81.8 mg, 0.568 mmol). The resulting suspension was stirred at room temperature for 15 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The product was isolated by lyophilization of pure fractions yielding N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide (29.9 mg, 21% yield). 1H NMR (CDCl3) 8.41 (d, 1H), 7.91 (s, 2H), 7.82 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 5.47 (s, 2H), 3.70-3.65 (m, 8H) ppm.
Reaction SMILES: [Na].[OH2:2].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[OH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:7]([C@@H:5]([CH2:4][OH:3])[OH:6])[OH:2])[OH:8])[OH:6]
Reactant: O
Reactant: OCC(O)CO
Agent: [Na]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A high speed propeller mixer provided with a scraper was charged with the PEG-400, and the cross-linked CMC sodium was added, while stirring. After all lumps were broken up and a uniform slurry was obtained, the ground limestone was added in portions, and stirring was continued until all of the solids were suspended. The resulting slurry was homogenized and dearated and then filled into #11 oblong A size soft gelatin capsules by means of a rotary die encapsulator. The shell of the capsules was formed from gelatin, water, sorbitol and glycerin, and contained vanillin flavoring agent and titanium dioxide opacifier.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[I:17][C:18]1[CH:31]=[CH:30][C:21]([CH:22]=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[I:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cccnc1Br
Reactant: CC(C)(C)S(=O)N=Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(I)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-3-(trifluoromethyl)pyridine (750 mg, 3.32 mmol) (prepared as described in Schlosser, M. et al. Eur. J. Org. Chem. 2003, 1559) in THF (5.0 mL) at −78° C. was added n-butyllithium (3.94 mL, 6.31 mmol, 1.6 M in n-hexane). The resulting mixture was then stirred for 15 min. N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (556 mg, 1.66 mmol) in THF (5 mL) was added, and the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and stirred rapidly for 1 h. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were dried (MgSO4) and concentrated. The product thus obtained was taken into the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2sccc2c(=O)[nH]1
Product: Cc1cc2sccc2c(Cl)n1

Procedure:
A solution of 6.2 g of 6-methylthieno[3,2-c]pyridin-4(5H)-one in 30 ml of phosphoryl chloride was heated under reflux for 1 hour. After being cooled, the excess phosphoryl chloride was removed under reduced pressure, and the residue was poured into ice water, made basic with aqueous 2N sodium hydroxide and extracted with chloroform. The extract was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 7.0 g of 4-chloro-6-methylthieno[3,2-c]pyridine as a brown oily material.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[CH:10]=[N:11][C:12](Cl)=[N:13][CH:14]=1>C1COCC1.O>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:13][CH:14]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94.7 %

Procedure:
A suspension of 607.92 mg (15.20 mmol) of sodium hydride in 50 mL of THF is prepared under argon. A solution of 1.10 g (15.20 mmol) of cyclopropanemethanol in 5 mL of THF is added dropwise. The mixture is stirred for 50 minutes at room temperature. 1 g (5.07 mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added. The mixture is stirred at room temperature overnight. The reaction mixture is taken up in water and extracted with ethyl acetate. The organic phase is washed with aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried and evaporated to dryness to give 1.10 g of 5-bromo-2-cyclopropylmethoxypyrimidine, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10]1([CH3:33])[CH:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]2[C:19](=[O:32])[CH:20]([NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]2[S:11]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:9][C:10]2([CH3:33])[CH:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]3[C:19](=[O:32])[CH:20]([NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:12]3[S:11]2)=[N:4][N:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Reactant: Cc1nnc(S)s1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CSc1nnc(C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.4 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture of pH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To this solution was added a solution of methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80 g) in acetone (10 ml) and the mixture was stirred for 4 hours at room temperature. After the reaction was completed, acetone was distilled off from the reaction mixture and the residue was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (60 g) and eluted with chloroform. The eluate was separated into fractions of each about 30 ml to give methyl 2-(5-methyl-1,3,4-thiadiazol-2yl)thiomethyl-2-methyl-6(2-phenoxyacetamido)penam-3-carboxylate (0.28 g) from the fourth to seventh fractions.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][CH2:50][NH:51][CH:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:37]1([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35][NH:34][C:30]2[N:29]=[C:28]([CH2:49][CH2:50][NH:51][CH:52]([CH2:53][CH3:54])[CH2:55][CH3:56])[N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:10]2[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)NCCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.1 %

Procedure:
N-(2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}ethyl)-N-(1-ethylpropyl)amine (250 mg, 0.31 mmol) (preparation 19) was dissolved in dry tetrahydrofuran (1 ml), a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 ml, 1 mmol) added and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue purified by column chromatography eluting with a gradient system of dichloromethane:methanol:ammonia (94:6:0.6) changing to dichloromethane:methanol:ammonia (90:10:1) to give the crude product as a foam. This was dissolved in ethyl acetate (15 ml) and the solution washed sequentially with dilute aqueous sodium hydroxide solution, brine and water, then dried with anhydrous sodium sulfate. The solvent removed under reduced pressure to give the title compound as a powder (100 mg). MS: 575 (MH+)
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26].FC1C=C(F)C=CC=1N>>[OH:26][CH2:25][CH2:24][O:23][C:22]1[CH:21]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(OCCO)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: Nc1ccc(F)cc1F
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OCCO)c1
Yield: 48.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2-(3-aminophenoxy)ethanol in 20 place of the 2,4-difluoroaniline. 180 mg of N-[3-(2-hydroxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:13]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C1CCNC1
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(Cl)n1
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(N2CCCC2)n1
Yield: 80.2 %

Procedure:
4-(1-Adamantylamino)-2,6-dichloropyrimidine is reacted with pyrrolidine as described in Example 12 to obtain the title product in a yield of 80.2%, m.p.: 186°-190° C.