Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:23]3[C:28]([F:29])=[CH:27][C:26]([O:30][CH3:31])=[C:25]([Cl:32])[C:24]=3[F:33])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:14])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O1CCOCC1>O>[Cl:32][C:25]1[C:24]([F:33])=[C:23]([C:17]2[C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:15]([C:13]([NH:12][C:5]3([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]3)=[O:14])[CH:16]=2)[C:28]([F:29])=[CH:27][C:26]=1[O:30][CH3:31]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3c(F)cc(OC)c(Cl)c3F)c2)CCC(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(C)CC2)cc1-c1c(F)cc(OC)c(Cl)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.5 %

Procedure:
150 mg of 1-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic acid methyl ester and 25 mg NaOH were dissolved using 5 ml of dioxane and 0.5 ml of water. The mixture was stirred at 80° C. for 6 h. Then, 15 ml of water were added, the dioxane evaporated and acidified to pH=3 using aqueous NaHSO4-solution. The mixture was stirred for 30 minutes at room temperature. The product was then isolated by filtration and dried in vacuo to yield 110 mg of the title compound.
Reaction SMILES: O[C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]=1.BrBr.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(Cl)(Cl)Cl.C(O)C>[CH3:26][C:25]1[S:27][C:3]2[CH2:4][CH2:5][C:6]3[C:11](=[N:10][C:9]([NH:12][C:13]4[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[N:8][CH:7]=3)[C:2]=2[N:28]=1
Reactant: CC(N)=S
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)C(O)=CCC3)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1nc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-(8-hydroxy-5,6-dihydro-quinazolin-2-ylamino)benzenesulfonamide (100 mg, 0.314 mmol) in chloroform (1 mL) was treated with a solution of bromine (32 μl, 0.628 mmol) in chloroform (1 mL) and the mixture stirred at room temperature for 2 hours giving an insoluble black residue. The solvent was decanted and the residue treated with thioacetamide (47 mg, 0.6 mmol) in ethanol (3 mL). The mixture was stirred at 80° C. for 3 hours and filtered to give a black solid (75 mg). The solid was dissolved in DMSO and purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to give a yellow solid (6.9 mg) which was further purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound (1.9 mg) as a pale yellow solid. MS (ES+) 374, (ES−) 372. δH (CD3OD) 2.78 (3H, s), 3.01-3.07 (2H, m), 3.10-3.16 (2H, m), 7.46 (1H, t), 7.53 (1H, d), 7.65 (2H, s, partially exchanged), 7.83 (1H, d), 8.27 (1H, s), 8.48 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(F)c(F)cc1O
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl-silane as a clear oil (5.22 g, 81%).
Reaction SMILES: [N:1]1([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:29])[C:26]([O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:9]=[CH:8][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:27]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cnccc1N=CN1CCCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCCCC1

Procedure:
A mixture prepared from 4-[[(hexahydro-azepin-1-yl)methylene]amino]-3-pyridinol (2.9 g), triethylamine (2.86 ml), dimethylcarbamyl chloride (1.83 ml) and tetrahydrofuran (85 ml) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. The eluate was concentrated and dried under high vacuum to obtain 3.88 g of oil. The oil solidified in a refrigerator over the weekend, and was triturated with cold pentane to yield 3.31 g of solid, m.p. 68°-70° C.
Reaction SMILES: C(NC/C=C\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O)C.COC([N:37]([C:52]1[C:61]([C:62]([O:64][CH3:65])=[O:63])=[C:60]2[C:55]([CH:56]3[CH2:66][CH:57]3[CH2:58][O:59]2)=[CH:54][CH:53]=1)[S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1/[CH:48]=[CH:49]\[CH2:50]O)(=[O:40])=[O:39])=O.[OH:67][CH:68]1[CH2:71][NH:70][CH2:69]1>>[OH:67][CH:68]1[CH2:71][N:70]([CH2:50]/[CH:49]=[CH:48]\[C:42]2[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=2[S:38]([NH:37][C:52]2[C:61]([C:62]([O:64][CH3:65])=[O:63])=[C:60]3[C:55]([CH:56]4[CH2:66][CH:57]4[CH2:58][O:59]3)=[CH:54][CH:53]=2)(=[O:39])=[O:40])[CH2:69]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: OC1CNC1
Agent: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC(O)C2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and 3-hydroxyazetidine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:21].C(=O)(O)[O-].[Na+].O>ClCCl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reaction time: 2 h

Procedure:
Compound 69B was suspended in 100 ml dichloromethane. SOCl2 was added and allowed to stir for 2 h. 20 ml Saturated sodium bicarbonate was added followed by 20 ml water and stirred for 5 minutes. The dichloromethane layer was seperated and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered through silica and eluted with dichloromethane until clear. Concentration of the filtrate gave a pink solid. MS m/z 262 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(I)cc2)c1Br
Yield: 65 %

Procedure:
4-Iodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-iodobenzenesulfonyl chloride according to the procedures described in Example 1b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 166°-173° C., yield 65 %.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.Cl[C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:29][C:28]=2[O:38][CH3:39])=[CH:25][CH:26]=1.O>C1COCC1>[CH3:39][O:38][C:28]1[CH:29]=[C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[N:22][C:21]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:26][CH:25]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)nn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.98 mL, 0.98 mmol) was added to tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.18 g, 0.98 mmol) in THF (3.3 mL) at 0° C. and the mixture was stirred for 10 min at 50° C. 3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (0.12 g, 0.40 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 h at RT. Water (0.1 mL) was added and the solvent was concentrated under reduced pressure to afford (0.18 g, 100%) of a brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([F:24])=[CH:17][C:18]=3F)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([F:24])=[CH:17][C:18]=3[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCBr
Reactant: C1CCNC1
Product: Cc1cc(-c2nc3cc(F)cc(N4CCCC4)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1

Procedure:
A solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-one (1.38 g, crude) and pyrrolidine (10 mL) was stirred at room temperature for 16 hours. Excess pyrrolidine was evaporated, the residue was purified by column chromatography (silica gel 230-400 mesh; 30-50% ethyl acetate in hexanes as eluent). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 260 mg (13% for two steps). MP 206.6-206.8° C. 1H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 6.63 (d, J=8 Hz, 1H), 6.51 (d, J=12 Hz, 1H), 3.90 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.50 (s, 6H), 2.30 (s, 4H), 1.89 (s, 4H), 1.70 (s, 4H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].P(Br)(Br)[Br:15]>N1C=CC=CC=1>[Br-:15].[Br-:15].[CH2:11]([OH:12])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13]
Reactant: BrP(Br)Br
Solvent: OCCOCCOCCOCCO
Solvent: c1ccncc1
Product: [Br-]
Temperature: 25 °C

Procedure:
300 g. of tetraethylene glycol and 100 g. of anhydrous pyridine are slowly added to 727 g. of phosphorus tribromide, while agitating and cooling the mixture. After cooling to room temperature, the mixture is poured on to ice and the organic phase is decanted, washed with water and dilute hydrochloric acid and dried over sodium sulphate. After distillation under vacuum (123° C.-125° C. and 0.4 mm. Hg) the title comound is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12]([C:9]4[CH:8]=[N:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)=[O:14])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Product: CC#CCOc1cnc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)cn1
Yield: 25.6 %

Procedure:
The title compound (28 mg, 24% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid (Intermediate 36, 58 mg, 0.30 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 63 mg, 0.27 mmol). The crude product was purified by flash chromatography (4 g silica, gradient elution of (EtOAc/MeOH/conc. NH3 (80/20/1) in heptane) followed by preparative chromatography. The pure fractions were combined and evaporated. The residual oil was solidified by evaporation with EtOAc and heptanes: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (t, 3H), 1.88-1.96 (m, 2H), 2.23 (s, 3H), 4.28-4.48 (m, 2H), 5.07 (q, 2H), 6.55 (s, 2H), 6.79 (d, 1H), 7.02-7.10 (m, 1H), 7.55-7.64 (m, 1H), 8.39 (d, 1H), 8.84 (d, 1H), 10.26 (s, 1H); MS (APCI+) m/z 405 [M+H]+.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>C(O)C>[C:5]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:29]=3[O:28][CH3:27])[C:33]([OH:35])=[O:34])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCCC
Product: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, are placed 1 g of 1-acetoxyadamantane and 50 ml of n-heptane. After dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop at a temperature of approximately 22° C. and 0.783 g of 4-methoxybenzoic acid is poured in slowly. After leaving the mixture well agitated for 48 hours, 50 ml of denatured ethanol are added and the insoluble material is filtered Concentration of the filtrate volume to three quarters yields a solid white precipitate which is filtered with sintered glass. It is dried in a vacuum oven for 24 hours at 30° C. and 0.680 g of expected raw product was collected (Melting point: 245°-246° C.).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13]1[O:15][CH2:14]1>CS(C)=O>[CH2:14]1[O:15][CH2:13]1.[OH:15][CH2:14][CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CO1
Solvent: CS(C)=O
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100° C. for 5 hours at which time it was cooled to 20° C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm).
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CN[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[C:22]([S:26]([C:29]3[CH:30]=[C:31]4[C:36](=[C:37]([CH3:39])[CH:38]=3)[N:35]=[CH:34][C:33]([C:40]([NH2:42])=[O:41])=[C:32]4[NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=3)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[NH2:64][CH2:65][C@@H:66]([C:68]1[CH:73]=[CH:72][C:71]([OH:74])=[C:70]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:69]=1)[OH:67]>>[Si:77]([O:76][CH2:75][C:70]1[CH:69]=[C:68]([C@@H:66]([OH:67])[CH2:65][NH:64][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:21]=[C:22]([S:26]([C:29]4[CH:30]=[C:31]5[C:36](=[C:37]([CH3:39])[CH:38]=4)[N:35]=[CH:34][C:33]([C:40]([NH2:42])=[O:41])=[C:32]5[NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=4)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH2:14][CH2:13]2)[CH:73]=[CH:72][C:71]=1[OH:74])([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:78])[CH3:79]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(NC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)CC5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN)ccc1O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(NC[C@H](O)c6ccc(O)c(CO[Si](C)(C)C(C)(C)C)c6)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 150, using Intermediate 9 in place of Intermediate 2. ES/MS calcd. for C45H56N5O8SSi+ 854.4. Found m/z=854 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[OH:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(I)ccc1Oc1ccc(OCCO)cc1
Yield: 98.9 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (2.5 g, 10 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol (2.7 g, 10 mmol) and K2CO3 in N,N-dimethylacetamide at 170° C. for 0.5 h to give 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde as a yellow solid (Yield 3.8 g, 98%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Product: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
The process according to claim 9 which comprises reacting 5-acetyl-6-methyl-2(1H)-pyridinone with dimethylformamide dimethyl acetal to produce 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH2:18][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
The mixture of methyl 6-hydroxynicotinate (6 g), 4-biphenylylmethyl bromide (7.7 g), silver carbonate (4.8 g), and toluene (60 ml) was stirred at 50° C. for 12 hr. The reaction mixture was further stirred at 100° C. for 6 hr and filtrated.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16].O>C(OC(=O)C)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C2CCC2)c([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g, 20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL) 0° C. was added dropwise fuming HNO3 (5 mL, 97%). The resulting mixture was stirred at 30° C. in an oil bath. After 2 h, 30 mL of water was carefully added and the mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with aqueous saturated NaHCO3 (note: gas evolution), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:25) as eluent to furnish 3.00 g (64%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[CH2:7][Br:8].[CH3:9][N:10]1C=NN=C1CO.Cl.NCCS>Br>[BrH:8].[BrH:8].[NH2:10][CH2:9][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[N:5][N:4]=1
Reactant: Cn1cnnc1CO
Reactant: Cn1cnnc1CBr
Agent: Br
Agent: Cl
Agent: NCCS
Product: Cn1cnnc1CCN

Procedure:
The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.), water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration, the residue was extracted with ethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.), b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours, concentrated to dryness and the residue obtained (a mixture of 4-methyl-3-bromomethyl-1,2,4-triazole and 4-methyl-3-hydroxymethyl-1,2,4-triazole) was used directly in the reaction with cysteamine hydrochloride and hydrobromic acid as described in Example 1 (i)(a) to give 3-(2-aminoethyl)-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:26][CH2:25]3)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][CH:29]([F:39])[C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:36]([C:33]4[CH:32]=[N:31][C:30]([CH:29]([F:39])[F:28])=[CH:35][N:34]=4)=[O:37])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:25][CH2:26]3)[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3cnc(C(F)F)cn3)ccc1OC(C)(C)C21CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To an ice-water cooled mixture of tert-butyl[(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (430 mg, 1.15 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (221 mg, 1.27 mmol) and 1H-benzotriazol-1-ol (170 mg, 1.26 mmol) in chloroform (8.6 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (244 mg, 1.28 mmol). The mixture was stirred at room temperature overnight and directly purified by silica gel column chromatography (precolumn: basic silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:100) to afford tert-butyl[(4′R)-6′-({[5-(difluoromethyl)pyrazin-2-yl]carbonyl}amino)-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (373 mg).