Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Cl:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:27][CH:26]=1
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(Cl)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
A mixture of 1.14 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.20 g of 3-(4-chlorophenoxy)propyl bromide, 0.83 g of potassium carbonate and 20 ml of N,N-dimethylformamide was stirred at 80° C. for 6 hours. The reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.01 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-chlorophenoxy)propyloxy)benzene (55% yield), nD25.0 1.5822.
Reaction SMILES: Cl[SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11].[NH3:13]>CCCCCC>[NH2:13][SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Reactant: N
Solvent: CCCCCC
Product: CC(C)N1C=CN(C(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
In an argon atmosphere, 4.06 g (19.8 mmol) of Si(iPrNCHCHNiPr)(H)Cl was dissolved in 20 mL of hexane. The resulting solution was deaerated by Freeze-Pump-Thaw cycling and after creating an ammonia atmosphere in the reaction vessel by connecting thereto a balloon having an internal volume of 5 L and being filled with ammonia, the solution was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./8.8×102 Pa) to obtain 2-amino-1,3-diisopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NH2) as a colorless liquid (yielded amount: 2.11 g, yield: 58%).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[H-].[Na+].CS(O[CH2:18][CH2:19][CH:20]([O:22]S(C)(=O)=O)[CH3:21])(=O)=O.O>CN(C=O)C.C(OCC)(=O)C>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:18][CH2:19][CH:20]([O:22][C:1]1[C:6]([I:7])=[CH:5][C:4]([I:9])=[CH:3][C:2]=1[I:10])[CH3:21]
Reactant: CC(CCOS(C)(=O)=O)OS(C)(=O)=O
Reactant: Oc1c(I)cc(I)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CCOc1c(I)cc(I)cc1I)Oc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of triiodophenol (5.78 g, 12.3 mmol) and sodium hydride (0.49 g, 60% dispersion, 12.3 mmol) in DMF (15 ml) was stirred at room temperature for 1 hour and then a solution of 1,3-bis-(methanesulfonyloxy) butane (1.37 g, 5.58 mmol) in DMF (5 ml) was added. The mixture was heated to 90° C. for 6 hours and then poured into water after cooling. Ethyl acetate was added and the mixture was allowed to stand overnight. The precipitated solid was collected and dried to give 3.0 g (54%) of the desired product, Mp 173-175° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:17](=[O:19])[CH2:16][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(CCC(=O)O)ccc1OC
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCc1cc2c(cc1OC)C(=O)CC2
Temperature: 80 °C

Procedure:
18.5 g (69.9 mmol) of 3-(3-hexyl-4-methoxyphenyl)propanoic acid dissolved in 100 ml of xylene are added to a mixture of 100 g of polyphosphoric acid and 100 ml of xylene heated to 80° C. The mixture is then heated at 135° C. for 1 hour 30 minutes. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution. The solvents of the organic phase are dried (Na2SO4) and evaporated off, and the residue is purified by flash chromatography (9 g; 52%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:24]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[C:19]4[S:18][CH:17]=[CH:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=12.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[C:19]4[S:18][CH:17]=[CH:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6ccsc56)cc34)cn2)CC1
Agent: Cl
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4ccsc34)oc12
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of tert-butyl 4-{4-[7-amino-2-(1-benzothiophen-7-yl)furo[2,3-c]pyridine-4-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate in DCM (1.50 mL) was treated with HCl (1 M in Et2O, 5.00 mL, 5.00 mmol) and stirred for 30 min. The reaction was concentrated in vacuo to afford 86 mg (71%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.08 (s, 1 H), 7.00 (d, J=7.58 Hz, 1 H), 6.82 (d, J=7.83 Hz, 1 H), 6.79 (s, 1 H), 6.59 (s, 1 H), 6.50-6.54 (m, 2 H), 6.36 (t, J=7.71 Hz, 1 H), 6.32 (d, J=5.56 Hz, 1 H), 3.39-3.52 (m, 1 H), 2.36 (d, J=13.14 Hz, 2 H), 1.96-2.02 (m, 2 H), 1.09-1.19 (m, 4 H); MS (ESI): 416.12 [M+H]+; HPLC tR=2.19 min.
Reaction SMILES: C[CH:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17]([CH2:18][CH2:19][C@@H:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:16]([OH:30])[CH2:15][C@@H:14]1[OH:31])=[O:6])C>CO.CC(O)=O>[OH:30][C@@H:16]1[CH2:15][C@H:14]([OH:31])[C@H:13]([CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:5]([O:4][CH3:2])=[O:6])[C@H:17]1[CH2:18][CH2:19][C@@H:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O

Procedure:
To Latanoprost free acid in MeOH at 0° C. was added TMS-CH2N2 until the solution persisted a yellow color. AcOH (2 drops) were added to quench excess TMS-CH2N2 and the solvents were evaporated. Column chromatography 70%-100% EtOAc/Hexanes gave pure (Z) -methyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy -5-phenylpentyl)cyclopentyl)hept-5-enoate (2).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].CI.[CH2:13](OCC)C>O.O1CCOCC1.CCCCCC>[CH3:3][C:4]1([CH3:13])[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CC1C(=O)CCC1=O
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of potassium hydroxide (15.0 g, 0.27 mol) in water (40 ml) was added to a stirred solution of 2-methylcyclopentane-1,3-dione 1 (25.0 g, 0.22 mol) in 1,4-dioxane (120 ml) at room temperature. Methyl iodide (100 g, 0.70 mol) was then added and the resulting solution was heated under reflux for 15 hours. The mixture was then cooled to room temperature and extracted with ethyl acetate (4×160 ml). The combined extracts were then dried over MgSO4 and evaporated in vacuo. Flash chromatography (SiO2, 60% diethyl ether in hexane) gave the dione 2 (18.0 g, 0.14 mol, 64%) as a white solid; δH (300 MHz, CDCl3) 2.80 (4H, s, CH2CH2), 1.16 (3H, s, CH3), 1.15 (3H, s, CH3); δC (75.5 MHz, CDCl3) 216.3 (s), 52.6 (s), 34.5 (t), 20.2 (q).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:34][CH3:35])[C:20]3[C:25]([C:26](N4C=CN=C4)=[O:27])=[CH:24][N:23]=[CH:22][C:21]=3[N:33]=2)=[N:15][O:16][N:17]=1>CN(C=O)C>[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:34][CH3:35])[C:20]3[C:25]([C:26]([N:1]4[CH2:5][CH2:4][CH2:3][C@H:2]4[CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[O:27])=[CH:24][N:23]=[CH:22][C:21]=3[N:33]=2)=[N:15][O:16][N:17]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)n3ccnc3)c21
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCC[C@H]3CN3CCCC3)c21
Yield: 43.2 %

Procedure:
A mixture of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.142 g; 0.93 mmol) and the product from Step 1 (0.1 g; 0.31 mmol) in DMF (2 ml) was warmed at 60° C. for 18 h. The cooled mixture was partitioned between water (10 ml) and ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (2×20 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a colourless gum. The crude material was purified by preparative HPLC using Dynamax C18 column, 8 micron particle size; 250 mm×41.4 mm i.d.; 10-90% acetonitrile/water (0.1% TFA); 70 ml/min; UV detection at 254 nm) to afford the title compound, (0.055 g, 28%); MS (ES+) m/e 411 [M+H]+.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>C(#N)C.C(OCC)C>[I:1][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(I)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
86 g of iodine are added at ambient temperature to a suspension of 89 g of triphenylphosphine and 22 g of imidazole in 800 ml of acetonitrile. The reaction is exothermic. After return to ambient temperature, 45.9 g of the product obtained in Step 1 in 250 ml of acetonitrile are added in the course of 30 minutes. After 18 hours' stirring at ambient temperature, the reaction mixture is filtered and rinsed with 200 ml of acetonitrile and the resulting filtrate is concentrated in vacuo. The residue obtained is stirred in 250 ml of diethyl ether for 1 hour and the precipitate is filtered off. After concentration of the filtrate in vacuo, chromatography on silica gel (dichloromethane/ethyl acetate: 90/10) enables the expected product to be isolated.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[ClH:21].C(=O)([O-])O.[Na+]>C(O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][Cl:21])[OH:16])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of fumagillol (200 mg) in ethanol (2 ml) was added 0.5N hydrochloric acid (1 ml), and the mixture was stirred at room temperatures for one hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent:hexane-ethylacetate=3:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(chloromethyl)-1,4-cyclohexanediol (200 mg: yield 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[Br-:24].[Li+]>CC(C)=O>[Br:24][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:23])([CH3:1])[O:6]2)=[CH:10][CH:11]=1
Reactant: [Br-]
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](COc2ccc(CCCBr)cc2)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid 3-[4-((R)-2,2-dimethyl [1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester (11.8 g, 34.2 mmol) in acetone (200 ml) is treated with lithium bromide (8.9 g, 100 mmol) and then heated at reflux for 5 h. After cooling to room temperature, the mixture is concentrated in vacuo. The resulting residue is dissolved in EtOAc (150 ml), washed with water (2×50 ml), brine, dried (MgSO4), filtered and concentrated in vacuo to give an oil. Purification by chromatography on silica eluting with 4:1 iso-hexane/EtOAc gives (R)-4-[4-(3-Bromo-propyl)-phenoxymethyl]-2,2-dimethyl-[1,3]dioxolane as a colourless oil which solidifies; 1H NMR (CDCl3): 1.39 (3H, s), 1.43 (3H, s), 2.02 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.38 (2H, tr, J=6.9 Hz), 3.90 (2H, m), 4.02 (1H, m), 4.15 (1H, m), 4.46 (1H, pent, J=6.9 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9](=[O:16])[N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH3:24][NH:25][CH3:26].CC([O-])(C)C.[Na+].Cl>C1(C)C=CC=CC=1.CO.O1CCOCC1>[CH3:24][N:25]([CH3:26])[C:2]1[N:3]=[C:4]2[N:10]([CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(Br)nc21
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(CC)n1c(O)nc2ncc(N(C)C)nc21
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
A mixture of tert-butyl 5-bromo-2-oxo-3-(pentan-3-yl)-2,3-dihydroimidazo[4,5-b]pyrazine-1-carboxylate (200 mg, 0.52 mmol), dimethylamine (0.5 mL, 2M in THF, 1.0 mmol), Pd3(dba)2 (48 mg, 0.052 mmol), BiPhP(Cy)2 (37 mg, 0.10 mmol) and NaOtBu (150 mg, 1.56 mmol) in anhydrous toluene (4 mL) was purged with N2 for 15 second and then stirred at 120° C. for 20 minutes in microwave. The mixture was diluted with EtOAc, washed with NaHCO3 solution, dried over Na2SO4, and then concentrated in vacuo to give a dark muddy residue. The residue was dissolved in MeOH (10 mL) and treated with 1 mL 4M HCl in dioxane. After one hour, the reaction was concentrated, diluted with EtOAc, washed with NaHCO3, dried over Na2SO4, and concentrated in vacuo. Purification over silica gel (Biotage MPLC 10-70% EtOAc/hexanes) gave the title compound as a light yellow solid (42 mg, 32%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)[CH:8](Br)[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].Cl>CC(O)(C)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)C(Br)C(Br)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5.00 g (13.0 mmol) 3-biphenyl-4-yl-2,3-dibromo-propionic acid are added to 40 mL tBuOH. Over a period of 25 min 5.80 g (52.1 mmol) KOtBu are added in several portions while keeping the temperature below 35° C. Then the reaction mixture is stirred at 40° C. for 2 h. Again 1.40 g (12.5 mmol) potassium tert-butoxide are added and the mixture is stirred for additional 2 h at 40° C. Then the mixture is allowed to cool to r.t. and poured onto icewater/concentrated HCl. The precipitate is filtered and partitioned between EtOAc and water. The organic layer is washed with water, dried and the solvent is removed in vacuo. The crude product is triturated with PE, filtered and dried at 80° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 74 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (150 mg, 0.51 mmol), using 6-chloro-3-pyridinecarbonitrile instead of 4-fluoroacetophenone, was converted to the title compound (149.5 mg, 74%) which was obtained as a white solid. MS: m/e=398.3 [M−H]−.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[C@@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[Na]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:8]=[C:7]([O:12][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCCCCCC)cc(C(=O)OCC)c1

Procedure:
50 m mol of 3,5-dihydroxybenzoic acid ethyl ester, 120 m mol of stearyl bromide, and 110 m mol of sodium were made to react in ethanol, thereby forming 35 m mol of 3,5-dioctadecyloxybenzoic acid ethyl ester. This ester, 25 m mol, was first hydrolyzed into the corresponding acid, which in turn was converted into its acid chloride. The acid chloride was reacted in the same way as in Example 1, whereby 10 m mol of N-(3,5-dioctadecyloxybenzoyl)-N'methylsulfonyl-p-quinonediimine was obtained which is represented by the following formula: ##STR30##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)ccn1
Temperature: 80 °C
Yield: 44.3 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (2.465 g, 4.72 mmol), 2-methylpyridine-4-boronic acid (0.966 g, 7.05 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.579 g, 0.709 mmol) and K2CO3 (1.959 g, 14.17 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL)/H2O (2.5 mL). The reaction mixture was degassed for 5 min, heated to 80° C. overnight, cooled to RT and diluted with EtOAc. Reaction was filtered through Celite and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted with EtOAc (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-75% EtOAc in hexanes to yield 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.09 mmol, 44%) as a solid. MS ESI calc'd. for C31H24ClN4 [M+1]+487, found 487.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1CCCCC1.[CH3:21][CH:22](C(O)=O)[C:23]([OH:25])=[O:24].C(OCC)C>N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[C:22](/[C:23]([OH:25])=[O:24])\[CH3:21])[C@@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: CC(C(=O)O)C(=O)O
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C/C(=C\[C@H]1[C@H](C(=O)OC(C)(C)C)C1(C)C)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Under a nitrogen atmosphere, 0.202 g of tert-butyl (±)-trans-2,2-dimethyl-3-formylcyclopropanecarboxylate was dissolved in 5 mL of anhydrous pyridine. One-fifth milliliter (0.20 mL) of piperidine and 0.242 g of methylmalonic acid was then added thereto, and the resulting mixture was stirred at a temperature of about 60° C. for a time period of about 1 hour. After the mixture was allowed to cool to room temperature, 100 mL of diethyl ether was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter the solvent was evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel column chromatography, wherein the eluent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1 to give 0.249 g of tert-butyl (±)-trans-2,2-dimethyl-3-{2-carboxy-(E)-1-propenyl}cyclopropanecarboxylate.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH3:2])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN1CCC[C@H]1C
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(R)-2-methyl-pyrrolidine hydrochloride (1.0 g, 8.2 mmol, 1.1 eq) was dissolved in 2-butanone (25 mL) and potassium carbonate (2.2 g, 15.7 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (1.07 mL, 7.5 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and solid was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.5 g of the title compound (yield 99%) which was used in the next step without further purification.