Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C@@H:6]([CH3:12])[CH2:7][CH2:8][C@@H:9](O)[CH3:10])[CH2:2][CH2:3][CH3:4].[C:13]([OH:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CCOCC>[C:13]([O:21][C@@H:9]([CH2:8][CH2:7][C@@H:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:12])[CH3:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCO[C@@H](C)CC[C@H](C)O
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCO[C@@H](C)CC[C@@H](C)OC(=O)c1ccccc1
Yield: 79.6 %

Procedure:
That is, 1.23 g of (2S,5S)-5-butoxy-2-hexanol, 0.86 g of benzoic acid and 2.78 g of triphenylphosphine were dissolved in 25 ml of dry ether. Thereto was dropwise added 2.29 g of diethyl azodicarboxylate (DEAD) at room temperature with stirring. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluting solvent: dichloromethane) to obtain 1.56 g of (2R,5S)-5-butoxy-2-hexyl benzoate as a colorless oily substance. 1.56 g of the product was dissolved in 20 ml of methanol. Thereto was dropwise added 516 ml of a 1 N methanol solution of sodium hydroxide at room temperature with stirring. The mixture was stirred for 8 hours at room temperature. The reaction mixture was mixed with 15 ml of water and stirred for 8 hours. To the resulting reaction mixture was added water. Then, extraction with dichloromethane was effected. The extract was dried and concentrated. The residue was subjected to Kugel-rohr distillation under reduced pressure to obtain 0.57 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.C(OCC)C.C([Li])CCC.[F:23][C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:25]=1[C:39]([F:43])=[C:40](F)[F:41]>C1(C)C=CC=CC=1>[F:43]/[C:39](/[C:25]1[CH:26]=[CH:27][C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)=[CH:29][C:24]=1[F:23])=[C:40](/[F:41])\[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1
Reactant: CCCC1CCC(c2ccc(C(F)=C(F)F)c(F)c2)CC1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC1CCC(c2ccc(/C(F)=C(\F)c3ccc(C(F)(F)F)c(F)c3)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (2.28 g) and diethyl ether (70 ml) were added, and cooling was carried out to −70° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (7.10 ml) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for another 1 hour. Subsequently, a diethyl ether (10 ml) solution of compound (T-9) (2.68 g) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for 4 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (100 ml), and mixing was carried out. Toluene (100 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with a 1 N hydrochloric acid solution, a saturated aqueous solution of sodium hydrogencarbonate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by fractionation by means of column chromatography (silica gel; heptane), and further purified by recrystallization from a heptane/Solmix A-11 mixed solvent, and thus (E)-1-(1,2-difluoro-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl)-2-fluoro-4-(4-propylcyclohexyl)benzene (1-1-25) (2.24 g) was obtained. The yield based on compound (T-9) was 57%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([NH:28]C(=O)C)=[CH:24][CH:23]=3)[C:20](=[O:32])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:33]>Cl>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:21]2[C:20](=[O:32])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:8]2[CH:7]=[C:6]([CH3:33])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:10]([CH3:11])[CH:9]=2)=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Agent: Cl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Yield: 74.7 %

Procedure:
A solution of N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide (2.0 g, 4.50 mmol) in 2N HCl (50 mL) was stirred at reflux temperature for 30 minutes. The solids were filtered off solids and the aqueous filtrate was basified with NaOH, extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH in CH2Cl2, afforded 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one as an off-white solid (1.35 g, 75%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17]S(C)=O>C1COCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]2([O:16][CH2:17]2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC3(CO3)C2)cc1
Yield: 71 %

Procedure:
Sodium hydride (583 mg, 14.6 mmol) in DMSO (6 mL) was heated to 55 C for 1 h. The reaction mixture is cooled to 0 C and Me3SI (3 g, 14.62 mmol) dissolved in THF (9.8 mL) was added dropwise. 1-Benzyl-piperidine-3-one (1.5 g, 6.64 mmol) dissolved in DMSO (10 mL) was added 15 minutes later. After completion of addition the reaction proceeded at RT. After 30 min. the reaction was quenched with water. The aqueous layer was extracted with hexanes. Combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified using silica gel chromatography (9:1 DCM:hexanes in 2 M ammonia in EtOH) to yield 5-benzyl-1-oxa-5-aza-spiro[2.5]octane (960 mg, 71%). MH+(204).
Reaction SMILES: C([C:4]1[C:5](O)=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9]C1NN=NN=1)=[O:8])(=O)C.[N+]([O-])(O)=O.O>S(=O)(=O)(O)O>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:15]=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: CC(=O)c1cccc(C(=O)Nc2nnn[nH]2)c1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
3-Acetyl-2-hydroxy-N-(tetrazol-5-yl)benzamide (6.0 g) was dissolved in concentrated sulphuric acid (30 ml). The solution was then cooled to 0° C. and, with stirring, was treated with concentrated nitric acid (density 1.42; 1.62 ml) at such a rate that the temperature did not exceed 10° C. The mixture was left to stand at between 0° and 5° C. for 20 hours, and was then poured into a mixture of ice and water (300 ml). The precipitated solid was collected, washed with water, and recrystallized from 98% w/w formic acid to give 3-acetyl-2-hydroxy-5-nitro-N-tetrazol-5-yl)benzamide, m.p. 255° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)O1.C([O-])(=O)C.[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1ncc2c(Cl)cc(-c3ccc4[nH]ncc4c3)nc21

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.180 g, 0.89 mmol) was dissolved in 2 mL dioxane and 2 mL acetonitriile in a microwave tube, and nitrogen was bubbled through the solution. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.217 g, 0.89 mmol) and a 1M solution of potassium acetate (2 mL, 2 mmol) were added. Nitrogen gas was bubbled through the mixture followed by the addition of 5 mole % of tetrakis(triphenylphosphine) palladium (0). The resultant mixture was microwaved at 125° C. for 30 minutes. Purification via Biotage reverse phase system (4:1 ethyl acetate/hexanes) gave 12.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[O:6][N:5]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)OC)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)on1
Temperature: 25 °C

Procedure:
A stirred solution of methyl 3-ethoxy-5-isoxazolecarboxylate, prepared according to Example 78, (3.00 g, 17.53 mmole) in 75 ml of 2N sodium hydroxide was stirred at room temperature for ten minutes, cooled in an icebath and acidified to pH 3 with concentrated hydrochloric acid. The precipitated solid was collected by filtration. The remaining desired product was isolated by saturating the aqueous filtrate with solid sodium chloride and extracting with ethyl acetate (3× 100 ml). A total of 2.46 g (89% yield) of title compound was obtained in this way. The sample was recrystallized from acetonitrile, m.p. 210°-13° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([I:25])=[N:7]1.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]1>>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([I:25])=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(I)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Reactant: O=C(O)C1CCNCC1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid following general procedure C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)=[O:4].O[CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[O:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccoc1
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1coc(CNC(=O)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a suspension of N-methyl-3-furancaboxamide (0.404 g) (prepared as described in Synthetic Communications (1992), 22(16), 2381-92) in concentrated aqueous sulphuric acid (10 ml) at 0-5° C. was added N-(hydroxymethyl)-trifluoroacetamide (0.483 g). The suspension was allowed to warm to 20° C. and stirred for 1 h. The mixture was poured onto ice (100 g) and diluted with ethyl acetate (150 ml). The phases were separated and the organic phase washed with saturated sodium hydrogen carbonate (50 ml×2), brine (30 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give a yellow solid. The residue was purified by silica SPE (10 g) eluting with 4:1 to 1:3 cyclohexane:ethyl acetate to give the title compound as a white solid (0.286 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]2=[O:19])=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC=C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) (55 mg) in DCM (4 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (51 mg), HOBt-hydrate (71 mg), EDAC.HCl (61 mg) and N-methyl morpholine (34 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (82 mg, 80%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][O:11]C(=O)C)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(COC(C)=O)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Yield: 81 %

Procedure:
A solution of crude 2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole (250 g) in methanol (200 mL) was treated with 10% sodium hydroxide solution (700 mL) and the mixture was heated on a steam bath for 4 hours. After cooling, methylene chloride was added, the organic phase was separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled, and seeded to give the crude product. Recrystallization from ethyl acetate gave 176 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86°-88° C. This material was identical in all respects to the product prepared by Method 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:20][C:21]([CH3:27])([CH2:25][CH3:26])[C:22](Cl)=[O:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[C:2]([NH:1][C:22](=[O:23])[C:21]([CH3:27])([CH3:20])[CH2:25][CH3:26])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)Nc1cc(NC(C)=O)ccc1NCC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step E, using N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (10.5 g, 40 mmol), DMAP (2.4 g, 20 mmol) and 2,2-dimethylbutyryl chloride (5.9 g, 44 mmol) in 350 mL of DCM. Yield: 14.2 g (98%); 1H NMR (400 MHz, CHLOROFORM-D) δ 0.94 (t, J=7.52 Hz, 3 H), 1.29 (s, 6 H), 1.32-1.46 (m, 2 H), 1.66 (q, J=7.42 Hz, 2 H), 1.68-1.75 (m, 2 H), 1.78-1.90 (m, 1 H), 2.13 (s, 3 H), 2.97 (d, J=7.03 Hz, 2 H), 3.34-3.45 (m, 2 H), 3.77-3.86 (m, 1 H), 3.94-4.06 (m, 2 H), 6.75 (d, J=8.79 Hz, 1 H), 7.05 (s, 1 H), 7.21 (dd, J=8.59, 2.54 Hz, 1 H), 7.49 (s, 1 H), 7.55 (d, J=2.34 Hz, 1 H); MS (ESI) (M+H)+=362.06.
Reaction SMILES: [CH2:1]([Si:3]([CH2:9]C)([CH2:7]C)[C:4]#[C:5][CH3:6])C.[Li]CCCC.CCCCCC.Br[CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>C1COCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]#[C:24][CH2:23][CH2:6][C:5]#[C:4][Si:3]([CH3:1])([CH3:7])[CH3:9])=[CH:27][CH:28]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC#C[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of triethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stirring 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1 h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:36][CH2:37][OH:38]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([CH2:36][CH2:37][OH:38])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: OCCBr
Solvent: ClCCl
Product: CCOC(=O)C1CN(CCO)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of 0.6 g (1.24 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (see Example 31, Step 1) in CH2Cl2 (10 mL) and TEA (0.313 mL, 3.1 mmol) at 0° C. was added 2-bromoethanol (0.1 mL, 1.36 mmol). The resulting reaction mixture was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate-hexanes, to provide 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester as a white solid (0.6 g, 92%). MS: 528 (M+H)+
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].CC1(C)CCCC(C)(C)N1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C(#N)C>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: Fc1ccccc1CCl
Reactant: CNCCC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
A mixture of 3-hydroxy-N-methyl-3-phenylpropylamine (8.3 g, 50 mM), 2,2,6,6-tetramethylpiperidine (8.4 ml, 50 mM), o-fluorobenzyl chloride (7.25 g, 50 mM) and acetonitrile (100 ml) was stirred for 24 hours at ambient temperature. The resulting precipitate was removed by filtration, the precipitate washed with acetonitrile and the combined filtrate and washings evaporated under reduced pressure. The residue was partitioned between 2 N hydrochloric acid (100 ml) and ether (100 ml), the aqueous layer basified and extracted with ether (2×100 ml). The ether extract was dried and the solvent removed under reduced pressure to yield an oil (10.3 g). Distillation gave the title compound b.p. 160°-2° C./0.6 mbar. Found: C, 74.4; H, 7.3; N, 5.4%; C17H20FNO requires: C, 74.7; H, 7.4; N, 5.1%.
Reaction SMILES: C1(N[C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)CC1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>>[CH:33]1([NH:36][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][NH:13][CH:8]([CH3:9])[CH3:7])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:35][CH2:34]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CO)cn2)cc1
Reactant: CC(C)N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CNC(C)C)cn2)cc1

Procedure:
Using an analogous procedure to that described in Example 27, N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide was oxidised and the resulting aldehyde reacted with isopropylamine to give the title compound; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.68 (m, 2H), 1.00 (d, 6H), 2.25 (s, 3H), 2.70 (m, 1H), 2.86 (m, 1H), 3.71 (s, 2H), 5.76 (s, 2H), 7.14 (d, 2H), 7.33 (d, 1H), 7.49 (d, 1H), 7.64 (m, 1H), 7.80 (m, 2H), 7.99 (d, 2H), 8.40 (d, 1H), 8.55 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7].[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:21]=[O:22])=[C:14]([CH3:16])[CH:15]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To the ice-cold 3 mL (39.2 mmol) of dimethylformamide (DMF) was added phosphorus oxychloride (0.67 mL, 7.18 mmol) drop wise and the resultant mixture was stirred for 30 minutes. A solution of 1 g (6.53 mmol) of 4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester in 3 mL of DMF was added to the reaction. After 1 h, the reaction was warmed to room temperature for another 2.5 h. The reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N sodium hydroxide solution. The precipitate was removed by filtration, rinsing with water and dried to afford 0.8 g (68%) of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:11]2[O:12][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[N:18]=1.[H-].[Na+]>CS(C)=O>[CH3:1][C:2]1([CH3:15])[CH:11]([OH:12])[CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1
Reactant: Cn1nc(N)ccc1=O
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1nc(NC2c3cc(C#N)ccc3OC(C)(C)C2O)ccc1=O
Reaction time: 4 h

Procedure:
2.0 g of 2,2-dimethyl-3,4-epoxy-6-cyanochroman ("IIa") are added to a mixture of 1.2 g of 3-amino-1-methyl-1,6-dihydropyridazin-6-one and 0.3 g of NaH (80% strength) in 50 ml of dimethyl sulfoxide (DMSO) at 25°, and the mixture is stirred for 4 hours. Customary working-up and purification by column chromatography (ethyl acetate/methanol) give 2,2-dimethyl-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3chromanol, m.p. 117°-119°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10][C:11]3([O:21][CH2:20][CH2:19][O:14]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: COC(=O)C1(c2ccc(Br)cc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a round bottom flask containing methyl 1-(4-bromophenyl)-4-oxocyclohexanecarboxylate (4.64 g, 14.91 mmol) was added toluene (33 ml), ethylene glycol (8.32 ml, 149 mmol) and p-toluenesulfonic acid (85 mg, 0.45 mmol) at room temperature. The mixture was heated to 80 C. for 2 hours. The content was then cooled to room temperature and quenched with a saturated solution of sodium bicarbonate. The organic portion was washed with saturated sodium bicarbonate and the aqueous portion extracted with MTBE twice. The combined organic portion was dried over sodium sulfate and concentrated to afford a crude oil. Column purification afforded the title compound as viscous oil (5.30 g, quantitative yield). LC/MS, ESI-MS(+): 357.1, RT: 1.38 (Condition E).