Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3]>C1COCC1.C(O)C.[C].[Rh]>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3=[N:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19][N:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 15 mg) and 9-[4-(1-methylethyl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (143 mg) as a gray white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: CO[C:3](=[C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]1=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[CH:33][CH:32]=1>CN1C(=O)N(C)CCC1.C(OCC)(=O)C>[CH3:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:3](=[C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[O:29])[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:12]4)=[CH:6][CH:5]=3)=[CH:32][CH:33]=2)[N:38]=[CH:39]1
Reactant: Cn1cnc(-c2ccc(N)cc2)c1
Reactant: C=CCOC(=O)NC1(c2ccc(C(OC)=C3C(=O)Oc4ccccc43)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: C=CCOC(=O)NC1(c2ccc(C(Nc3ccc(-c4cn(C)cn4)cc3)=C3C(=O)Oc4ccccc43)cc2)CC1

Procedure:
1.05 g of allyl (1-{4-[methoxy-(2-oxobenzofuran-3-ylidene)methyl]phenyl}cyclopropyl)-carbamate and 0.47 g of 4-(4-aminophenyl)-1-methylimidazole in 3 mL of DMPU were reacted in the microwave reactor at 180° C. After cooling, the mixture was diluted to 150 mL with ethyl acetate, extracted 2× with water, and the organic phase was dried over MgSO4 and evaporated down to the residue with silica gel. The substance was chromatographed with dichloromethane/methanol (97:3) on silica gel 70 at a flow rate of 30 mL/min Residue: 0.6 g of yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1.[CH3:18]I>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([CH3:18])[C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (80% dispersion in oi; 1.15 g) in dry THF (50 ml) under nitrogen was added 8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (6.5 g) in dry THF (50 ml), and the mixture was stirred for 1 h. Methyl iodide (4.1 ml) was added, and the mixture was stirred for 3 h. The mixture was then poured into brine (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (5.77 g), m.p. 126°-128°.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:11]2[C:12]3[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=3[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[CH:8]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:10]2=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (46 mg, 0.098 mmol), β-alanine (699 mg, 7.8 mmol) and NaOMe solution (11.8 mL, 5.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 5 mg of the title compound. MS: (+) m/z 527.45 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[C:36]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:31])[CH:37]=2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 5, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and 2-chloropyridine-4-boronic acid. The desired product was obtained in a yield of 7% as white solid. MS (m/e): 609.0 (M+H, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][CH:22]1[C:26](=[O:27])[O:25][CH:24]2[CH2:28][CH2:29][CH2:30][CH:23]12.[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@:22]1([CH2:21][C:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:26](=[O:27])[O:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@H:23]12)[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: O=C1OC2CCCC2C1Cc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@]1(Cc2ccc3ccccc3c2)C(=O)O[C@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 1.9 ml of a 1 molar solution of lithium bis-(trimethylsilyl)-amide in THF are added dropwise to a solution, cooled to −78° C., of 0.5 g (1.88 mmol) of the compound from Example 1 in 20 ml of THF such that the temp. of the mixture does not exceed −65° C. After the addition has ended, stirring is continued at −78° C. for 10 min, and 0.26 g (2.25 mmol) of allyl bromide are then added in one portion. Immediately afterwards, the cooling bath is removed and the mixture is allowed to warm to room temp. After 16 h of stirring at room temp., the mixture is taken up in ammonium chloride solution and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and then concentrated. The residue was chromatographed over silica gel (mobile phase: dichloromethane). Yield: 255 mg (44%) of a colourless oil. 1H-NMR (200 MHz; CDCl3) δ[ppm]=1.55-2.2 (br m,6H), 2.3 (m, 2H), 2.61 (m,1H), 3.12 (d,1H), 3.3 (d,1H), 4.91 (m,1H), 5.05 (dd,1H), 5.11 (dd, 1H), 5.8 (ddt,1H), 7.35-7.5 (br m,3H), 7.72 (s,1H), 7.80 (m,3H). Diastereomeric purity: >99% de (HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2cc(C)no2)cc1
Yield: 81 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206 using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 2-methoxybenzeneboronic acid resulting in an 81% yield of the final product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1>>[OH:15][CH:14]([C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)[C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:40]2[CH:41]=[CH:42][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:44][CH:45]=2)=[CH:3][CH:4]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1

Procedure:
Prepared according to the procedure described in Example 94, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([O:15][C:13]([CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3 g of p-hydroxyphenylacetonitrile, 3.6 ml of t-butyl bromoacetate, 6.5 g of potassium carbonate in 45 ml of dimethylformamide is stirred at room temperature for 16 hours. After dilution with water the product is extracted with ether. The ether layer is washed with 1 N sodium hydroxide, dried over magnesium sulfate and the solvent removed in vacuo to yield p-(t-butoxycarbonylmethoxy)-phenylacetonitrile which is reduced to p-(t-butoxycarbonylmethoxy)-2-phenethylamine with sodium borohydride/cobalt chloride as described for the starting material under a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH2:27][C:26]([O:25][CH3:24])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(COc2ncnc3nc[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21
Reaction time: 0.25 h

Procedure:
6-Benzyloxypurine (4.18 g; 18.5 mmol) was added to a suspension of potassium carbonate (3.1 g; 22.4 mmol) in DMF (100 ml). After 15 min., bromoacetic acid methyl ester (1.93 ml; 20.4 mmol) was added. The reaction was monitored by TLC in butanokacetic acidiwater 4:1:1. Upon completion, the reaction mixture was partitioned between water (600 ml) and ethyl acetate (600 ml). The organic phase was dried over magnesium sulfate and evaporated to a volume of ˜10 ml and precipitated with pet. ether. The two products were separated by column chromatography using ethyl acetate as the solvent. The products were precipitated in pet. ether. Yield: 2.36 g (43%). Melting point: 111.5-115° C. UV λmax=250 nm (9-alkylated); λmax=260 nm (7-alkylated). 1H-NMR (DMSO-d6): 8.60 (1H, s); 8.43 (1H, s); 7.6-7.35 (5H, m); 5.69 (2H, s); 5.26 (2H, s); 3.75 (3H, s).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10]CC)=O)[CH3:2].[NH3:13]>CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH2:13])=[O:10])[CH3:2]
Reactant: N
Reactant: CCOC(=O)[C@@H]1CCCN1CC
Solvent: CO
Product: CCN1CCC[C@H]1C(N)=O
Temperature: 50 °C

Procedure:
Ethyl (-)-(S)-1-ethyl-2-pyrrolidinecarboxylate (3.4 g, 0.02 mol) was added to a cooled solution of MeOH (10 ml) and liquid NH3 (10 ml) in a stainless steel reaction bottle containing 3 g of 3 Å molecular sieves. The bottle was heated at 50° C. for 20 h. After cooling the solvent was allowed to evaporate. The product was dissolved in dry MeOH, filtered and the filtrate was evaporated under reduced pressure to give the title compound as white crystals in a quantitative yield (2.8 g). Recrystallization from n-hexane afforded 2.5 g (88%) of the amide, mp 107°-108° C. [α]D25 =-119° (c=0.5 MeOH). The enantiomeric purity was determined to 99.7% S-isomer.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:35]=[CH:34][C:17]3[NH:18][C:19]([C@@H:21]4[CH2:25][C@H:24]([CH3:26])[CH2:23][N:22]4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:20][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>[Cu]I.CN(C=O)C>[CH3:26][C@@H:24]1[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:21]([C:19]2[NH:18][C:17]3[CH:34]=[CH:35][C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:9][CH:10]=4)=[CH:15][C:16]=3[N:20]=2)[CH2:25]1
Reactant: C[C@H]1C[C@@H](c2nc3cc(-c4ccc(Br)cc4)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2nc3cc(-c4ccc(C#C[Si](C)(C)C)cc4)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Ethynyl-trimethyl-silane (34.44 mg, 49.55 μL, 0.3506 mmol), tert-butyl (2S,4S)-2-[5-(4-bromophenyl)-1H-benzimidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (80 mg, 0.1753 mmol), Pd(DPPF)(Cl)2.CH2Cl2(14.32 mg, 0.01753 mmol), TEA (35.48 mg, 48.87 μL, 0.3506 mmol) and CuI (3.339 mg, 0.01753 mmol) are dissolved to dry DMF (2 mL). The mixture is stirred at 70° C. under N2 overnight. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography on silica gel SP1 25M using methanol/CH2Cl2 (0-5%) in 20 cv to provide tert-butyl (2S,4S)-4-methyl-2-[5-[4-(2-trimethylsilylethynyl)phenyl]-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylate (40 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:30][CH3:31])[CH:28]=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:6][CH2:7][CH3:8])=[CH:28][C:27]([CH3:26])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])[CH3:2]
Reactant: CCC(C)(C=O)c1ccccc1
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC(C)(CC)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
To a chilled (0° C.) solution of 7.4 g of (diethoxyphosphoryl)ethoxy acetic acid ethyl ester in 30 mL of THF was added 16 mL of a 1.8M solution of LDA. After 30 minutes, 4.2 g of 2-methyl-2-phenylbutyraldehyde in 30 mL of THF was added dropwise by syringe. The mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 8.3 g of 2-ethoxy4-methyl-4-phenylhex-2-enoic acid ethyl ester as an orange oil and a mixture of geometric isomers (2:1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][NH:23]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[NH:23][CH:24]=2)=[O:33])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1c[nH]c(=O)c2ccccc12

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.059 g). Title compound obtained as white solid (0.047 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:43])=[O:28])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.30 g), 1-hydroxybenzotriazole ammonia complex (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide as colorless crystals (0.25 g, yield 83%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 187-188° C.
Reaction SMILES: CO.C(OC([NH:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[NH2:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](N)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.5 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 35 ml of methylene chloride is cooled to 0° C. Then, there is added a solution of 7.7 ml of trifluoroacetic acid in 40 ml of methylene chloride and the mixture is left to stand under stirring at first 30 minutes at a temperature of 0°-5° C., then 4 hours at room temperature. After neutralization with a solution of sodium bicarbonate, the organic phase is separated, washed with water, dried and evaporated to dryness. The residue is taken up with 15 ml of ethyl acetate and made acid with a solution of hydrochloric acid in ethanol. The precipitated so obtained is filtered and washed with ether. Thus, 1.1 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride is obtained; m.p. 168°-171° C., /alpha/=+51.14° (methanol, c=1%). (b) To a solution of 5.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 135 ml of absolute ethanol there is added at room temperature 82 ml of a 7.2. N solution of hydrogen chloride in ethanol. The mixture is left under stirring at room temperature for 150 minutes, then it is evaporated to dryness under reduced pressure. The residue is taken up with ethyl ether and filtered. Thus, 4.6 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride are obtained; m.p. 170°-171° C., /alpha/=+51° (methanol, c=1%). By crystallization from methanol, the melting point remains unchanged (170°-172° C.) and the /alpha/ rises to +51.6° (methanol, c=1%).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C([Mg]Br)C.[CH3:12][Si:13]([CH3:20])([CH3:19])[C:14]#[C:15][C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.C1COCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:16]([OH:18])([C:15]#[C:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[CH3:17])=[N:3]1
Reactant: Cn1ccc(I)n1
Reactant: CC(=O)C#C[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ccc(C(C)(O)C#C[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1-methyl-1H-pyrazole (378 mg, 1.82 mmol) in dry DCM (15 mL) at 0° C. under an atmosphere of nitrogen, was introduced ethylmagnesium bromide (2.0 mL of a 1.0M solution in THF, 2.0 mmol). After 30 minutes at 0° C., the reaction mixture was warmed to RT for 15 minutes, then introduced to a solution of 4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.18 mmol) in dry DCM (5 ml) at 0° C. under an atmosphere of nitrogen. The reaction mixture was warmed to RT for 16 hr. Following addition of saturated aqueous ammonium chloride (5 ml), the reaction mixture was extracted with DCM (3×5 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (heptane/EtOAc gradient) furnished the title compound as an orange-brown oil: 1H NMR (500 MHz, CDCl3) delta 0.15 (9H, d, J=3.5 Hz), 1.82 (3H, s), 3.18 (1H, s), 3.86 (3H, s), 6.28 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=2.2 Hz); LC-MS: m/z=+222.95 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CO.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([Cl:1])=[C:12]([Cl:17])[N:11]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: O
Product: Nc1nc(N)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
50 g of N-chlorosuccinimide are added in portions at 23° C. to a solution of 45 g of 2,4-diamino-6-chloropyrimidine in methanol (1030 ml). On completion of addition, the reaction mixture is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the crude product obtained is taken up under reflux in 850 ml of water for 1 hour. After filtering, the crude product is recrystallized two times from an EtOH:H2O (80:20) mixture to give 44.5 g of 2,4-diamino-5,6-dichloropyrimidine.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC>CN(C1C=CN=CC=1)C>[S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O:6][CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Yield: 92 %

Procedure:
This compound was synthesized as a colorless oil from 2-pentanol (122.0 mg, 1.384 mmol), TsCl (316.6 mg, 1.66 mmol), Et3N (280.3 mg, 2.77 mmol), and DMAP (169.0 mg, 1.384 mmol) in 92% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3; δH) 7.75 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.63-4.51 (m, 1H), 2.40 (s, 3H), 1.56 (dddd, J=14.0, 10.0, 7.2, 5.4 Hz, 1H), 1.49-1.35 (m, 1H), 1.35-1.04 (m, 5H), 0.77 (t, J=1A Hz, 3H); 13C NMR (100 MHz, CDCl3, δC) 144.57, 134.63, 129.84, 127.78, 80.55, 38.70, 21.73, 20.90, 18.28, 13.74. ESI-MS: 243.1 (M+H+), 265.1 (M+Na+).