Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:22]2[CH2:23][CH2:24][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20][CH2:21]2)=[O:15])=[CH:4][N:3]=1
Reactant: C1CC2(CCN1)COC2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCC4(CC3)COC4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-7-azaspiro[3.5]nonane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:21])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:24])[F:23])=[N:3]1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:21][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:23])[F:24])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)c(C(O)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)c(C(OC(=O)C(C)(C)C)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Temperature: 0 °C
Yield: 26.3 %

Procedure:
0.5 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-hydroxyacrylonitrile and 0.14 g of triethylamine were added to 15 ml of THF at room temperature and stirred to give a uniform solution. 0.16 g of pivaloyl chloride was dropwise added to the solution with cooling with ice, then gradually heated, and stirred at room temperature for 8 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed thrice with saturated saline. After having been dried over sodium sulfate, the resulting product was passed through a short column filled with silica gel. The solvent was distilled off under reduced pressure, and the residual product was applied to silica gel thin-layer chromatography (developer solvent: chloroform) to obtain 0.16 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-pivaloyloxyacrylonitrile (III-6) and 0.35 g of its geometric isomer (III-15).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH3:10][NH2:11].C>O>[CH3:10][N:11]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9]
Reactant: CN
Reactant: Cc1occc(=O)c1O
Solvent: O
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 0.5 h

Procedure:
In particular, 3-hydroxy-2-methyl-4-pyrone (10 g) was refluxed for 6.5 hours with three equivalents of aqueous methylamine (40%) in 200 ml of water. The reaction mixture was allowed to cool after which decolorizing charcoal was added to the solution, and the mixture was stirred for 0.5 hours. After filtration, the solvent was evaporated under reduced pressure, and the solid residue recrystallized three times from water to yield 1,2-dimethyl-3-hydroxypyrid-4-one (HK-1, L1, CP20, DMHP) as fine white needles.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)([O-:11])=[O:10].C([O-])(O)=O.[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8])([O-:11])=[O:10]
Reactant: O=Cc1sccc1Br
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1sccc1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.5 %

Procedure:
The compound 3-bromothiophen-2-aldehyde (2) (5.20 g, 27 mmol), solubilized in ethylene glycol dimethyl ether (105 ml) was treated with (Ph3P)4Pd (936 mg, 0.81 mmol), with 2-nitrophenylboronic acid (5 g, 30 mmol) and an aqueous solution of 2M NaHCO3 (70 ml). The reaction mixture was then refluxed for 5 hrs. Then the mixture was cooled to room temperature, the solvent was partially removed under reduced pressure and the resulting mixture was extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was chromatographed using 80/20 petroleum ether/ethyl acetate, thus giving the derivative (8) (4.5 g, 83% yield).
Reaction SMILES: [CH3:1]O.[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[C:3]([O:11][CH3:1])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1
Reactant: CO
Solvent: O
Product: COC(=O)c1ccccc1
Yield: 70 %

Procedure:
The acid-catalyzed condensation of alcohols to esters has been known for some time. For example, the acid-catalyzed condensation of an alcohol with a carboxylic acid is known to yield an ester and water. This is generally known as a Fischer esterification reaction. It is a reversible process and the equilibrium lies slightly to the side of the production of the products when the reactants are simple alcohols and carboxylic acids. When the reaction is used for preparative purposes, the position of the equilibrium can be made more favorable by using either the alcohol or the carboxylic acid in excess. For example, methanol (0.6 mol.) plus benzoic acid (0.1 mol.) can be reacted to form methyl benzoate (isolated in 70% yield based on benzoic acid) and water. The reaction requires the addition of heat and sulfuric acid as a catalyst. The use of other acids such as, hydrochloric acid and trifluoro acetic acid are also known.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCSc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
To a degassed solution of 6-(4-bromo-phenylsulfanyl)-hexanoic acid methyl ester (500 mg, 1.58 mmol) in ethylene glycol dimethyl ether (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (131 mg, 0.16 mmol). The resulting mixture was stirred for 5 min at room temperature under an argon atmosphere. 4-Chlorophenylboronic acid (494 mg, 3.16 mmol) was added. A solution of cesium carbonate (1.8 g, 5.54 mmol) in water (3 mL) was added. The mixture was stirred at reflux for 1 hour, allowed to cool down to room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (2×50 mL) and brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5:95 to 10:90 diethyl ether:40-60° C. petroleum ether) to give a solid that was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (465 mg, 84%) as a solid, mp 87-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-indol-2-one (23 mg, 0.11 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridin-1-carbaldehyde (29.7 mg, 0.18 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 26 mg (67%) of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Cl:25]Cl.O>C(O)(=O)C>[Cl:25][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: ClCl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiaz-3-one in 12.5 L of glacia acetic acid was added 1.25 kg of ptassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 L of H2O with vigorous stirring. The 4-chlorophenothiazin-3-one precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chlorophenothiazin-3-one which was recrystallized from toluene.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[C:19]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH2:32])[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[C:19]([C:23]2[C:24]3[N:25]([N:29]=[C:30]([NH:32][CH:11]4[CH2:12][CH2:13][N:8]([C:4]5[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5cccc(N(C)C)c5)cccn4n3)CC2)ncn1

Procedure:
Prepared in analogy to example 1h employing 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b) and 8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cc(C)nc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
2-Chloro-6-methyl-pyridine-4-carbaldehyde (13-2, 0.609 g, 3.91 mmol), tert-butylcarbamate (0.550 g, 4.70 mmol), cesium carbonate (1.91 g, 5.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.040 mmol) and Xantphos (0.068 g, 0.030 mmol) were stirred in 10 mL of anhydrous dioxane under N2. The reaction was heated to 80° C. and after 18 hours the reaction was cooled to room temperature. The mixture was diluted with water and extracted 3× with EtOAc. The extracts were dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography afforded impure tert-butyl 4-formyl-6-methylpyridin-2-ylcarbamate. This aldehyde was dissolved in 2 mL of 1,2-dichloroethane. N-Acetylpiperazine (0.074 g, 0.58 mmol) was added followed by addition of 0.05 mL HOAc and NaBH(OAc)3 (0.122 g, 0.58 mmol). After 3 hours the reaction was quenched by the addition of half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM (dichloromethane) and the extracts were dried over Na2SO4, filtered and concentrated to afford the titled compound, 13-3. 1H NMR (CDCl3) δ 7.67 (s, 1H), 7.47 (s, 1H), 6.84 (s, 1H), 3.64 (t, 2H, J=4.9 Hz), 3.47 (m, 4H), 2.44 (m, 7H), 2.09 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:7][CH:4]2[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]2)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: OC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OC1CCC(O)CC1
Reaction time: 2 h

Procedure:
To a stirred mixture of 46.46 parts of 1,4-cyclohexanediol and 135 parts of N,N-dimethylformamide were added 5.28 parts of sodium hydride dispersion 50% at a temperature below 20° C. Stirring was continued for 2 hours at room temperature under nitrogen atmosphere. Then there were added dropwise 15.9 parts of 1,4-difluoro-2-nitrobenzene at about 20° C. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and taken up in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was boiled in 2-propanol. Upon cooling, the precipitate was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in petroleumether. The product was filtered off and dried, yielding 17.1 parts of 4-(4-fluoro-2-nitrophenoxy)-cyclohexanol; mp. 150.8° C. (intermediate 85).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH3:60])([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][C:41]([CH3:60])([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 34.4 %

Procedure:
To a solution of 45 (30 mg, 36.3 μmol) in a mixture of MeOH (3.0 mL) and THF (1 mL) was added Pd(OH)2/C (30 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The aromatic chloride was partially cleaved. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 53 (5.8 mg, 34%). 1H NMR (300 MHz, CD3OD) δ 7.50 (s, 1H), 7.00-7.07 (m, 4H), 6.77 (s, 1H), 3.98 (s, 2H), 3.93 (dd, J=2.1, 11.7 Hz, 1H), 3.65-3.82 (m, 3H), 3.55 (dd, J=8.1, 9.6 Hz, 1H), 3.27 (t, J=9.6 Hz, 1H), 2.80 (d, J=11.1 Hz, 1H), 2.57 (q, J=7.5 Hz, 2H), 1.96 (d, J=11.4 Hz, 1H), 1.68 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 447 (M−OH).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:14])[NH:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([PH3+])[C:8]1=[O:13])=[O:6].[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH:22]=O)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>>[CH3:2][N:3]([CH3:14])[NH:4][C:5]([N:7]1[CH2:11][CH2:10][C:9](=[CH:22][C:21]2[CH:20]=[C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[C:8]1=[O:13])=[O:6]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN(C)NC(=O)N1CCC([PH3+])C1=O
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CN(C)NC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 46.4 %

Procedure:
Substantially in the same manner as in Example 39 (3), 8.31 g of the thus obtained {1-(N-dimethylaminocarbamoyl)-2-oxopyrrolidin-3-yl}phosphonium bromide, 3.79 g (16.2 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 4.51 ml (32.4 mmol) of triethylamine were treated to give 2.91 g of the objective compound (Ia-26) in 46.4% yield.
Reaction SMILES: [N+](C1C=CC([C:10]2[C:18]([CH2:19][C@H:20]3[C@@H:25]([OH:26])[C:24]4[CH:27]=[C:28]([O:31][CH2:32][C:33]5[S:34][C:35]6[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:36]=6[N:37]=5)[CH:29]=[CH:30][C:23]=4[O:22][CH2:21]3)=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-])=[O:13])=CC=1)([O-])=O.[H-].[Na+].[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>>[F:42][C:39]1[CH:40]=[CH:41][C:35]2[S:34][C:33]([CH2:32][O:31][C:28]3[CH:29]=[CH:30][C:23]4[O:22][CH2:21][C@@H:20]([CH2:19][C:18]5[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=5)[C:12]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:13])[C@@H:25]([OH:26])[C:24]=4[CH:27]=3)=[N:37][C:36]=2[CH:38]=1
Reactant: CS(N)(=O)=O
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)NC(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1

Procedure:
Synthesis was carried out as in example 1, but using 1.7 grams optically pure (+)cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro -4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate, 410 milligrams sodium hydride and 1.65 grams methanesulfonamide. 187 milligrams of product was obtained. αD =33.4°; c=0.005 in tetrahydrofuran.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][C@@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@H:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H), 3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2

Procedure:
(±)-(E)-3-{1′-(4-Fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester was synthesized starting from Intermediate 5 (339 mg, 1.00 mmol), according to the procedure described in Example 40, Step A, using 4-fluorobenzaldehyde (0.13 ml, 1.2 mmol) and NaBH3CN (76 mg, 1.2 mmol). The product was obtained as a white solid (320 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (170 mg, 0.411 mmol) in DCM (10 mL) and DIPEA (0.15 mL, 0.89 mmol) is added methane sulfonylchloride (0.04 mL, 0.49 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl ester (200 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=493.26.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:33])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.CCOC(C)=O>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:33][CH2:1][CH3:2])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNc1ccc2nc(-n3cc(C(=O)OCC)cn3)n(COCC[Si](C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Acetaldehyde (1 mL) was added to 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.582 mol) and 4 Å molecular sieves (0.35 g) in ethanol (1.9 g). The reaction mixture was stirred at room temperature for 18 h and was then filtered. Ethanol and acetaldehyde were removed under high vacuum. The residue was redissolved in DCE (1.5 mL) and sodium triacetoxyborohydride (0.308 g, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for 6 d, then diluted with EtOAc (30 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified via FCC (5-65% EtOAc/hexanes) to yield the titled compound (87.0 mg, 33% yield). MS (ESI/Cl): mass calcd. for C22H31N5O4Si, 457.2; m/z found, 458.2 [M+H]+.