Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:4]=2.[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:4]=2
Reactant: CCCCCCCCc1ccc2c(c1)c(F)c(F)c1cc(Br)ccc12
Reactant: CCCCCC[Mg]Br
Product: CCCCCCCCc1ccc2c(c1)c(F)c(F)c1cc(CCCCCC)ccc12

Procedure:
In analogy to Example 2, from 9,10-difluoro-2-bromo-7-octylphenanthrene and 10 mmol of hexylmagnesium bromide. The catalyst used is 0.2 mmol of 1,3-bis(diphenylphosphine)propanenickel(lI) chloride. Chromatography gives 9,10-difluoro-2-hexyl-7-octylphenanthrene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[H][H]>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCC(CCC1C(C=CC=CC=CC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CCC1C(CCCCCCC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Yield: 92.6 %

Procedure:
Ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}hepta-2,4,6-trienoate (6.1 g.) [prepared as described in (n) above] was dissolved in ethanol (100 ml.) and catalytically hydrogenated using a 5% palladium on charcoal catalyst, with a hydrogen pressure of 15 kg./cm2, at room temperature. The catalyst was then filtered off and the ethanol removed in vacuo to give ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}heptanoate (5.7 g.), which was used as starting material in the following preparation (p) of ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:25]1C=CC(S(OC)(=O)=O)=CC=1)([O-])=O.O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:8]([CH3:25])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)cc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cccc(Cl)c2)cc2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
7-Bromo-3-(3-chlorophenyl)isoquinolin-1(2H)-one (Intermediate 23A) (0.1 g, 0.299 mmol) was dissolved in THF (4 mL), under an atmosphere of nitrogen. Sodium hydride (0.018 g, 0.448 mmol) was added and reaction stirred for 30 minutes. The reaction was then cooled using an ice bath and methyl 4-nitrobenzenesulfonate (0.065 g, 0.299 mmol) was added. The reaction was allowed to warm to room temperature and left to stir overnight. Water was added to the reaction mixture and extracted with EtOAC (×2). The organics were combined and washed with brine, dried (MgSO4) filtered and concentrated under reduced pressure. The mixture was purified on silica (25 g column on Isolera 4) eluting with 0-10% methanol in dichloromethane to afford 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1(2H)-one (51 mg, 0.15 mmol).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=C([CH:19]=[CH:20][CH:21]=2)C(O)=O)[CH2:9][CH2:8]1>C(Cl)Cl.CN(C)C=O>[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:1]([CH:19]=[CH:20][CH:21]=2)[C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid (0.28 g) in methylene chloride (10 ml) which contained N,N-dimethylformamide (2 drops). The reaction mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated and azeotroped with toluene to yield 3-morpholinobenzoyl chloride (0.3 g); M/z M+H+ 222.
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1>CO>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10])=[CH:22][CH:21]=1
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1ccc(C=O)cc1)OC
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1ccc(C=Cc2cccc[n+]2C)cc1)OC
Yield: 70.6 %

Procedure:
In 50 ml of methanol, 12.7 g of 1,2-dimethylpyridinium iodide and 11.96 g of p-(2,2-dimethoxyethoxy)benzaldehyde were dissolved. The resultant solution, with 1 ml of piperidine added thereto, was refluxed for five hours. The solution was left to cool and the crystals which consequently deposited in the solution were collected through filtration and thoroughly washed with acetone. Consequently, there was obtained 16.30 g of 1-methyl-2[p-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide. In water, this product showed the highest absorption at 360 nm (ε=2.67×104). The infrared absorption spectrum (KBr) of the product showed peaks at 1630, 1615, 1595, 1568, 1512, 1450, 1298, 1260, 1180, 1140, 1073, 965, 862, 821 and 776 cm-1. The yield was 67%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH:21][CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[CH:18]=[CH:17][C:16]=2[F:28])([CH3:14])[N:13]=1)(C)(C)C.Cl.O1CCOCC1.C(O)(C(F)(F)F)=O>>[F:28][C:16]1[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][C:15]=1[C:12]1([CH3:14])[CH2:11][O:10][CH2:9][C:8]([NH2:7])=[N:13]1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NCc3ccco3)ccc2F)COC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC1(c2cc(NCc3ccco3)ccc2F)COCC(N)=N1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A solution of (5-{2-fluoro-5-[(furan-2-ylmethyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (29 mg, 0.072 mmol) in 4M HCl/dioxane (0.719 ml, 2.88 mmol) was stirred at rt for 2 h, then heated at 50° C. for 2 h. TFA (0.005 ml, 0.072 mmol) was added and stirring at 50° C. was continued for 7 h. The reaction mixture was quenched with water and diluted with EtOAc. The phases were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to leave the crude title compound that was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 90% ACN+0.1% TFA) and obtained as a free base after filtration over an SCX cartridge.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:15]=3[CH:16]=1)=[O:11])[CH2:2]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH:74]1([C:77]([CH3:79])=[O:78])[CH2:76][CH2:75]1>O1CCOCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]3[CH:20]=[C:19]([CH2:79][C:77]([CH:74]4[CH2:76][CH2:75]4)=[O:78])[CH:18]=[CH:17][C:15]=3[CH:16]=1)=[O:11])[CH2:2]2
Reactant: CC(=O)C1CC1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(CC(=O)C3CC3)cc2o1
Temperature: 85 °C

Procedure:
150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide, 27 mg (0.04 mmol) of rac-BINAP, 45 mg (0.47 mmol) of sodium tert-butoxide and 20 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are dried under high vacuum for 1 h. Under an atmosphere of argon, 2 ml of dioxane are added. 72 mg (0.86 mmol) of methyl cyclopropyl ketone are added dropwise, and the mixture is heated at 85° C. overnight. The crude product is purified by preparative HPLC. The solvent is removed under reduced pressure. Finally, any last solvent residues are removed under high vacuum. 75 mg (50% of theory) of the title compound are isolated.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[O:12][C:11]([CH3:20])([CH3:19])[CH2:10][C:9]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[O:12][C:11]([CH3:19])([CH3:20])[CH:10]=[C:9]2[CH2:1][CH3:2]
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: CC[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure C, ethylmagnesium bromide (3.0 M in THF, 7.04 mL, 21.1 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 1.2 g, 4.2 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.O=P(Cl)(Cl)Cl.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[N:26]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: Nc1cccnc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cccnc3[nH]2)c(OC)c1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Ex-76A: To a suspension of 2,4-dimethoxybenzoic acid (0.36 g, 2 mmol) and 8 ml of POCl3 in a 50 ml of a round-bottom flask, 2,3-diaminopyridine (0.22 g, 2 mmol) was added. The mixture was heated to reflux for 4 hours and then cooled to room temperature. The reaction mixture was then concentrated to remove most of the POCl3. The residue was carefully treated with 1N HCl at 0° C. using a water-ice bath, then neutralized with NaOH (50%). The off-white solid was filtered to give 2-(2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 88%). 1H-NMR (DMSO-d6) δ 8.28–8.36 (m, 2H), 7.97 (d, J=8 Hz, 1H), 7.21–7.25 (m, 1H), 6.80 (s, 1H), 6.78 (d, J=9 Hz, 1H), 4.05 (s, 3H), 3.91 (s, 3H). HRMS (ES+) Calcd. for C24H19N3O5: 430.1403. Found: 430.1414.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20]
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,5-dichlorobenzenesulfonyl chloride (2.46 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as apale yellow solid (1.65 g, 51%). 1H-NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.55 (s, 2H), 6.56 (s, 2H), 6.46 (s, 1H), 5.29 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl[Si:14]([CH3:22])([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH3:21][Si:14]([CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccnc1
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(c1ccccc1)c1cccnc1
Reaction time: 1 h
Yield: 9.8 %

Procedure:
In a 1 liter, 4 neck round bottom flask stirring under N2 was charged 80.6 milliliters (ml) of n-BuLi (1.55 Molar (M) solution, 0.125 moles, 1.25 equivalents (eq.)) to 300 ml of ether with stirring at -78° C. To the reaction was added, dropwise, 15.8 grams (g) of 3-bromopyridine (0.10 moles, 1.0 eq.) in 100 ml of ether, over 20 minutes while maintaining the temperature between -50° C. and -70° C. After stirring for 20 minutes, 21.3 g of chlorodimethylphenylsilane (0.125 moles, 1.25 eq.) in 50 ml of ether was added dropwise maintaining the temperature below -50° C. after which the reaction was allowed to come to ambient temperature. After 1 hour, gas liquid chromatography (GLC) indicated complete consumption of the silyl chloride. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by adding 200 ml of water, and extracted with ether/ethyl acetate (200 ml/450 ml) and washed with water (2×200 ml). Drying and concentrating afforded 26.0 g of crude product of which 6.7 g was purified by flash chromatography with 3:7 ethyl acetate/hexane and afforded 2.1 g of an oil (31.2% yield based on the 6.7 g chromatographed portion).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:11][C:12]([C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=3)=[CH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]([O:16][CH3:28])[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=3)[N:11]=2)[CH:22]=1)[CH3:25]
Reactant: CI
Reactant: CCOc1ccnc(-c2cc(=O)cc(-c3cc(OCC)ccn3)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccnc(-c2cc(OC)cc(-c3cc(OCC)ccn3)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 506 mg (1.5 mmol) of 4,4″-diethoxy-1′H-[2,2′;6′,2″]terpyridin-4′-one (L17, Example 23) are added at 0° C. to a suspension of 78 mg (approximately 60% dispersion in paraffin oil, 1.95 mmol) of sodium hydride in 15 ml of absolute N,N-dimethylformamide. The mixture is then stirred for 15 minutes at 0° C. and for 15 minutes at room temperature. After cooling again, 0.12 ml (1.95 mmol) of methyl iodide is added. Stirring is then carried out at room temperature for a further 45 minutes. 15 ml of water are added and filtration is carried out, yielding 4,4″-diethoxy-4′-methoxy-[2,2′;6′,2″]terpyridine in the form of a beige powder. 1H-NMR (360 MHz, CDCl3): 1.39 (t, 6 H, J=7.2 Hz); 3.90 (s, 3H); 4.12 (q, 4H, J=7.2 Hz); 6.73 (dd, 2H, J=5.6, 2.5 Hz); 7.88 (s, 2H); 8.01 (d, 2H, J=2.5 Hz); 8.39 (d, 2H, 5.6 Hz). MS (EI pos, 70 eV), m/z=351 (90, [M+]); 350 (70); 336 (100); 323 (70); 295 (45).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1.[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36])(=[O:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]([NH:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1)=[O:36])(=[O:25])[CH3:24]
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(OC)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of 2-amino-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole, 1 g of 1-acetylindole-2-carboxylic acid, 0.7 ml of triethylamine and 2.39 g of BOP are dissolved in 15 ml of dichloromethane. The reaction mixture is stirred overnight at room temperature and then concentrated under vacuum. The residue is taken up in ethyl acetate and the solution is successively washed with a buffer solution, pH=2, with a 5% solution of NaHCO3 and with water, and then the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is purified by chromatography on a silica gel, eluent:dichloromethane/ethyl acetate 100/2.5 (v/v).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].S(Cl)(Cl)=O.[F:13][S:14](O)(=[O:16])=[O:15].Cl.[OH-].[K+]>>[C:2]([S:3]([NH:6][S:14]([F:13])(=[O:16])=[O:15])(=[O:5])=[O:4])([F:8])([F:7])[F:1]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(O)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Temperature: 120 °C

Procedure:
A three neck dry round bottom flask equipped with a condenser, argon line adapter, stir bar, and a thermometer is charged with trifluoromethane sulfonamide (8.00 g, 0.054 mole), thionyl chloride (10.12 g. 6.20 ml, 0.085 mole), and fluorosulfonic acid (5.40 g, 3.93 ml, 0.054 mole). The resulting mixture is heated with oil bath to temperature of 120° C. and is stirred for 20 h. The released HCl and SO2 gases are scrubbed with aqueous KOH solution. The obtained crude product is distilled at reduced pressure to afford CF3SO2NHSO2F in very good yield.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[CH2:3]1.[OH-:20].[Na+].OO>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:20])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[CH2:3]1
Reactant: CSc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
4-((1R,3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carbonitrile (0.335 g, 1.203 mmol; synthesis described herein) was dissolved in DMSO (3 mL). Then aqueous sodium hydroxide solution (1.003 mL, 6 M, 6.02 mmol) and aqueous hydrogen peroxide solution (0.682 mL, 6.02 mmol, 30%) were added at room temperature. Then the reaction mixture was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and it was poured into 100 mL of ice water. The white precipitate was collected and was washed twice with water. The solid was dried to give 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (0.260 g, 0.877 mmol, 72.9% yield); MS (ESI) m/z 297.7 [M+1]+.
Reaction SMILES: [CH2:1]([Si:19](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]>CCCCCCC>[CH2:1]([Si:19]([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COCCOCCOCCO
Reactant: CCCCCCCCCCCCCCCCCC[Si](Cl)(Cl)Cl
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCC[Si](OCCOCCOCCOC)(OCCOCCOCCOC)OCCOCCOCCOC

Procedure:
The procedure of Example 1 was repeated with 387.5 g (1.0 mole) of octadecyltrichlorosilane and 800 mL of heptane. Under nitrogen 508.4 g (3.10 mole) of 2-(2-(2-methoxyethoxy)ethoxy)ethanol was added at 80° C. over 4 hours. After heating the reaction for an additional 48 hours and removal of all volatile components under vacuum, 780 g of the pale yellow liquid product were obtained.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>CN(C)C=O>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccccc1C=O
Reaction time: 1 h
Yield: 87.9 %

Procedure:
244 g (2 mols) of salicylaldehyde in 400 ml of dimethylformamide are added dropwise to a suspension of 60 g (2 mols) of 80% strength sodium hydride in 2,000 ml of absolute dimethylformamide, while cooling and stirring. After one hour at room temperature, 312.9 g (2.1 mols) of dimethylallyl bromide are added dropwise, again at 0° C. The mixture is stirred at room temperature overnight and thereafter the solvent is largely evaporated off and the residue is carefully hydrolyzed. The product is extracted with three 400 mL portions of methylene chloride and the combined organic phases are washed with two 400 ml portions of water. After drying over sodium sulphate and stripping off the solvent, the residue which remains is distilled in vacuo. 334.4 g (88% of theory) of 2-(3-methyl-2-butenyloxy)-benzaldehyde of boiling point 110° C./10 mm Hg are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:27][CH3:28])[CH:19]=1>>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c(OC)cc1Cl
Yield: 48.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloro-2,5-di-methoxyaniline (122 mg, 0.65 mmol) to provide 203 (80 mg, 48% yield) as a white solid. LC-MS (M+H=382, obsd.=382).