Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:14]([C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:20][CH3:21])=[C:3]([C:17](=[O:19])[CH3:18])[CH:4]=2)[O:9][C:8]([CH3:13])([CH3:12])[CH:7]=1)([CH3:15])[CH3:16]
Reactant: CCI
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
As described in General Procedure A, a solution of 1-(7-hydroxy-4 isopropyl-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 62, 205 mg, 0.69 mmol) in acetone were added ethyl iodide (0.3 mL, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) to give rise to the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH:37]1([CH2:36][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:40][CH2:39][CH2:38]1
Reactant: BrCC1CCC1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC1CCC1)N1CCC(F)(F)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and (bromomethyl)cyclobutan in N,N-dimethylformamide, to give the desired product as a white foam (73%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H].[OH-].[Na+]>[Pd].C(O)C>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
2.6 Grams of 5% palladium on carbon catalyst was added to a mixture of 260 grams of 5-nitrotetrahydroanthraquinone and 24,000 grams of ethanol, into which was injected hydrogen for absorption in the 5-nitro compound in an amount of 2 mols per mol of the 5-nitro compound at normal (ambient) temperature and under normal atmospheric pressure. The solution which was first pale yellow turned reddish brown in color as the reaction proceeded and a small amount of precipitate appeared in the solution. When the hydrogenation was continued, the solution became almost transparent and dark reddish brown upon completion of the reaction. The hydrogen in the reactor was replaced by nitrogen, to which was added 400 grams of a 20% sodium hydroxide solution and the color of the resultant solution turned dark yellowish brown immediately after the addition of the alkali during which a small amount of glossy crystals were precipitated. The reaction was completed immediately, dark yellowish brown being the color of leuco-1-aminoanthraquinone which is obtained by catalytical hydrogenation of 1-aminoanthraquinone or by having 1 mol of hydrogen absorbed in 1 mol of 1-aminoanthraquinone under the same reaction conditions, and then air was fed into the solution for oxidation. Upon determination, it was found that 0.5 mol of oxygen was absorbed per mol of the 5-nitro compound. As a result, the reaction solution turned reddish orange with a precipitate of a reddish orange color. The resultant solution was subjected to filtration, followed by extraction of the cake with acetone for separation of the catalyst. The resultant filtrate was dried up to obtain 220 grams of 1-aminoanthraquinone having a purity of 98%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(=O)n(Cc2ccc(OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl coumalate (1 g, 6.49 mmol, 1 eq) in ethanol (30 mL) was added p-anisidine (0.79 g, 6.49 mmol, 1 eq). The reaction mixture was heated to reflux for 16 h. After this time, the solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with 3:2 ethyl acetate/hexane to afford 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester. Mass Spec m/z=260 [M+H+]. To a solution of 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (400 mg, 1.54 mmol, 1 eq) in 3:1 tetrahydrofuran/methanol (20 mL) was added lithium hydroxide (148 mg, 6.17 mmol, 4 eq). The mixture was stirred at rt for 48 h then heated to 50° C. for 16 h. After this time, the mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer was acidified with a 2N aqueous solution of hydrochloric acid then extracted with ethyl acetate. The organic layers were combined and washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid, which is used without further purification.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[O:14])[CH3:13]>>[CH3:3][N:4]([CH3:6])[CH:5]=[CH:13][C:12](=[O:14])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)N(C)C
Reactant: COC(OC)C(C)=O
Product: COC(OC)C(=O)C=CN(C)C
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethoxy-N,N-dimethylmethanamine (5.0 g, 41.96 mmol) and 1,1-dimethoxypropan-2-one (5.0 g, 41.96 mmol) was heated to 80° C. for 16 h. The solvent was removed under reduced pressure to afford 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one as a black colored liquid. The material was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH:33][CH3:34])[CH3:32]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27](=[O:26])[N:33]([CH2:31][CH3:32])[CH3:34])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CCNC
Solvent: C1COCCO1
Product: CCN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 24 μl of N-ethyl-N-methylamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a mixture of petroleum ether and ethyl acetate (gradient 40/60 to 0/100 by volume) followed by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 12 mg of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)-1-ethyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2].[OH-:27].[Na+].Cl>CS(C)=O.CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11]([OH:27])([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1NC(C)=O)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 14 (1.8 g) in 5 ml of DMSO and 30 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water, dried over Na2SO4. Removal of the solvent afforded 22 (1.9 g) as a syrup, which was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Li+].CC([N-]C(C)C)C.[CH2:19]1[O:21][CH2:20]1>C1COCC1>[Cl:1][C:2]1[C:9]([CH2:19][CH2:20][OH:21])=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(CCO)c1Cl
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (20.0 g, 128.6 mmol) in THF (200 mL) added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at −78° C. After addition, the mixture was stirred at the same temperature for 5 h, then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by SiO2 column to give 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (17.0 g, 66%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.58 (dd, J=5.5, 8.6 Hz, 1H), 7.10 (t, J=8.6 Hz, 1H), 3.88 (m, 2H), 3.13 (t, J=6.8 Hz, 2H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[N:41]([CH3:50])[C:42]([C:45]([CH3:49])([CH3:48])[CH:46]=O)=[N:43][N:44]=1>C1COCC1>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[N:41]([CH3:50])[C:42]([C:45]([CH3:49])([CH3:48])/[CH:46]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:43][N:44]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C=O
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
Benzyltriphenylphosphonium bromide (1.15 g) was suspended in THF (30 ml) and, under ice cooling, n-butyllithium (1.60M hexane solution, 1.50 ml) was added thereto, followed by stirring at room temperature for 30 minutes. A THF (20 ml) solution of 2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanal (633 mg) was added dropwise to the reaction solution and the whole was stirred under heating and refluxing for 20 hours. The reaction mixture was quenched with water (50 ml) and then extracted with ethyl acetate (50 ml×2). The organic layer washed with a 1M aqueous hydrochloric acid solution (30 ml), a saturated aqueous sodium bicarbonate solution, and a brine (30 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) and preparative thin layer chromatography (ethyl acetate:hexane=3:1) to obtain 86 mg of 3-(2-chlorophenyl)-5-[(2E)-1,1-dimethyl-3-phenylprop-2-en-1-yl]-4-methyl-1,2,4-triazol (white solid).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C>O1CCCC1>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:19]1[CH:20]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[CH:17][C:18]=1[N+:21]([O-:23])=[O:22])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 149.1 %

Procedure:
To a stirred solution of N-Boc-1,4-butanediamine (0.400 g; 2.12 mmol) and 1-fluoro-2,4-dinitrobenzene (280 μL; 2.23 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) was added triethylamine (886 μL; 6.36 mmol). The reaction solution was stirred at ambient temperature for 17 hours and was then concentrated. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3 and saturated NaCl. The organic solution was dried over MgSO4 and concentrated to give a yellow oil (1.12 g). Purification using a Thomson Instruments Single StEP™ silica gel column (25 g) and eluting with 20% ethylacetate/80% hexanes followed by 50% ethyl acetate/50% hexanes produced the product as a yellow oil (0.751 g, 100%). 1H NMR (d6-DMSO) 1.36 (9H, s), 1.44 (2H, m) 1.58 (2H, m), 2.93 (2H, m), 3.46 (2H, m), 6.82 (1H, t, J=5.6 Hz), 7.23 (1H, d, J=9.5 Hz), 8.27 (1H, dd, J=2.7 Hz, J=9.6 Hz), 8.85 (2H, m).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([NH:20][CH:21]([C:23]([OH:25])=[O:24])[CH3:22])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CO[CH:28](OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[CH3:22][CH:21]1[C:23](=[O:25])[O:24][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(OC)c1ccccc1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC1C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Boron trifluoride diethyl etherate (12.56 mL, 100 mmol) was added to a −78° C. solution of N-carbobenzoxy-dl-alanine (4.47 g, 20 mmol) and benzaldehyde dimethyl acetal (2.97 mL, 19.8 mmol) in diethyl ether (100 mL). After stirring at ambient temperature for 4 days, the reaction mixture was recooled to 0° C., quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 5-45% ethyl acetate/hexane afforded benzyl 4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: IC[CH2:3][CH2:4][CH:5]([S:15][CH:16](CCCI)[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])CCC(F)(F)C(F)(F)F.[CH3:30][NH2:31]>O1CCCC1>[CH3:30][NH:31][CH2:3][CH2:4][CH2:5][S:15][CH2:16][CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)C(F)(F)CCC(CCCI)SC(CCCI)CCC(F)(F)C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCSCCCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 133.5 %

Procedure:
In a solution of 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentylsulfide in 200 ml of absolute tetrahydrofuran, 45 g of methylamine is condensed at a bath temperature of -78° C., and it is stirred for 1.5 hours at room temperature and for 4 hours at 60° C. in the pressurized reactor. To open the reactor, it is allowed to cool overnight to room temperature and then to -78° C. Then, it is allowed to reach room temperature, excess methylamine is evaporated, diluted with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 15.7 g of N-methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-amine is obtained as an oil.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH:11]=[C:12]2[C@H:18]([CH3:21])[CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(OC(=O)C)C.[Pd]>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C@@H:12]2[C@H:18]([CH3:21])[CH2:19][OH:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](CO)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 2.27 g (6.7 mMol) of (S)-2-[(4aR,5S,8aS)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphtalen-1-yl]-propan-1-ol in 22.7 ml of ethylacetate were added 227 mg of Pd/C 10% and 227 mg of sodium bicarbonate. The reaction mixture was stirred under hydrogen atmosphere overnight, filtered over Speedex using ethylacetate for washing thoroughly and the solvent evaporated in vacuo. The residue was chromatographed over a 250 g Lobar column with hexane/ethylacetate 9/1 to yield 2.18 g (95.5%) of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphtalen-1-yl]-propan-1-ol as an oily product.
Reaction SMILES: I[C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN(C)C=O>O>[C:17]([C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: CN1CC(=O)Nc2cccc(I)c2C1=O
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2cccc(C#N)c2C1=O

Procedure:
A mixture of 5.7 g (0.018 mol) of 3,4-dihydro-6-iodo-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione, 2.4 g (0.026 mol) of copper (I) cyanide and 60 ml of dimethylformamide is heated to 50° for 45 minutes. After cooling, the mixture is diluted with water and extracted several times with chloroform/isopropanol (4:1). The combined organic extracts are dried over magnesium sulphate and evaporated. The yellow-brown crude product is recrystallized from methanol, there being obtained 6-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 253°-256° (decomposition).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]([CH:15]1[C:23]2[C:18](=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14].I[CH3:26]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH3:26])[C:23]2[C:18](=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: CI
Reactant: COC(=O)C1CCc2cc(Br)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (6.16 ml, 6.16 mmol, 1M solution in THF) was added dropwise to a solution of (rac)-5-bromo-indan-1-carboxylic acid methyl ester (1.31 g, 5.14 mmol) in dry THF (25 ml) at −78° C. After the addition was completed, the solution was stirred at −78° C. for 45 minutes. Then, iodomethane (2.19 g, 959 μl, 15.4 mmol) was added, the solution was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched by addition of sat. NH4Cl solution and extracted two times with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining yellow oil was purified by chromatography (silica gel; heptane/EtOAc 95:5) to obtain the title compound as yellow oil (1.319 g, 95%). MS: 269.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[Si:19]([O:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(C(C)O)on1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
5.55 g of ethyl 5-(1-hydroxyethyl)-isoxazole-3-carboxylate was dissolved in 30 ml of N,N-dimethylformamide, and 2.38 g of imidazole and 5.28 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 8.95 g of ethyl 5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazole-3-carboxylate.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:30])=O>>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:30])=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Undecyloxypyrimidine-2-yl)benzoic acid (1.86 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-undecyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21].N([Cl:24])=O>C(#N)C.ClCCl>[Cl:24][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: O=NCl
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (1 g) in acetonitrile (15 ml) at 0° C. was added dropwise nitrosyl chloride (2.7 ml of a ˜1M solution in dichloromethane). The reaction mixture was heated under reflux for 10 minutes. The reaction mixture was then evaporated and the residue was purified by column chromatography on silica gel eluted with hexane: toluene (2:1) and then toluene. Combination and evaporation of suitable fractions gave the title compound as a pale orange solid, m.p. 115.7-116.3° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.C(OC([NH:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21](O)=[O:22])=O)(C)(C)C>>[NH2:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1scnc1C(=O)O
Reactant: Cn1cc(N)cn1
Product: Cn1cc(NC(=O)c2ncsc2N)cn1
Yield: 32 %

Procedure:
Following the procedures as described in Example 113, 1-methyl-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid were reacted to give 5-amino-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide as a white solid (13 mg, 32%) over two steps. ESIMS m/z=336.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])[C:2]=1[NH:1][C:20](=[O:22])[CH3:21])#[N:8]
Reactant: Cc1cc(C)c(-n2c(C)c(C)c(C#N)c2N)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C#N)c(C)c(C)n1-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared as a tan solid by the procedure analogous to that of Example 1A starting with the compound of step A and acetic anhydride in acetic acid. The crude material was pure and used directly for the next cyclization step. 1H NMR (CDCl3) δ 1.75(s, 3H), 1.80(s, 6H), 1.95(s, 3H), 2.18(s, 3H), 2.30(s, 3H), 6.60(brs, 1H), 6.93(s, 2H) ppm.