Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1C.C([Si](C)(C)[O:35][C:36]1C=C[C:39](NC)=[C:38](C)[CH:37]=1)(C)(C)C.COC(=O)C1C=CC(C=O)=CC=1OCCCC>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])=[CH:15][C:14]=2[CH3:27])[CH3:12])=[CH:6][C:5]=1[O:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Reactant: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Agent: CCCCOc1cc(C=O)ccc1C(=O)OC
Product: CCCCOc1cc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)ccc1C(=O)OC

Procedure:
The title compound is prepared essentially according to the preparation of 4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoic acid methyl ester starting from [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine and 2-butoxy-4-formyl-benzoic acid methyl ester. The title compound is obtained as syrup after workup and is used without further purification. LC-ES/MS m/e 472.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[CH:48][C:47]([Cl:52])=[CH:46][N:45]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:44]([Cl:43])=[N:45][CH:46]=[C:47]([Cl:52])[CH:48]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cc(Cl)cnc1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(Cl)cnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,5-dichloro-3-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=[CH:4][C:3]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[NH:10][C:9]2=[O:18])=[CH:4][C:3]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(C)(C)NC(=O)Nc1ccc(F)c(-c2cccs2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(c2ccc(F)c(-c3cccs3)c2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.62 g of compound 267.3 was dissolved at room temperature in 5 ml of dry tetrahydrofuran, admixed with 0.62 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was taken up in ethyl acetate and washed with saturated sodium hydrogencarbonate solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with diisopropyl ether, filtered and dried. 3-(4-Fluoro-3-thiophen-2-yl-phenyl)-5,5-dimethylimidazolidine-2,4-dione (267.2) was obtained. Molecular weight 304.06 (C15H13FN2O2S); retention time Rt=2.25 min. [E]; MS (ESI): 346.09 (MH++CH3CN).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:10]=1[CH2:11][N:12]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]SC)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:48]1C=CC=C(C(OO)=O)C=1.[S:58]([O-:62])([O-])(=[O:60])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:10]=1[CH2:11][N:12]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=1)[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][S:58]([CH3:48])(=[O:62])=[O:60])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)CCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methylsulfanyl-ethoxy)-pyrimidin-2-yl]-amine (1.21 g) is dissolved in chloroform (15 ml) and thereto is added m-chloroperbenzoic acid (75%) (906 mg) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added saturated aqueous sodium thiosulfate solution and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→7:3) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amine (1.09 g). MS (m/z): 708 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.N1C=CC=N1.Cl[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cn[nH]c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 26.8 %

Procedure:
10 g of 3-amino-5-t-butylpyrazole as prepared in Reference Example (this pyrazole compound being hereinafter referred to as "Compound [II]") was dissolved in 100 ml of carbon tetrachloride, and 6.8 g of methyl chloroformate was added to the solution. The mixture was then allowed to react for 5 hours under refluxing. After cooling the reaction solution, a potassium carbonate aqueous solution was added thereto whereby crystals were formed. The crystals were collected by filtration, and washed with carbon tetrachloride and water to obtain 3.8 g of methyl N-(5-t-butyl-3-pyrazolyl)carbamate. This compound was recrystallized from a mixed solvent of carbon tetrachloride and chloroform and found to have a melting point of 177° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].[C:10](=[S:12])=[S:11].I[CH3:14]>CN(C=O)C>[CH3:14][S:11][C:10](=[S:12])[O:7][CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCCCO
Reactant: S=C=S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCCOC(=S)SC
Temperature: 7.5 °C
Reaction time: 5 h

Procedure:
The title compound is prepared by the method described in Bull. Chem. Soc. Jpn. (2000), 73, 477f.: To a cooled solution of 3-ethoxy-1-propanol (24.4 g, 0.227 mol) in DMF (150 mL) is added NaH (60% dispersion in oil; 10.0 g, 0.250 mol) in portions over 1 hour, keeping the reaction temperature below 5° C. Stirring is continued for 5 hrs at room temperature, the mixture is cooled to 5 to 10° C. followed by dropwise addition of CS2 (27.5 mL, 0.454 mol). The mixture is gradually warmed to ambient temperature overnight and then cooled to <10° C. before adding iodomethane (17.9 mL, 0.284 mol). Stirring is continued for 18 hrs at room temperature, the mixture is then poured into ice-cold diluted aqueous HCl and extracted with diethyl ether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography on silica gel (hexane/AcOEt 20:1) gives the title compound as yellow liquid. TLC, Rf (hexane/AcOEt 3:1)=0.56. 1H-NMR (CDCl3): δ 1.23 (t, 3H), 2.11 (m, 2H), 2.60 (s, 3H), 3.52 (t, 2H), 3.58 (t, 2H), 4.79 (t, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(C(=O)O)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc(CO)c1F
Temperature: 0 °C
Yield: 50.1 %

Procedure:
3-amino-2-fluorobenzoic acid (APIN, 250 mg, 1.612 mmol) was dissolved in 10 mL of anhydrous THF under N2 atmosphere. Solution was cooled at 0° C. in an ice-water bath. LiAlH4 (FLUKA, 183 mg, 4.83 mmol) was added. Reaction was stirred under nitrogen at room temperature. After 2 h one equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added to the mixture and reaction was stirred at room temperature overnight. Another equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added. After 5 h The reaction mixture was quenched by adding MeOH. Solvent was evaporated to obtain an orange syrup that was dissolved in EtOAc and partitioned with saturated NaHCO3 (aqueous) (10 mL of saturated solution+15 mL of distilled water). Aqueous phase was extracted with EtOAc, organic layers were combined and dried with MgSO4 (anh), filtered off and concentrated. Crude was purified using silica gel cartridge with linear gradient 0-85% DCM/MeOH to yield the title compound (114 mg, 0.808 mmol, 50.1% yield) as yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.50-6.85 (m, 3H), 4.95-5.08 (m, 3H), 4.44 (d, 2H).
Reaction SMILES: CC1[CH:7]=[CH:6][C:5]([C:8]23[CH2:18][C:12]4([CH3:19])[CH2:13][C:14]([CH3:17])([CH2:16][C:10]([C:20]5[CH:25]=[CH:24]C(C)=[CH:22][CH:21]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][CH:3]=1.[C:27]([OH:30])(=[O:29])[CH3:28].Cl.[C:32]([O:35]CC)(=[O:34])[CH3:33]>O.O.O.O.O.O.[Co](Br)Br>[C:27]([C:28]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:18][C:12]4([CH3:19])[CH2:13][C:14]([CH3:17])([CH2:16][C:10]([C:20]5[CH:25]=[CH:24][C:33]([C:32]([OH:35])=[O:34])=[CH:22][CH:21]=5)([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:6][CH:7]=1)([OH:30])=[O:29]
Reactant: Cc1ccc(C23CC4(C)CC(C)(C2)CC(c2ccc(C)cc2)(C4)C3)cc1
Reactant: CCOC(C)=O
Reactant: CC(=O)O
Agent: Br[Co]Br
Agent: Cl
Solvent: O
Product: CC12CC3(C)CC(c4ccc(C(=O)O)cc4)(C1)CC(c1ccc(C(=O)O)cc1)(C2)C3
Reaction time: 6 h
Yield: 82 %

Procedure:
In the method of Example III, 2.0 grams of 1,3-di(4-methylphenyl)-5,7-dimethyl adamantane were allowed to reflux with 300 ml of acetic acid containing 5.26 grams (0.022 moles) cobalt acetate tetrahydrate and, 2.39 grams cobalt bromide hexahydrate. An oxygen gas flow of 1 cubic foot per hour was bubbled through the refluxing mixture. Over a period of 6 hours, 5.39 grams of 1,3-di(4-methylphenyl)-5,7-dimethyl adamantane were added for a total of 7.39 grams. The reaction mixture was allowed to reflux an additional 28 hours. The reaction mixture was then mixed with water and the mixture was filtered. The resulting filter cake was dissolved in dilute sodium hydroxide. The filtrate was extracted with ether. The ether extracts was evaporated, but gave no residue. The basic solution was acidified with hydrochloric acid followed by an ethyl acetate extraction. Drying and concentration of the ethyl acetate gave 7.12 grams of 1,3-di(4-carboxyphenyl)-5,7-dimethyl adamantane (82% yield), M.P. 252°-255° C.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:6](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.O>CO>[Cl:4][CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(Cl)(c2ccccc2F)C(Cl)n2cncn2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1ccc(C(c2ccccc2F)C(Cl)n2cncn2)cc1
Yield: 96.4 %

Procedure:
5.4 g of sodium methylate are added to a solution of 17.8 g (0.0503 mol) of 1,2-dichloro-1-(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethane in 125 ml of methanol. After the reaction mixture has been refluxed for one hour, 100 ml of water are added to the solution, which is then extracted several times by shaking with methyl tert-butyl ether. The organic phase isolated is washed twice with water, dried over sodium sulfate and evaporated down, 15.5 g (97%) of 1-chloro-1-(1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-(4-fluorophenyl)-ethane being obtained as a 1:1 E/Z mixture.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[OH:15].N1C=CC=CC=1.[C:22](Cl)(=[O:25])[O:23][CH3:24]>C(Cl)Cl.C(OCC)C>[OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:22]([O:23][CH3:24])=[O:25]
Reactant: COCOC1CC2=NOCC2C(O)C1O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COCOC1CC2=NOCC2C(O)C1OC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
4,5-Dihydroxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (217 mg) was dissolved in 10 ml of methylene chloride, and 1 ml of pyridine and then 100 mg of methyl chlorocarbonate were added under ice cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentrated was under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 137 mg of 4-hydroxy-5-methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 50%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20]3)=[O:17])[C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[C:18]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: c1ccc2c(c1)CCNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 1, 2, 3, 4 Tetrahydroisoquinoline (25 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 7.9 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 55.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.19 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.21 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[N:13]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15][CH:14]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:23]2[C:21]2[CH:20]=[N:19][CH:18]=[C:17]3[C:22]=2[N:13]=[CH:14][CH:15]=[CH:16]3)[CH2:3][CH2:2]1
Reactant: O=Cc1cncc2cccnc12
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2nc(-c3cncc4cccnc34)n(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.080 g, 0.48 mmol) in DMF (1.17 mL) and water (0.04 mL) were added the title compound from Example 8 Step A (0.084 g, 0.53 mmol) and OXONE® (0.192 g, 0.313 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: LCMS m/z 304.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1 H), 9.13 (m, 1 H), 9.07 (s, 1 H), 8.43 (d, J=8.3 Hz, 1 H), 7.78 (dd, J=8.7, 4.8 Hz, 1 H), 7.63 (dd, J=8.2, 4.2 Hz, 1 H), 7.34 (dd, J=8.7, 2.2 Hz, 1 H), 7.07 (m, 1 H), 3.55-3.53 (m, 1 H), 0.62-0.61 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
17.1 2.5 g (9.763 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride are dissolved in 100 ml of DCM. 1.574 ml (19.5 mmol) of pyridine and 1.086 ml (9.760 mmol) of N-methylpiperazine are added, and the mixture is stirred at room temperature for 14 h. The reaction mixture is washed 3× with water, the organic phase is dried using sodium sulfate, filtered, and the solvent is removed, giving 1-(4-chloro-3-nitrobenzenesulfonyl)-4-methylpiperazine; EI-MS [M]+ 319.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:24])[CH2:21][NH:22][CH3:23].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:14]([N:22]([CH3:23])[CH2:21][C:20]([O:19][CH3:18])=[O:24])=[O:16])[CH3:13])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCC(=O)OC
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)CN(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a mixture of N-{[(phenylmethyl)oxy]carbonyl}-D-alanine (133.53 g, 598.2 mmol) in DCM (1100 mL) was added powdered sarcosine methyl ester hydrochloride (83.49 g, 598.2 mmol), 1-hydroxybenzotriazole (80.81 g, 598.1 mmol), and 4-methylmorpholine (242 mL, 2201 mmol). The mixture was stirred for 10 min, and then EDC (114.68 g, 598.2 mmol) was added. The mixture was stirred overnight, and was then washed with water (500 mL), 1 N aqueous HCl (2×300 mL), and brine (300 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude methyl N-{[(phenylmethyl)oxy]carbonyl}-D-alanyl-N-methylglycinate (162.35 g, 88% yield) as a yellow oil. LCMS: (M+H)+: 309.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:4]=1[C:5](N)=[O:6].C(O)(=[O:19])C>Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:4]=1[C:5]([OH:19])=[O:6]
Reactant: COc1cccc(-n2cncn2)c1C(N)=O
Reactant: CC(=O)O
Agent: Cl
Product: COc1cccc(-n2cncn2)c1C(=O)O

Procedure:
0.116 mol of the above crude 2-methoxy-6-(1,2,4-triazol-1-yl)-benzamide are stirred in a mixture of 120 ml of concentrated hydrochloric acid and 60 ml of glacial acetic acid for 5 h at 100° C. The mixture is evaporated down under reduced pressure and the process is repeated with the residue. After further evaporation of the mixture, the residue is dissolved in a little water and the solution is brought to pH 3 with sodium hydroxide solution. 30-40 ml of ethanol are added, after which the precipitate is filtered off under suction and dissolved in methanol. After the solution has been dried and evaporated down, 14.7 g of the above acid of melting point 200°-202° C. (decomposition) are isolated.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9](=[O:11])[CH3:10].I[CH3:14].O>CS(C)=O>[CH3:14][N:5]1[CH:6]=[C:7]([CH3:12])[C:8]([C:9](=[O:11])[CH3:10])=[C:4]1[CH3:3]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1c(C)cn(C)c1C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
KOH (818 mg, 14.6 mmol) was partially dissolved in DMSO (115 mL) and stirred for 5 min. 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (1 g, 7.3 mmol) was added in small portions and the mixture was stirred for 45 min. Iodomethane (0.54 mL, 8.75 mmol) was added dropwise at such a rate as to maintain the internal temperature ≦30° C. The mixture was stirred for a further 45 min then poured into H2O (50 mL) and extracted with Et2O (3×60 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo to afford 1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-ethanone (1.06 g) as a pink solid. This was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (3.6 mL, 17.5 mmol) in a N2-flushed flask and heated at 70° C. for 36 h. The mixture was evaporated in vacuo and the residue triturated in EtOAc. The titled compound (973 mg) was obtained as a reddish solid. 1H-NMR (DMSO-d6) δ: 1.30 (s, 3H, CH3), 1.51 (s, 3H, CH3), 2.20 (br. s, 6H, CH3), 2.66 (s, 3H, CH3), 4.57 (d, 1H, J=12.5 Hz, CH), 5.53 (s, 1H, pyrrolyl-H), 6.72 (d, 1H, J=12.7 Hz, CH).