Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)(=O)=O)=CC=1)([O-])=O.[CH2:22]([O:24][C:25](=[O:38])[CH2:26][NH:27][S:28]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=O)(=[O:30])=[O:29])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:21][C:17]1([CH3:20])[O:16][CH:15]([CH2:14][N:27]2[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:38])=[CH:36][C:35]3[CH:34]=[CH:33][S:32][C:31]=3[S:28]2(=[O:30])=[O:29])[CH2:19][O:18]1
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C=O
Reactant: CC1(C)OCC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CC1COC(C)(C)O1
Temperature: 55 °C
Reaction time: 12 h
Yield: 16.5 %

Procedure:
The product from Step A (46.5 g, 0.292 mol) was added in portions to a solution (room temperature) of (N-[[3-formyl-thien-2-yl]sulfonyl]glycine ethyl ester (27 g, 0.97 mol) in dimethylsulfoxide (200 mL) which contained potassium carbonate (40.45 g, 0.292 mol). This mixture was stirred at 55° C. for 12 h, cooled to 0° C, diluted with water, and extracted with ethyl acetate (3×200 mL). The combined extracts were dried (MgSO4) and evaporated to a crude oil which was purified by column chromatography (silica, 30% ethyl acetate in hexane) to give 18 g (50%) of the desired product as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].F[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>CS(C)=O>[N:1]1([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Under nitrogen atmosphere, a solution of pyrazole (2.43 g) in DMSO (90 mL) was cooled to 0° C., and thereto was added successively NaH (1.57 g, 60%), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added ethyl 4-fluorobenzoate (6.00 g) and the mixture was stirred at 110-120° C. for 20 hours. The mixture was cooled to room temperature, and thereto was added ice water (150 mL). The mixture was extracted twice with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=50/3→50/4) to give ethyl 4-(1H-pyrazol-1-yl)benzoate (6.12 g, 79%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of 40i (0.110 g, 0.73 mmol.) in 8 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.274 g, 0.645 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1i (70.1%). 1H NMR (CDCl3) δ 7.87-7.85 (m, 2H), 7.72 (s, 2H), 7.53-7.49 (m, 3H), 7.05 (s, 1H), 7.82 (d, 1H, J=1.5 Hz), 3.97 (s, 3H), 3.96 (s, 6H); MS (ESI) m/z 362.1 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].CC[O-].[Na+].[F:12][C:13]([F:33])([F:32])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19]>C(O)C>[F:12][C:13]([F:32])([F:33])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]1[C:23](=[O:24])[NH:7][CH:5]=[N:6][C:18]1=[O:19]
Reactant: N=CN
Reactant: CCOC(=O)C(Cc1ccccc1C(F)(F)F)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1N=CNC(=O)C1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 g of formamidine acetate in 40 ml of absolute ethyl alcohol was treated with 1.2 g of sodium ethylate at room temperature, stirred at room temperature for 30 minutes and then treated dropwise at room temperature with a solution of 1.6 g of diethyl [o-(trifluoromethyl)benzyl]malonate in 8 ml of absolute ethyl alcohol. After stirring at 50° C. for 4 hours, the reaction mixture was worked-up and yielded 5-[o-(trifluoro-methyl)benzyl]-4,6(1H,5H)pyrimidinedione, melting point >290° C.
Reaction SMILES: Cl.N1([C:14](=[O:15])[C:13]2[N:11](C)C=N[C:8]=2N(C)C1=O)C.C([O-])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[OH2:26]>>[CH2:22]([O:26][C:14](=[O:15])[C@H:13]([CH2:8][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:11])[CH2:17][CH2:18][CH3:19]
Reactant: O
Reactant: O=C([O-])c1ccccc1
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Agent: [Na+]
Product: CCCCOC(=O)[C@@H](N)Cc1ccccc1

Procedure:
HCl (100 g) was dissolved in water (1 L). Caffeine (30 g) and sodium benzoate (50 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26].[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38]N(C)[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:33][N:34]([CH3:45])[C:35]([C:37]1[CH2:38][N:26]([CH2:25][C:24]([CH3:28])([CH3:27])[CH3:23])[C:40](=[O:43])[C:41]=1[OH:42])=[O:36]
Reactant: CC(C)(C)CN
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(C)(C)C)C1
Yield: 4 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2,2-dimethyl-propylamine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (7.9 mg, 4% yield). 1H NMR (500 MHz, DMSO) δ: 7.42 (d, 1H, J=8.24), 7.36 (s, 1H), 7.12 (d, 1H, J=8.24), 4.61 (s, 2H), 4.26 (s, 2H), 3.27 (s, 2H), 3.04 (s, 3H), 0.93 (s, 9H). HRMS (M+H) calcd for C18H23N2Cl2O3: 385.1085; found: 385.1079.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:19])([F:18])[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](=[O:14])[CH2:12]Br>CO>[N:1]([CH2:12][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([O:7][C:6]([F:5])([F:18])[F:19])[CH:9]=1)=[O:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Add sodium azide (583 mg, 8.96 mmol) to a solution of 3-(trifluoromethoxy)-phenacyl bromide (2.17 g, 7.66 mmol) in methanol (20 mL). Stir at room temperature for 2 h. Concentrate the mixture in vacuo. Dissolve the residue in EtOAc (20 mL) and wash with water (10 mL). Dry the organic layer (Na2SO4), filter, and concentrate filtrate in vacuo to provide 2-azido-1-(3-(trifluoromethoxy)phenyl)ethanone (1.70 g, 91%). 1H-NMR (CDCl3): δ7.83 (m, 1H), 7.77 (s, 1H), 7.56 (m, 1H), 7.49 (m, 1H), 4.55 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])=[C:12]([CH:22]=1)[CH:13]([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].O>C(OCC)C.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:12]([CH:22]=1)[CH:13]([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: O=C(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of 0.25 g of lithium aluminum hydride in 20 ml of absolute ethyl ether, a solution of 1.2 g of 5-chloro-α-(2-chlorophenyl)-2-(trifluoroacetylamino)benzyl alcohol in 5 ml of tetrahydrofuran was added dropwise. After mixture stirring at room temperature for 1 hour, water was added, and the organic layer was dried, after which the solvent was removed and the residue was subjected to silica gel column chromatography to yield 1.0 g of an oily compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([Si](C)(C)C)#[CH:13]>>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[CH:13]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc2cccnc12
Product: C#Cc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH:1]1([C:4](=[O:30])[C:5](=[CH:26]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:32]O.C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([C:4]2[O:30][N:32]=[CH:26][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])[CH2:2][CH2:3]1.[CH:1]1([C:4](=[O:30])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(CC(=O)C1CC1)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Product: O=C(c1cnoc1C1CC1)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl

Procedure:
To a mixture of 3-cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}-2-ethoxymethylenepropan-1,3-dione (3.22 g) and hydroxylamine hydrochloride (0.54 g) in ethanol (15 ml), sodium acetate (0.62 g) was added in several portions while stirring and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off the mixture under reduced pressure and the residue was extracted with ethyl acetate (120 ml), washed with salt water and dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the ethyl acetate, was purified by silica column chromatography (ethyl acetate:n-hexane=1:1) to obtain the objective 5-cyclopropyl-4-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl}isoxazole (2.37 g, 84% yield from 3-cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}propan-1,3-dione. nD20: 1.5929.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(N(CC)CC)C.[CH:64]1([C:67](Cl)=[O:68])[CH2:66][CH2:65]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:67]([CH:64]3[CH2:66][CH2:65]3)=[O:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)C4CC4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (from Example 3) in dry methylene chloride (0.4 ml) was cooled to 0° C. To this solution was added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was purified by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) to give 20 mg of the title compound. (Mass, 1H and 13C data were consistent with the proposed structure).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[CH:19]=[CH:18][C:17]=12>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22]([C:20]1[CH:19]=[CH:18][C:17]2=[N:13][O:14][N:15]=[C:16]2[CH:21]=1)=[O:23]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc2nonc2c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc2nonc2c1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2,1,3-benzoxadiazole-5-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 166 mg of the title compound (77%) as a orange solid in 99.1% purity by HPLC (Rt: 5.65, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH:1]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Cc1cccc(N)c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: Cc1cccc(NC2CCCCC2)c1
Yield: 60 %

Procedure:
200 parts of cyclohexanol, 214 parts of m-toluidine and 10 parts of triphenyl phosphite are heated for 20 hours at 230° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, unconverted toluidine and excess alcohol are distilled off. 227 parts of N-cyclohexyl-m-toluidine, corresponding to a yield of 60% of theory, distil at a boiling point of 165° - 170° C/15 mm Hg.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[H][H].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
5.10-2 mol of NaH was added little by little to a solution of 5.10-2 mol of 4-hydroxy benzonitrile in 100 ml DMF so as to obtain a temperature of 25° C. The solution was then heated to 50° C. until No more hydrogen was liberated. After cooling to 0° C., 5.10-2 benzyl chloride was added. The reaction mixture was heated to 40° C. for 1 hour, then poured into 300 ml iced water. The resulting solid was separated by filtration.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][NH:60][CH:61]2[CH2:64][CH2:63][CH2:62]2)[CH:56]=[CH:55][N:54]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][N:60]([CH:61]2[CH2:62][CH2:63][CH2:64]2)[C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH:56]=[CH:55][N:54]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: Brc1cc(CNC2CCC2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2ccnc(Br)c2)C2CCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.7 %

Procedure:
After a solution of methyl-1H-imidazole-4-carboxylic acid (300 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.27 g) and diisopropylethylamine (431 mg) in dimethylformamide (7 mL) was stirred at room temperature for 15 min, N-[(2-bromopyridin-4-yl)methyl]cyclobutanamine (574 mg) was added thereto and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20-50:50) to afford the title compound (1.46 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Br:22][C:23]1[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:51]C([N-]C(C)C)C>>[Br:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:23]([Br:22])[C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:51])=[CH:14][CH:13]=2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: Brc1cccc(Br)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3c(Br)cccc3Br)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2,6-dibromobenzyl)(triphenyl)phosphonium bromide (516) prepared as described in example 107 using the procedure described in example 37, except that the ratio of LDA:aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (517) as a yellow solid (the pure E isomer) (80%), mp 140–141° C. 1H NMR (CDCl3) δ 8.20 (br s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.05 (br s, 1H), 7.03 (d, J=16.7 Hz, 1H), 6.96 (t, J=8.0 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=16.7 Hz, 1H), 6.61 (d, J=1.9 Hz, 1H), 3.86 (s, 3H). Found: C, 50.37; H, 3.24; N, 3.37. C17H13Br2NO requires C, 50.16; H, 3.22; N, 3.44.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[S:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C([Mg]Br)(C)C.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:14][N:2]([CH3:1])[C:3](=[S:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(CC(=S)N(C)C)cc1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COc1ccc(C(C(=S)N(C)C)C2(O)CCCCC2)cc1
Yield: 62.9 %

Procedure:
N,N-Dimethyl-p-methoxyphenylthioacetamide (20.9 g) in toluene was added to a solution of 1.45M isopropyl magnesium bromide in methyl t-butyl ether (80 ml) and toluene (400 ml) under an inert atmosphere of nitrogen whilst the internal temperature was maintained below 10° C. After 2 hours a solution of cyclohexanone (9.82 g) in toluene (50 ml) was added to the reaction mixture under nitrogen. After a further 15 minutes the mixture was blown over onto 1N hydrochloric acid (150 ml). The organic phase was washed, dried and evaporated. Recrystallisation of the residue from di-isopropyl ether gave the title compound (19.3 g, 64% yield), melting point 132° to 3° C.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc([N+](=O)[O-])ccc1Cl
Yield: 80.5 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (1.0 g) and 2-chloro-5-nitrobenzoic acid (1.22 g) to give the title compound as a yellow solid (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl.CO.ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH2:8][C:9]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:11])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(CC(=O)N2CCOCC2)c1
Temperature: 40 °C
Yield: 78.9 %

Procedure:
2-(5-Methyl-2-nitro-phenyl)acetic acid (250 mg, 1.28 mmol) and HATU (443 mg, 1.17 mmol) were suspended in dichloromethane (5 mL) and treated with triethylamine (162 μL, 1.17 mmol) and morpholine (112 μL, 1.28 mmol). The solution was heated at 40° C. for 10 min. The reaction was washed with 1N HCl and saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (1-10% methanol/dichloromethane) provided 2-(5-methyl-2-nitro-phenyl)-1-morpholino-ethanone as a white solid (267 mg, 87% yield). LC/MS m/z 265.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 7.97 (d, J=8.3 Hz, 1H), 7.33 (dd, J=1.3, 8.3 Hz, 1H), 7.27 (s, 1H), 4.10 (s, 2H), 3.66-3.64 (m, 2H), 3.59-3.54 (m, 4H), 3.43-3.41 (m, 2H), 2.39 (s, 3H).