Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)(=O)C.O>O1CCCC1>[CH2:18]([O:17][C:15]([N:14]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:13][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH3:19]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NN(C(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A solution of 3,4-dimethoxyphenylmagnesium bromide (prepared from 10.85 g, 50 mmol of 3,4-dimethoxybromobenzene and 1.34 g, 55 mmol magnesium) in 200 ml tetrahydrofuran (hereinafter THF) was cooled to -75° C. and added to a solution of diethyl azodicarboxylate (8.71 g, 50 mmol) in 250 ml THF at -75° C. under an inert atmosphere. The solution was allowed to warm to 0° C. and acetic acid (3 g, 50 mmol) and H2O (20 ml) were added. The organic solution was dried over MgSO4, filtered and evaporated, providing N,N'-bis(ethoxycarbonyl)-3,4-dimethoxyphenylhydrazine as a red oil (15 g, 96% yield). This material was dissolved in isopropanol (500 ml) and 15 g potassium hydroxide was added. The mixture was refluxed under nitrogen for four hours, cooled, and neutralized with acetic acid (15 ml). The mixture was evaporated, the residue was treated with ether and aqueous sodium hydroxide, and the ether solution was dried over MgSO4, filtered and distilled in vacuo. Veratrole was distilled from the mixture, followed by 3,4-dimethoxyphenylhydrazine, which was crystallized from carbon tetrachloride to provide 1.0 g off-white powder, mp 103°-106° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[NH2:36][CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:36][CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[N:5][OH:6]
Reactant: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CCNC(=O)CN
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)CNC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 75 °C
Yield: 53 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde Oxime (i.e. the Product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (81 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2-amino-N-ethyl-acetamide (58 mg) and triethylamine (0.15 mL, 0.11 g) in THF (10 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (164 mg, 53%).
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[C:5](\[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][CH3:30])[C:12]=1[CH2:31][CH3:32])/[C:6]([O:8]C)=[O:7].[OH-].[Na+].CO.Cl>C(Cl)(Cl)Cl>[CH2:31]([C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10]/[C:5](=[CH:4]\[C:3]([OH:33])=[O:2])/[C:6]([OH:8])=[O:7])[CH3:32]
Reactant: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)OC)C(=O)OC)c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)O)C(=O)O)c1CC

Procedure:
A solution of 42.0 parts of dimethyl 2-ethyl-3-(3-[2-propylphenoxy] propoxy)phenoxyfumaric acid and 7.36 parts of sodium hydroxide in 50% v /v aqueous methanol was refluxed for four hours. The reaction mixture was cooled, acidified with excess 2N hydrochloric acid and extracted with chloroform. Evaporation of the chloroform and trituration of the residue with 40/60 light petroleum ether gave an oily solid. This solid was dissolved in hot chloroform and addition of 40/60 light petroleum ether to the solution gave 33.8 parts of 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumaric acid, m.pt. 104°-105°.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[Si:12]([O:29][C@@H:30]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[CH:49]=[O:50])[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:49]([C@H:39]1[CH2:38][CH2:37][C@H:36]2[C@H:35]3[C@H:44]([CH2:43][CH2:42][C@:40]12[CH3:41])[C@:45]1([CH3:48])[C@H:32]([CH2:31][C@H:30]([O:29][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:47][CH2:46]1)[CH2:33][CH2:34]3)[OH:50]
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(O)C#C[Si](C)(C)C)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of trimethylsilylacetylene (0.24 mL, 1.715 mmol) in anhydrous THF (5.7 mL) at 0° C. was added a solution of n-BuLi (1.07 mL, 1.715 mmol) 1.6 M in hexanes and the resulting mixture was stirred for 2 h. Subsequently, the mixture was cooled to −78° C. and a solution of 3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-carboxaldehyde (310 mg, 0.57 mmol) in THF (5.7 mL) was added and the mixture was stirred at this temperature for 3 h. Quenching of the reaction by the addition of NH4Cl was followed by extraction with ethyl acetate.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]1=[CH:15]N(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([NH2:23])=[NH:22]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2]2[N:22]=[C:21]([C:20]([F:25])([F:24])[F:19])[N:23]=[CH:15][C:3]=2[CH2:4]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: N=C(N)C(F)(F)F
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Product: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)F)ncc2C1

Procedure:
Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.78 g) from Intermediate 28, Step A with trifluoroacetamidine (0.86 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 18% ethyl acetate/hexanes as eluant), afforded the title compound as a viscous orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]=3[C:5]=2[CH:4]=1
Reactant: CCCBr
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)NCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCCc2c1c1cc(OC)ccc1n(Cc1ccc(OC)cc1)c2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
The compound of 9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (100 mg, 0.285 mmol) prepared in step 4 of Example 3 was dissolved in N,N-dimethylformamide (5 ml), added with sodium hydride (17 mg, 0.428 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature. After that, 1-bromopropane (0.039 ml, 0.428 mmol) was added and the mixture was stirred for one more hour at room temperature. The mixture was poured into water extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (56 mg, yield: 50%, yellow solid).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=1[NH2:13].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[CH3:10])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(Nc2cc(C)ccc2C)cc1
Temperature: 110 °C
Yield: 96.8 %

Procedure:
Following general procedure E, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 2,5-dimethylaniline (149 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (220 mg, 97%), mp 40-41° C. 1H NMR (300 MHz, CDCl3) δ: 7.11 (m, 3H), 6.96 (m, 3H), 6.75 (d, J=7.5 Hz, 1H), 5.27 (s, 1H), 3.88 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 155.3, 143.5, 136.8, 136.7, 131.0, 122.7, 122.5, 121.1, 116.2, 115.0, 55.9, 21.7, 17.7 ppm. IR (neat, cm−1): 3400, 2921, 1579, 1511, 1463, 1292, 1241, 1037, 828, 800. Anal. Calcd. for C15H17NO: C, 79.26; H, 7.54. Found: C, 79.11; H, 7.59.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])=[O:3].[CH3:19][S:20]([N:23]([CH2:38][CH2:39][Cl:40])[N:24]([S:34]([CH3:37])(=[O:36])=[O:35])C(OC1C=CC=CC=1)=O)(=[O:22])=[O:21]>>[CH3:19][S:20]([N:23]([CH2:38][CH2:39][Cl:40])[N:24]([S:34]([CH3:37])(=[O:36])=[O:35])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])=[O:3])(=[O:21])=[O:22]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Product: COc1cc(COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)c([N+](=O)[O-])cc1OC

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4,5-dimethoxy-2-nitrobenzyloxy)carbonyl]hydrazine (compound 12) was prepared by reacting 4,5-dimethoxy-2-nitrobenzyl chloroformate with compound 2 using a procedure similar to that described for compound 10d. The product was recrystallized from ethanol, and the Mp was about 154° C. Yield was about 17.6% by weight. 1H NMR (acetone d6): δ 7.7 and 7.4 (2H, 2s, aromatic H), 5.8 (2H, d, ArCH2), 3.7-4.1 (4H, m, CH2CH2Cl), 3.9-4.0 (6H, 2s, 2 OCH3), and 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[CH:10][C:11]=1[CH3:17]
Reactant: Cc1ccc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2-methyl-benzoic acid (310 mg, 2.07 mmol, 1.0 eq) in CH2Cl2 (30 mL) at 0° C. was added (COCl)2 (0.52 mL, 6.0 mmol, 3.0 eq) and DMF (2-3 drops). The reaction was stirred at 0° C. for 2 h, and then the solvent was removed in vacuo. The residue was taken up in THF (30 mL) and added to a suspension of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (195.4 mg, 2.07 mmol, 1.0 eq) and NaHCO3 (339.1 mg, 6.2 mmol, 3.0 eq) in THF (70 mL) at 0° C. The reaction was stirred for 3 h at 0° C. then quenched by addition of water and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (DCM:MeOH, 1:0 to 20:1) to give the title compound as a solid (230 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:7][CH:6]([OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CN
Reactant: Cc1ccc(C2CO2)cc1
Product: CNCC(O)c1ccc(C)cc1
Yield: 71.2 %

Procedure:
4-Methyl styrene oxide(1.0 g, 8.0 mmol) and 3 ml of methylamine in methanolic solution(28%) were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 90.5–93.2° C., yield 71.2%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([C:4]2([CH2:7][O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]4)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4cccc(Cl)c4)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 3-chlorobenzenesulfonyl chloride (78 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.82 (m, 1H), 7.72 (m, 3H), 7.32 (t, J=8.4 Hz, 1H), 7.11 (br s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.96 (d, J=6.4 Hz, 2H), 3.72 (br d, J=11.6 Hz, 2H), 2.32 (t, J=12 Hz, 2H), 1.84 (m, 3H), 1.36 (m, 2H). MS m/z (ESI) 448 (M+H)+.
Reaction SMILES: [C:1](O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].IC>CN1C(=O)CCC1.O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[N:23]=[N:24][N:25]([CH3:1])[N:26]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-n2ccc3cc(Cc4nnn[nH]4)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Solvent: O
Product: Cn1nnc(Cc2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the cyanomethyl compound, sodium azide, triethylamine hydrochloride in 1,2-dimethoxyethane was boiled at reflux for 2 days. After cooling to room temperature, the reaction mixture was filtered and the volatile solvents were evaporated in vacuo. Water (100 mL) and glacial acetic acid (15 mL) were added and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with water (200 mL) and brine (200 mL) and subsequently dried (Na2SO4). Evaporation of the solvents in vacuo gave 1-(4-fluorophenyl)-5-(tetrazol-5-ylmethyl)-1H-indole as an oil containing some residual acetic acid (14 g). A solution of the crude tetrazole in NMP (200 mL) was cooled with ice and potassium tert-butoxide (6.4 g) was added cautiously at 10-20° C. over 20 minutes. When the addition was complete the reaction mixture was cooled at 0° C. and iodomethane (7 mL) was added. After stirring at room temperature for 2 h, water (200 mL) was added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (2×200 mL) and brine (2×250 mL), dried (Na2SO4) and the volatile solvents evaporated in vacuo. The resulting mixture of 1- and 2-methyl-substituted tetrazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:2). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-ylmethyl)-1H-indole (11a) as an oil (3.7 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 4.30 (s, 2H), 6.60 (d, 1H), 7.10-7.20 (m, 3H), 7.20 (d, 1H), 7.30-7.45 (m, 3H), 7.60 (broad s,1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2([C:11]3[O:15][N:14]=[C:13]([CH:16]4[CH2:18][CH2:17]4)[N:12]=3)[CH2:10][CH2:9]2)[CH:7]=1.[B:19]1(B2OC(C)(C)C(C)(C)O2)[O:23]C(C)(C)C(C)(C)[O:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>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].O1CCOCC1>[CH:16]1([C:13]2[N:12]=[C:11]([C:8]3([C:6]4[CH:7]=[C:2]([B:19]([OH:23])[OH:20])[CH:3]=[N:4][CH:5]=4)[CH2:10][CH2:9]3)[O:15][N:14]=2)[CH2:18][CH2:17]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cncc(C2(c3nc(C4CC4)no3)CC2)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1cncc(C2(c3nc(C4CC4)no3)CC2)c1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 72 Step B (0.03 g, 0.10 mmol), bis(pinacolato)diboron (0.050 g, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.018 g, 0.020 mmol), tricyclohexylphosphine (11 mg, 0.039 mmol) and potassium acetate (0.029 g, 0.294 mmol) was added 1,4-dioxane (1.0 ml). The vial was capped tightly and heated to 80° C. overnight. The reaction was then concentrated under reduced pressure to provide the title compound: LCMS m/z 245.70 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2](OS(C)(=O)=O)[C:3]#[CH:4].[Cl:10][CH2:11][C:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])=[O:13].C([Zn]CC)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.[Pd](Cl)Cl.CC(CC#N)=N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)C)C>[Cl:10][CH2:11][C@@:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[C@@H:3]([CH3:4])[C:2]#[CH:1]
Reactant: O=C(CCl)c1cc(F)ccc1F
Reactant: C#C[C@@H](C)OS(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: CC(=N)CC#N
Agent: CC[Zn]CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#C[C@H](C)[C@](O)(CCl)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 118.8 %

Procedure:
887.3 mg (3.423 mmol) of palladium(II)-dichloride-diacetonitrile were dissolved in 325.0 ml of tetrahydrofuran. 2.243 g (8.530 mmol) of triphenylphosphine were added. The reaction mixture turned yellow and, after 6 minutes, turbid. The reaction mixture was stirred for 10 minutes at room temperature, whereafter 22.81 g (153.9 mmol) of (R)-methanesulfonic acid 1-methyl-prop-2-ynylester and 16.30 g (85.52 mmol) of 2-chloro-1-(2,5-difluoro-phenyl)-ethanone were added together with about 25 ml of totally 233.3 ml (256.6 mmol) of diethylzinc solution in toluene (1.1 M) dropwise. The temperature was permitted to rise to 36° C. The remaining diethylzinc solution was added dropwose within 12 minutes at 37–38° C., whereafter the temperature was prevented from rising over 39° C. After 40 minutes (temperature about 27° C.) the reaction mixture was poured onto 350 ml of ice-cold half-saturated aqueous sodium chloride solution, 500 ml of ethylacetate were added, the mixture was stirred for 5 minutes at room temperature, and 70 ml of 25% aqueous hydrochloric acid were added (everything in solution). The aqueous phase was washed once with 250 ml of ethyl acetate and the organic phases once with 150 ml of quarter-saturated aqueous sodium bicarbonate solution and once with 50 ml of 0.1N aqueous hydrochloric acid. The organic phases were combined, dried over sodium sulfate and evaporated to dryness. 24.85 g of (2R,3S)-1-chloro-2-(2,5-difluoro-phenyl)-3-methyl-pent-4-yne-2-ol were obtained, which were 70.5% pure and contained 86% of the stated diastereomer. Yield 83.1%.
Reaction SMILES: C[NH+:2](C)C.[Cl-].[NH4+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:2])=[O:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: C[NH+](C)C
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of trimethylammonium in toluene (10 mL of 2.0 M) is added over 30 minutes to a stirred suspension of ammonium choride (1.07 g, 20 mmol) in toluene (20 mL) at 5° C. under an argon atmosphere. The mixture is stirred at 20° C. for 2 h, treated with a solution of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.65 g, 4.3 mmol) in toluene (40 mL) and stirred at 60° C. for 18 h. The cooled mixture is washed with hydrochloric acid (50 mL of 0.5 M) followed by saturated aqueous sodium chloride (50 mL), dried (Na2SO2), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by crystallisation from ethyl acetate-t-butylethyl ether to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxamide as a colourless crystalline solid, m.p. 201-205° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1.CN(C)[CH:37]=[O:38]>O1CCCC1.CCCCCC>[F:13][C:14]1[C:19]([CH:37]=[O:38])=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCCCCCCOc1ccc(-c2ccc(C=O)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
2.55 ml (18.2mmol) of diisopropylamine in 30 ml of tetrahydrofuran are stirred at 0° C. with 11.4 ml (18.2mmol) of a 1.6-molar n-butyllithium solution in hexane for one hour. After addition of 170 ml of tetrahydrofuran and cooling to -78° C., 3.64 g (12.1 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine (prepared as described in EXAMPLE 2) in 90 ml of tetrahydrofuran are added dropwise, and the mixture is stirred at -78° C. for 4 hours. 1.86 ml (24.2mmol) of N,N-dimethylformamide are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. For workup, the mixture is poured onto sodium chloride solution, the resulting mixture is extracted with ether, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, CH2Cl2) gives 2.20 g of 2-fluoro-3-formyl-6-(4-octyloxyphenyl)pyridine. ##STR62##