Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:38]=[CH:39][CH:40]=3)[O:20][C:21]3[N:25](CC4C=CC(OC)=CC=4)[N:24]=[N:23][C:22]=3[C:35](O)=[O:36])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:40]=[CH:39][C:38]4[C:35](=[O:36])[C:22]5[NH:23][N:24]=[N:25][C:21]=5[O:20][C:19]=4[CH:18]=3)[CH2:11][CH2:12]2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=c1c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc2nn[nH]c12
Temperature: -20 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
The carboxylic acid from example 3 (150 mg, 0.25 mmole), was converted to its acid chloride using the same procedure as described. The acid chloride was suspended in dry dichloromethane, (10 ml), and the mixture stirred at -20° C. Aluminium chloride, (127 mg, 0.95 mmole), was added portionwise to the mixture and stirring continued for 2 hours at -20° C. The reaction was warmed to 0° C. over 1 hour, then stirred for 2 hours at 0° C., then quenched with dilute hydrochloric acid, (20 ml). After standing overnight the mixture was decanted and the residual orange gum was washed with a little water and triturated with hot methanol. Filtration of the cooled mixture gave 20 mg (16%) of the title compound as its hydrochloride. The free base was obtained by suspending the solid in water, neutralizing to pH 7 with dilute sodium hydrogen carbonate solution and filtering off the pale orange solid. After drying in vacuo 14 mg (12%) of the title compound was isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd]>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: O=C(c1ccc(Br)cc1)c1nccs1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)c1nccs1
Yield: 45 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and (4-bromophenyl)(1,3-thiazol-2-yl)methanone following the general method of Example 1 using cesium carbonate as the base and tris(dibenzylideneacetone)dipalladium (0) as the palladium source. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 95:5, as the eluent affording 0.126 g (45% yield) of the title compound as a yellow solid: mp (decomp.) 234-235° C.; MS (TSP) m/z 399 (M+1);
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[H][H]>CO.[C].[Pd]>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:6]2[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([CH3:1])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Yield: 88.3 %

Procedure:
To a mixture of 108a (1.0 g, 3.1 mmol) in methanol (15 mL) was added 10% palladium carbon (100 mg). The mixture was stirred at room temperature under the atmosphere of hydrogen for overnight. At the end of reaction, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10:1, UV) to afford 108b as a brown solid (800 mg, 88%). LCMS: [M+H]+ 293
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O[CH:12]=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:10]1
Reactant: NNc1ccccc1Br
Reactant: O=C1CCCCC1=CO
Agent: Cl
Solvent: CCO
Product: Brc1ccccc1-n1ncc2c1CCCC2

Procedure:
2-Bromophenylhydrazine hydrochloride (1.00 g, 4.47 mmol) was added to a solution of 2-(hydroxymethylene)cyclohexanone (0.564 g, 4.47 mmol) in ethanol (20 mL) and the resulting solution was refluxed 3 h before being concentrated. The crude material was taken up in DCM and washed with saturated ammonium chloride, 1N NaOH, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-indazole.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li+].CCC[CH2-].[CH:16]([Si:19]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]#[N:30])[C:23]=2[CH:22]=[CH:21]1)([CH3:18])[CH3:17].C(Br)(Br)(Br)[Br:38]>O1CCCC1>[Br:38][C:27]1[CH:26]=[N:25][C:24]2[N:20]([Si:19]([CH:16]([CH3:18])[CH3:17])([CH:31]([CH3:33])[CH3:32])[CH:34]([CH3:36])[CH3:35])[CH:21]=[CH:22][C:23]=2[C:28]=1[C:29]#[N:30]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C#N)ccnc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C#N)c(Br)cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
2,2,6,6-Tetramethylpiperidine (380 μL, 2.25 mol) was dissolved in tetrahydrofuran (3 mL) and cooled to 0° C. N-Butyllithium (2.5 M in hexanes, 1.06 mL, 2.66 mmol) was added dropwise and the mixture was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (613 mg, 2.04 mmol) in tetrahydrofuran (2 mL) was added at −78° C. and the mixture was stirred at −78° C. for 1 h. A solution of carbontetrabromide (2 g, 6.1 mmol) in tetrahydrofuran (5 mL) was added quickly at −78° C. and the mixture was stirred for 15 min. The reaction was quenched with saturated ammonium chloride solution. The mixture was warmed to ambient temperature and applied to a Varian chemelut cartridge and eluted with ethyl acetate. The crude product was purified by flash silica gel chromatography using a gradient of dichloromethane in hexanes to afford 5-Bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (160 mg, 0.42 mmol, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.88 (d, J=3.5 Hz, 1H), 6.83 (d, J=3.5 Hz, 1H), 1.85 (septet, J=7.5 Hz, 3H), 1.04 (d, J=7.5 Hz, 18H). MS: m/z 378.0/380.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[C:13](=[O:29])[CH2:12]1.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([OH:29])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(=O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-2,3-dione (1.514 g; 3.69 mmol) in anh. EtOH (20 ml) was treated with NaBH4 (700 mg; 18.49 mmol), and the mixture was stirred at rt, under nitrogen, for 2 h. After concentration to dryness under reduced pressure, the resulting residue was treated with 1 M aq. HCl and with water. After extractions with DCM, the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a colorless foam. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 412.27 g/mol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:13]([OH:26])[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[CH2:9][CH2:10][CH2:11][CH3:12])(C)(C)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:7][CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C@@H:13]([C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:15][CH2:16][CH2:17][CH2:18][S:19]1)[OH:26]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCC(N)[C@H](O)C1(c2ccccc2)SCCCS1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To {1-[hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester (608 mg, 1.47 mmol) in dioxane (2.7 mL) at 10° C. was added hydrochloric acid (2.7 mL, 4 M in dioxane). The solution was warmed to 23° C. After 3 h, the solution was diluted with toluene (5 mL) and concentrated under reduced pressure. The gummy solid was washed with diethyl ether resulting in the hydrochloride salt of 2-amino-1-(2-phenyl-[1,3]dithian-2-yl)-hexan-1-ol, 414 mg, 82% as a free flowing solid after removal of excess ether under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[OH:22])(=[O:3])[NH2:2].[C:23]1([CH:29]2[O:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:30][CH:29]([OH:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]=1[OH:22])(=[O:3])[NH2:2]
Reactant: c1ccc(C2CO2)cc1
Reactant: NC(=O)c1ccc(OCCCNCc2ccccc2)cc1O
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCCN(Cc2ccccc2)CC(O)c2ccccc2)cc1O

Procedure:
A solution of 12.7 g of N-[3-(4-carbamoyl-3-hydroxy-phenoxy)propyl]-benzylamine and 7.6 g of phenylethylene oxide in 80 ml of isopropanol is refluxed for 16 hours. The reaction mixture is evaporated, the residue is partitioned between 100 ml of 6N hydrochloric acid and 100 ml of ether and the aqueous phase is separated off and rendered alkaline with 2N ammonia solution. The N-[3-(4-carbamoyl-3-hydroxy-phenoxy)-propyl]-N-(2-hydroxy-2-phenyl-ethyl]-benzylamine thus obtained is isolated by extraction with ethyl acetate an debenzylated in the form of the crude product.
Reaction SMILES: C12CC1CCC(C(OC)=O)C2.[O:12]1[C:16]2([CH2:21][CH2:20][C:19]([C:22](OCC)=[O:23])=[CH:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>>[O:12]1[C:16]2([CH2:21][CH2:20][C:19]([CH2:22][OH:23])=[CH:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1=CCC2(CC1)OCCO2
Agent: COC(=O)C1CCC2CC2C1
Product: OCC1=CCC2(CC1)OCCO2

Procedure:
Following the procedure as described in Example 361 Step 2 and making non-critical variations to replace methyl bicyclo[4.1.0]heptane-3-carboxylate with ethyl 1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate, the title compound was obtained as a colourless liquid (5.0 g, 94%): 1H NMR (300 MHz, CDCl3) δ 5.62-5.57 (m, 1H), 4.04-3.91 (m, 6H), 3.47 (d, J=6.4 Hz, 1H), 2.31-2.20 (m, 4H), 1.82-1.71 (m, 4H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:18])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[CH3:19][CH:20]1[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[N:23]2[C:29](=[O:32])[CH:30]([NH2:31])[C@H:22]2[S:21]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:19][CH:20]1[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[N:23]2[C:29](=[O:32])[CH:30]([NH:31][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=3)=[O:18])[C@H:22]2[S:21]1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=CN=c1[nH]c(C(=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2S1
Temperature: -20 °C

Procedure:
To dimethylformamide (78 ml.) was added dropwise phosphorus oxychloride (11.9 g.) under stirring and icecooling, and the mixture was stirred for 30 minutes at 40° C. To the mixture was added 2-(2-formylaminothiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylic acid, (7.8 g.) under cooling at -20° C., and then the mixture was stirred for 30 minutes under cooling at -20° to -15° C. Thus obtained mixture was added to a solution, which was prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (8.35 g.) and bis(trimethylsilyl)acetamide (19.5 ml.) in dried methylene chloride (170 ml.) at room temperature, under cooling at -50° to -45° C. with stirring. The mixture was stirred for 1 hour at -45° to -40° C. and then the reaction mixture was poured into a solution of sodium bicarbonate (32 g.) in water (1.5 l) with shaking. The aqueous layer was separated and washed with ethyl acetate. The aqueous solution was layered with ethyl acetate and then adjusted to pH 1 to 2 with concentrated hydrochloric acid. The ethyl acetate layer was separated from the mixture, and the remaining aqueous layer was extracted with ethyl acetate (200 ml.×2). The ethyl acetate layers were combined together, washed with water and then concentrated to a small volume. The precipitates were collected by filtration, washed with a small amount of ethyl acetate and then dried to give 2-methyl-7-[2-(2-formylaminothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 2-methyl-7-[2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (7.9 g.), mp 210° to 215° C. (dec.).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([S:29]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36]C[C@H](CO)O3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])C=CC=CC=1>>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]3[C:13]([CH2:16][CH2:17][C@@H:18]([CH2:19][O:20][S:29]([C:32]4[CH:41]=[CH:40][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[O:21]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@@H](CO)CC2
Reactant: O=S(=O)(c1ccccc1)c1ccc(CC[C@@H](O)CO)c(Br)c1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc(S(=O)(=O)c4ccccc4)cc3O2)cc1

Procedure:
Toluene-4-sulfonic acid (S)-7-benzenesulfonyl-chroman-2-ylmethyl ester was prepared following the procedure described for the corresponding (R) enantiomer in step 9 of Example 6, but substituting ((S)-7-benzenesulfonyl-chroman-2-yl)-methanol for ((R)-7-benzenesulfonyl-chroman-2-yl)-methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([C:12](=[O:24])[CH:13]=[CH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:4][CH2:3]1.[Cl-].[Cs+].[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([CH:12]([OH:24])[CH:13]=[CH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:4][CH2:3]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)O)cc4)ccc32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)C=Cc4ccc(C(=O)O)cc4)ccc32)cc1
Reaction time: 0.5 h

Procedure:
2 g (4.7 mmol) of 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthyl)-3-oxopropenyl]benzoic acid are dissolved in 50 ml of methanol, and 2.1 g (5.6 mmol) of caesium chloride are then added. After 30 minutes, 0.18 g (4.8 mmol) of sodium borohydride is added. After 30 minutes, the medium is treated with ammonium chloride solution and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 50/50 heptane/ethyl acetate). A solid is obtained (0.42 g; yield=21%; m.p. >300° C., dec).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])[N:8]2[N:15]=[CH:16][CH:17]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[Br:18]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:17]1[CH:16]=[N:15][N:8]2[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1cc(CCCC)n2nccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(CCCC)n2ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 76.8 %

Procedure:
A solution of 7.0 g (0.03 mol) of 5,7-di-n-butylpyrazolo[1,5-a]-pyrimidine in 75 ml chloroform was treated with 5.8 g (0.035 mol) of N-bromosuccinimide at room temperature. The mixture was stirred for 5-10 minutes, then poured into ice water, made alkaline with 6N NaOH, and the organic layer separated and dried (Na2SO4). The chloroform solution was chromatographed on neutral alumina (Woelm, grade I) with chloroform as the eluant. Evaporation of the solvent and recrystallization from ligroine gave 7.15 g (72%) of the product, mp 47°-48° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].BrC1C2OCN(C(C)(C)C)CC=2C=C(C(C)(C)C)C=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44]Cl>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: COCCOCCl
Agent: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (5.0 g, 21.8 mmol) and triethylamine (4.4 g, 43.5 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen was added dropwise 2-methoxyethoxymethyl chloride (2.5 mL, 21.9 mmol) and the reaction mixture stirred overnight. The reaction mixture was poured into water (100 mL), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (5.0 g, 72% yield).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38]N(C)[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38][N:26]([CH2:25][C:24]([CH3:28])([CH3:27])[CH3:23])[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CC(C)(C)CN
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(C)(C)C)C1
Yield: 4 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2,2-dimethyl-propylamine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (7.9 mg, 4% yield). 1H NMR (500 MHz, DMSO) δ: 7.42 (d, 1H, J=8.24), 7.36 (s, 1H), 7.12 (d, 1H, J=8.24), 4.61 (s, 2H), 4.26 (s, 2H), 3.27 (s, 2H), 3.04 (s, 3H), 0.93 (s, 9H). HRMS (M+H) calcd for C18H23N2Cl2O3: 385.1085; found: 385.1079.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:8]2[NH:9][C:10]([C:14]3[CH:19]=[C:18]([S:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=3[O:30][CH2:31][CH3:32])=[N:11][C:12](=[O:13])[C:7]=2[N:6]([CH3:33])[N:5]=1.Cl.[Na].[NH2:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43]>C(O)C.O>[CH3:1][CH2:2][CH2:3][C:4]1[C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[C:18]([S:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=3[O:30][CH2:31][CH3:32])[NH:11][C:12](=[O:13])[C:7]=2[N:6]([CH3:33])[N:5]=1.[NH2:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44]
Reactant: CCCc1nn(C)c2c(=O)nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)[nH]c12
Agent: Cl
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
In a flask equipped with a magnetic stirrer, Sildenafil HCl (8.8 g) is dissolved in a mixture of ethanol (100 mL) and water (30 mL), added an ethanol solution of Arginine sodium then reacted at 50° C. for 60 mins. After cooling, a white precipitate is obtained and the sodium chloride is removed by filtration. The methanol is added under room temperature and being incubated over night for re-precipitation. The Sildenafil-L-Arginine complex salt (10.8 g) is obtained after filtering the crystal.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:6]=1.Br[C:18]([CH3:29])([CH3:28])[C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:15][O:16][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])([CH3:29])[CH3:28])[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[N:6]=1
Reactant: CC(C)(Br)C(=O)OCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(=NOC(C)(C)C(=O)OCC[Si](C)(C)C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
24.9 g (102 mmol) of t-butyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 400 ml of dimethylformamide. After the addition of 54.7 g (205 mmol) of 2-(trimethylsilyl)ethyl 2-bromo-2-methylpropionate, followed by 56.6 g (410 mmol) of finely ground potassium carbonate, the mixture is stirred at 25° C. for 4 hours in a nitrogen atmosphere. After the addition of 3 l of water, the mixture is extracted with 1.5 l of ethyl acetate. The organic phase is washed twice with 1.5 l of water. The aqueous phase is extracted with 1.5 l of ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. The product is purified by flash chromatography on silica gel [hexane/ethyl acetate (2:1)] and crystallized from methanol/water. There are obtained 28.6 g (65.3%) of t-butyl 2-(2-amino-4-thiazolyl)-2-[(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]-acetate of melting point 83° C.
Reaction SMILES: Cl.C([O:4][C:5](=[O:18])[CH2:6][NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)C.C([NH:29][C@H:30]([C:32](O)=[O:33])[CH3:31])(OCC1C=CC=CC=1)=O>>[NH2:29][C@H:30]([C:32]([N:7]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)[CH2:6][C:5]([OH:4])=[O:18])=[O:33])[CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNC1CCc2ccccc2C1
Agent: Cl
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2ccccc2C1
Yield: 54.2 %

Procedure:
By reacting 13.5 g of N-(1,2,3,4-tetrahydronaphthalen-2-yl)glycine ethyl ester hydrochloride with 11.6 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 7.5 g of L-alanyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)glycine as colorless amorphous powder.