Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4](=[O:23])[CH:3]=1.O.C(O)C.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4](=[O:23])[C:3]=1[N:28]=[O:29]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 232 gm of crude 6-amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (4), 4.0 L of water and ca. 2.0 L of ethanol at 80 degrees C. was added 55.3 gm of sodium nitrite in one portion, followed by the dropwise addition of 100 mL of glacial acetic acid. After stirring at 80 degrees C. for 20 minutes the mixture was allowed to cool to near room temperature, then was chilled in an ice bath to effect crystallization. The solids were isolated by filtration, washed with two 1.0 L portions of water and dried under vacuum to yield 244 gm of purple colored 6-amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1ccc(Cl)s1

Procedure:
N-[(tert-Butoxy)carbonyl]5-chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate (109) is synthesised from 5-chlorothiophene sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d) 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 1.48 (9H, s), 1.35 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]2[O:4][N:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc(O)c2c(C)noc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2c(C)noc2c1
Yield: 34.7 %

Procedure:
3,6-dimethyl-1,2-benzisoxazol-4-ol (Intermediate 19, 345 mg) was dissolved in acetonitrile (10.0 ml) and then 1-fluoro-4-nitrobenzene (298 mg, 2.11 mmol) and potassium carbonate (877 mg, 6.34 mmol) were added. The reaction mixture was stirred and heated at reflux overnight. After removal of the volatiles, the residue was purified by silica gel chromatography eluting with a gradient cHex/EtOAc from 100/0 to 50/50 to afford the title compound (208 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:18]2[N:17]=[CH:16][NH:15][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CN2CCC(NCc3c[nH]cn3)CC2)cc1
Yield: 86.3 %

Procedure:
To a solution of 1-benzyl-4-piperidinamine (3.4 g), imidazole-4-carbaldehyde (1.4 g) and acetic acid (1.7 ml) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (4.7 g), and mixed at room temperature for 15 hours. A 1 N aqueous sodium hydroxide solution was added to the reaction solution and pH of the aqueous layer was adjusted to about 12, and then extracted with chloroform (100 ml). The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil (3.4 g).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]>CC(N(C)C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1ccncc1F
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccncc1NCc1cccc(F)c1
Temperature: 168 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 3-fluorobenzylamine (308 μL, 2.84 mmol) were combined in DMA (3 mL) and the solution was stirred at 168° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified through a short plug of silica gel chromatography (20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 58 mg (33%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247. found 247.
Reaction SMILES: [CH:1]1([C:5]([O-:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1CC(C(OC)=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:4][C:1]([CH2:2][CH3:3])([C:5]([OH:7])=[O:6])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])C1CCC1
Product: CCC1(C(=O)O)CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described for Reference Example 10 substituting cyclobutanecarboxylate with methyl 1-tert-butoxycarbonylazetidine-3-carboxylate. 1H NMR (500 MHz, CD3OD): δ 4.12 (d, 2H), 3.70 (d, 2H), 1.82 (q, 2H), 1.42 (s, 9H), 0.90 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([O:6]C)=[O:5].[C:15]1([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: COC(=O)c1c(O)cc(C=O)cc1Cl
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(O)c(C(=O)O)c(Cl)c2)N1
Temperature: 50 °C
Reaction time: 6 h
Yield: 25.5 %

Procedure:
To a solution of methyl 2-chloro-4-formyl-6-hydroxybenzoate (Intermediate 86) (150 mg, 0.70 mmol), 1,2-diphenylethanone (165 mg, 0.84 mmol) and urea (126 mg, 2.1 mmol) in ethanol (5 mL) was added conc. HCl (0.2 mL) and mixture was refluxed under N2 overnight. The mixture was concentrated under reduced pressure. The residue was taken up in aqueous NaOH (2 M, 5 mL) and MeOH (5 mL) and was stirred at 50° C. under N2 atmosphere for 6 hours. The resulting mixture was cooled to room temperature and acidified with aqueous HCl (2 M, 6 mL), followed by a standard aqueous/EtOAc workup and purification by prep-HPLC (0.1% TFA as additive) to give Compound 163 (75 mg, 2-step yield 26%). 1H NMR (CD3OD 400 MHz): δ 7.30-7.25 (m, 5H), 7.15-7.05 (m, 3H), 6.95-6.87 (m, 4H), 5.26 (s, 1H). MS (ESI): m/z 421.4 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.ClC1C=CC=CC=1CN.[N+](C=CC1C=CC=CC=1)([O-])=O>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:14]2[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccccc3)cn2Cc2ccc(Cl)cc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: NCc1ccccc1Cl
Agent: O=[N+]([O-])C=Cc1ccccc1
Product: Clc1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)cc1

Procedure:
1-(4-Chloro-benzyl)-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. The desired compound (405.6 mg) was prepared from 0.53 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of 2-chlorobenzylamine, and 0.34 g of (2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C25H27ClN2O2, 422.18; found, m/z 423.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45](O)=[O:46])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:45](=[O:46])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: CCn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 72 %

Procedure:
Following the procedure for Example 506 starting with (R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (330 mg, 72%). 1H-NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.66 (s, 1H), 8.15-8.05 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.15 (m, 3H), 6.31 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 4.07 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.25-2.10 (m, 2H), 2.10-1.70 (m, 4H), 1.57 (s, 9H) 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1.[CH3:13][O:14][CH2:15]Cl>CN(C=O)C>[CH3:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: COCCl
Reactant: O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Solvent: CN(C)C=O
Product: COCn1cc([C@H]2CCCC[C@@H]2O)cn1
Yield: 72.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 169c by using the (1S,2R)-2-(1H-pyrazol-4-yl)cyclohexanol (144 mg, 0.866 mmol) prepared in Example 171a, chloromethyl methyl ether (0.069 mL, 0.908 mmol) and DMF (4.0 mL), to yield the title compound (132.2 mg, 73%) as a colorless oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=[CH:2]1.C[C@]12C3C=C(OC(NC)=O)C=CC=3N(C)[C@H]1N(C)CC2.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[CH:41]2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([Mg]Br)C.CI>C1COCC1>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][C:46]=1[CH:47]([CH3:49])[CH3:48])[NH:43][CH:42]=[C:41]2[CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)c1cc2[nH]ccc2cc1OCc1ccccc1
Agent: CC[Mg]Br
Agent: CNC(=O)Oc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(C(C)C)c(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The methylation carried out in this step follows the procedure for indole alkylation reported by Marino et al. in “The Enantioselective Synthesis of (−) Physostigmine Via Chiral Sulfoxides”, J. Am. Chem. Soc. (1992), 114, 5566-5572. 5-Benzyloxy-6-isopropyl-1H-indole (0.855 g, 3.22 mmol) was dissolved in 20 mL of dry THF, and the resulting solution was cooled in an ice bath. Ethyl magnesium bromide (4.9 ml, 4.9 mmol in ether) was added dropwise to the solution, and the solution was then stirred for 4 hours at room temperature. Methyl iodide (1.42 g, 10 mmol) was then added, and stirring was continued for an additional 18 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified with flash chromatography (ethyl acetate/hexanes=1/9) to yield 325 mg of 5-benzyloxy-6-isopropyl-3-methyl-1H-indole Mass Spec (M+H): 280.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C>[BrH:1].[CH3:17][C:16]1[S:18][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[N:19]=1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(N)=S
Solvent: CCO
Product: Br
Product: Cc1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2)cs1

Procedure:
A mixture of 3.12 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 849.3 mg of thioacetamide are heated to boiling under reflux for 18 hours in 40 ml of ethanol. After cooling, the crystals are filtered under suction and recrystallized from methanol/isopropanol. There is obtained 5-(2-methyl-4-thiazolyl)-3-nitropyrocatechol hydrobromide of m.p. 280°-282°.
Reaction SMILES: [C:1](=[O:19])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][NH:37][CH2:36]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C>ClCCCl.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][CH2:38][N:37]([C:1]([O:2][CH2:3][C:4]4[N:5]=[CH:6][S:7][CH:8]=4)=[O:19])[CH2:36]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccc(-c2ccc(OCC3CCNC3)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O
Product: O=C(OCc1cscn1)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
0.30 g (1.07 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate, 0.34 g (1.28 mmol) of 3-(4′-fluorobiphenyl-4-yloxymethyl)pyrrolidine, 0.20 g (1.61 mmol) of N,N-diisopropylethylamine and 0.01 g (0.11 mmol) of dimethylaminopyridine are dissolved in 10 ml of 1,2-dichloroethane. The mixture is stirred at 70° C. for 4 hours. After returning to ambient temperature, water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with a 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After having dried the organic phases over sodium sulphate, they are filtered and the filtrate is evaporated to dryness. After purification by chromatography on a column of silica gel, elution being carried out with dichloromethane and methanol (98/2), 0.16 g of the expected product is obtained in the form of a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=1)([CH2:8][OH:9])[CH2:6][OH:7])[CH3:2].[C@@:18]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:24]1)C[C:19]2=O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=2)[CH2:8][O:9][C:18]([CH3:24])([CH3:19])[O:7][CH2:6]1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(CO)(CO)c1ccnc(Br)c1
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccnc(Br)c2)COC(C)(C)OC1
Temperature: 80 °C

Procedure:
A mixture of 2-(2-bromo-pyridin-4-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethyl ester (30.0 g, 98.6 mmol) 2,2-dimethoxy propane (51.11 g, [60.5 ml], 493.1 mmol) and (1R)-(−)-10-camphor sulphonic acid (5.72 g, 24.65 mmol) in DMF (100 ml) was heated at 80° C. for 10 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and worked up by washing with water, brine, followed by drying over anhy. Na2SO4. Organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography using 10% ethyl acetate in Hexane to obtain title compound as a yellow solid. Yield=18.15 g (53%). TLC (30% ethyl acetate in hexane) Rf=0.52; LCMS: RtH7=1.487; [M+1]+=344.0 and 346.0; HPLC RtH9=7.6 min (74%); 1H NMR (300 MHz, CDCl3): b 8.41-8.34 (t, 1H), 7.54 (s, 1H), 7.32-7.28 (m, 1H), 4.51 (dd, 2H), 4.27-4.21 (q, 4H), 1.45 (s, 3H), 1.39 (s, 3H), 1.23 (t, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([CH2:26][CH3:27])[CH3:25]>>[CH:24]([C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:32][CH:33]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CCC(C)c1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
White solid. MS (ESI): 407.23 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-sec-butyl-phenylamine.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH2:18]1[C@@H:20]2[C:21](=[O:39])[CH:22]=[C:23]3[C@:36]([CH3:37])([CH:19]12)[C@@H:35]1[C@H:26]([C@H:27]2[C@@:31]([CH2:33][CH2:34]1)([CH3:32])[C:30](=[O:38])[CH2:29][CH2:28]2)[CH2:25][CH2:24]3.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]=[C:24]1[C:23]2[C@:36]([CH3:37])([CH:19]3[CH2:18][C@@H:20]3[C:21](=[O:39])[CH:22]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:38])[CH2:29][CH2:28]3)[CH2:25]1
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)[C@H]1CC12
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1,2β-methylenandrost-4-en-3,17-dione (0.806 g, 2.7 mmol) is stirred at reflux for about 5 hours, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline (ca. 1 hour). The organic layer is separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluent. Thus the pure 6-methylen-1,2β-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.194 g).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:5][C:4]=1[F:14].C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:5][C:4]=1[F:14]
Reactant: Fc1cc(-c2ncon2)ccc1C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Fc1cc(-c2ncon2)ccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirring mixture of 3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazole (5.34 g, 30 mmol), CCl4 (50 mL) and NBS (11.7 g, 66 mmol) was added AIBN (246 mg, 1.5 mmol). The reaction mixture was heated to 80° C. for 3 hour under nitrogen, cooled to room temperature, and 50 mL of saturated sodium bicarbonate solution was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated on a rotovap to give 3-(4-(dibromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole, (9.34 g, 93%) as a white solid which was used in the next step without further purification. A 200 mL round bottom flask was charged with 3-(4-(dibromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (8.37 g, 25 mmol) and THF (60 mL). The mixture was cooled to 0° C. and diisopropyl ethyl amine (3.48 g, 27 mmol) was added dropwise over 15 minutes, followed by diethyl phosphite (3.7 g, 26.8 mmol). The mixture was stirred at room temperature for 60 minutes and quenched with 40 mL of water. The aqueous layer was extracted with ether (2×80 mL). The combined organic layer was washed with 20 mL of sat aq. NH4Cl and 20 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated on a rotovap to give a crude solid which was purified by a short silica pad to afford 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (6.03 g, 94%). mp 87.3° C. 1H-NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 7.94 (dd, 1H), 7.87 (dd, 1H), 7.58 (t, 1H), 4.57 (s, 2H); 13C-NMR (CD)Cl3, 400 MHz) δ 166.97, 166.95, 165.45, 162.29, 159.73, 132.34, 132.30, 128.99, 128.90, 128.81, 124.04, 124.01, 115.56, 115.32, 25.22, 25.18; 19F-NMR (CDCl3, 400 MHz) δ −115.81, −115.84, −115.86. Anal. Calcd for C9H6BrFN2O: C, 42.05; H, 2.35; N, 10.90. Found: C, 42.17; H, 2.17; N, 10.63.
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](F)N=1.C([N-][CH:22]([CH3:24])[CH3:23])(C)C.[Li+].BrBr>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([C:7]1[CH:6]=[CH:5][C:24]([C:22]#[C:23][C:2]2[C:3]([F:9])=[N:4][C:5]([F:8])=[CH:6][CH:7]=2)=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cccc(F)n1
Reactant: Fc1ccc(Br)c(F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: [Li+]
Product: CCCCCc1ccc(C#Cc2ccc(F)nc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0,2 mM of Pd(Ph3P)2Cl2 and 0,1 mM of CuJ are added to a mixture of 0,01 M of 3-bromo-2,6-difluoropyridine (preparation: 2,6-difluoropyridine is reacted with lithiumdiisopropylamide (LDA) as described in example 3a, then Br2 is added at -60° to -70°. The mixture is allowed to warm up to room temperature and worked up, the product is purified by distillation), 0,01 M of 4-pentylphenylacetylene and 200 ml of triethylamine. The mixture is stirred for 8 hours at room temperature; after customary work-up and purification by crystallization and chromatography 1-(4-pentylphenyl)-2-(2,6-difluoropyridine-3-yl)acetylene is obtained.